California and most other coastlines around the world are being impacted by both long-term sea-level rise and short-term extreme events. Because of California’s long and intensively developed coastline, it is an important area for evaluating responses to these challenges. The predominant historic approach to coastal erosion in California and globally has been the construction of hard coastal armoring such as seawalls and rock revetments. The concept of living shorelines – defined as using natural elements like plants, sand or rocks to stabilize the coastline – has been widely proposed as a soft or green response to coastal erosion and flooding. These approaches have very limited application in high-energy environments, however, such as California’s 1,100-mile-long outer coast and are not realistic solutions for protection from wave attack at high tides or long-term sea-level rise. Each of the state’s coastal communities need to identify their most vulnerable areas, develop adaptation plans, and plan eventual relocation strategies in response to an accelerating sea-level rise.

Ostreid herpesvirus 1 (OsHV-1) is one of the most economically important pathogens of Pacific oysters. Understanding the pathogenesis of this virus is critical to developing tools to control outbreaks on shellfish farms. OsHV-1 is genetically related to vertebrate herpesviruses, which have a lytic and a latent stage, with the latent stage capable of being reactivated to the lytic stage. Here, OsHV-1 latency in Pacific oysters was investigated in experimentally and naturally infected oysters. Lytic infection in one-year-old oysters injected with the Tomales Bay strain of OsHV-1 was detectable between 1 and 4 days post-infection (dpi) but was not detectable after 5 dpi. The infected oysters shed 1102 to 1104 DNA copies/ml during the 4-day acute phase. At 21 dpi, the recovered oysters were temperature and chemically stressed and were found to shed 1104 to 1105 DNA copies/ml over a period of 48 h. Lytic shedding was not detectable in two-year-old oysters injected similarly with the same strain of OsHV-1; however, the OsHV-1 genome was detectable by qPCR in the adductor muscle, gill, mantle, and hemocytes within the first 3 dpi, after which it became undetectable. No OsHV-1 was detectable in the adductor muscle, gill, or mantle from experimentally infected oysters on days 15 and 21 post-infection or from oysters sampled 9 months after surviving an OsHV-1 mortality event; however, OsHV-1 DNA could be detected in hemocytes of both experimentally infected oysters at 21 dpi and naturally infected oysters. In addition, lytic viral gene transcription was detectable in hemocytes of experimentally infected oysters between 1 and 21 dpi and in hemocytes of naturally infected oysters.

The “Crisis of Reproducibility” has received considerable attention both within the scientific community and without. While factors associated with scientific culture and practical practice are most often invoked, I propose that the Crisis of Reproducibility is ultimately a failure of generalization with a fundamental scientific basis in the methods used for biomedical research. The Denominator Problem describes how limitations intrinsic to the two primary approaches of biomedical research, clinical studies and pre-clinical experimental biology, lead to an inability to effectively characterize the full extent of biological heterogeneity, which compromises the task of generalizing acquired knowledge. Drawing on the example of the unifying role of theory in the physical sciences, I propose that multi-scale mathematical and dynamic computational models, when mapped to the modular structure of biological systems, can serve a unifying role as formal representations of what is conserved and similar from one biological context to another. This ability to explicitly describe the generation of heterogeneity from similarity addresses the Denominator Problem and provides a scientific response to the Crisis of Reproducibility.

The Environmental interactions contributed to the processes of settlement and development of the first settlers at southern Peru 15,000 BC. The determination of this process is based on paleoclimatic studies at southern Peru and ethnoarchaeological evidence. The determination of this process is based on paleoclimatic studies of southern Peru and ethnoarchaeological evidence; establishing as a result of this analysis the hypothesis of environmental interaction and territorial occupation of the first hunter-gatherer populations until their consolidation, dominating the geographical space from Tacna. The Disruptive disaster events and their effects on climate during the Peruvian Paleolithic resulted in the origin of local societies that shaped the Tiawanaku societies of the early horizon at Southern Peru and Northern Chile.

Aymaraism, as a socio-cultural phenomenon, has given rise to components and elements of representativeness in the population of the Andes. However, the dialectic component of the Aymara as a nation is annulled by fundamental historiographical elements that underlie this process of identification. The empirical analysis of the historical data leads us to conclude that the Aymara language and culture contain ambiguous elements that cannot be defined according to the dialectical interpretation and the current narrative. Thus, the analysis of the cultural, linguistic and social elements of this population from the Early Horizon period to the present confirms the historical distortion towards a narrative component of origin and presence in the territory of the Qullasuyu, in the current geographical area of the Collao. In order to understand this phenomenon, this work promotes the complementarity of the analysis through the use of ethnoarchaeological and documentary elements in order to clarify the origin, synthesis and development of the Aymara from a historical perspective, leaving aside the dialectical component of the present.

The use of endophytic microbes is increasing in commercial agriculture. This review will describe the endophyte-plant relationship and the fungi and bacteria involved. Their abilities to alleviate biotic (diseases and pests) and abiotic stresses (drought, salt and flooding), remediate pollution and increase photosynthetic capabilities will be described. Their mechanisms of action will be elucidated. These frequently result in increased plant yields. Finally, methods and practices for formulation and commercial use will be described.

Taiwan's bed and breakfast (B&B) development has been more than 25 years ago, from the first generation of retirement to the B&B industry, serving tourists from all over the world accom-modation, providing breakfast and accommodation mode to the present, after the change of employees from the second generation, more and more attention is paid to the cultivation and cultivation of business ability. With the advent of the era of AI technology networking, the ca-pabilities required for B&B operation are more focused on all aspects of service, and the good marketing ability of B&B can promote a green chimney-free tourism economy, which is also a favorite industry of various governments and the public. This study explores the basic vocational competency indicators required for running a B&B, with (1)EQ emotion management skills, (2)Financial management ability, (3)(SK) technical skills, and (4)Marketing and promotion management capabilities. Through the study method, the K-S Z test was determined by the con-sensus conclusion of expert reliability and validity p value

Fitting parameters on spline curves produces more parsimonious models, maintaining fit quality. Smoothing the splines reduces predictive variance. Individual splines are often fit by type of variable, e.g., in age-period-cohort models. Linear and cubic splines are most common. Several smoothing criteria have been used for parameter curves, with cubic splines fit by constraining the integral of splines’ squared-second derivatives popular recently. Constraining the sum of squared second differences for linear splines is analogous. Generally the degree of smoothing is selected using cross-validation. Known spline dummy-variable matrices allow regression estimation of splines, with smoothing done via constrained regression. Smoothing criteria based on sums of squares or absolute values of parameters, as in ridge regression or LASSO, improves predictive accuracy and produces splines similar to smoothing by second-derivative constraints. Variables with very low t-statistics represent points where curve-shapes barely change. Eliminating those variables leaves knots concentrated where spline shapes change. A Bayesian version of this puts shrinkage priors on spline parameters. This yields realistic joint parameter distributions, avoids problems associated with using cross-validation for parameter estimation, and readily expands to non-linear modeling, such as interactions among variable types. Regularized regression and Bayesian spline methods are compared for two example datasets.

Abstract Bacteria and fungi are both used in biological seed treatments. While all have potential uses, some organisms are more widely and successfully used than others. Shelf life is an important consideration. For this reason, organisms that lack cell walls are more difficult to use than ones with long-lasting spores. Bacillus and Trichoderma are both widely effective, have good shelf life, and are frequently used. However, Rhizobiacae lack cell walls, which is a limitation; they are widely used because their symbiosis with legumes facilitates nitrogen fixation which is an important factor that provides economic, agricultural and environmental sustainability. For all organisms, proper formulation is critical for success; this is especially true for Rhizobiacae and other gram-negative bacteria. There are several specialized processes to deliver microbial agents or to enhance their biological activity, such as solid matrix priming and hydroseeding. Biorational chemicals derived from microorganisms are also frequently used. Both living organisms and biorationals provide benefits to plant agriculture. They can control diseases and increase resistance to abiotic stresses such as drought, temperature, salt, and flooding. They also can enhance mineral nutrition and photosynthesis. For these applications, the most effective ones colonize roots internally and provide season-long benefits. These endophytes induce systemic changes in plants’ gene expression and encoding of proteins.

Risk management strategies protect the company as a whole as well as employees from unforeseen financial impacts. As in the case of personal finance, preparing for certain scenarios helps to face any difficulties that the company may encounter and allows it to get out of this impasse.For any project to be successful, the way the project executing agency will deal with potential risks must be determined so that it can identify, mitigate or avoid problems when it needs to do so. Successful project managers realize that risk management is important, because the achievement of project objectives depends on planning, preparation, results and evaluation that contribute to the achievement of strategic goals, especially the sustainable development of societies.Risk management strategies work to protect the company as a whole as well as employees from unexpected financial effects, and as is the case in personal finance, preparing for certain scenarios helps to face any difficulties that the company may face and allows it to get out of this impasse.To ensure the success of your project, determine how you will handle potential risks so that you can identify, mitigate or avoid problems when you need to do so. Successful project managers understand that risk management is important, because the achievement of project objectives depends on planning, preparation, results, and evaluation that contribute to the achievement of strategic objectives.

Two welcome extensions of evolutionary thinking have come to prominence over the last thirty years: the so-called “extended evolutionary synthesis” (EES) and debate about biological kinds and individuals. These two agendas have, however, remained orthogonal to one another. The EES has mostly restricted itself to widening the explanations of adaptation offered by the preceding “modern evolutionary synthesis” by including additional mechanisms of inheritance and variation; while discussion of biological kinds has turned toward philosophical questions of essential vs. contingent properties of life forms and realist vs. epistemological approaches to categorization and classification. Here we attempt to broaden the explanatory scope of evolutionary theory by linking these two agendas. We expand on the mechanistic orientation of the EES, using new understandings of networked systems of components in order to engage the distinct intellectual challenge of the origination of historical kinds. With this phrase we designate a subset of natural kinds that acquires, through evolutionary processes, a quasi-independent lineage-history. Such kinds emerge in both biology and culture, and we enlarge the limited number of historical kinds that have thus far been recognized in evolutionary biology in a series of paradigmatic exemplars, from genes and cell types to rituals and music. For each exemplar we discern specific mechanisms by which it arose and persists; comparing these, we suggest a general unity in the ways in which diverse historical kinds originate.

Since its inception, evolutionary theory has experienced a number of extensions. The most important of these took the forms of the Modern Evolutionary Synthesis (MES), embracing genetics and population biology in the early 20^th century, and the Extended Evolutionary Synthesis (EES) of the last thirty years, embracing, among other factors, non-genetic forms of inheritance. While we appreciate the motivation for this recent extension, we argue that it does not go far enough, since it restricts itself to widening explanations of adaptation by adding mechanisms of inheritance and variation. A more thoroughgoing extension is needed, one that widens the explanatory scope of evolutionary theory. In addition to adaptation and its various mechanisms, evolutionary theory must recognize as a distinct intellectual challenge the origin of what we call “historical kinds.” Under historical kinds we include any process that acquires a quasi-independent and traceable lineage-history in biological and cultural evolution. We develop the notion of a historical kind in a series of paradigmatic exemplars, from genes and homologues to rituals and music, and we propose a preliminary characterization.

It has been known for nearly over 150 years that fatigue life data exhibits a considerable amount of variability. Furthermore, statistically modeling fatigue life adequately is challenging. Different empirical approaches have been used, each of which has merit; however, none is appropriate universally. Even when a sufficiently robust database exists, the scatter in the fatigue lives may be extremely large and difficult to characterize. The complications in empirical modeling are exacerbated for long life estimation when experimental observations are rare. The purpose of this work is to review traditional and more modern empirically based methodologies for estimating the cumulative distribution functions for fatigue life, given an applied load. To assess the applicability of the methods confidence bounds will be estimated. The analyses will be performed on an historic set of data for annealed aluminum wire tested in reverse torsion fatigue. These data are available in publications. It is recommended that a time dependent distribution function that is an based on principles of reliability that can be generalized for a variety of modeling applications should be considered for fatigue life estimation.

Carcinogenesis is the process whereby a normal cell is transformed into a neoplastic cell. This action involves several steps starting with initiation and followed by promotion and progression. Driving these stages are oxidative stress and inflammation, which in turn encompasses a myriad of aberrant gene expressions, both within the transforming cell population and the cells within the surrounding lesion. Chemoprevention of cancer with bioreactive foods or their extracted/purified components occurs via normalizing these inappropriate gene activities. Various foods/agents have been shown to affect different gene expressions. In this review we discuss whereby the chemoprevention activities of the red beetroot itself may disrupt carcinogenesis and the activities of the water soluble betalains extracted from the plant.

Background—In 2011, Miller and Goldman published a study in Human and Experimental Toxicology that found a counterintuitive, positive correlation, r = 0.70 (r² = 0.49, p < .0001), demonstrating that as nations require more vaccine doses for their infants, infant mortality rates (IMRs) tend to increase (worsen). The dataset (n = 30) included the United States, a nation that required the most vaccines for their infants, and all nations with better IMRs than the United States. Dr. E. Bailey, a professor at BYU, and her students, recently read the Miller-Goldman study and found it "troublesome that this manuscript is in the top 5% of all research outputs" and falsely claimed that its findings were due to "inappropriate data exclusion," i.e., failure to analyze the "full dataset" of all 185 nations. The "Bailey reanalysis," titled Infant vaccination does not predict increased infant mortality rate: correcting past misinformation, was posted to the medRxiv preprint server on September 10, 2021 (version 1) and October 5, 2021 (version 3) and Europe PMC preprint server on September 10, 2021. Objective—This present study examines the various claims postulated by the Bailey reanalysis and assesses the robustness of their methodology, analyses, and reported results and conclusions. Methods—Data discussed in this paper are based on the previously mentioned study by Miller and Goldman and the Bailey reanalysis. Results—Linear regression analysis of IMR and the number of vaccine doses for each country yield a statistically significant positive correlation of r = 0.70 (p < .0001) for the top nations (n = 30) chosen by Miller-Goldman and r = 0.16 (p < .04) for the "entire dataset" chosen by Bailey et al (n = 185). Bailey also conducted linear regression analyses (for the year 2019) of IMRs as a function of vaccination rates for each of eight different vaccines and reported statistically significant inverse correlations for 7 of 8 vaccines over the entire range of vaccination rates. However, Miller and Goldman reanalyzed the Bailey analyses for nations with vaccination rates below 60% and found no statistically significant correlation for six vaccines (DPT, Hib, hepatitis B, polio, rotavirus, and measles) and statistically significant positive correlations for tuberculosis (r = 0.8, p < .005) and pneumococcal (r = 0.6 p < .023) vaccines. Conclusions—Bailey’s reanalysis corroborates a statistically significant positive correlation originally reported by Miller and Goldman. However, Bailey’s reported correlation (r = +0.16, p < .04) is small, likely due to poor methodology (failing to account for covariates, i.e., disparities among numerous socioeconomic factors that add uncertainty to their conclusion). The r-value reported by the Bailey reanalysis demonstrates an effect size that is about one-fourth (0.16/0.70) that reported by Miller-Goldman—underscoring how critically important it is for Bailey's reanalysis to eliminate confounding variables. Moreover, Bailey’s linear regression analyses of IMR as a function of vaccination rates for each of eight different vaccines demonstrate that some countries with low vaccination rates have low IMRs, while other countries with high vaccination rates have high IMRs. Rather than supporting a strong inverse correlation, the Bailey reanalysis demonstrates high vaccination rates are neither necessary nor sufficient to cause low IMR.

A survey of the trends in metal-ligand coordination and hydrogen bonding has been carried out on complexes of singly deprotonated cyanuric acid CY− and alkaline earth metals, synthesised from aqueous solution and characterised by X-ray crystallography. Involvement of cyanurate in the metal coordination increases from Mg through Ca and Sr to Ba relative to coordination by water, in parallel with the increasing ionic radius and coordination number. The incidence of bridging of metal centres by both water and cyanurate also increases in this series. The Mg complex contains hexaaqua-coordinated cations, uncoordinated CY− anions, and additional water molecules. Ca and Sr complexes feature polymeric chains of coordinated metal ions, the Ca complex with uncoordinated anions and the Sr complex with all potential ligands coordinated. The Ba complex has a two-dimensional coordination network. Extensive hydrogen bonding plays a key role in generating a three-dimensional network in all four structures. The competition between cyanurate and water for coordination to the alkaline earth metal cations, and that between coordination and hydrogen bonding propensities of the cyanurate anion, appear to be finely balanced, with the structural outcomes depending on the relative sizes and degrees of hardness of the four cations of the group.

We present a new theory to explain the expansion of the universe that augments general relativity to create a container within which quantum effects can be explained by treating time as an artefact of a fourth spatial dimension. The theory is tested by accurately modelling against stellar luminosity data that is available for redshifts, z

Fluorescent bioprobes are invaluable tools for visualizing live cells and deciphering complex biological processes by targeting intracellular biomarkers without disrupting cellular functions. In addition to protein-binding concepts, fluorescent probes utilize various mechanisms, including membrane, metabolism, and gating-oriented strategies. This study introduces a novel fluorescent mechanism distinct from existing ways. Here, we developed a B-cell selective probe, CDrB, with unique transport mechanisms. Through SLC-CRISPRa screening, we identified two transporters, SLCO1B3 and SLC25A41, by sorting out populations exhibiting higher and lower fluorescence intensities, respectively, demonstrating contrasting activities. We confirmed that SLCO1B3, with comparable expression levels in T and B cells, facilitates the transport of CDrB into cells, while SLC25A41, overexpressed in T lymphocytes, actively exports CDrB. The observation suggests that SLC25A41 plays a crucial role in discriminating between T and B lymphocytes. Furthermore, it reveals the potential for reversible localization of SLC25A41 to demonstrate its distinct activity. This study is the first report to unveil a novel strategy of SLC by exporting the probe. We anticipate that this research will open up new avenues for developing fluorescent probes.

Background: Antibiotic resistance is an urgent issue everywhere in the globe. It is necessary to look into new sources of antibiotics to address this issue. Aim of the study: studying the purification of Corallopyronin B from various soil conditions in Egypt, as well as the antibacterial effectiveness of Corallopyronin B in preclinical animal testing and randomized human clinical trials phases 1/2. Type of the study: Screening experimental study. Methodology: Several soil conditions in Egypt were examined to create bacterial isolates that generated the antibiotic chemical Corallopyronin B. Using reversed-phase HPLC, Myxopyronin B was purified. The test antibiotic's minimum inhibitory concentration( MIC) and in vitro antibacterial activity were ascertained using the paper disc diffusion assay and the broth microdilution technique. Furthermore, in stages 1/2 of randomized clinical trials including human and animal models, pharmacokinetics, adverse drug reactions, and the in vivo antibacterial spectrum were discovered. Results: The soil bacterial isolate Corallococcus coralloides DSM 2259, grown on a Casein yeast peptone( CYP) plate, produced Corallopyronin B from its culture supernatant. At MICs more than 100 mcg/ml, the test antibiotic inhibited the growth of many Gram -ve bacteria, including Escherichia coli, while preventing the growth of numerous Gram +ve bacteria, with MICs ranging from 1 to 10 mcg/ml. Eukaryotic cells, on the other hand, including those in humans and fungi, were unharmed. The test antibiotic was shown to have a bactericidal effect by inhibiting bacterial DNA-dependent RNA polymerase( RNLP). In phases 1/2 of randomized human clinical trials, when 600 mg of the dose per 70 kg of body weight was administered SC, the Cmax was 8.6 mcg/ml at Tmax 1 hour; T1/2 reached 136 min following first-order kinetics of elimination. It stopped acting around 6-7 hours after SC was administered. In the preclinical and randomized human clinical trial phases 1/2, less than 6 percent of experimental candidates had uncommon toxicity, showing reduced bile flow. Protein binding with plasma albumin was detected which reached about 83%. Conclusion: The current work was noteworthy since it involved the production of the bactericidal antibiotic Corallopyronin B from Corallococcus coralloides DSM 2259 which was isolated from several soil environments in Egypt.

Viral tropism is most commonly linked to receptor use, but host cell protease use can be a notable factor in susceptibility to infection. Here we review the use of host cell proteases by human viruses, focusing on those with primarily respiratory tropism, particularly SARS-CoV-2. We first describe the various classes of proteases present in the respiratory tract, as well as elsewhere in the body, and incorporate the targeting of these proteases as therapeutic drugs for use in humans. Host cell proteases are also linked to the systemic spread of viruses and play important roles outside of the respiratory tract; therefore, we address how proteases affect viruses across the spectrum of infections that can occur in humans, intending to understand the extrapulmonary spread of SARS-CoV-2.

Atopic dermatitis (AD) is a chronic inflammatory condition which significantly affects quality of life in both patients and their caregivers. Calcineurin inhibitors (CNI) are a class of immunosuppressive drugs predominantly inhibiting T cell mediated immune processes. CNI form complex by binding with immunophilins and in turn inhibit calcineurin and suppress downstream inflammatory pathway. Tacrolimus and pimecrolimus are topical CNI approved for the treatment of mild to severe AD in both children and adults. Application site reactions are frequently seen. They have been issued with black box warning towards increased risk of malignancies but supportive evidence is lacking. Cyclosporine, though highly effective, is used off-label for AD management. It is used for controlling acute flares of AD due to its very rapid onset of action. Nephrotoxicity and hypertension are its serious complications. CNI have not been reported with teratogenicity and may be used conditionally during pregnancy and lactation.

Background: Antibiotic resistance is an urgent issue everywhere in the globe. It is necessary to look into new sources of antibiotics to address this issue. Aim of the study: studying the purification of Corallopyronin B from various soil conditions in Egypt, as well as the antibacterial effectiveness of Corallopyronin B in preclinical animal testing and randomized human clinical trials phases 1/2. Type of the study: Screening experimental study. Methodology: Several soil conditions in Egypt were examined to create bacterial isolates that generated the antibiotic chemical Corallopyronin B. Using reversed-phase HPLC, Myxopyronin B was purified. The test antibiotic's minimum inhibitory concentration( MIC) and in vitro antibacterial activity were ascertained using the paper disc diffusion assay and the broth microdilution technique. Furthermore, in stages 1/2 of randomized clinical trials including human and animal models, pharmacokinetics, adverse drug reactions, and the in vivo antibacterial spectrum were discovered. Results: The soil bacterial isolate Corallococcus coralloides DSM 2259, which was grown on a Casein yeast peptone( CYP) plate, produced Corallopyronin B from its culture supernatant. At MICs more than 100 mcg/ml, the test antibiotic inhibited the growth of many Gram -ve bacteria, including Escherichia coli, while also preventing the growth of numerous Gram +ve bacteria, with MICs ranging from 1 to 10 mcg/ml. Eukaryotic cells, on the other hand, including those in humans and fungi, were unharmed. The test antibiotic was shown to have a bactericidal effect by inhibiting bacterial DNA-dependent RNA polymerase( RNLP). In phases 1/2 of randomized human clinical trials, when 600 mg of the dose per 70 kg of body weight was administered SC, the Cmax was 8.6 mcg/ml at Tmax 1 hour; T1/2 reached 136 min following first-order kinetics of elimination. It stopped acting around 6-7 hours after SC was administered. In the preclinical and randomized human clinical trial phases 1/2, less than 6 percent of experimental candidates had uncommon toxicity, which showed up as reduced bile flow. Protein binding with plasma albumin was detected which reached about 83%. Conclusion: The current work was noteworthy since it involved the production of the bactericidal antibiotic Corallopyronin B from Corallococcus coralloides DSM 2259 which was isolated from several soil environments in Egypt.

To achieve n-type doping in diamond, extensive investigations employing first principles have been conducted on various models of phosphorus doping and boron-phosphorus co-doping. The primary focus of this study is to comprehensively analyze the formation energy, band structure, density of states, and ionization energy of these structures. It is observed that within a diamond structure solely composed of phosphorus atoms, the formation energy of an individual carbon atom is excessively high. However, the substitution of two carbon atoms leads to the conversion of diamond into a p-type semiconductor. Upon examining the P-B co-doping structure, it is revealed that the doped impurities exhibit a tendency to form more stable cluster configurations. As the separation between the freely doped atoms and the cluster impurity structure increases, the overall stability of the structure diminishes, consequently resulting in an elevation of the ionization energy. Analysis of the electronic density of states demonstrates that the electron orbit of the B atom makes negligible contributions to the impurity levels during P-B doping.

Intermolecular interactions are the fabrics underlying almost all processes in living organisms, where two cornerstone concepts, intermolecular binding affinity (K d ) and binding energy (ΔG), have long been established to physically describe the strengths of biomolecular interactions, e.g., drug-target K d and ΔG to describe the strength of drug-target interaction. The past two-three years saw a big step forward in the use of artificial intelligence (AI) in structural biology (e.g., AlphaFold for protein structure prediction) and drug discovery & design. In light of the roles of K d and ΔG in drug discovery & design, the speed of this AI progress raises a question of what’s next for its practical application in the pharmaceutical industry, in addition to a system-wide account of biomolecular structures and motions. Last August, the concept of a general intermolecular binding affinity calculator (GIBAC) was for the first time coined and proposed in an MDPI-published preprint. Here, this article puts forward an updated conceptual and practical framework of GIBAC, including its inception, definition, construction, practical applications, technical challenges and limitations, and future directions. Moreover, this article argues that the time is now ripe for the construction of such an accurate, precise and efficient GIBAC to be on the agenda of the entire drug discovery & design community, to ensure its applicability & reliability, and to enhance its value in drug R&D in future.

This paper reports the findings from a pilot study designed to explore the barriers, facilitators and similarities with the delivery and implementation of two distinct models of Advance Care Planning (ACP) documentation for older adults in their last year of life used by health care professionals in their clinical practice. PACe (Proactive Anticipatory Care Plan): a GP led model and PEACE (Proactive Elderly Persons’ Advisory CarE): a nurse led model with community geriatrician oversight were used by participants in their clinical practice. Telephone interviews were conducted with general practitioners (GPs) to explore their views of using the PACe tool. Hospital admission avoidance matrons took part in face to face interviews and care staff employed in private residential care homes took part in individual telephone interviews to explore their views of using the PEACE tool. GPs and admission avoidance matrons were employed by Clinical Commissioning Groups (CCGs) and all study participants were recruited from the South East of England where data collection took place in 2015. Nine telephone interviews and two face-to-face interviews (one joint and one individual) were conducted with twelve participants. The data was analysed thematically. Participants highlighted the similarity of both tools in providing focus to ACP discussions to inform individual end-of-life care preferences. The importance of relationships was a pivotal theme-established, trusting inter-professional relationships to enable multidisciplinary teamwork and a prior relationship with the older person (or their proxy in the case of cognitive impairment) to enable conversations of this nature. Using both tools enabled participants to think critically and reflect on their own practice was another theme identified. Notwithstanding participants’ views to improve the layout of both tools, using a paper-based approach to deliver streamlined ACP and end-of-life care was a theme to emerge as a barrier which focused on the problems with access to paper-based documentation, accuracy and care co-ordination in the context of multidisciplinary team working. The value of technology in overcoming this barrier and underpin ACP as a means to help simplify service provision, promote integrated professional practice and provide seamless care was put forward as the solution.

Xenorhabdus nematophila and Photorhabdus luminescens are entomopathogenic symbionts that produce several toxic proteins that can interfere with the immune system of insects. Here, we showed that outer membrane proteins (OMPs) could be involved as virulence factors during bacterial symbiont pathogenesis. Purified OMPs from bacterial culture were injected fifth instar larvae of Spodoptera exigua Hübner. Larvae were surveyed for fluctuations in total haemocyte counts (THC), granulocyte percentage (cellular defence), protease, phospholipase A2 (PLA₂), and phenoloxidase (PO) activities (humoral defence) at specific time intervals. Changes in the expression of the three antimicrobial peptides (AMPs), cecropin, attacin, and spodoptericin, were also measured. Larvae treated with both types of OMPs had more haemocytes than did the negative controls. OMPs of X. nematophila caused more haemocyte destruction than did the OMPs of P. luminescens. The OMPs of both bacterial species initially activated insect defensive enzymes post-injection, their activating fluctuated in different ways. Attacin, cecropin and spodoptericin were up-regulated by OMP injections more than in normal larvae. The expression of these three AMPs was maximal at four hpi with P. luminescens OMPs treatment. Expression of the three AMPs in X. nematophila treatment was irregular and lower than in the P. luminescens OMPs treatment. These findings provide insights into the role of OMPs of entomopathogenic nematode bacterial symbionts in countering the physiological defenses of insects.

Localizing the source of a signal is often as important as deciphering the signal’s message. Localization mechanisms must cope with the challenges of representing the spatial information of weak, noisy signals. Comparing these strategies across modalities and model systems allows a broader understanding of the general principles shaping spatial processing. In this review we focus on the electrosensory system of knifefish and provide an overview of our current understanding of spatial processing in this system, in particular, localization of conspecific signals. We argue that many mechanisms observed in other sensory systems, such as the visual or auditory systems, have comparable implementations in the electrosensory system. Our review therefore describes a field of research with unique opportunities to provide new insights into the principles underlying spatial processing.

A new process is reported for the incorporation of a fluoropolymer into a solid perovskite film. Poly(trifluoroethyl methacrylate) [CH2C(CH3)(CO2CH2CF3)]n was delivered to methylammonium lead iodide (CH3NH3PbI3) perovskite films by crystallizing the film in supercritical carbon dioxide/ethanol containing the dissolved fluoropolymer. The surface was characterized before and after fluoropolymer exposure using scanning electron microscopy, Raman spectroscopy and contact angle measurements. The results indicate that the fluoropolymer was incorporated into the perovskite film during the supercritical fluid crystallization process.

In this paper, we examine the mathematical and physical consistencies of the three primary couple stress theories: original Mindlin-Tiersten-Koiter couple stress theory (MTK-CST), modified couple stress theory (M-CST) and consistent couple stress theory (C-CST). As has been known for many years, MTK-CST suffers from some fundamental inconsistencies, such as the indeterminacy of the couple-stress tensor. Therefore, despite the fact that MTK-CST has a fundamental position in the evolution of size-dependent continuum mechanics, it is not a reliable theory within continuum mechanics, for example, in developing new size-dependent multi-physics formulations. We also observe that M-CST not only inherits all inconsistences from the original MTK-CST, but also suffers from new additional inconsistencies, such as the introduction of a new non-physical governing equation. These inconsistencies refute the claim of those who state that the couple-stress tensor may be chosen symmetric. Therefore, the apparent success of MTK-CST and M-CST in describing a size-effect for some problems, such as two-dimensional plate and beam bending, is not enough to justify these theories as suitable for general cases. In fact, the symmetric couple-stresses in M-CST create torsional or anticlastic deformation, not bending. On the other hand, C-CST, with a skew-symmetric couple-stress tensor, is the consistent continuum mechanics suitable for solving different size-dependent solid, fluid and multi-physics problems.

During the last few years, the world witnessed one of the worst calamities to humankind- the COVID-19 pandemic. We also witnessed the development of vaccines at an unprecedented pace against the SARS-CoV-2- the causative agent. India was among the hard-hit countries by COVID-19, developed its indigenous vaccine and implemented vaccines developed in other countries as well. Initially, the antibody level and the neutralizing antibody titer against the pathogen were considered as the correlates of immune protection from the disease. However, the long-term protection from the pathogen was provided by the immune memory cells viz. T and B memory cells and their ability to efficiently make recall responses. In this regard, globally the research studies focused mainly on the mRNA-based vaccines. The studies on immune memory response, particularly- the B cell memory response bestowed by the vaccines given to Indians is relatively obscure. We studied the level of RBD specific memory B cells in the peripheral circulation of the study participants and the ability of B cells to secrete antigen-specific antibodies among Indians vaccinated with Covaxin (BBV152), Covishield (AZD1222), Corbevax (BECOV2D) and Sputnik Light (Gam-COVID-Vac) as well as unvaccinated individuals. Our study revealed that Corbevax and Sputnik Light conferred better antibody-secreting cell (ASC) responses.

Lung cancer is the leading cause of cancer related mortality worldwide. In order to improve its overall survival, early diagnosis is required. Since current screening methods still face some pitfalls, such as high false positive rates for low-dose computed tomography, researchers are still looking for early biomarkers to complement existing screening techniques in order to provide a safe, faster and more accurate diagnosis. Biomarkers are biological molecules found in body fluids, such as plasma, that can be used to diagnose a condition or disease. Metabolomics has already shown to be a powerful tool in the search for cancer biomarkers since cancer cells are characterised by impaired metabolism, resulting in an adapted plasma metabolite profile. The metabolite profile can be determined using nuclear magnetic resonance, or NMR. Although metabolomics and NMR metabolite profiling of blood plasma are still under investigation, there is already evidence for its potential for early-stage lung cancer diagnosis, therapy response, and follow-up monitoring. This review highlights some key breakthroughs in this research field, where the most significant biomarkers will be discussed in relation with their metabolic pathways and in light of the altered cancer metabolism.

This study reports rapid hydrolysis, acylation, and lipolysis with lipase B from Candida antarctica (CalB) and nanofructosome encapsulated CalB (CalB@NF) enzymes immobilized on silica-coated magnetic nanoparticles (Si-MNPs). Enzymatic hydrolysis was confirmed for conversion to p-nitrophenol (p-NP, λex=400 nm) from p-nitrophenyl butyrate (p-NPB, λex=270 nm), and various catalytic parameters such as Km, Vmax, and Kcat were calculated from Michaelis-Menten and Lineweaver-Burk plot. Efficiency of enzymatic hydrolysis was in the order of CalB > Si-MNPs@CalB > CalB@NF > Si-MNPs@CalB@NF, and reusability was much better with the enzyme immobilized on Si-MNPs than with the native enzyme. Enzymatic acylation was confirmed by the formation of benzyl benzoate (λex=229 nm) from benzoic anhydride (λex=240 nm), and efficiency exceeded 99% in all samples. Finally, enzymatic lipolysis was confirmed by the decomposition of olive oil to fatty acid such as oleic acid (λex=230 nm) using thin-layer chromatography (TLC), column chromatography, and proton nuclear magnetic resonance (1H -NMR). The lipases immobilized on Si-MNPs have the advantage of good thermal stability and reusability and are thus applicable to a wide range of industries.

β-Ga2O3 is a well-known semiconductor material for power devices and other applications. Recently, β-Ga2O3 has also been reported as a scintillator material with a light yield of approximately 8400 ph./MeV, scintillation decay time of &lt;1 μs, and density of 6.44 g/cm3. In this study, 2-inch diameter β-Ga2O3 single crystals were prepared by oxide crystal growth using the cold crucible (OCCC) method under various oxygen partial pressures. In the OCCC method, as in the cold crucible method, a high frequency is applied directly to the oxide materials, which are heated and melted, and the melt is held by the outermost solid material itself that is cooled by water using a copper hearth. In the OCCC method, crystal growth is performed while rotating the seed crystal, as in the Czochralski method, to increase the crystal diameter. The optical properties and radiation responses of the crystals grown under various oxygen partial pressures were evaluated.

Developmental hazard evaluation is an important part of assessing chemical risks during pregnancy. Toxicological outcomes from prenatal testing in pregnant animals result from complex chemical-biological interactions, and while New Approach Methods (NAMs) based on in vitro bioactivity profiles of human cells offer promising alternatives to animal testing, most of these assays lack cellular positional information, physical constraints, and regional organization of the intact embryo. Here, we engineered a fully computable model of the embryonic disc in the compucell3d.org modeling environment to simulate epithelial-mesenchymal transition of epiblast cells and self-organization of mesodermal domains (chordamesoderm, paraxial, lateral plate, posterior/extraembryonic). Cell fate in the model is determined by an autonomous homeobox (HOX) clock driven by morphogenetic signals (e.g., FGF, WNT, ATRA, CDX). Executing the model renders a quantitative cell-level computation of mesodermal subpopulations and consequences of perturbation based on known embryogeny. For example, synthetic perturbation of the control network rendered altered phenotypes (cybermorphs) mirroring experimental mouse embryology, with 50% reductions in FGF4, FGF8 and BMP4 signaling resulting in 86%, 98% and 59% reductions, respectively in the posterior mesodermal population, while ATRA exposure also resulted in a 78% decrease in this population. This model enables integration of in vitro chemical bioactivity data for specific molecular targets with known embryology to test mechanistic veracity and quantitative prediction of altered development.

Background/Objectives: Vitamin D’s effect on risk health outcomes is often evaluated using prospective cohort studies. Risk ratios (RRs; e.g., hazard ratios or odds ratios) are determined for incidence for participants with baseline serum 25-hydroxyvitamin D [25(OH)D] concentrations below or above specified values. Serum 25(OH)D concentrations vary over time, thereby diluting the effect of 25(OH)D for long follow-up periods. Inverse relationships between RR and follow-up period have been reported for all-cause mortality rate and cancer incidence rates. Here I evaluate the effect for neurological outcomes. Methods: I analyzed how follow-up period affected results from 10 cohort studies of all-cause dementia, 6 studies of Alzheimer’s disease, and 9 for cognitive impairment with respect to vitamin D deficiency. Results: For all-cause dementia, Alzheimer’s disease, and cognitive impairment, respectively, the linear regression fits are RR = 2.9 – 0.14 × years, r = 0.73, p = 0.02; RR = 2.9 – 0.14 × years, r = 0.69, p = 0.13; and RR = 1.8 – 0.066 × years, r = 0.72, p = 0.03. The regression fit to RR for the shortest follow-up period for each outcome is considered the best estimate of vitamin D deficiency’s effect on risk. Those values are approximately twice that found by averaging all RRs without considering the effect of follow-up period. Conclusions: Vitamin D’s effect on risk of neurological conditions should be determined with relatively short follow-up periods after repeated 25(OH)D measurements as warranted during follow-up.

Abstract: This article reports the results of an ecological study of cancer incidence rates by state in the US for the period 2016-2020. The goals of this study were to determine the extent to which solar UVB doses still reduced cancer risk compared to findings reported in 2006 for cancer mortality rates for the periods 1950–1969 and 1970-1794 as well as cancer incidence rates for the period 1998–2002 and to determine which factors were recently associated with cancer risk. The cancer data for non-Hispanic white (European American) men and women were obtained from the Centers for Disease Control and Prevention. Indices were obtained for solar UVB at the surface for July 1992, and alcohol consumption, and diabetes and obesity prevalence near the 2016–2020 period. Lung cancer incidence rates were also used in the analyses as a surrogate for smoking, diet, and air pollution. The cancers for which solar UVB is significantly associated with reduced incidence are bladder, brain (males), breast, corpus uteri, esophageal, gastric, non-Hodgkin’s lymphoma, pancreatic, and renal cancer. Lung cancer was significantly associated with colorectal, laryngeal, and renal cancer. Diabetes was also significantly associated with breast, liver, and lung cancer. Obesity prevalence was significantly associated with breast, colorectal and renal cancer. Alcohol consumption was associated with bladder and esophageal cancer. Thus diet has become a very important driver of cancer incidence rates. The role of solar UVB in reducing risk of cancer has been reduced due to people spending less time outdoors, wearing sunscreen that blocks UVB but not UVA radiation, and population increases in overweight and obesity, which lowers 25-hydroxyvitamin D concentrations and generates systemic inflammation, a risk factor for cancer. The dietary approach that would reduce the risk of diabetes, obesity, lung cancer, and, therefore cancer, would be one based mostly on whole-plants and restrictions on red and processed meats and ultraprocessed foods. Solar UVB exposure for a few minutes before applying sunscreen and taking vitamin D supplements would also help reduce risk of cancer.Keywords: alcohol consumption; cancer incidence;

Distant Retrograde Orbits in the Earth-Moon system are gaining in popularity as stable `parking' orbits for various conceptual missions. To investigate the stability of potential Distant Retrograde Orbits, simulations were executed, with propagation running over a thirty-year period. Initial conditions for the vehicle state were limited such that the position and velocity vectors were in the Earth-Moon orbital plane, with the velocity oriented such that it would produce retrograde motion about Moon. The resulting trajectories were investigated for stability against the eccentric relative orbits of Earth and Moon in an environment that also included gravitational perturbations from Sun, Jupiter, and Venus, and the effects of radiation pressure. The results appear to indicate that stability is enhanced for certain resonant states within the Earth-Moon system.

A systematic study has been conducted on barbiturate complexes of all five alkali metals Li–Cs prepared from the metal carbonates or hydroxide in aqueous solution without other potential ligands present, varying the stoichiometric ratio of metal ion to barbituric acid (BAH). Eight polymeric compounds (two each for Na, K, and Rb and one each for Li and Cs) have been characterised by single-crystal X-ray diffraction. All contain some combination of barbiturate anion BA− (necessarily in a 1:1 ratio with the metal cation M+), barbituric acid, and water. All organic species and water molecules are coordinated to the metal centres via oxygen atoms as either terminal or bridging ligands. Coordination numbers range from 4 (for the Li complex) to 8 (for the Cs complex). Extensive hydrogen bonding plays a significant role in all the crystal structures, almost all of which include pairs of N–H…O hydrogen bonds linking BA− and/or BAH components into ribbons extending in one dimension. Factors influencing the structure adopted by each compound include cation size and reaction stoichiometry as well as hydrogen bonding.

The observation that certain therapeutic strategies for targeting inflammation benefit patients with distinct immune-mediated inflammatory diseases (IMIDs) is exemplified by the success of TNF blockade in conditions including rheumatoid arthritis, ulcerative colitis and skin psoriasis, albeit only for subsets of individuals with each condition. This suggests intersecting "nodes" in inflammatory networks at a molecular and cellular level may drive and/or maintain IMIDs, being “shared” between traditionally distinct diagnoses without mapping neatly to a single clinical phenotype. In line with this proposition, integrative tumour tissue analyses in oncology have highlighted novel cell states acting across diverse cancers, with important implications for precision medicine. Drawing upon advances in the oncology field, this narrative review will first summarise learnings from the Human Cell Atlas in health as a platform for interrogating IMID tissues. It will then review cross-disease studies to date that inform this endeavour, before considering future directions in the field.

Sweetness drives consumption of added sugars, so understanding how individuals differ is important for developing strategies to lower sugar intake. However, methods to assess hedonic response to sweetness vary, making results across studies difficult to integrate. We compared methods to measure optimal sucrose concentration in 21 healthy adults (1) using paired-comparison preference tracking vs. ratings of liking, (2) with participants in the laboratory vs. at home, and (3) using aqueous solutions vs. vanilla milk. Tests were replicated on separate days to assess test-retest reliability. Test-retest reliability was similar between laboratory and home testing, but tended to be better for vanilla milk and preference tracking. Optimal sucrose concentration was virtually identical between laboratory and home, slightly lower when estimated via preference tracking, and about 50% lower in vanilla milk. However, individual optimal sucrose concentration correlated strongly between Methods, test Locations, and Stimuli. More than 50% of the variability in optimal sucrose concentration could be attributed to consistent differences among individuals while much less variability was attributable to differences in Methods, test Locations or Stimuli. These results demonstrate convergent validity between measures of preference and liking, support testing at home to lower participant burden, and suggest that aqueous solutions can be useful proxies for some commonly consumed beverages for measuring individual differences.

The purpose of this study was to elucidate patterns and mechanisms driving seasonal and inter-annual variations of carbon and nitrogen stable isotopes in the zooplankton crustacean commu-nity of Lake Maggiore (Italy), during the period 2009-2020. Different zooplankton taxa and groups revealed different ranges of d13C signatures, giving an insight into food sources and niche partition. In particular, cyclopoids had a restricted range with most negative d13C‰ values and increase in d13C fractionation with the establishment of water thermal vertical stratification, high-lighting the importance of vertical distribution as key factor for taxa coexistence in a vertically heterogenous environment. d13C of the zooplankton community and of Daphnia were positively related to water temperature (R2=0.58 p <0.0001 and R2=0.68 p <0.0001, respectively) and d13C Daphnia signature to chlorophyll-a (R2=0.32, p < 0.0001). Decomposition of time series data for zooplankton carbon and nitrogen signatures and environmental parameters identified increasing trends in water temperature, chlorophyll-a and water conductivity and decrease in nitrate, that matched changes in carbon isotopic signature trend in some zooplankton taxa (Bosmina, Daphnia and diaptomids). Overall, the observed patterns in zooplankton isotopic signatures were interpreted as integrations of climate warming effects in Lake Maggiore, affecting both food sources availability and environmental conditions.

Recently a new class of experiments in the field of surface gravity waves has emerged. These experiments serve as demonstration of an analogy to a broad variety of phenomena in optics and quantum mechanics. In particular, experiments involving Airy water-wave packets were carried out. The Airy wave packets have attracted tremendous attention in optics and quantum mechanics owing to their unique properties, spanning from an ability to propagate along parabolic trajectories without spreading, and to accumulating a phase that scales with the cubic power of time. Non-dispersive Cosine-Gauss wave packets and self-similar Hermite-Gauss wave packets, also well known in the field of optics and quantum mechanics, were recently studied using surface gravity waves as well. These wave packets demonstrated self-healing properties in water wave pulses as well, preserving their width despite being dispersive. Finally, this new approach also allows to observe diffractive focusing from a temporal slit with finite width.

The production of recombinant enzymes, mainly used for obtaining pure and functional target molecules, holds significant importance in modern biotechnology. This study aimed to produce recombinant α-amylases (Amy3500 and Amy1974), derived from B. amyloliquefaciens MDC1974 and B. subtilis MDC3500 respectively, using the pBE-S shuttle vector, and to characterize them. Both α-amylase genes were molecularly cloned into the E. coli/B. subtilis pBE-S shuttle vector, both with (Amy1974sig and Amy3500sig) and without their own signal peptides (Amy1974 and Amy3500), along with a signal peptide originating from the plasmid, and tested in flask fermentations. For recombinant Amy3500, the amylase variants resulted in similar levels of volumetric activity (700-750 U/mL). In contrast, the expression of Amy1974 nearly doubled compared to Amy1974sig with double signal peptides, reaching 2000 U/mL. The SDS-PAGE estimated the molecular weight of Amy1974 α-amylase to be 54.6 kDa, which was in accordance with the theoretical molecular mass calculations. However, the estimated molecular weight of Amy3500 amylase was significantly reduced when exiting the producer cells. Ca2+ had no significant activating effect on the activities of Amy1974 amylase and Amy3500 amylase, likely due to its tight binding to the protein scaffold. Both enzymes exhibited broad activity peaks between 45-70°C, with a maximum at 65°C. The Amy1974 and Amy3500 α-amylases demonstrated broad pH optima and pH-dependent thermostability, with optimum pH values at 6.5 and 5.8, and thermal stability peaks at pH 7.6 and 5.9, respectively. Both α-amylases displayed high relative activity against various starches, including corn amylopectin and potato amylose, while showing comparatively lower activity towards cyclodextrins. The Amy1974 amylase converts starch to dextrins of varying lengths, whereas Amy3500 almost entirely converts starch into glucose.

Objectives: This study aimed to evaluate the risk of hepatitis B virus reactivation (HBVr) in COVID-19 patients receiving immunosuppressive treatment, which has been insufficiently studied to date. Secondarily, we aimed to evaluate the seroprevalence of HBV infection in COVID-19 patients. Methods: We performed an HBV screening in all Romanian adults hospitalized in 4 COVID-19 wards between October 2021 and September 2022. We enrolled patients with positive hepatitis B core antibody (anti-HBc) without protective hepatitis B surface antibody (anti-HBs), HBV treatment or immunosuppressive conditions, whom we followed virologically at 3 months. Results: We identified 333/835 (39.9%) anti-HBc-positive patients. Follow-up was performed in 13 patients with positive hepatitis B surface antigen (HbsAg) and 19 HBsAg-negative/anti-HBc-positive patients. Among those who received immunosuppressants, 4/23 (17.4%) patients experienced HBVr: 1 out of 8 (12.5%) HBsAg-positive patients (with 1.99 log increase in HBV DNA level) and 3 out of 15 (20%) HBsAg-negative/anti-HBc-positive patients (with de novo detectable HBV DNA level). Conclusions: Administration of COVID-19 immunosuppressants may result in a significant risk of HBVr in co-infected patients. We recommend performing an HBV triple screen panel (HBsAg, anti-HBs, anti-HBc) in all COVID-19 patients receiving immunosuppressive treatment. HBV prophylaxis may be indicated in certain patients. Larger studies are needed in order to establish an appropriate and cost-effective management in these patients.

Duchenne muscular dystrophy (DMD) is caused by genetic mutations in the cytoskeletal-sarcolemmal anchor protein dystrophin. Repeated cycles of sarcolemmal tearing and repair lead to a variety of secondary cellular and physiological stressors that are thought to contribute to weakness, atrophy, and fibrosis. Collectively, these stressors can contribute to a pro-inflammatory milieu in locomotor, cardiac, and respiratory muscles. Given the many unwanted side effects that accompany current anti-inflammatory steroid-based approaches for treating DMD (e.g., glucocorticoids), there is a need to develop new therapies that address inflammation and other cellular dysfunctions. Adiponectin receptor (AdipoR) agonists, which stimulate AdipoR1 and R2 isoforms on various cell types, have emerged as therapeutic candidates for DMD due to their anti-inflammatory, anti-fibrotic, and pro-myogenic properties in pre-clinical human and rodent DMD models. Although these molecules represent a new direction for therapeutic intervention, the mechanisms through which they elicit their beneficial effects are not yet fully understood, and DMD-specific data is limited. The overarching goal of this review is to investigate how adiponectin signaling may ameliorate pathology associated with dystrophin deficiency through inflammatory-dependent and -independent mechanisms, and to determine if current data supports their future progression to clinical trials.

Non-coding RNAs (ncRNAs) comprise a diverse class of non-protein coding transcripts that regulate critical cellular processes associated with cancer. Advances in RNA-sequencing (RNA-Seq) have led to the characterization of non-coding RNA expression across different types of human cancers. Through comprehensive RNA-Seq profiling, a growing number of studies demonstrate that ncRNAs, including long non-coding RNA (lncRNAs) and microRNAs (miRNA), play central roles in progenitor B-cell Acute Lymphoblastic Leukemia (B-ALL) pathogenesis. Furthermore, due to their central roles in cellular homeostasis and their potential as biomarkers, the study of ncRNAs continues to provide new insight into the molecular mechanisms of B-ALL. This article reviews the ncRNA signatures reported for all B-ALL subtypes, focusing on technological developments in transcriptome profiling and recently discovered examples of ncRNAs with biologic and therapeutic relevance in B-ALL.

Annually, more than 1.5 million preventable new hepatitis B (HBV) infections continue to occur, with an estimated global burden of 296 million individuals living with chronic hepatitis B infection. This substantial health challenge results in over 820,000 annual deaths attributed to complications such as liver cirrhosis and hepatocellular carcinoma (HCC). HBV vaccination remains the cornerstone of public health policy to prevent chronic hepatitis B and its related complications. It serves as a crucial element in the global effort to eliminate HBV, as established by the World Health Organization (WHO), with an ambitious 90% vaccination target by 2030. However, reports on global birth dose coverage reveal substantial variability, with an overall coverage rate of only 46%. This comprehensive review thoroughly examines global trends in HBV vaccination coverage, investigating the profound impact of vaccination on HBV prevalence and its consequences across diverse populations, including both high-risk and general demographics. Additionally, the review addresses the formidable challenges and facilitating factors essential for achieving WHO's HBV vaccination coverage objectives and elimination strategies in the coming decade and beyond.

This study introduces and demonstrates a comprehensive, accurate, unbiased approach to robust quantitative comparison of Electronic Nicotine Delivery Systems (ENDS) appropriate for establishing substantial equivalence (or lack thereof) between tobacco products. The approach is demonstrated across a family of thirteen pen- and pod-style ENDS products. Methods employed consist of formulating a robust emissions surface regression model, quantifying the empirical accuracy of the model as applied to each product, evaluating relationships between product design characteristics and maximum emissions characteristics, and presenting results in formats useful to researchers, regulators, and consumers. Results provide a response surface to characterize emissions (total particulate matter and constituents thereof) from each ENDS appropriate for use in a computer model and for conducting quantitative exposure comparisons between products. Results demonstrate that emissions vary as a function of puff duration, flow rate, E-Liquid composition, and device operating power. Further, results indicate that regulating design characteristics of ENDS devices and consumables may not achieve desired public health outcomes; it is more effective to regulate maximum permissible emissions directly. Three emissions outcome measures (yield per puff, mass concentration and constituent mass ratio) are recommended for adoption as standard quantities for reporting by manufacturers and research laboratories. The approach provides a means of (a) quantifying and comparing maximal emissions from ENDS products spanning their entire operating envelope, (b) comparative evaluation of ENDS devices and consumable design characteristics, and (c) establishing comparative equivalence of maximal emissions from ENDS. A consumer-oriented product emissions dashboard is proposed for comparative evaluation of ENDS exposure potential. Maximum achievable power dissipated in the coil of ENDS is identified as a potentially effective regulatory parameter.

PET imaging of bacterial infection could potentially provide added benefit for patient care by non-invasive means. [68Ga]Ga-desferrioxamine B – a radiolabelled siderophore – shows specific uptake by human-pathogenic bacteria like Staphylococcus aureus or Pseudomonas aeruginosa as well as sufficient serum stability for clinical application. Here, we provide data for automated production of [68Ga]Ga-desferrioxamine B on two different cassette based synthesis modules (Modular-Lab PharmTracer and GRP 3V) using commercially available cassettes together with an approved 68Ge/68Ga radionuclide generator. Quality control including determination of radiochemical purity as well as a system suitability test was set up via RP-HPLC on a C18 column. The two described production processes, using an acetic acid/acetate buffer system with ascorbic acid as a radiation scavenger for radiolabelling, yield ready-to-use formulations with sufficient activity yield. Batch data showed radiochemical purity of &gt;95 % as determined by RP-HPLC and ITLC as well as excellent stability over 2 hours post production. Specifications for routine production were set up and validated with four master batches for each synthesis module. Based on this study, an academic clinical trial for imaging of bacterial infection was initiated. Both described synthesis methods enable reproducible, automated in-house production of [68Ga]Ga-desferrioxamine B for clinical application.

Urban tree planting initiatives can experience high levels of mortality during establishment years. Mortality tied to the stresses of transplanting can be partially negated or exacerbated depending on the species selected, nursery materials used, site conditions present, and management practices employed. Past research has quantified post-planting survival, health, and growth. However, varying climates, species, land use types, and management practices warrant additional region-specific research. The purpose of this study is to assess the success of plantings along Florida highways and identify species, site, and management factors related to tree and palm health and establishment. Results show high annual establishment survival (98.5%) across 21 planting projects ranging from 9 to 58 months after installation, (n = 2711). For transplanted palms, the presence of on-site irrigation significantly improved establishment from 96.2% to 99.4%. No establishment differences were detected with regard to irrigation treatment for small-stature trees, shade trees, and conifers. Additionally, there were significant differences in tree health response among tree groups given species, management, and site factors.

COVID-19, previously known as “2019 novel coronavirus”, is a newly discovered virus which causes severe acute respiratory syndrome, similar to corona virus 2 (SARS-CoV-2), which has spread widely through human to human contact and was declared a pandemic by the WHO in March 2020. To cope with this pandemic many countries have adopted nationwide lockdowns which restrict nonessential activities and encourage their populations to avoid public transport, work from hone wherever possible, and to maintain social distancing at all times. While the severity of these shutdowns has varied with country, large geographic regions of the world (including China, India, Iran, Italy, Spain, and the USA) have all been severely affected, not just in the loss of human life, but also in terms of the financial impacts the lockdowns will have on their countries future prosperityIt was previously reported that a number of environmental factors, including humidity and temperature, played an important role in development and spread of the SARS-Corona Virus infection with the virus retaining viability for over 5 days at temperatures between 22–25^oC and relative humidity (RH) of 40–50%. Whereas, elevated temperatures and higher RH (38^oC, and >95% RH) decreased virus viability (Kroumpouzos et al., 2020). The spread of COVID-19 started in low temperature areas of China, with major outbreaks subsequently occurring in Iran, Japan, Northern Italy and South Korea. These new virus epicenters all had similar temperature and latitude, along the 30-50^◦N” zone. Subsequently, the virus was spread to regions of elevated temperature, such as India, the Middle East and Thailand, due to international travel (Kroumpouzos et al., 2020).The aim of this study was to consider the environmental impact of COVID-19, including water pollution. The paper is divided into four sections. In the first section the current literature related to COVID-19 is reviewed. In the second section a recent update on COVID-19 globally is presented, followed by a descriptive impact on the environment in the third section and finally in the fourth section the COVID-19 related worldwide environmental impact is discussed. Since COVID-19 is a currently an active pandemic with no end in sight, while constructive conclusions can only be made on the limited data currently, which may be prone to high errors. However, these conclusions may provide some preliminary suggestions for assisting in assessing spreading patterns of COVID-19 across the globe, and may be of long-term significances with respect to assessing the environmental impact of lockdown policies due to COVID-19 worldwide.

Background: Across the world, antibiotic resistance is a grave problem. To address this issue, it is necessary to investigate new antibiotic sources. Aim of the study: Egypt's diverse soil habitats were used to produce bacterial Myxopyronin B, which was then tested for antimicrobial activity in preclinical animal studies and randomized human clinical trials stages 1/2. Type of the study: Screening experimental study. Methodology: Egypt's various soil conditions were examined for the development of bacterial isolates that produced the antibiotic compound Myxopyronin B. Reversed phase HPLC was used to purify Myxopyronin B. To determine the test antibiotic's minimum inhibitory concentration( MIC) and invitro antibacterial activity, the Broth microdilution method and the Paper disc diffusion assay were utilized. Moreover, in vivo antibacterial spectrum, adverse medication responses, and pharmacokinetics were found in preclinical animal testing stages and phases 1/2 of randomized clinical studies involving volunteer humans. Results: Myxopyronin B was generated from the culture supernatant of Myxococcus SDU36, the main soil bacterial isolate cultured on a Casein yeast peptone plate. With MICs less than 100 mcg/ml, the test antibiotic prevented the growth of several Gram +ve bacteria, whereas, at MICs higher than 100 mcg/ml, it inhibited the development of a small number of Gram -ve bacteria, including Escherichia coli. However, eukaryotic cells—such as those found in fungi and humans—were unaffected. The test antibiotic was seen to inhibit prokaryotic DNA-dependent RNA polymerase( RNLP), indicating its bactericidal activity. Mean Cmax was 9-10 mcg/ ml at mean Tmax 1 hour when 600 mg dose was orally administered in randomized human clinical trials phases 1/2, and T1/2 reached 2.25 hours following first-order kinetics of elimination. Duration of its action was nearly 8 hours after oral administration. Rare toxicity was detected during preclinical and randomized human clinical trials phases 1/2 in the form of mild diarrhea and GI upset in less than 7 % of experimental candidates. It exhibited approximately 90% plasma protein binding, especially with albumin which resulted in prolonged therapeutic action. It showed a concentration dependant antibiotic killing effect. With the concentration-dependent killing pattern, the higher the drug concentration relative to the pathogen minimum inhibitory concentration( MIC), the greater the rate and extent of antimicrobial activity. Conclusion: The present study was promising due to the production of the bactericidal antibiotic Myxopyronin B from Myxococcus sp. SDU36 isolated from different soil environments in Egypt.

A Wireless Body Area Network (WBAN) is a network of wirelessly connected sensing and actuating devices. WBANs used for recording biometric information and administering medication are classified as part of a Cyber Physical System (CPS). Preserving user security and privacy is a fundamental concern of WBANs, which introduces the notion of using biometric readings as a mechanism for authentication. Extensive research has been conducted regarding the various methodologies (e.g. ECG, EEG, gait, head/arm motion, skin impedance). This paper seeks to analyze and evaluate the most prominent biometric authentication techniques based on accuracy, cost, and feasibility of implementation. We suggest several authentication schemes which incorporate multiple biometric properties.

The aim of this study was to determine the extent to which the Tyme Wear smart shirt is as reliable and valid in detecting personalized ventilatory thresholds when compared to the Parvo Medics TrueOne 2400. In this validation study, 19 subjects were recruited to conduct two graded exercise test (GXT) trials. Each GXT trial was separated by seven to ten days of rest. During the GXT, gas exchange and heart rate data were collected by the TrueOne 2400 (TRUE) in addition to the ventilation data collected by the Tyme Wear smart shirt (S-PRED). Gas exchange data from TRUE was used to detect VT1 and VT2. TRUE and S-PRED VT1 and VT2 were compared to determine the reliability and validity of the smart shirt. Of the 19 subjects, data from 15 subjects were used during analysis. S-PRED exhibited excellent (ICC &gt; 0.90) reliability for detection of VT1 and VT2 utilizing time point and workload and moderate (0.90 &gt; ICC &gt; 0.75 ) reliability utilizing heart rate. TRUE exhibited excellent reliability for detection of VT1 and VT2 utilizing time point, workload, and heart rate. When compared to TRUE, S-PRED appears to underestimate the VT1 workload (p &gt; 0.05) across both trials and heart rate (p &lt; 0.05) for trial 1. However, S-PRED appears to underestimate VT2 workload (p &lt; 0.05) and heart rate (p &lt; 0.05) across both trials. The result from this study suggests that the Tyme Wear smart shirt is less valid but is comparable in reliability when compared to the gold standard. Moreover, despite the underestimation of S-PRED VT1 and VT2, the S-PRED detected personalized ventilatory thresholds will provide an adequate training workload for most individuals. In conclusion, the Tyme Wear smart shirt provides easily accessible testing to establish threshold-guided training zones but does not devalue the long-standing laboratory equivalent.

Coronaviruses (CoVs) are enveloped positive-sense single-stranded RNA viruses with a genome 27-31kbases in length. Critical genes include the spike (S), envelope (E), membrane (M), nucleocapsid (N) and 9 accessory open reading frames encoding for non-structural proteins (NSPs) that have multiple roles in the replication cycle and immune evasion (1). There are 7 known human CoVs that most likely appeared after zoonotic transfer, the most recent being SARS-CoV-2 responsible for the Covid-19 pandemic. Antivirals that have been approved by the FDA for use against Covid-19 such as Paxlovid can potentially target and successfully inhibit the main protease (MPro) activity of multiple human CoVs, however alternative proteomes encoded by CoV genomes have a closer genetic similarity to each other, suggesting that antivirals could be developed now that target future CoVs. New zoonotic introductions of CoVs to humans are inevitable and unpredictable. Therefore, new antivirals are required to control not only the next human CoV outbreak, but also the 4 common human CoVs (229E, OC43, NL63, HKU1) that circulate frequently and to contain sporadic outbreaks of the severe human CoVs (SARS-CoV, MERS and SARS-CoV-2). The current study found that emerging antiviral drugs, such as Paxlovid, have only been proven to target SARS-CoV-2. Other drugs which have the potential to target other human CoVs, are still within clinical trial and are not yet available for public use. Monoclonal antibody (mAb) treatment and vaccines for SARS-CoV-2 can reduce mortality and hospitalisation rates, however they target the Spike protein whose sequence mutates frequently and drifts. Spike also is not applicable for targeting other HCoVs as these are not well conserved sequences among human CoVs. Thus, there is a need for readily available treatments globally that target all 7 human CoVs and improve the preparedness for inevitable future outbreaks. Here we discuss antiviral research contributing to the control of common and severe CoV replication and transmission, including the current SARS-CoV-2 outbreak. The aim was to identify common features of CoVs for antivirals, biologics and vaccines that could reduce the scientific, political, economic and public health strain caused by CoV outbreaks now and in the future.

Abiotic stress is responsible for significant reduction in crop plant productivity worldwide. Ultraviolet (UV) radiation is a natural component of sunlight and a permanent environmental stimulus. This study investigated the distinct responses of young wheat and einkorn plants to excessive UV-B radiation (180 min at λmax 312 nm) following foliar pretreatment with 1 µM synthetic cytokinin 4PU-30. Results demonstrated that UV radiation significantly amplified hydrogen peroxide levels in both wheat and einkorn, with einkorn exhibiting more pronounced increase compared to wheat. This elevation indicated the induction of oxidative stress by UV radiation in the two genotypes. Intensified antioxidant enzyme activities and increased accumulation of typical stress markers and non-enzyme protectants were evidenced. Transcriptional activity of genes encoding key antioxidant enzymes was also investigated aiming to elucidate the genetic regulation of the antioxidant systems in both wheat and einkorn seedlings. Our results suggested a role for POX1 and POX7 genes in the UV-B tolerance of the two wheat species as well as a cytokinin stimulated UV-B stress response in einkorn mediated through upregulation of the tau subfamily gene GSTU6. Based on these findings it could be concluded that 4PU-30 had the potential of alleviating oxidative stress by attenuating the symptoms of superfluous UV-B illumination in the two examined plant species.

Systemic Lupus Erythematosus (lupus) and B-cell lymphoma (lymphoma) are serious diseases. Lupus and lymphoma co-occur at higher-than-expected rates and primarily depend on B-cells for their pathology, implicating shared inflammation-related B-cell molecular mechanisms as a potential cause of co-occurrence. We consequently implemented a novel Immune Imbalance Transcriptomics (IIT) algorithm and applied IIT to lupus, lymphoma, and healthy B-cell RNA-seq data to find shared- and contrasting mechanisms potentially targetable for treatment. We observed 8,562 genes significantly dysregulated in both lupus and lymphoma. Of those genes, we found 5,335 to have a significant immune imbalance, defined as significant dysregulation by both diseases, as determined by IIT. Gene Ontology (GO) term and pathway enrichment of IIT genes yielded immune-related “Neutrophil Degranulation” and “Adaptive Immune System”, validating that the IIT algorithm isolates biologically relevant genes in immunity and inflammation. We found that 389 IIT gene products are drug-targetable with established or repurposed drugs. Among our results, we found 40 known and 349 novel lupus targets, along with 151 known and 238 novel lymphoma targets. Known disease drug targets in our IIT results further validate that IIT isolates genes with disease-relevant mechanisms. We anticipate the IIT algorithm and shared and contrasting gene mechanisms uncovered here will contribute to the development of immune-related therapeutic options for lupus and lymphoma patients.

The cancelation factor (CF) is a model for the ratio between gravity wave perturbations in the airglow intensity to that in the ambient temperature. The CF model allows to estimate the momentum and energy flux of gravity waves seen in nightglow images as well as the divergence of these fluxes due to waves propagating through the mesosphere and lower thermosphere region, where the nightglow and the Na layers are located. This study uses a set of T/W Na Lidar data and zenith nightglow image observations of the OH and O(1S) emissions to test and validate the CF model from the experimental perspective. The dataset analyzed was obtained during campaigns carried out at the Andes Lidar Observatory (ALO), Chile in 2015, 2016, and 2017. The CF modeled function was compared with observed points from an empirical method for vertically propagating waves that calculates directly the ratio of the gravity wave amplitude seen in nightglow images to the wave amplitude seen in lidar temperatures. We show that the CF analytical relationship underestimates the observed results generally. However, the O(1S) emission line has better agreement respect to the theoretical value due to simpler nightglow photochemistry. In contrast, the observed CF ratio from the OH emission deviates by a factor of two from the modeled asymptotic value.

One of the oldest problems in physics is that of calculating the motion of N particles under a specified mutual force: the N-body problem. Much is known about this problem if the specified force is non-relativistic gravity, and considerable progress has been made by considering the problem in one spatial dimension. Here I review what is known about the relativistic gravitational N-body problem. Reduction to one spatial dimension has the feature that gravitational radiation is absent, thereby allowing for a clear comparison between the physics of one-dimensional relativistic and non-relativistic self-gravitating systems. After describing how to obtain a relativistic theory of gravity coupled to N point particles, I discuss in turn the 2-body, 3-body, 4-body, and N-body problems. Quite general exact solutions can be obtained for the 2-body problem, unlike the situation in general relativity in 3 spatial dimensions for which only highly specified solutions exist. The 3-body problem exhibits mild forms of chaos, and provides one of the first theoretical settings in which relativistic chaos can be studied. For N4 other interesting features emerge. Relativistic self-gravitating systems have a number of interesting problems awaiting further investigation, providing us with a new frontier for exploring relativistic many-body systems.

Chronic Hepatitis B (CHB) Virus infection is major etiological factor for liver cirrhosis and/ or liver cancer. The viral protein, major contributor in predisposition of chronicity and Hepatocellular Carcinoma (HCC) is Hepatitis B x (HBx) protein. Its dynamic subcellular distribution to an extent determines its multifactorial role. It is a regulatory protein which modulates viral as well as host machinery in favours to HBV persistence. An insight on HBx stabilising factors is critical for therapeutic purpose. The precise role of HBx in the pathogenesis of Chronicity of HBV is not known. Summary: This review comprehensively summarizing different mechanisms and their regulation by HBx protein with respect to chronicity and HCC emphasising viral persistence. Key Messages 1. HBx is a key protein for viral persistence. 2. Dynamic subcellular distribution of HBx determines its function. 3. HBx modulates cellular machinery to favours HBV survival. 4. HBx affects various intermediary mechanisms contributing to disease progression. 5. HBx may be a potent target to prevent the disease progression towards HCC.

Background: Previous studies have associated slowed ventricular conduction in the arrhythmogenesis mediated by the gap junction and sodium channel inhibitor heptanol in mouse hearts but did not study the propagation patterns that might contribute to the arrhythmic substrate. This study used a multi-electrode array mapping technique, to further investigate different conduction abnormalities in Langendorff-perfused mouse hearts exposed to 0.1 or 2 mM heptanol. Methods: Multi-electrode array recordings were made from the left ventricular epicardium in spontaneously beating hearts, during right ventricular regular 8 Hz pacing or S1S2 pacing. Results: In spontaneously beating hearts, heptanol at 0.1 and 2 mM significantly reduced the heart rate from 314±25 to 189±24 and 157±7 bpm, respectively (ANOVA, P<0.05 and P<0.001). During regular 8 Hz pacing, Mean LATs were increased by 0.1 and 2 mM heptanol from 7.1±2.2 ms to 19.9±5.0 ms (P<0.05) and 18.4±5.7 ms (P<0.05). The standard deviation of mean LATs was increased from 2.5±0.8 ms to 10.3±4.0 ms and 8.0±2.5 ms (P< 0.05), and the median of phase differences was significantly increased from 1.7±1.1 ms to 13.9±7.8 ms and 12.1±5.0 ms by 0.1 and 2 mM heptanol (P<0.05). P5 took a value of 0.2±0.1 ms and was not significantly altered by heptanol at 0.1 or 2 mM (1.1±0.9 ms and 0.9±0.5 ms, P>0.05). P50 was increased from 7.3±2.7 ms to 24.0±12.0 ms by 0.1 mM heptanol and then to 22.5±7.5 ms by 2 mM heptanol (P< 0.05). P95 was increased from 1.7±1.1 ms to 13.9±7.8 ms by 0.1 mM heptanol and to 12.1±5.0 ms by 2 mM heptanol (P<0.05). These changes led to increases in the absolute inhomogeneity in conduction (P5-95) from 7.1±2.6 ms to 31.4±11.3 ms, 2 mM: 21.6±7.2 ms, respectively (P<0.05). The inhomogeneity index (P5-95/P50) was significantly reduced from 3.7±1.2 to 3.1±0.8 by 0.1 mM and then to 3.3±0.9 by 2 mM heptanol (P<0.05). Conclusion: Increased activation latencies, reduced CVs and increased dispersion index of conduction were associated with both spontaneous and induced ventricular arrhythmias.

Evaluation of the effects of a high-frequency acceleration (HFA) device on patient pain response to orthodontic forces. A multi-centered trial investigating pain sensitivity to orthodontic forces on 75 subjects at 4 study centers. Subjects underwent clear aligner treatment, with or without adjunctive HFA and documented their pain intensity using the validated NRS10 numeric rating scale. In-Office and At-Home ratings were measured separately for each subject for immediate and extended effect evaluations. Use of HFA devices in conjunction with clear aligner orthodontic treatment demonstrated significant reduction in subjects’ recorded pain ratings vs controls within 5 minutes of aligner exchange, (p = 0.006) and significant reduction in recorded pain ratings vs controls over a 7-day period following aligner exchange (p = 0.018). A 99.6% daily compliance rate with at home use of the HFA device was recorded for all subjects in the study. HFA significantly reduces pain attributed to orthodontic force. HFA delivers clinically significant immediate pain relief, and clinically significant extended pain relief over the 7 days following adjustment.

Background: Approximately 10-20% of subjects vaccinated with HBsAg-based hepatitis B virus (HBV) vaccines are non-responders. BM32 is a recombinant grass pollen allergy vaccine containing the HBV-derived preS surface antigen as immunological carrier protein. PreS includes the binding site of HBV to its receptor on hepatocytes. We investigated if immunological non-responsiveness to HBV after repeated HBsAg-based vaccinations can be overcome by immunization with VVX001 (i.e., Alum-adsorbed BM325, a component of BM32). Methods: A subject failing to develop protective HBV-specific immunity after HBsAg-based vaccination received five monthly injections of 20 µg VVX001. PreS-specific antibody responses were measured by ELISA and micro-array technology. Serum reactivity to subviral particles of different HBV genotypes was determined by sandwich ELISA. PreS-specific T cell responses were monitored by CFSE staining and subsequent FACS analysis. HBV neutralization was assessed using cultured HBV-infected HepG2 cells. Results: Vaccination with VVX001 induced a strong and sustained preS-specific antibody response composed mainly of the IgG1 subclass. PreS-specific IgG antibodies were primarily directed to the N-terminal part of preS containing the NTCP attachment site. IgG reactivity to sub-viral particles as well as to the N-terminal preS-derived peptides was comparable for HBV genotypes A-H. A pronounced reactivity of CD3+CD4+ lymphocytes specific for preS after the complete injection course remaining up to one year after the last injection was found. Maximal HBV neutralization (98.4%) in vitro was achieved 1 month after the last injection which correlated with the maximal IgG reactivity to the N-terminal part of preS. Conclusion: Our data suggest that VVX001 may be used as a preventive vaccination against HBV even in non-responders to HBsAg-based HBV vaccines.

The proliferation and survival signals emanating from the B-cell receptor (BCR) constitute a crucial aspect of mature lymphocyte’s life. Dysregulated BCR signaling is considered a potent contributor to tumor survival in different subtypes of B cell non-Hodgkin lymphomas (B-NHLs). In the last decade, emergence of BCR-associated kinases as rational therapeutic targets has led to the development and approval of several small molecule inhibitors targeting either Bruton's tyrosine kinase (BTK), spleen tyrosine kinase (SYK), or phosphatidylinositol 3 kinase (PI3K), offering alternative treatment options to standard chemoimmunotherapy, and making some of these drugs valuable assets in the anti-lymphoma armamentarium. Despite their initial effectiveness, these precision medicine strategies are limited by primary resistance in aggressive B-cell lymphoma like diffuse large B cell lymphoma (DLBCL) and mantle cell lymphoma (MCL), especially in the case of first generation BTK inhibitors. In these patients, BCR-targeting drugs often fail to produce durable responses, and nearly all cases eventually progress with a dismal outcome, due to secondary resistance. This review will discuss our current understanding of the role of antigen-dependent and antigen-independent BCR signaling in DLBCL and MCL and will cover both approved inhibitors and investigational molecules being evaluated in early preclinical studies. We will discuss how the mechanisms of action of these molecules, and their off/on-target effects can influence their effectiveness and lead to toxicity, and how our actual knowledge supports the development of more specific inhibitors and new, rationally based, combination therapies, for the management of MCL and DLBCL patients.

The volume of vehicular traffic in large cities has increased in recent years, the devices that collect vehicular GPS data such as cameras, GPS receivers and others generate millions of records at every instant of time generating problems in processing and storage of these data which becomes important for researchers. Intelligent Transportation Systems perform vehicle monitoring and control by collecting GPS trajectories, this large volume of information is necessary to have an optimal storage process. Its processing by means of compression techniques and simplification algorithms allow to reduce the necessary storage space. This paper presents a GPS trajectory simplification algorithm that considers noise reduction, point simplification and analysis of road network information. The results obtained on two data sets from the cities of California and Beijing are satisfactory, achieving a higher compression ratio without affecting data quality

This study describes the seasonal course of denitrifying and nitrate reducing bacteria in a dimictic mesotrophic lake (Lake Scharmützelsee, Brandenburg, Germany) within a three-year period from 2011 to 2013. The bacterial cell numbers were quantified by fluorescence microscopy, most probable number (MPN) and PCR dependent quantification of the chromosomal 16S rDNA and of the nirS and nirK gene copy number. The highest seasonal differences (up to three orders of magnitudes) has been measured by MPN in the epilimnion. This variation was not reflected by PCR dependent approaches or direct microscopical enumeration. At adverse conditions (low temperature and/or low nitrate concentrations), the differences between MPN and gene copy numbers increased up to five orders of magnitudes and decreased to one magnitude at favorable environmental conditions. These results can be explained best by an increasing ratio of viable but not cultivable (VBNC) cells or dead cells at impairing conditions. In the hypolimnion, the courses of MPN and nir gene copy numbers were similar. This can be explained by higher feeding pressure and therefore smaller amounts of dormant cells. In the pelagial in general, the total cell numbers enumerated by either microscopical or molecular approaches were similar. In the sediment, more than 99 % of the DNA was obviously not related to viable bacteria but was rather “dead DNA” in dead cells or adsorbed to particle surfaces.

This paper aims to outline the effectiveness of modern universal gate quantum computers when utilizing different configurations to solve the B-SAT(Boolean Satisfiability) problem. The quantum computing experiments are performed using Grover’s Search algorithm to find a valid solution. The experiments are performed under different variations to demonstrate their effects on the results. Changing the number of shots, qubit mapping, and using a different quantum processor are all among the experimental variables. The study also branches into a dedicated experiment highlighting a peculiar behavior that IBM quantum processors exhibit when running circuits with a certain number of shots.

Peanut hulls (PH) are an edible food waste that is an underutilized food source for human consumption. While edible and palatable, they are mainly diverted to livestock feed or building materials. Here, we describe existing literature on human food valorization of PHs and propose methods to optimize recapturing nutrients (e.g. protein, fiber, polyphenols) lost by treating PHs as waste. Incorporated into common foods, PHs can be processed into functional ingredients to improve nutrient-density and the corresponding positive health outcomes associated with increases in plant foods. PH valorization can also address additional priorities of the UN Sustainable Development Goals using a Food Systems Approach (FSA) including food waste, increasing economic opportunities for farmers, and increasing the availability of healthy shelf-stable foodstuffs to address food security. Recent advances in sustainable food processing technologies can be utilized to safely incorporate peanut hulls into human food streams. We propose future applications that could make meaningful impacts to food availability and the nutritional composition of common foods. While the limited literature on this topic spans several decades, no global operations exist to incorporate peanut hulls and most publications precede the technological ‘green revolution’. The approaches outlined in this review may help bolster commercialization of this underutilized and nutritious food potentially improving opportunities for multiple global stakeholders.

Abstract: Medication overuse headaches is a frequent phenomenon observed in individuals suf-fering from chronic headaches. It arises due to the excessive consumption of pain-relief medica-tions, resulting in the escalation and continuous persistence of headache symptoms. Nevertheless, the prevalence and distinctive characteristics of medication overuse headaches in the pediatric population have not been comprehensively explored. The primary objective of this research is to delineate the features of medication overuse headaches in children, particularly emphasizing the investigation of its epidemiology and the diagnostic patterns for headaches. We conducted a ret-rospective study by and analyzed the medical records of children and adolescents who were evaluated at outpatient pediatric headache clinic at the Bnai Zion medical center for headache during the period spanning 2007 to 2017. Our study encompassed a cohort of 1008 patients expe-riencing headaches. Among these participants, 268 individuals (26.6%) were diagnosed with mi-graine, 250 (24.8%) exhibited tension-type headaches (TTH), and 490 (48.6%) were classified as having undifferentiated headaches. Out of the whole group, 65 had chronic headaches: 35 (54%) with migraine, 20 (30%) with tension-type headaches (TTH), and 10 (15%) with undifferentiated headache of childhood, with the majority (73%) being female.In summary, medication overuse headaches are a prevalent issue among children grappling with chronic headaches. Intriguingly, they appear to be more pronounced within the tension-type headache (TTH) group compared to migraine sufferers, and exhibit a higher prevalence among females. This study underscores the significance of early detection and careful management of medication overuse headaches in pedi-atric cases, shedding light on its distinct characteristics in the realm of childhood headache disor-ders. Further research is warranted to elucidate the underlying factors contributing to the ob-served gender disparity and the distinct prevalence rates among different headache subtypes.

Hemicellulose is one of the most important natural polysaccharides in nature. Hemicellulose from different sources varies in chemical composition and structure, which in turn affects the modification effects and industrial applications. Grain and oil by-products (GOBP) are important raw materials for hemicellulose. This article reviews the modification methods of hemicellulose in GOBP. The effects of chemical and physical modification methods on the properties of hemicellulose biomaterials were evaluated. The potential applications of GOBP hemicellulose in films, hydrogel, Three-dimensional (3D) printing and adsorbent are discussed. Future research directions and recommendations are also proposed to provide theoretical foundations and technical support for the efficient utilization of these by-products.

The BNT162b2 vaccine is globally used for preventing morbidity and mortality related to COVID-19. Cancer patients have had priority for receiving the vaccine due to their diminished immunity. This study reports the response of administering the 3rd and 4th vaccine doses to can-cer patients receiving active anti-neoplastic treatment. 142 patients have received two doses of the mRNA-based BNT162b2 COVID-19 vaccine, while 76 and 25 patients have received three and four doses, respectively. The efficacy of the humoral response following two vaccine doses was diminished in cancer patients, especially in the group of patients receiving chemotherapy. In a multivariate analysis, patients after three and four BNT162b2 vaccine doses were more likely to have antibody titers in the upper tertile compared to patients after two doses of the vaccine (odds ratio (OR) 7.62 (95% CI 1.38-42.12), p=0.02 and 17.15 (95% CI 5.01-58.7), p<0.01, respective-ly). Unlike the response after two doses, the 3rd and 4th BNT162b2 vaccine booster doses, had an increased efficacy of 95-100% in cancer patients while on active treatment. This result could be explained by different mechanisms including the development of memory B cells.

Hepatitis B virus (HBV) is known to cause severe liver diseases such as acute or chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Chronic hepatitis B (CHB) infection is a major health problem with nearly 300 million individuals infected worldwide. Currently, nucleos(t)ide analogs (NAs) and interferon alpha are clinically approved treatments for HBV infection. NAs are potent antiviral agents that bind to HBV polymerase and block viral reverse transcription and replication. Besifovir dipivoxil maleate (BSV) is a newly developed NA against HBV in the form of acyclic nucleotide phosphonate that is available for oral administration similar to adefovir and tenofovir. Until now, resistance to BSV treatment has not been reported. In this study, we found a CHB patient who showed viral breakthrough after long-term treatment with BSV. The isolated HBV DNA from patient’s serum were cloned into the replication-competent HBV 1.2mer and the sequence of reverse transcriptase (RT) domain of HBV polymerase were analyzed. We also examined the drug susceptibility of generated clones in vitro. Several mutations were identified in HBV RT domain. A particular mutant harboring ten RT mutations showed resistance to BSV treatment in vitro. The ten mutations include rtV23I (I), rtH55R (R), rtY124H (H), rtD134E (E), rtN139K (K), rtL180M (M), rtM204V (V), rtQ267L (L), rtL269I (I) and rtL336M (M). To further identify the responsible mutations for BSV resistance, we performed in vitro drug susceptibility assay on several artificial clones. As a result, our study revealed that rtL180M (M) and rtM204V (V) mutations, already known as lamivudine-resistant mutations, confer resistance to BSV in the CHB patient.

Polylactic Acid (PLA) is an organic polymer commonly used in fused deposition (FDM) printing and biomedical scaffolding that is biocompatible and immunologically inert. However, variations in source material quality and chemistry make it necessary to characterize the filament and determine potential changes in chemistry occurring as a result of the FDM process. We used several spectroscopic techniques, including laser confocal microscopy, Fourier-Transform Infrared (FTIR) spectroscopy and photoacousitc FTIR spectroscopy, Raman spectroscopy, and X-ray photoelectron Spectroscopy (XPS) in order to characterize both the bulk and surface chemistry of the source material and printed samples. Scanning Electron Microscopy (SEM) and Differential Scanning Calorimetry (DSC) were used to characterize morphology, crystallinity, and the glass transition temperature following printing. Analysis revealed calcium carbonate-based additives which were reacted with organic ligands and potentially trace metal impurities, both before and following printing. These additives became concentrated in voids in the printed structure. This finding is important for biomedical applications as carbonate will impact subsequent cell growth on printed tissue scaffolds. Results of chemical analysis also provided evidence of the hygroscopic nature of the source material and oxidation of the printed surface, and SEM imaging revealed micro and sub-micron scale roughness that will also impact potential applications.

Acidic ostreolysin A/pleurotolysin B (OlyA/PlyB, formerly known as ostreolysin (Oly), and basic 20 kDa equinatoxins (EqTs) are cytolytic proteins isolated from the edible mushroom Pleurotus ostreatus and the sea anemone Actinia equina, respectively. Both toxins, although from different sources, share many similar biological activities: (i) colloid-osmotic shock by forming pores in cellular and artificial membranes enriched in cholesterol and sphingomyelin; (ii) increased vascular endothelial wall permeability in vivo and perivascular oedema; (iii) dose-dependent contraction of coronary vessels; (iv) haemolysis with pronounced hyperkalaemia in vivo; (v) bradycardia, myocardial ischemia and ventricular extrasystoles accompanied by progressive fall of arterial blood pressure and respiratory arrest in rodents. Both types of toxins are haemolytic within nanomolar range concentrations, and it seems that hyperkalaemia plays an important role in toxin cardiotoxicity. However, it was observed that the haemolytically more active EqT III is less toxic than EqT I, the most toxic and least haemolytic EqT. In mice, EqT II is more than 30 times more toxic than OlyA/PlyB when applied intravenously. These observations imply that haemolysis with hyperkalaemia is not the sole cause of the lethal activity of both toxins. Additional mechanisms responsible for lethal action of the two toxins are direct effects on heart, coronary vasoconstriction and related myocardial hypoxia. In this review, we appraise the pathophysiological mechanisms related to the chemical structure of OlyA/PlyB and EqTs, as well as their toxicity.

Background: Osteoporosis and bone fractures affect health and quality of life. Since bone disease is multifactorial, identifying risk factors is key in prevention. There are multiple reports on how viral hepatitis especially chronic hepatitis B (CHB) and chronic hepatitis C (CHC) are affecting bone disease, but results vary. Here, we analyzed the potential association between CHB/CHC and osteoporosis or bone fractures in a large outpatient cohort in Germany. Methods: We included 3,136 outpatients with CHB and 15,608 matched non-hepatitis individuals as well as 2,867 outpatients with CHC and 14,335 matched non-hepatitis individuals from the Disease Analyzer Database between 2005 and 2022. The main outcome was the 5-year cumulative incidence of osteoporosis and bone fractures as a function of either CHB or CHC. Results: Within 5 years of the index date, 2.9% vs. 1.6% of patients with and without CHB were diagnosed with osteoporosis (p=0.001) and 1.0% vs. 0.4% were diagnosed with bone fractures (p<0.001). Moreover, 3.3% of CHC patients and 2.2% of individuals without hepatitis were diagnosed with osteoporosis (p=0.002). In Cox-regression analyses, CHB was significantly associated with an increased risk for osteoporosis (HR: 1.76) and fractures (HR:2.43) and CHC with osteoporosis (HR: 1.54). For both CHB and CHC, the association with osteoporosis was restricted to the female subgroup. Conclusion: CHB and CHC are associated with osteoporosis in women. CHB in male patients is associated with a higher risk of fractures. More research is are needed to understand the underlying pathophysiological mechanisms.

Viruses can induce the fusion of infected and neighboring cells, leading to the formation of syncytia. Cell-cell fusion is mediated by viral fusion proteins on the plasma membrane of infected cells that interact with cellular receptors on neighboring cells. Viruses use this mechanism to spread rapidly to adjacent cells or escape host immunity. For some viruses, syncytium formation is a hallmark of infection and a known pathogenicity factor. For others, the role of syncytium formation in viral dissemination and pathogenicity remains poorly understood. Human cytomegalovirus (HCMV) is an important cause of morbidity and mortality in transplant patients and the leading cause of congenital infections. Clinical HCMV isolates have broad cell tropism but differ in their ability to induce cell-cell fusions, and little is known about the molecular determinants. We developed a system to analyze HCMV glycoprotein B (gB) variants in a defined genetic background. HCMV strains TB40/E and TR were used as vectors to compare the fusogenicity of six gB variants from congenitally infected fetuses with those from three laboratory strains. Five of them conferred the ability to induce fusion of MRC-5 human embryonic lung fibroblasts to one or both backbone strains, as determined by a split GFP-luciferase reporter system. The same gB variants were not sufficient to induce syncytia in infected ARPE-19 epithelial cells, suggesting that additional factors are involved. The system described here allows a systematic comparison of the fusogenicity of viral envelope glycoproteins and may help to clarify whether fusion-promoting variants are associated with increased pathogenicity.

Dengue virus is a global health problem most prevalent in tropical and subtropical regions. However, after the approval of two vaccines, Dengvaxia, TV003/TV005 of Takeda, for its prevention, problems were reported, like enhanced risks of infection or less efficiency of protection. Since then, more struggles have been in demand for the development of better vaccines. Here, we conducted a new design through an in-silico strategy. Initially, epitopes were chosen based on their antigenicity, immunogenicity, and binding affinity with MHC molecule, while excluded with allergenicity, toxicity and potential risk of antibody dependent enhancement. Subsequently, a core antigen was constructed with selected epitopes and linked with distinct adjuvant proteins to achieve three candidate vaccines, PSDV-1~3. PSDV-2 was chosen for further validation based on their advantage in physicochemical and structural properties. With a panel of simulations, this artificial protein showed tight binding with pattern recognition receptors, good stability, robust immune induction, and ultimately was confirmed as a high quality vaccine candidate. The plasmid for its recombinant expression was then designed accordingly. With our new design, one more choice was obtained for the effective protection from Dengue virus. Further experimental validations are still require to confirm it protection capacity and safety.

The immune system is central in controlling acute hepatitis B infection and in patients resolving chronic hepatitis B (CHB). Given that 221 million (75%) of CHB patients reside in low- and middle-income countries, developing a vaccine with therapeutic properties represents a rational and cost-effective approach more than a romantic endeavor. This review systematically analyses the critical variables related to the safety, efficacy, and effectiveness of CHB treatments. HeberNasvac's experience is revisited to address the challenges and potentialities of therapeutic vaccines, as well as the current roadblocks in research and development, registration, and large-scale implementation.

Urolithins (e.g., UroA and B) are gut microbiota-derived metabolites of the natural polyphenol ellagic acid. Urolithins are associated with various health benefits, including attenuation of inflammatory signaling, anti-cancer effects and repression of lipid accumulation. The molecular mechanisms underlying the beneficial effects of urolithins remain unclear. We hypothesize that some of the human health benefits of urolithins are mediated through the aryl hydrocarbon receptor (AHR). Utilizing a cell-based reporter system, we tested urolithins for the capacity to modulate AHR activity. Cytochrome P450 1A1 (CYP1A1) mRNA levels were assessed by real-time quantitative polymerase chain reaction. Competitive ligand binding assays were performed to determine whether UroA is a direct ligand for the AHR. Subcellular AHR protein levels were examined utilizing immunoblotting analysis. AHR expression was repressed in Caco-2 cells by siRNA transfection to investigate AHR-dependency. UroA and B were able to antagonize 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced AHR-mediated transcriptional activity. Furthermore, UroA and B attenuated TCCD-mediated stimulation of CYP1A1 mRNA levels. In addition, competitive ligand binding assays characterized UroA as a direct AHR ligand. Consistent with other AHR antagonists, UroA failed to induce AHR retention in the nucleus. AHR is necessary for UroA-mediated attenuation of cytokine-induced interleukin 6 (IL6) and prostaglandin-endoperoxide synthase 2 (PTGS2) expression in Caco-2 cells. Here we identified UroA as the first dietary-derived human selective AHR antagonist produced by the gut microbiota through multi-step metabolism. Furthermore, previously reported anti-inflammatory activity of UroA may at least in part be mediated through AHR.

The main motive of this study was to find an auxiliary application of the discarded agricultural remnants and poultry waste. Rice straw and chicken feathers are disposed off as landfills or incinerated causing pollution and environmental threats after their primary consumption. In this study epoxy composites were made using varying proportions of these raw and alkali treated materials. Flexural strength of the composites decreased till 35% fiber loading, followed by an increase. Chicken feather composites showed increased impact strength with fiber addition. Alkali treatment improved the mechanical properties of rice straw composites. Alkali treated chicken feather composites showed better impact strength but no significant change in flexural strength. Hybrid composites explicated enhanced properties both before and after alkali treatment corroborating noteworthy interfacial adhesion and synergistic effect of these fibers as ascertained from SEM images. The study evinced a better option for averting environmental problems by recycling these disposed materials.

Vehicular traffic in urban areas continues to be a constant challenge today, due to the continuous population growth and the increase of vehicles in circulation. Vehicular congestion, as a recurrent problem, generates a negative impact on urban mobility and citizens’ quality of life. It is hypothesized that a dynamic clustering method of vehicle trajectory data can provide an accurate and up-to-date representation of real-time traffic behavior. To evaluate this hypothesis, data were collected from three different cities: San Francisco, Rome and Guayaquil. A dynamic clustering algorithm was applied to identify traffic congestion patterns and an indicator was applied to identify and evaluate the congestion conditions of the areas. The results show a high precision and recall in congestion classification compared to a method based on static cells.

The implementation of Emissions Trading System (ETS) poses significant challenges for the Indian maritime sector. This paper investigates the regulatory implications of ETS, focusing on how these regulations impact compliance and operational practices within the Indian shipping sector. It also analyzes the economic effects, including the financial burden and competitive dynamics faced by the Indian shipping companies in a global context. Additionally, the paper explores various adaptation strategies, emphasizing technological innovations and operational adjustments essential for navigating ETS requirements. By integrating recent industry data and case studies, this study offers a comprehensive overview of how the Indian shipping industry can effectively address the evolving regulatory landscape of ETS.

Lamin A, B and C, the nuclear intermediate-filament proteins, play a role in epigenetic regulation. While Lamin B is expressed in all nucleated cells studied, Lamin A/C are transcribed in most somatic cell types except mature B lymphocytes. Since Epstein-Barr virus (EBV), a human gammaherpesvirus, is associated with tumorigenic processes and is known to alter the epigenotype of its host cells, we studied the expression of the LMNA gene and its epigenetic marks in EBV-carrying human lymphoid cell lines. We observed a high lamin A/C mRNA and protein expression in EBV-immortalized lymphoblastoid cell lines (LCLs) and in group III Burkitt lymphoma (BL) lines where hypomethylated first exons were observed with activating histone marks. In most cell lines with low promoter activity a highly methylated first exon could be detected. Our data showed that methylation of the first exon of LMNA was associated with the downregulation of LMNA expression whereas euchromatic histone marks were enriched at active LMNA promoters in EBV-immortalized LCLs. These data suggest a role for viral latency products to activate LMNAp in EBV-infected latency type III B cells in vitro. Expression of lamin A/C may contribute to the establishment of activated B cell phenotype that needs further explorations.

The prevalence of hepatitis B and delta viruses (HBV/HDV) among people who use drugs (PWUD) remains largely unknown. In the context of one Philadelphia-based harm reduction organization (HRO), this study aimed to assess HBV/HDV prevalence and facilitate linkage to care. Participants completed a demographic HBV/HDV risk factor survey and were screened for HBV and reflexively for HDV if positive for HBV surface antigen or isolated core antibody. Fisher’s exact tests and regression were used to understand relationships between risks and HBV blood markers. Of the 498 participants, 126 (25.3%) were susceptible to HBV, 52.6% had been vaccinated against HBV, and 17.9% had recovered from a past infection. Eleven (2.2%) participants tested positive for isolated HBV core antibody, 10 (2.0%) for HBV surface antigen, and one (0.2%) for HDV antibody. History of incarceration was associated with current HBV infection, while transactional sex and experience of homelessness were predictive of previous exposure. This study found high rates of current and past HBV infection, and a 10% HBV/HDV co-infection rate. Despite availability of vaccine, one quarter of participants remained vulnerable to infection. Findings demonstrate the need to improve low-threshold HBV/HDV screening, vaccination, and linkage to care among PWUD. The study also identified gaps in the HBV/HDV care cascade, including lack of point-of-care diagnostics and lack of support for HROs to provide HBV services.

Clinical, pathological, and imaging evidence in multiple sclerosis (MS) shows that inflammation starts early and progresses with age. B cells play a central role in this process, contributing to cytokine production, defective regulatory functions, and abnormal immunoglobulin production, even in the central nervous system. Anti-CD20 (aCD20) therapies, which deplete CD20+ B cells, are effective for both relapsing-remitting (RR) and progressive-relapsing (PR) MS. While effective against MS symptoms and lesions detectable by magnetic resonance imaging, aCD20 therapies can reduce the immune response to COVID-19 vaccination. By using high-parameter flow cytometry, we examined the antigen-specific (Ag+) immune response six months post-third COVID-19 mRNA-vaccination in MS patients with RR and PR forms on aCD20 therapy. Despite lower Ag+ B cell responses and lower levels of anti-SARS-CoV2, both total and neutralizing antibodies, RR and PR patients developed strong Ag+ T cell responses. We observed similar percentages and numbers of Ag+ CD4+ T cells and high proportion of Ag+ CD8+ T cells, with slight differences in T cell phenotype and functionality, that however suggested the presence of differences in immune responses driven by age and disease severity.

The BAFF-APRIL system is crucial for the pathogenesis of systemic lupus erythematosus (SLE) by promoting B cell survival, differentiation and the maintenance of humoral autoimmunity. Here, we investigated the relationship of BCMA expression on B cell subsets with its ligands BAFF and APRIL, together with soluble BCMA, and with clinical and serologic variables in a cohort of 100 SLE patients (86 under conventional and 14 under belimumab therapy) and 30 healthy controls (HC) using multicolor flow cytometry and ELISA. We found that BCMA expression in SLE patients was significantly increased on all B cell subsets compared to HCs, with all examined components of the BAFF-APRIL system being upregulated. BCMA expression was significantly increased on switched and unswitched memory B cells compared to naïve B cells, both in HCs and SLE. BCMA expression on B cells correlated with plasmablast frequencies, serum anti-dsDNA antibodies and complement consumption, while soluble BCMA correlated with plasmablast frequency, highlighting its potential as clinical biomarker. Belimumab treatment significantly reduced BCMA expression on most B cell subsets and soluble TACI, and contributes to the inhibition of almost the entire BAFF-APRIL system and restoration of B cell homeostasis. These results provide insights into the complex dysregulation of the BAFF-APRIL system in SLE and highlight the therapeutic potential of targeting its components, particularly BCMA, in addition to its use as biomarker for disease activity.

Background and Objectives: Obesity-related elevated body mass index (BMI) across life is associated with chronic low-grade inflammation and increased levels of C-reactive protein (CRP) in blood. CRP is a marker and promoter of inflammation. The objectives of this study were to examine the effect of obesity on the relationship between peripheral and gingival CRP levels and examine the effects of gingival CRP levels on gingival fluid inflammatory cytokines in periodontitis resistant obese individuals. Materials and Methods: Thirty-nine, periodontally healthy subjects were enrolled. Based on BMI scores, 20 subjects were categorized as lean and 19 as obese. A comprehensive periodontal examination was performed. Gingival crevicular fluid (GCF) and blood samples were collected. Both GCF and blood samples were assessed for interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-8 (IL-8), tumor necrosis factor-α (TNF-α), interleukin-10 (IL-10), interleukin-17A (IL-17A) and CRP. Results: GCF CRP levels were significantly higher in obese than lean individuals. No statistically significant differences were noted between the two groups in both GCF and blood on any of the inflammatory cytokine levels. IL-17A was not detected in GCF of most subjects in both groups. GCF CRP levels were positively associated with blood CRP levels, the association tended to be stronger in obese individuals. GCF CRP showed no associations with GCF IL-10 in both groups. Although GCF CRP levels positively associated with multiple GCF inflammatory cytokines (e.g., IL-1β, IL-6, IL-8 and TNF-α) in all subjects, the associations tended to be weaker in obese individuals (e.g., IL-1β, IL-6, TNF-α). Furthermore, the levels of GCF inflammatory cytokines IL-6 and TNF-α were depressed in obese individuals. Conclusions: Obesity unfavorably influences the relationship between blood and GCF CRP levels and promotes increased CRP levels in GCF. Collectively, the findings suggest a dysregulated inflammatory cytokine response in the gingival tissues of obese individuals.

Software testing is an integral yet time-consuming component of software development, and even with capable software testing resources (technology and people), it is still regarded as problematic. Test automation is widely being utilised within the software industry to provide increased testing capacity to ensure high product quality and reliability. In this paper, we are specifically addressing automated testing whereby test cases are manually written. Test automation has its benefits, drawbacks, and impacts on different stages of development. Furthermore, there is often a disconnect between non-technical and technical roles, where non-technical roles (e.g., management) predominantly strive to reduce costs and delivery time whereas technical roles are often driven by quality and completeness. Although it is widely understood that there are challenges with adopting and using automated testing, there is a lack of evidence to understand the different attitudes toward automated testing (AtAT), focusing specifically on why it is not adopted. In this paper, the authors have surveyed practitioners within the software industry from different roles to determine common trends and draw conclusions. A two-stage approach is presented, comprising a comprehensive descriptive analysis and the use of Principle Component Analysis. In total, 81 participants were provided with a series of 22 questions and their responses are compared against job role types and experience levels. In summary, 6 key findings are presented covering expertise, time, cost, tools and techniques, utilisation, organisation, and capacity

Background: Despite their generally favorable prognosis, hepatic fibrosis remains a possible complication for hepatitis B virus (HBV) inactive carriers. This study aimed to estimate the prevalence of significant fibrosis and associated risk factors among Omani HBV inactive carriers. Methods: A retrospective study was conducted of 200 Omani HBV inactive carriers visiting a tertiary hospital in Muscat, Oman, between January 2017 and December 2018. Significant fibrosis (stage F2 or higher) was identified using two-dimensional shear-wave elastography. Baseline clinical, laboratory, and radiological data were analyzed to determine associations. Results: Of the total sample, 106 patients (53%) were male, and the mean age was 44.6 ± 9.3 years. The prevalence of significant fibrosis was 20% (n = 40). Male gender (p = 0.007), age ≥60 years (p = 0.024), and fatty changes in liver ultrasound (p = 0.044) were found to be independent factors for significant fibrosis. Conclusion: the prevalence of significant fibrosis was relatively high among a sample of Omani HBV inactive carriers, with several sociodemographic and clinical risk factors identified. Periodic assessment of liver function is needed for patients with these risk factors; moreover, routine biochemical parameters could be useful predictors of disease prognosis. Further research is recommended to substantiate these findings.

Hepatitis B virus (HBV) is the dominant risk factor for hepatocellular carcinoma (HCC). HBV X protein (HBx) plays crucial roles in HCC carcinogenesis. HBx interferes with several signaling pathways including Notch1 pathway in HCC. In our study, we found that Notch1 was highly expressed in HCC especially in large HCC. Notch1 and HBx co-localized in HCC and their levels were positively correlated with each other. Notch1 expression was more elevated in HepG2.2.15 than that in HepG2. HBx activated Notch1 pathway in HepG2.2.15. Repression of HBx and Notch1 pathway attenuated the growth of HepG2.2.15. Notch1, ERK and AKT pathways were inhibited after a γ-secretase inhibitor treatment. Dual-specificity phosphatase 1 (DUSP1) and phosphatase and tensin homolog (PTEN) were up-regulated after the γ-secretase inhibitor treatment and Hes1 inhibition. Luciferase reporter assays showed that Hes1 repressed the promoters of DUSP1 and PTEN and this was reverted by γ-secretase inhibitor treatment. Western blotting demonstrated that DUSP1 dephosphorylated pERK and PTEN dephosphorylated pAKT. Collectively, we reported a link among HBx, Notch1 pathway, DUSP1/PTEN, and ERK/AKT pathways, which influenced HCC cell survival and could be a therapeutic target for HCC.

In this work, zinc oxide (ZnO)/ granular activated carbon (GAC) composites at different ZnO concentration (0.25M-ZnO@GAC, 0.5M-ZnO@GAC, and 0.75M-ZnO@GAC) were prepared by an in-situ hydrothermal method and demonstrated synergistic photocatalytic degradation and ad-sorption of Rhodamine B (RhB). The thermal stability, morphological structure, elemental com-position, crystallographic structure, and textural properties of developed catalysts were charac-terized by thermal gravimetric analysis (TGA/DTG), scanning electron microscopy equipped with energy dispersive-x-ray (SEM-EDS), x-ray diffraction (XRD), and Brunauer–Emmett–Teller (BET) analysis. Successful loading of ZnO onto GAC was confirmed by SEM-EDS and XRD analysis. The BET surface areas of GAC, 0.25M-ZnO@GAC, 0.5M-ZnO@GAC, and 0.75M-ZnO@GAC were 474 m2/g, 450 m2/g, 453 m2/g, and 421 m2/g, respectively. The decrease in GAC could be attributed to the successful loading of ZnO on the GAC surface. Notably, 0.5M-ZnO@GAC exhibited the best photocatalytic degradation efficiency of 82% and 97% under UV-A and UV-C light over 120 min, attributed to improved crystallinity and visible light absorption. The photocatalytic degradation parameters revealed that lowering the RhB concentration, raising the catalyst dosage and pH be-yond the point of zero charge (PZC) would favor the RhB degradation. Photocatalytic reusability was demonstrated over 5 cycles. Scavenger tests revealed that the hydroxyl radicals (•OH), su-peroxide radicals (O2−•), and photoinduced hole (h+) radicals play a major role during the RhB degradation process. Based on the TOC results, the RhB mineralization efficiency of 79.1% was achieved by 0.5M-ZnO@GAC. Additionally, GAC exhibited a strong adsorptive performance towards RhB with adsorption capacity and RhB removal of 487.1 mg/g and 99.5% achieved within 90 min equilibrium time. The adsorption characteristics were best described by pseu-do-second-order kinetics, suggesting chemical adsorption. This research offers a new strategy for the development of effective photocatalyst materials with potential for wider wastewater treat-ment applications.

Majority of the studied MADS box members are linked with flowering and fruit traits. However, higher volumes of studies on the type II of their two types so far suggest that florigenic effect of the gene members could just be tip of the iceberg. In current study we used a systematic approach to have general overview on the MADS box members their cross-trait and multifactor associations as well as their pleiotropic potentials based on local reference database curated for MADS box members. While doing so, we screened for the co-occurrence of the terms of interest within the title or abstract of each reference with threshold of 3 hits. Analysis results showed that our approach can retrieve multi-faceted information on the subject of study (MADS box gene members in current case) which could otherwise have been skewed depending on the authors’ expertise and/or volume of literature reference base. Overall, our study discusses on the roles of MADS box members in association with plant organs and traits-linked factors among plant species. Our assessment showed that plants with majority of the MADS box member studies include tomato, apple, rice etc., after Arabidopsis. Furthermore, based on the degree of their multi-trait associations, FLC, SVP, SOC1, etc. are suggested to have relatively higher pleiotropic potential among others in plant growth, development and flowering process. The approach devised in this study is expected applicable for having basic understanding on any study subject of interest regardless of depth prior knowledge.

In this paper we develop and explore a methodical pipeline for swimmer localisation in outdoor environments. The developed framework is intended to be used for enhancing swimmer safety. A main issue we deal with by the proposed approach is the lack of real world training data in such outdoor environments. Natural lighting changes, dynamic water textures and possibly barely visible swimming persons are key elements to approach. We account for these difficulties by adopting an effective background removal technique with available training data. This allows us to edit swimmers into natural environment backgrounds for the use in subsequent image augmentation. We created 17 training datasets with real images, synthetic images and a mixture of both to investigate different aspects and characteristics of the proposed approach. The datasets are used to train a YOLO architecture for the possible future application in real-time detection. The trained framework is then tested and evaluated on outdoor environment imagery acquired by a safety drone to investigate and confirm the usefulness for outdoor swimmer localisation.

Human papillomavirus (HPV) can potentially compromise both unassisted conception and success rates with assisted reproductive technology (ART). We aimed to evaluate the rates of HPV vaccination among women presenting for fertility care. This was a prospective study analyzing a self-reported intake form completed by all new patients presenting to a fertility clinic. The primary outcome was HPV vaccination status. Among the 523 new patients included in this study 172 (32.9%) were fully vaccinated, 237 (45.3%) were unvaccinated, and 95 (18.2%) patients didn’t respond. There was a significant age difference between fully vaccinated patients (33.1 years) compared to unvaccinated patients (37.4 years) p&lt;0.001 and a significant difference in gravidity between fully vaccinated patients (average 0.65) and unvaccinated patients (average 1.11) p=0.0005. No significant association was found between HPV vaccination status and history of abnormal Pap smears or relationship status (single vs. married). Less than half of patients presenting to our fertility center were vaccinated against HPV, despite being eligible to receive the vaccine. Younger patients with lower gravidity were more likely to be vaccinated against HPV than older patients with higher gravidity. Reproductive Endocrinologists have the opportunity to recommend HPV vaccination for eligible patients presenting for fertility care.

Freezing of gait (FOG), a debilitating symptom of Parkinson’s disease (PD), can be safely studied using the stepping in place (SIP) task. However, clinical, visual identification of FOG during SIP is subjective and time consuming, and automatic FOG detection during SIP currently requires measuring center of pressure on dual force plates. This study examines whether FOG elicited during SIP in 10 individuals with PD could be reliably detected using kinematic data measured from wearable inertial measurement unit sensors (IMUs). A general, logistic regression model (AUC = 0.81) determined that three gait parameters together were overall the most robust predictors of FOG during SIP: arrhythmicity, swing time coefficient of variation, and swing angular range. Participant-specific models revealed varying sets of gait parameters that best predicted FOG for each participant, highlighting variable FOG behaviors, and demonstrated equal or better performance for 6 out of the 10 participants, suggesting the opportunity for model personalization. The results of this study demonstrated that gait parameters measured from wearable IMUs reliably detected FOG during SIP, and the general and participant-specific gait parameters allude to variable FOG behaviors that could inform more personalized approaches for treatment of FOG and gait impairment in PD.

Background: Inflammatory Bowel disease (IBD) is one of the worldwide health issues with increasing incidence. Recent data point out that those patients can have a defective immune system, rendering response to vaccinations suboptimal. Since 1990, Hepatitis B Virus (HBV) vaccination has been introduced among the compulsory childhood vaccinations in Oman. Given the questionable immunogenicity of vaccinations in IBD patients, we designed this study to quantify the immune response to scheduled HBV vaccine in IBD patients and compare it with that in a matching control cohort of healthy blood donors at Sultan Qaboos University Hospital (SQUH). Methods: This is a retrospective case-control study that was conducted between the 1st of July 2023 and the 31st of May 2024 at SQUH. Using the hospital information System (HIS), a total of 252 participants were enrolled in our study and divided into two groups. Group (1) included 126 IBD patients and group (2) included 126 healthy controls. Baseline demographics, medical comorbidities and viral serologies before and after vaccination were collected. The primary outcome of the study was to compare the long term immune response to HBV vaccine between the two groups. The secondary outcomes included identifying possible risk factors for suboptimal vaccine response. Results: One hundred and twenty-six participants were included in each group. Durable protective immune response to HBV vaccine was attained in 29 patients (23%) of the IBD group compared to 109 participants (86.5%) of the control group. There was a statistically significant association (p = 0.0156) between prednisolone treatment and low immune response to HBV vaccine. Moreover, esomeprazole usage exhibited a statistically significant association (p < 0.0001) with suboptimal response to HBV vaccine. Meanwhile, there was no statistically significant correlation between low immunogenicity to HBV vaccine and age, sex, type of IBD, comorbidities, and BMI. Conclusions: IBD patients are less immunogenic to HBV vaccination compared to healthy controls. Factors like esomeprazole and/or corticosteroid therapy might be associated with poor immune response. These findings highlight the importance of reassessing the immunogenicity of HBV vaccination and probably other protective vaccinations in all IBD patients as part of their standard of care.

We have now identified two thermodynamically distinct types (A and B) of energetic processes naturally occurring on Earth. Type A energy processes such as the classical heat engines, apparently well follow the second law of thermodynamics; Type B energy processes, such as the newly discovered thermotrophic function that isothermally utilizes environmental heat energy to do useful work in driving ATP synthesis, which follows the first law of thermodynamics (conservation of mass and energy) but does not have to be constrained by the second law, owing to their special asymmetric functions. Several Type-B energy processes such as asymmetric-function-gated isothermal electricity and epicatalysis have been created through human efforts. The innovative efforts on Type-B processes to enable isothermally utilizing endless environmental heat energy could help to liberate all peoples from their dependence on fossil fuel energy, thus helping to reduce greenhouse gas CO2 emissions and control climate change towards a sustainable future for the humanity on Earth.

Biochar application to soil has been proposed as a means for reducing soil greenhouse gas emissions and mitigating climate change. The effects, however, of interactions between biochar, moisture and temperature on soil CO₂ and N₂O emissions, remain poorly understood. Furthermore, the applicability of lab-scale observations to field conditions in diverse agroecosystems remains uncertain. Here we investigate the impact of a mixed wood gasification biochar on CO₂ and N₂O emissions from loess-derived soils using: (1) controlled laboratory incubations at three moisture (27, 31 and 35%) and three temperature (10, 20 and 30°C) levels, and (2) a field study with four cropping systems (continuous corn, switchgrass, low diversity grass mix, and high diversity grass-forb mix). Biochar reduced N₂O emissions under specific temperatures and moistures in the laboratory and in the continuous corn cropping system in the field. However, the effect of biochar on N₂O emissions was only significant in the field, and no effect on cumulative CO₂ emissions was observed. Cropping system also had a significant effect in the field study, with soils in grass and grass-forb cropping systems emitting more CO₂ and less N₂O than corn cropping systems. Observed biochar effects were consistent with previous studies showing that biochar amendments can reduce soil N₂O emissions under specific, but not all, conditions. The disparity in N₂O emission responses at the lab and field scales suggests that laboratory incubation experiments are not reliable for predicting the impact of biochar at the field scale.

Ovarian cancer is among the most common causes of female mortality. Despite improvements in diagnostic methods, non-specific symptoms and delayed gynecological exams can lead to late-stage ovarian tumor discovery. In this study, the effect of an anti-cancer compound, 3-amino-N-(3-chloro-2-methylphenyl)-5-oxo-5,6,7,8-tetrahydrothieno[2,3-b]quinoline-2-carboxamide (Compound 1) was examined. Cytotoxicity, apoptosis, and metabolomic changes in ovarian cancer cell lines SK-OV-3 and OVCAR-3, as well as glycosphingolipid (GSL) expression, both on cancer stem cells (CSCs), marked as CD49f+ and non-CSCs (CD49f-) were explored. Treatment with Compound 1 reduced the percentage of CSCs compared to non-treated cells (P &lt; 0.001). The expression of eight GSLs on CSCs and non-CSCs was examined using flow cytometry. Both cell lines showed a change in the glycophenotype of the cells, either up or down of its expression, after the treatment. These findings raise the possibility of specifically targeting CSCs in ovarian cancer therapy. Additionally, treatment of Compound 1 resulted in a statistically significant increase in both early and late apoptosis (P&lt;0.001) suggesting a pivotal role in initiating programmed cell death by the apoptotic pathway. The metabolic analysis revealed that the treated cancer cells showed reduced metabolic activity compared to the control group (P &lt; 0.001)

Given the remarkable progress in global health and overall quality of life, the significant rise in life expectancy has become intertwined with the surging occurrence of neurodegenerative disorders (ND). This emerging trend is poised to pose a substantial challenge to the fields of medicine and public health in the years ahead. In this context, Alzheimer's disease (AD) is regarded as a ND that causes recent memory loss, motor impairment and cognitive deficits. AD is the most common cause of dementia in the elderly and its development is linked to multifactorial interac-tions between the environment, genetics, aging and lifestyle. The pathological hallmarks in AD are the accumulation of beta amyloid (A) peptide, the hyperphosphorylation of tau protein, neuro-toxic events and impaired glucose metabolism. Due to pharmacological limitations and in view of the prevailing glycemic hypometabolism, the ketogenic diet (KD) emerges as a promising non-pharmacological possibility for managing AD, an approach that has already demonstrated efficacy in addressing other disorders, notably epilepsy. KD consists of a food regimen in which carbohydrate intake is discouraged at the expense of increased lipid consumption, inducing met-abolic ketosis, whereby the main source of energy becomes ketone bodies, instead of glucose. Thus, under these dietary conditions, neuronal death through lack of energy would be decreased, inasmuch as the metabolism of lipids is not impaired in AD. In this way, the clinical picture of patients with AD would potentially improve, through the slowing down of symptoms and delaying the progression of the disease. Hence, this review aims to explore the rationale behind utilizing the KD in AD treatment while emphasizing the metabolic interplay between KD and the improvement of AD indicators, drawing insights from both pre-clinical and clinical investigations.