Mental healthcare conditions in India are severely deficient, particularly concerning the living conditions of patients. Post-treatment, numerous individuals with mental illness are abandoned by their families, who may lack the willingness or financial means to care for them. These recovered patients often experience setbacks due to the absence of facilities aimed at developing the skills necessary for reintegrating into society. The lack of separate accommodations for recovered individuals forces them to reside with other patients, worsening their condition. The government is struggling to accommodate and finance the care of recovered patients, affecting those in need of treatment as hospital bed space becomes overwhelmed by the increasing number of cured individuals. Therefore, there is an urgent need for halfway homes. These facilities offer a range of services, including social, medical, psychological, and educational support, alongside housing. The term "halfway houses" reflects their position between fully independent living and highly regulated in-patient or correctional facilities. Following treatment, many patients experience abandonment by their families or encounter difficulties returning home due to memory loss. Recovered patients often live in confined spaces, lacking essential social skills. Therefore, establishing a workspace focused on teaching social and other necessary skills before reintegrating them into society would be a beneficial approach. This would provide a structured environment for individuals who have spent significant time in seclusion, assisting them in developing the skills needed to navigate societal challenges effectively. Recent reports indicate that over 2,000 cured patients are still housed in mental hospitals across the country, according to the NHRC. The NHRC has raised concerns about the situation, noting that all 46 Government Mental Healthcare Institutions in India display very poor and inhumane treatment of patients, leading to the issuance of notices. NHRC visits have revealed deplorable conditions in all 46 mental institutes across the country.

This study aims to analyse the technical viability and economic feasibility of rainwater harvesting systems for single and multifamily residential buildings in the city of Florianópolis, Brazil. Simulations were conducted for representative buildings in the city under different water usage scenarios and system designs, in a total of 36 simulation scenarios. An economic analysis was performed for four scenarios over a twenty-year period. Both initial and operational costs were considered and net present value, internal rate of return and payback used as feasibility indicators. Almost all of the cases simulated were technically viable for the group of houses, and up to 78.9% for flats. As for the economic analysis, for houses, between 60.1% and 74.8% of the cases were economically feasible, achieving a discounted payback period ranging from 6.2 to 8.6 years. For flats, between 57.8% and 64.2% of the cases were economically feasible, achieving a discounted payback period ranging from 4.8 to 5.6 years. As the water tariff in the city underwent changes recently, the former and current tariff formats were compared. The current tariff format provides more economic benefits for saving potable water, and leads to a higher net present value and a shorter discounted payback period.

Although research has long established that the interaction with the natural environment is associated with better overall health and well-being outcomes, the Western model mainly focuses on treating the symptoms. In Aotearoa-New Zealand, the Indigenous Māori have long demonstrated significantly more negative health outcomes than non-Māori. Little research has examined the causes compared to Western populations or the role of the natural environment in health outcomes for Māori. An exploration of rongoā Māori (traditional healing system) was conducted to ascertain the importance of landscape in the process of healing. Eight rongoā healers or practitioners took part in semi-structured narrative interviews from June to November 2020. Transcribed interviews were analysed using an interpretative phenomenological analysis and Kaupapa Māori techniques. The findings show how rongoā is underpinned by a complex set of cultural values and beliefs, drawing from the connection to wairua (spirit), tinana (body), tikanga and whakaora (customs and healing), rākau (plants), whenua (landscape) and whānau (family). Incorporating such constructs into the landscape can foster our understanding of health and well-being and its implications for conceptualising therapeutic environments and a culturally appropriate model of care for Māori and non-Māori communities.

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.

Background: Antibiotic resistance is an overwhelming serious difficulty globally. This necessitates the exploration of novel sources of antibiotics to overcome this challenge. Aim of the study: Bacterial Myxopyronin A production from various soil environments Egypt; as well as testing its antimicrobial activity in preclinical animal testing and randomized human clinical trials phases 1/2. Type of the study: Screening experimental study. Methodology: Different soil environments in Egypt were screened for the growth of bacterial isolates producing Myxopyronin A as an antimicrobial agent. Purification of Myxopyronin A was performed via reversed-phase HPLC. Paper disc diffusion assay, as well as the Broth dilution technique, were exploited to assess the invitro antimicrobial and minimum inhibitory concentration( MIC) of the test antibiotic. Furthermore, in vivo antimicrobial spectrum, adverse drug reactions, and pharmacokinetics were detected during animal model testing stages and human randomized clinical trials phases 1/2. Results: From the culture supernatant of the Myxobacterium Myxococcus fulvus 124B02 which was the predominant soil bacterial isolate grown on the Casein yeast peptone plate, Myxopyronin A was produced. The test antibiotic blocked the growth of many Gram +ve bacteria with MICs less than 100 mcg/ ml. In contrast, it inhibited the growth of a few Gram -ve bacteria such as Escherichia coli at MICs greater than 100 mcg/ ml. On the other hand, Eukaryotic cells such as fungal and human cells were not affected. Prokaryotic DNA-dependant-RNA polymerase( RNLP) was noticed to be inhibited via the test antibiotic suggesting its bactericidal action. The maximum concentration was 7-8 mcg/ ml at a maximum time of 2 hours when 600 mg dose was orally administered in randomized human clinical trials phases 1/2, and T1/2 reached 2.5 hours following first-order kinetics of elimination. The duration of its action was nearly 12 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 cholestatic jaundice in less than 5 % of experimental candidates. Conclusion: The present study was promising due to the bactericidal antibiotic Myxopyronin A production from Myxococcus fulvus 124B02 isolated from different soil environments in Egypt.

BACKGROUND: Thromboembolic disorders including Myocardial infarction[ MI] and stroke represent the leading causes of death worldwide. Fibrinolytic enzymes extracted from microbial sources showed high efficacy in the dissolution of different blood clots. AIM OF THE STUDY: Screening and the bacterial recombinant DNA manufacture of bacterial fibrinolytic enzymes from different soil environments in Egypt. METHODOLOGY: A total of 50 soil samples were screened for their fibrinolytic enzyme production. The potent fibrinolytic enzyme-producing bacterial isolates were evaluated for their thrombolytic activities using the plasma plate method. The characterization of the enzyme activity and thermostability were carried out; also, the determination of molecular mass using a mass spectrometer and western blot technique was performed. The purification of the fibrinolytic enzymes was done through the affinity chromatography technique. On the other hand, the production of the purified bacterial fibrinolytic enzyme was achieved via bacterial recombinant DNA technology. Formulation of fibrinolytic enzymes in different dosage forms was tried. RESULTS: In the present study, the purified bacterial fibrinolytic enzyme was approximately 83% pure through affinity chromatography and SDS-PAGE assay. The predominating bacterial isolate secreting fibrinolytic enzymes was found to be Bacillus cereus. The fibrinolytic enzyme activities of 50 soil samples were found to be in the range of 0.167-1.853 U/ ml. The fibrinolytic activity of the extracellular enzyme refined from the culture supernatant of Bacillus cereus was relatively stable over the PH range from 7.4-10 for 18 hours and also it showed stability with the highest productivity at a temperature of 43 0C for nearly 60 minutes. The enzyme was called fibrin-proteinase[ FP] in the present study. The FP degraded the fibrin clots via direct thrombolysis. The specific activity and the molecular mass of the FP were estimated to be nearly 40.71 Units/ mg protein and nearly 30 KDa respectively. Protease activity was noticed to be slightly increased in the presence of Fe+3; While it was inhibited in the presence of EDTA. On the other hand, the FP fibrinolytic activity was enhanced greatly after the addition of monovalent cations such as K+1 and Na +1. The enzyme was also active over the temperature range of 20- 65 0C with the highest activity at 55 0C. The optimum temperature and PH of protease production was at 35-43 0C and PH 8.0-10. Conclusion: During the present study, the thermostable fibrinolytic enzyme FP purified from Bacillus cereus in different soil environments in Egypt was a promising fibrinolytic enzyme because it showed a broader efficacious fibrinolytic activity as well as less adverse effects than the current fibrinolytic enzymes globally. It is recommended in the future advanced exploration of the optimization of suitable formulation of bacterial fibrinolytic enzymes to aid in the dissolution of various blood clots and as a consequence overcoming the high rate of mortality globally.

Positioning based on wireless signals such as mobile communication networks has become an important means to provide high-precision location services in environments where satellite signals are blocked. In complex environments such as indoor and underground, wireless signal propagation is obstructed and non-line-of-sight (NLOS) phenomena appears due to serious occlusion and reflection. The time delay caused by NLOS effects has little impact on communication system but can significantly increase positioning errors in positioning systems. Therefore, effective suppression of NLOS errors is crucial to improving 5G positioning accuracy. To address the insufficient feature extraction of existing NLOS error suppression methods, the neglect of residual NLOS measurement errors, and poor stability of position estimation results, this paper innovatively proposes a NLOS mitigation and location estimation method for 5G positioning terminals. Simulation and experimental test results demonstrate that the proposed method outperforms the comparative methods both theoretically and practically, achieving an average positioning accuracy of 1.85 meters in complex indoor NLOS environments. The method proposed in this paper provides a new strategy for NLOS error suppression in indoor 5G positioning, which can significantly contribute to high-precision location services based on commercial 5G networks.

The mechanism underlying microbiologically induced carbonate precipitation have not been thoroughly characterized, although numerous scholars and experts have specifically investigated questions regarding minerals induced by bacteria. The study of the precipitation of carbonate minerals induced by halophilic bacteria has aroused wide concern. The present study aimed to investigate the characterization and process of biomineralization in high salt systems by a halophilic bacterium, Chromohalobacter israelensis strain LD532 (GenBank: KX766026), which was isolated from the Yinjiashan Saltern in China. Carbonate minerals induced by LD532 were investigated in several sets of comparative experiments that employed magnesium sulfate and magnesium chloride as Mg resources. Magnesium calcite and aragonite were induced by LD532 bacteria, whereas these minerals did not appear in the control group. The mineral phases, micromorphologies, and crystal structures were analysed using X-ray powder diffraction, scanning electron microscopy, and energy dispersive X-ray detection. The carbonic anhydrase and urease secreted by strain LD532 through metabolism increased the pH value of the liquid medium and promoted the process of carbonate precipitation. Further study using high resolution transmission electron microscopy, energy dispersive X-ray detection and analysis of ultrathin slices showed that the nucleation sites of carbonate minerals were located on extracellular polymeric substances and the membranes of intracellular vesicles of LD532 bacteria, which provided favourable conditions for the growth of carbonate mineral crystals. The morphologies and compositions of minerals formed in solutions of MgSO₄ and MgCl₂ display significant differences, indicating that different sources of Mg²⁺ may also affect the physiological and biochemical activities of microorganisms and thus mineral deposition. This study will be of some interest for the interpretation of carbonate biomineralization in natural salt environments and has some value as a reference in understanding sedimentary carbonates in ancient marine environments, such as tidal flats.

This review focuses on the therapeutic effects of metallic ions when released in physiological environments. Recent studies have shown that metallic ions like Ag+, Sr2+, Mg2+, Mn2+, Cu2+, Ca2+, P+5, etc., have shown promising results in drug delivery systems and regenerative medicine. These metallic ions can be loaded in nanoparticles, mesoporous bioactive glass nanoparticles (MBGNs), hydroxyapatite (HA), calcium phosphates, polymeric coatings, and salt solutions. The metallic ions can exhibit different functions in the physiological environment such as antibacterial, antiviral, anti-cancer, bioactive, biocompatible, and angiogenic effect. Furthermore, the metallic ions can be loaded in scaffolds to improve osteoblast proliferation, differentiation, bone development, fibroblast growth, and improved wound healing efficacy. Moreover, different metallic ions possess different therapeutic limits. Therefore, further mechanisms need to be developed for the highly controlled and sustained release of these ions. This review paper summarizes the recent progress in the use of metallic ions in regenerative medicine and encourages further study of metallic ions as a solution to cure diseases.

The problem addressed in this article consists of the motion control of a quadrotor, comprising model disturbances and uncertainties. In order to tackle model uncertainty, adaptive control based on reinforcement learning is used. The distinctive feature of this article, in comparison with other works on quadrotor control using reinforcement learning is the exploration of the underlying optimal control problem in which a quadratic cost and a linear dynamics allow an algorithm that runs in real time. Instead of identifying a plant model, adaptation is obtained by approximating the performance index given by the Q-function using directional forgetting recursive least squares that rely on a linear regressor build from quadratic functions of input/output data. The adaptive algorithm proposed is tested in simulation in a cascade control structure that drives a quadrotor. Simulations show the improvement in performance that results when the proposed algorithm is turned on.

Fever control is essential in patients with severe traumatic brain injury (TBI). The efficacy of therapeutic hypothermia (TH) in severe TBI has been investigated over the last few decades; however, in contrast to experimental studies showing benefits, no evidence of efficacy has been demonstrated in clinical practice. In this review, the mechanisms and history of hypothermia were briefly outlined, while the results of major randomized controlled trials (RCTs) and meta-analyses investigating TH for adult TBI are introduced and discussed. The retrieved meta-analyses showed conflicting results, with a limited number of studies indicating benefits of TH. Some studies have shown benefits of long-term TH compared with short-term TH. Although TH is effective at lowering elevated intracranial pressure (ICP), reduced ICP does not lead to favorable outcomes. Low-quality RCTs overestimated the benefits of TH, while high-quality RCTs showed no difference or worse outcomes with TH. RCTs assessing standardized TH quality demonstrated the benefits of TH. As TBI has heterogeneous and complicated pathologies, applying a uniform treatment may not be ideal. A meta-analysis of young patients who underwent early cooling and hematoma removal showed better TH results. TH should not be abandoned, and its optimal should be advocated on an individual basis.

The hospital indoor environment plays a significant role in shaping the microbial exposures that humans encounter. Resistance to antibiotics is one of the mechanisms employed by bacteria to develop resilience against stress in indoor environments. The extensive usage of antibiotics has been a key factor in driving changes in the ecological function of antibiotic resistance genes (ARGs) and their acquisition by pathogenic bacteria. By integrating the 16S rRNA Illumina sequencing and high throughput-qPCR approaches with water and air dust samples across seven departments at Peking University Shenzhen Hospital, China, this study yielded intriguing findings regarding the department-specific variation, transmission, and correlation of bacteria, ARGs and MGEs within the hospital indoor environment. One notable observation was that the seasonal variation played a vital role in shaping the bacterial composition in the overall hospital indoor environment across seven studied departments. Nevertheless, a similar significant seasonal impact was only observed in the blood test room and emergency departments, rather than in the other five departments. Another intriguing finding was the correlation between ARGs and MGEs abundance. This correlation was evident in the overall hospital indoor environment, which was conversely not found in the emergency, pneumology and gynecology departments. Additionally, while there was no significant relationship that occurred between bacterial communities and ARGs/MGEs within the hospital, the gynecology department demonstrated a close link between bacterial communities and the presence of ARGs/MGEs. Notably, the gynecology department also stood out as an important source of bacteria and ARGs/MGEs for other departments. This study underscores the need for careful surveillance and monitoring of antibiotic resistance, particularly in Legionella spp. in man-made water systems. The findings also show the importance of monitoring and understanding the genetic elements such as Tp614 involved in gene transfer and recombination, as well as their impact on antimicrobial treatment efficacy.

Glycosphingolipids (GSLs), a subtype of glycolipids containing sphingosine, are critical components of vertebrate plasma membranes, playing a pivotal role in cellular signaling and interactions. In human articular cartilage in osteoarthritis (OA), GSL expression is known notably to decrease. This review focuses on the roles of gangliosides, a specific type of GSL, in cartilage degeneration and regeneration, emphasizing their regulatory function in signal transduction. The expression of gangliosides, whether endogenous or augmented exogenously, is regulated at the enzymatic level, targeting specific glycosyltransferases. This regulation has significant implications for the composition of cell surface gangliosides and their impact on signal transduction in chondrocytes and progenitor cells. Different levels of ganglioside expression can influence signaling pathways in various ways, potentially affecting cell properties, including malignancy. Moreover, gene manipulations against gangliosides have been shown to regulate cartilage metabolism and chondrocyte differentiation in vivo and in vitro. This review highlights the potential of targeting gangliosides in the development of therapeutic strategies for osteoarthritis and cartilage injury and addresses promising directions for future research and treatment.

A detailed review of the scientific literature was undertaken to examine the most recent developments in plasma processing in the field of medicine. The first part of the review includes a detailed breakdown of the different types of coatings that can be applied onto medical devices using plasma, with a specific focus on antimicrobial surfaces. The developments during 2023 in plasma deposited biocompatible, drug delivery and adhesive coatings are described and specific applications in additive manufacturing are highlighted. The use of plasma and plasma activated liquids as standalone therapeutics continues to evolve and pertinent advances in this field are described. In addition, the combination of plasma medicine with conventional pharmaceutical interventions was reviewed and key emerging trends were highlighted, including the use of plasma to enhance drug delivery directly into tissue. The potential synergies between plasma medicine and chemotherapeutics for oncology and infection treatment is a growing area and recent advancements are noted. Finally, the use of plasma to control excess antibiotics and to intentionally degrade such materials in waste streams is described.

Accurately estimating shrub biomass in arid and semi-arid regions is critical for understanding ecosystem productivity and carbon stocks at both local and global scales. However, capturing the shrub biomass accurately by satellite observations is challenging due to the short and sparse features of shrubs. In this study, we presented a framework to estimate shrub biomass at a 10m spatial resolution by integrating ground in-situ data, unmanned aerial vehicle (UAV), Sentinel-2, and Sentinel-1 observations. The pilot study was conducted in the Helan mountains of Ningxia province, China. First, the spatial distribution map of shrubland and other land cover types was generated in 2023. Then, a prediction model of shrub biomass was developed in a Random Forest Regression (RFR) approach driven by different predicted variable datasets based on in-situ measurements, UAV, and satellite images. Finally, the developed model was used to produce the biomass map of shrubland in 2023. The uncertainty was characterized by creating a standard deviation (SD) map using the Leave-One-Out Cross-Validation (LOOCV) method in the shrub biomass estimates. The resultant shrubland distribution map in 2023 has an F1 score of 0.92. The shrub biomass model driven by spectral bands and vegetation indices (R2= 0.62) demonstrated superior performance than that only driven by spectral bands (R2=0.33) or vegetation indices (R2=0.55). The uncertainty of the estimated biomass was lower than 4%, with the lowest values (<2%) happening in the high shrub coverage (>30%) and biomass production (>30kg/m2) regions. Furthermore, the findings show that the magnitude of shrub biomass was affected by the aridity and precipitation significantly in the study region. This study provides a workflow to accurately monitor the biomass of shrublands in a complicated environment based on remote sensing images from multi-platform observations.

Background: Peritoneal sclerosis (PS) and its most severe form, encapsulating PS (EPS), are rare entities that can occur in various procedures (liver transplantation, intraperitoneal chemotherapy), secondary to medications ( beta-blockers); however, PS or EPS typically occur in patients undergoing peritoneal dialysis as a form of renal function substitution. Medical or surgical treatments can be applied, but morbidity and mortality have high rates . This condition typically presents clinically as an intestinal obstruction caused by the inclusion of the intestinal loops in the peritoneal fibrous membrane. Methods: Herein we present data from a single tertiary surgery center that has dedicated teams for patients receiving dialysis. In 12 years we analyzed a group of 63 patients admitted for catheter replacement/removal or for acute surgical pathology. In 5 cases (7,9%) we diagnosed EPS . Two patients with EPS presented with atypical abdominal pathologies requiring emergency surgery: one case of hemoperitoneum caused by a ruptured ovarian cyst and one case of uterine fibroids and metrorrhagia. Results: The definitive diagnoses were established intraoperatively and by analyzing the morpho-pathological changes of the peritoneum. The possible intraoperative challenges included laborious dissection, difficulties in restoring the correct anatomical landmarks, increased duration of the surgical intervention and a high rate of incidents and accidents Conclusions: The aim of the present study was to emphasize the possibility of other surgical pathologies overlapping with EPS, increasing the complexity of the surgical intervention. Also, we sought to determine whether there is a correlation between the morpho-pathological results of these patients who underwent emergency surgery and the common EPS morpho-pathological changes.

The gastrointestinal tract is colonized by trillions of different microorganisms, named the gut microbiota, which is key to degrade undigested food such as dietary fibers. The fermentation of these food components leads to the production of short-chain fatty acids (SCFA) acetate, propionate, and butyrate, which exploit several beneficial roles for the host’s health. Their production and absorption happen in different ways in the human intestine and depend on the type of dietary fiber reaching the gut and the microorganisms involved in the fermentation. The supplementation of SCFAs, mostly butyrate, in treating gastrointestinal, metabolic, cardiovascular, and gut-brain-related diseases has been reported in the medical literature. This review aims to give an overview of the production and absorption dynamics of acetate, propionate, and butyrate in the human gut, with a final focus on the role played by these SCFAs on gastrointestinal and metabolic health and the present therapeutic implications.

Fibrodysplasia Ossificans Progressiva (FOP) is an enigmatic, ultra-rare genetic disorder characterized by progressive heterotopic ossification, wherein soft connective tissues undergo pathological transformation into bone structures. This incapacitating process severely limits patient mobility and poses formidable challenges for therapeutic intervention. Predominantly caused by missense mutations in the ACVR1 gene, the disorder has hitherto defied comprehensive mechanistic understanding and effective treatment paradigms. This write-up offers a comprehensive overview of the contemporary understanding of FOP's complex pathobiology, underscored by advances in molecular genetics and proteomic studies. We shed light on targeted therapy, spanning genetic therapeutics, enzymatic and transcriptional modulation, stem cell therapies, and innovative immunotherapies. We also focused on the intricate complexities surrounding clinical trial design for ultra-rare disorders like FOP, addressing fundamental statistical limitations, ethical conundrums, and methodological advancements essential for the success of interventional studies. We advocate for the adoption of a multi-disciplinary approach that converges bench-to-bedside research, clinical expertise, and ethical considerations to tackle the challenges of ultra-rare diseases like FOP and comparable ultra-rare diseases. Overall, this article serves a dual role: as a definitive scientific resource for ongoing and future FOP research and as a call to action for innovative solutions to address methodological and ethical challenges that impede progress in the broader field of medical research for ultra-rare conditions.

Osteoporosis (OP), a prevalent skeletal disorder characterized by compromised bone strength and increased susceptibility to fractures, poses a significant public health concern. This review aims to provide a comprehensive analysis of the current state of research in the field, focusing on the application of proteomic techniques to elucidate diagnostic markers and therapeutic targets for OP. The integration of cutting-edge proteomic technologies has enabled the identification and quantification of proteins associated with bone metabolism, leading to a deeper understanding of the molecular mechanisms underlying OP. In this review, we systematically examine recent advancements in proteomic studies related to OP, emphasizing the identification of potential biomarkers for OP diagnosis and the discovery of novel therapeutic targets. Additionally, we discuss the challenges and future directions in the field, highlighting the potential impact of proteomic research in transforming the landscape of OP diagnosis and treatment.

The retinoblastoma (RB) transcriptional corepressor 1 (RB1) is a critical tumor suppressor gene, governing diverse cellular processes implicated in cancer biology. Dysregulation or deletion in RB1 contributes to the development and progression of various cancers, making it a prime target for therapeutic intervention. RB1's canonical function in cell cycle control and DNA repair mechanisms underscores its significance in restraining aberrant cell growth and maintaining genomic stability. Understanding the complex interplay between RB1 and cellular pathways is beneficial to fully elucidate its tumor-suppressive role across different cancer types and for therapeutic development. As a result, investigating vulnerabilities arising from RB1 deletion-associated mechanisms offers promising avenues for targeted therapy. Recently, several findings highlighted multiple methods as a promising strategy for combating tumor growth driven by RB1 loss, offering potential clinical benefits in various cancer types. This review summarizes the multifaceted role of RB1 in cancer biology and its implications for targeted therapy.

Emerging autologous cellular therapies that utilize platelet-rich plasma (PRP) applications have the potential to play adjunctive roles in a variety of regenerative medicine treatment plans. There is a global unmet need for tissue repair strategies to treat musculoskeletal (MSK) and spinal disorders, osteoarthritis (OA), and patients with chronic complex and recalcitrant wounds. PRP therapy is based on the fact that platelet growth factors (PGFs) support the three phases of wound healing and repair cascade (inflammation, proliferation, remodeling). Many different PRP formulations have been evaluated, originating from human, in vitro, and animal studies. However, recommendations from in vitro and animal research often lead to different clinical outcomes because it is difficult to translate non-clinical study outcomes and methodology recommendations to human clinical treatment protocols. In recent years, progress has been made in understanding PRP technology and the concepts for bioformulation, and new research directives and new indications have been suggested. In this review, we will discuss recent developments regarding PRP preparation and composition regarding platelet dosing, leukocyte activities concerning innate and adaptive immunomodulation, serotonin (5-HT) effects and pain killing. Furthermore, we discuss PRP mechanisms related to inflammation and angiogenesis in tissue repair and regenerative processes. Lastly, we will review the effect of certain drugs on PRP activity, and the combination of PRP and rehabilitation protocols.

Gastric cancer is an aggressive disease with increasing global incidence in recent years. Human epidermal growth receptor 2 (HER2) is overexpressed in approximately 10-20% of gastric cancers. The implementation of targeted therapy against HER2 as part of the standard of care treatment in metastatic disease has improved the prognosis of this subset of patients. However, gastric cancer still has high mortality rates and urgently requires new treatment strategies. The combination of immunotherapy with HER2-targeted therapies has shown synergistic effects in preclinical models, being the rationale behind exploring this combination in clinical trials in locally advanced and metastatic settings. Additionally, the irruption of antibody-drug conjugates and other novel HER2-targeted agents has led to the development of numerous clinical trials showing promising results. This review presents the molecular mechanisms supporting the use of HER2-targeted drugs in combination with immunotherapy and provides an overview of the therapeutic scenario of HER2-positive disease. We focus on the role of immunotherapy but also summarize emerging therapies and combinations under clinical research that may change the standard treatment in HER-2 positive disease in the future.

Clusterin (CLU) protein is involved in various pathophysiological processes including carcinogenesis and tumor progression. In recent years, the role of the secretory isoform has been demonstrated in tumor cells, where it inhibits apoptosis and favors the acquisition of resistance to conventional treatments used to treat cancer. To determine the possible therapeutic potential of inhibiting this protein, numerous studies have been carried out in this field. In this paper, we show the existing knowledge on the inhibition of this protein in different types of cancer and discuss the importance it could have in the development of new therapies directed against this pathology.

Sarcopenia is an age-related condition that involves a progressive decline in muscle mass and function, leading to increased risks of falls, frailty, and mortality. Although the exact mechanisms are not fully understood, aging-related processes like inflammation, oxidative stress, reduced mitochondrial capacity, and cell apoptosis contribute to this decline. Disruption of the circadian system with age may initiate these pathways in skeletal muscle, preceding the onset of sarcopenia. At present, there is no pharmacological treatment for sarcopenia, only resistance exercise and proper nutrition may delay its onset. Melatonin, derived from tryptophan, emerges as an exceptional candidate for treating sarcopenia due to its chronobiotic, antioxidant, and anti-inflammatory properties. Its impact on mitochondria, organelle where it is synthesized and crucial in aging skeletal muscle, further highlights its potential. In this review, we discuss the influence of clock genes in muscular aging, with special reference to peripheral clock genes in the skeletal muscle, as well as their relationship with melatonin, which is proposed as a potential therapy against sarcopenia.

Background: The Liver Imaging Reporting and Data System (LI-RADS) combines standardized terminology with a classification system for imaging findings in patients with HCC, therefore rendering diagnostic biopsy unnecessary in many cases. This retrospective study included 23 patients with a biopsy diagnosis of HCC, performed either before or after local interventional procedures, in order to evaluate the histopathologic changes induced by previous procedures and their potential influence on the response to immune therapy. Material and Methods: The study encompassed a cohort of patients diagnosed with Hepatocellular Carcinoma (HCC). Diagnosis was established through contrast-enhanced computer tomography or magnetic resonance imaging that identified LI-RADS-5 nodules in conjunction with historical liver disease and elevated alpha-fetoprotein (AFP) levels, or through histological examination confirming positivity for glypican3, heat shock protein70, and glutamine synthetase. The study detailed the liver disease etiology, LI-RADS scores, characteristics and dimensions of HCC nodules, serum AFP concentrations, Edmondson-Steiner grading, and the expression of programmed cell death ligand 1 (PD-L1) in the tumor cells. Results: Among the study's cohort of Hepatocellular Carcinoma (HCC) patients, a portion had not received any prior treatments, while the remainder experienced local HCC recurrence following trans-arterial chemoembolization or radiofrequency ablation. Observations indicated elevated alpha-fetoprotein (AFP) levels in those who had not undergone any previous interventions, showing statistical significance. The Edmondson-Steiner classification predominantly identified grade III differentiation across patients, irrespective of their treatment history. Furthermore, an increase in intra-tumoral programmed cell death ligand 1 (PD-L1) expression was noted in patients who had not been subjected to previous therapies. Conclusion: Liver biopsy offers valuable insights for patients with Hepatocellular Carcinoma (HCC), assisting in the tailoring of immune therapy strategies, particularly in cases of recurrence following prior local interventions.

Extracellular vesicle (EV) release, which occurs in most eukaryotic cells, has recently been associated with peptidylarginine deiminase (PAD)-driven protein deimination. Evidence points to the involvement of deiminated cytoskeletal proteins and changes in histone deimination. Both PADs and EVs are associated with various pathologies including cancers, autoimmune and neurodegenerative diseases. The elevated PAD expression observed in cancers may contribute to increase in EV shedding observed from cancer cells, contributing to cancer progression. Similarly, elevated PAD expression observed in neurodegenerative diseases may cause increased EV shedding and spread of neurodegenerative EV cargo, contributing to disease progression and pathologies. Pharmacological inhibition of PAD-mediated deimination using pan-PAD inhibitor Cl-amidine, reduced cellular EV release in prostate cancer cells, rendering them significantly more susceptible to chemotherapeutic drugs. Studies on models of central nervous system damage have demonstrated critical functional roles for PADs and neuroprotective effects using PAD inhibitors in vivo, while human neurodegenerative iPSC in vitro models showed evidence of increased protein deimination. Besides using refined PAD inhibitors to selectively manipulate EV biogenesis for novel combination therapies in cancer treatment, we also speculate how EV biogenesis could be targeted via the newly identified PAD-pathway to ameliorate neurodegenerative disease progression.

Melatonin is a ubiquitous molecule found in living organisms, ranging from bacteria to plants and mammals. It possesses various properties, partly due to its robust antioxidant nature and partly owed to its specific interaction with melatonin receptors present in almost all tissues. Melatonin regulates different physiological functions and contributes to the homeostasis of the entire organism. In the human eye, a small amount of melatonin is also present, produced by cells in the anterior segment and the posterior pole, including the retina. In the eye, melatonin may provide antioxidant protection along with regulating physiological functions of ocular tissues, including intraocular pressure (IOP). Therefore, it is conceivable that the exogenous administration of sufficiently high amounts of melatonin to the eye could be beneficial in several instances: for the treatment of eye pathologies like glaucoma, due to the IOP-lowering and neuroprotection effects of melatonin; for the prevention of other dysfunctions, such as dry eye and refractive defects (cataract and myopia) mainly due to its antioxidant properties; for diabetic retinopathy due to its metabolic influence and neuroprotective effects; for macular degeneration due to the antioxidant and neuroprotective properties; and for uveitis, mostly owing to anti-inflammatory and immunomodulatory properties. This paper reviews the scientific evidence supporting the use of melatonin in different ocular districts and provides data suggesting that the topical administration of melatonin as eye drops is a real possibility. This way, its distribution and concentration in different ocular tissues may support its pleiotropic therapeutic effects.

Myocardial hypertrophy is the most common condition that accompanies heart changings in children. Transcriptional pathways regulating gene expression playing a critical role both in cardiac embryogenesis and in the pathogenesis of congenital hypertrophic cardiomyopathy, neonatal posthypoxic myocardial hypertrophy and congenital heart diseases. This paper describes the state of cardiac gene expression and potential pharmacological modulators at different transcriptional levels. An experimental model of perinatal cardiac hypoxia showed downregulated expression of genes responsible for cardiac muscle integrity and overexpressed genes associated with energy metabolism and apoptosis, which may provide a basis for a therapeutic approach. Current evidence suggests that RNA drugs, theaflavin, neuraminidase, proton pump and histone deacetylase inhibitors are promising pharmacological agents in progressive cardiac hypertrophy. The different points of application of the above drugs makes combined use possible, potentiating the effects of inhibition in specific signaling pathways. The special role of N-acetyl cysteine in both the inhibition of several signaling pathways and the reduction of oxidative stress was emphasized.

This study focuses on enhancing controllable fibrin-based hydrogels for tissue engineering, addressing existing weaknesses. By integrating a novel copolymer, we improve the foundation for cell-based angiogenesis with adaptable structural features. Tissue engineering often faces challenges like waste disposal and nutrient supply beyond the 200 µm diffusion limit. Angiogenesis breaks through this limitation, allowing the construction of larger constructs. Our innovative scaffold combination significantly boosts angiogenesis, resulting in longer branches and more capillary network junctions. The copolymer attached to fibrin fibers enables precise adjustment of hydrogel mechanical-dynamic properties for specific applications. Our material proves effective for angiogenesis, even under suppression factors like suramin. In our study, we prepared fibrin-based hydrogels with and without the copolymer PVP12400-co-GMA10mol%. Using a co-culture system of human umbilical vein endothelial cells (HUVEC) and mesenchymal stem cells (MSC), we analyzed angiogenetic behavior on and within the modified hydrogels. Capillary-like structures were reproducibly formed on different surfaces, demonstrating the general feasibility of three-dimensional endothelial cell networks in fibrin-based hydrogels. This highlights the biomaterial's suitability for in vitro pre-vascularization of biohybrid implants.

The study evaluated potassium peroxymonosulfate (PPMS) efficacy against rifampicin-resistant Salmonella Infantis (rif-SI), Escherichia coli (E. coli), Salmonella Infantis (SI), Newcastle disease virus (NDV) and avian influenza virus (AIV). The assessment encompassed varied concentrations, organic material conditions, and exposure durations to comprehensively evaluate PPMS efficacy. Moreover, PPMS’s efficacy was tested on diverse carrier surfaces and clothing to evaluate its bactericidal and virucidal potential. At the recommended concentrations (1X), PPMS effectively inactivated all pathogens within 5 sec, except for NDV, which required 30 sec in the presence of organic materials. At 0.5X, PPMS successfully inactivated E. coli, AIV and NDV within 5 sec in the absence of organic material. However, rif-SI and SI necessitated 30 sec for inactivation. Most pathogens were inactivated within 30 sec, with the exception for AIV, which was inactivated within 5 sec. PPMS effectively eliminated rif-SI on all carriers within 30 sec. Moreover, at both concentrations, PPMS successfully inactivated AIV on all carriers within 30 sec, except on stainless steel at 0.5X. Furthermore, PPMS at both concentrations required 5 and 30 sec, respectively, to inactivate AIV on the rayon sheet. Therefore, due to its demonstrated efficacy against a wide range of pathogens across diverse surfaces, PPMS emerges as a crucial alternative disinfectant significantly enhancing biosecurity on and around chicken farms. found in and around animal farms, slaughterhouses, and hospitals.

Several recent studies have indicated that miR-30a plays critical roles in various biological processes and diseases. However, the mechanism of miR-30a participation in the regulation of idiopathic pulmonary fibrosis (IPF) is ambiguous. Our previous study demonstrated that miR-30a may function as a novel therapeutic target for lung fibrosis by blocking mitochondrial fission, which is dependent on dynamin-related protein-1 (Drp-1). However, the regulatory mechanism between miR-30a and Drp-1 has yet to be investigated. In addition, whether miR-30a can act as a potential therapeutic has not been verified in vivo. In this study, the miR-30a expression in IPF patients was evaluated. Computational analysis and a dual luciferase reporter system assay were used to identify the target gene of miR-30a, and cell transfection was used to confirm this relationship. Ten-eleven translocation 1 (TET1) was validated as a direct target of miR-30a, and the transfection of miR-30a mimic/inhibitor significantly reduced/increased the expression of TET1 protein. Further experiment verified that the interference on TET1(siRNA) could inhibit the hydroxymethlation of the Drp-1 promoter. Finally, miR-30a agomir was designed and applied to identify and validate the therapeutic effect of miR-30a in vivo. Our study demonstrated that miR-30a could inhibit the TET1 expression by base pairing with complementary sites in the 3′ untranslated region to regulate the hydroxymethlation of the Drp-1 promoter. Furthermore, miR-30a could act as a potential therapeutic target for IPF.

Metabolic-associated fatty liver disease (MASLD) is not only associated with traditional cardiovascular risk factors such as T2DM and obesity, but it is also an independent risk factor for the development of cardiovascular disease. MASLD has been shown to be independently related to endothelial dysfunction and atherosclerosis. MASLD is characterized by a chronic proinflammatory response that, in turn, may induce a prothrombotic state. Several mechanisms such as endothelial and platelet dysfunction, changes in the coagulation cascade, decreased fibrinolytic activity can contribute to induce the prothrombotic state. Platelets are players and addresses of metabolic dysregulation; obesity and insulin resistance are related to platelet hyperactivation. Furthermore, platelets can exert a direct effect on liver cells, particularly through the release of mediators from granules. Growing data in literature support the use of antiplatelet agent as a treatment for MASLD. The use of antiplatelets drugs seems to have potential clinical implication for the prevention of HCC patients with MASLD, since platelets contribute to fibrosis progression and cancer development. This review aims to summarize the main data on the role of platelets in the pathogenesis of MAFLD and its main complications such as cardiovascular events and the development of liver fibrosis. Furthermore, we will examine the role of antiplatelet therapy not only in the prevention and treatment of cardiovascular events but also as a possible anti-fibrotic and anti-tumor agent.

In everyday life, the birth of a number of blind people takes place and millions of people are already available. Visually impaired people struggle to walk safely and in- dependently because they have trouble detecting obstacles. In this work, we suggest a novel approach to detecting obstacles utilizing an Arduino UNO board and an ul- trasonic sensor (HC-SR04). The main goal of this research is to increase the mobility and security of blind people in a variety of settings. The suggested system makes use of the HC-SR04 ultrasonic sensor’s capability to precisely measure distance and identify nearby obstructions. As the main processor component, the Arduino UNO board processes algorithms for real-time obstacle detection while also collecting data from the sensor. The device is intended to give the visually impaired user immedi- ate aural input while informing them of the location and proximity of obstacles. To Extensive testing is done in controlled and real-world settings to assess the system’s performance and dependability. In the studies, the effectiveness of obstacle detec- tion, the system’s response time, and its practicality and usefulness for blind people are all measured. The findings show that the suggested obstacle detection method provides very accurate obstacle identification at a safe distance. Users who are blind or visually handicapped may successfully understand their surroundings thanks to the aural feedback system, which helps them to navigate by making judgments that are well-informed. Additionally, the system responds quickly, guaranteeing that the user receives real-time obstacle updates to increase safety and confidence while mov- ing. The study’s conclusions demonstrate the possibility of using the Arduino UNO board with the HC-SR04 ultrasonic sensor as a practical and affordable approach for detecting obstacles.

Migraine and neuropathic pain (NP) are evocative of painful, disabling, chronic conditions which exhibit resembling symptoms and thus considered to share a common etiology. Calcitonin gene-related peptide (CGRP) has gained credit as a target for migraine management; nevertheless, the efficacy and the applicability of CGRP modifiers warrant search for more effective therapeutic targets for pain management. This scoping review overviews human studies of common pathogenic factors in migraine and NP to explore potential novel therapeutic targets. CGRP causes inflammation in the meninges; monoclonal antibodies and inhibitors target CGRP. Gluta-mate-induced hyperexcitability and subsequent sensitization are closely linked to an alteration of the tryptophan (Trp)-kynurenine (KYN) metabolic system; the Trp-KYN system may serve as a potential target. Microglial overaction is observed in migraine and NP; modifying the microglial activity may be a possible approach. Cytokine-induced inflammation is a leading hypothesis of the pathogenesis of the conditions; alleviating neuroinflammation may complement a pain-relieving armamentarium. Transient receptor potential (TRP) ion channels evoke the release of several substances; TRP ion channels may potentially emerge as new targets. The endocannabinoid system plays a major role in the pain trafficking pathway; modification of the system may open a new path toward discovery of new analgesics. Here we highlight the mechanism of those common pathogenic factors to explore therapeutic targets for innovative pain management in migraine and NP.

Most recent university campuses follow the North American model, built on city limits or countryside, with large separate buildings in open green spaces. Studies suggest that prevalence and severity of mental health issues among university students are increasing over the past decade in most countries. University services were created to face this growing problem, however individual based interventions have limited effects on mental health and well-being of a large population. Our aim was to verify if and how the natural environment in Campuses is focused on programs to cope with the issue of mental health and well-being among students. Systematic review of literature was undertaken with search in Scopus and LILACS with the keywords “green areas” AND “well-being” AND “Campus”, following PRISMA guidelines. As a result, 32 articles were selected. Research on the topic is recent, mostly in the USA, Bulgaria, and China. Most studies used objective information on campuses’ greenness and/or university students’ perception. Mental health was usually measured by validated scores. Findings of all the studies indicated positive association between campus greenery and well-being of students. We conclude that there is a large potential for use of university campuses in programs and sites for students´ restoration and stress relief.

Wireless power transfer promises to revolutionize the way we use and power mobile devices. However, low transfer efficiencies prevent this technology from seeing wide scale real-world adoption. The aim of this work is to use quasioptics to develop a system composed of a dielectric lens fed by a phased array to reduce spillover losses, increasing the beam efficiency, while working on the antenna system’s Fresnel zone. The DC-RF electronics, digital beamforming and beam-steering by an FPGA, and radiating 4x4 microstrip patch phased array have been developed and experimented upon, while the lens has been designed and simulated. This paper details these preliminary results, where the phased array radiation pattern was measured, showing that the beam is being generated and steered as expected, prompting the lens construction for the complete system experimentation.

The mobile devices caused a constant struggle for the pursuit of data privacy. Nowadays, it appears that the number of mobile devices in the world is increasing. With this increase and technological evolution, thousands of data associated with everyone are generated and stored remotely. Thus, the topic of data privacy is highlighted in several areas. There is a need for control and management of data in circulation inherent to this theme. This article presents an approach of the interaction between the individual and the public environment, where this interaction will determine the access to information. This analysis was based on a data privacy management model in public environments created after reading and analyzing the current technologies. A mobile application based on location via Global Positioning System (GPS) was created to substantiate this model, which it considers the General Data Protection Regulation (GDPR) to control and manage access to the data of each individual.

Flow sensing in hostile environment is of increasing interest for applications in automotive, aerospace, and chemical and resource industries. Compared to their counterparts, thermal flow sensors are attractive candidates due to the ease of fabrication, lack of moving parts and higher sensitivity. Recently, a number of thermal flow sensor prototypes have been reported in the literature demonstrating the measurement of fluid flows under hostile conditions. This paper summarizes the concept of thermal flow sensing, operational modes and transduction mechanisms. Then, the choice of materials and their corresponding properties are presented in details. The paper also reports recent progress in the development of thermal flow sensors for harsh environment. In addition, the issues and considerations in packaging are reviewed. Finally, we conclude the review with the future prospects.

Hypertensive disorders of pregnancy (HDP), including preeclampsia (PE) and gestational hypertension (GH), are major causes of maternal and fetal morbidity and mortality. This review elucidates the role of regulatory T cells (Tregs) in the immunological aspects of HDP and explores their therapeutic potential. Tregs, known for maintaining immune tolerance, are crucial in pregnancy to prevent immune-mediated rejection of the fetus. In HDP, Treg numbers and function imbalance are observed, correlating with disease severity. The review highlights that Tregs contribute to immunological adaptation in normal pregnancy, ensuring fetal acceptance and placental development. In contrast, HDP is associated with Treg dysfunction, marked by decreased numbers and impaired regulatory capacity, leading to inadequate immune tolerance and abnormal placental development. This dysfunction is particularly evident in PE, where Tregs fail to adequately modulate the maternal immune response against fetal antigens, contributing to the pathophysiology of the disorder. Therapeutic interventions aiming to modulate Treg activity represent a promising avenue for HDP management. Studies in animal models and limited clinical trials suggest that enhancing Treg functionality could mitigate HDP symptoms and improve pregnancy outcomes. However, the review acknowledges the complexity of translating these findings into effective clinical therapies, given the multifactorial nature of HDP and the intricate regulatory mechanisms of Tregs. In conclusion, while the precise role of Tregs in HDP is still being unravelled, their central role in immune regulation during pregnancy is indisputable. Further research is needed to fully understand the mechanisms by which Tregs contribute to HDP and to develop targeted therapies that can safely and effectively harness their regulatory potential for treating hypertensive diseases of pregnancy.

Proprotein convertase subtilisin/Kexin type 9 (PCSK9) is a proteolytic enzyme that indirectly regulates serum LDL cholesterol by destroying LDL receptors. In clinical studies, the main role of the proprotein convertase subtilisin/Kexin type9 (PCSK9) inhibitor in cholesterol regulation was elucidated. It is produced in the liver but is also present in the kidney and intestine. It prevents HMGCo from synthesizing cholesterol. SREBP-2 is a reductase that is induced by statins. In a dose-dependent manner, increasing SREBP-2 levels enhanced LDL-R and PCSK9 gene expression. At the minimum, two procedures have been developed to overcome the plasma level of PCSK9. This is the LDLR test, polyclonal antibodies, and sentience oligonucleotide. Lower dosage statin treatment with a proprotein convertase subtilisin/Kexin type9 inhibitor will be most efficient in lowering LDL and avoiding statin adverse effects. In multiple long-term trials, statins have been found to reduce cardiovascular mortality by 30% and stroke incidence by 20%. In this way, we conclude the role of PCSK9 in hypercholesterolemia.

Recent progress in deep learning has led to accurate and efficient generic object detection networks. Training of highly reliable models depends on large datasets with highly textured and rich images. However, in real-world scenarios, the performance of the generic object detection system decreases when (i) occlusions hide the objects, (ii) objects are present in low-light images, or (iii) they are merged with background information. In this paper, we refer to all these situations as challenging environments. With the recent rapid development in generic object detection algorithms, notable progress has been observed in the field of object detection in challenging environments. However, there is no consolidated reference to cover state-of-the-art in this domain. To the best of our knowledge, this paper presents the first comprehensive overview, covering recent approaches that have tackled the problem of object detection in challenging environments. Furthermore, we present the quantitative and qualitative performance analysis of these approaches and discuss the currently available challenging datasets. Moreover, this paper investigates the performance of current state-of-the-art generic object detection algorithms by benchmarking results on the three well-known challenging datasets. Finally, we highlight several current shortcomings and outline future directions.

Spectacular shifts have been led to by The COVID-19 crisis in consumer behavior. Retailers will have to work hard to meet ever-evolving customer service experience with respect to the ways in which it may be differently affected by offline or online transactions in order to win and stay relevant. We suggest an integrative framework and construct customer service experience hypotheses, based on its antecedents and consequences that will contribute to academic study as well as managerial implications. The hypotheses are tested by a simultaneous equation model employing two data sets of the retail industry's offline and online customers. In this study, 571 samples of these businesses, 319 and 252 respondents from offline and online retail channels, respectively, were collected by means of an online web survey of consumers. The results show that the impact of consequences and antecedents of CSX differs based on the media utilized. The integrative framework of CSX in its online medium is far more effective than its explanatory power offline. The outcomes are reasonably counterintuitive in so far as they demonstrate that while most elements of CSX where a service is selected offline is the same in terms of customer loyalty and value equity, the emotional element related to the service provider is higher when the service is selected offline rather than online. These outcomes indicate that, contrary to popular fears, the online medium enables firms to develop a loyal customer foundation. These findings offer perceptivity into how an online channel could be used to better complement the offline channel, contributing towards new knowledge and understanding on CSX and how it may be utilized for managerial decision-making.

Indole is a versatile pharmacophore widely distributed in bioactive natural products. This privileged scaffold has been found in a variety of molecules isolated from marine organisms such as algae and sponges. Among these, indole alkaloids represent one of the biggest, most promising family of compounds, having shown a wide range of pharmacological properties, including anti-inflammatory, antiviral and anticancer activities. The aim of this review is to show the current scenario of marine indole alkaloid derivatives, covering not only the most common chemical structures, but also new synthetic routes developed during the last years as well as promising therapeutic applications.

The skin beetle Reesa vespulae is regularly found beyond North America where it originated. The larvae cause considerable concern in museums as it damages hides or furs in addition to being a special source of damage to collections of dried plants in herbaria or collections of insects and other zoological specimens. It arrived in Europe in the mid-20th century and was associated mostly with stored food products, but over time it has become recognised as a museum pest. Although still uncommon and may only be observed in a small fraction of museums, where the insect is found in large numbers it can cause problems. As a single female can continue to breed because the beetle is parthenogenetic, presence can persist over long periods of time. Although small populations in museums are typically found as the adult, the larval forms are more common where a site is infested by high numbers, perhaps because the larvae and adults must range more widely for food. Although Reesa vespulae can be controlled using pesticides, it is also possible to kill the larvae within infested materials through freezing or anoxia.

We investigated fault gases (helium, radon, CO₂) in two seismically active Cenozoic sedimentary environments: a) Meinweg (in 2015) at a tectonically quiet horst structure in the Lower Rhine Embayment and b) Bodanrück (in 2012; Lake of Constance) at the Molasse Basin and part of the Freiburg–Bonndorf–Bodensee Fault Zone (FBBFZ). Both study areas were selected because recent “GeoBio-Interactions” findings showed, that red wood ants (RWA) are biological indicators of otherwise undetected degassing systems. A total of 817 soil gas samples was analyzed. Currently, Meinweg can be considered “no ants land” due to the very low background-level geogas concentrations. Thus, anomalies (Rn-CO₂) weakly trending in NE-SW extension direction emerged. This could probably indicate the onset of (re)activation of the NE-SW trending (Variscan) structures or the development of new fractures as an aftershock process of the 1992 Roermond earthquake that occurred about 15 km to the west. Results at Bodanrück (3 RWA clusters and two RWA-free corridors) revealed degassing patterns in NW-SE and NNE-SSW directions in the clusters corresponding to re-activated and recent strike-slip fault systems. No gas anomalies were found in RWA-free corridors. The RWA nest distribution was shown to be a valuable tool for identifying areas of even actively degassing spotty anomalies caused by macro- and microscale brittle deformation masked by sediment cover.

Many classic visual monocular SLAM systems have been developed over the past decades, however, most of them will fail when dynamic scenarios dominate. DM-SLAM is proposed for handling dynamic objects in environments based on ORB-SLAM. The article mainly concentrates on two aspects. Firstly, DLRSAC is proposed to extract static features from the dynamic scene based on awareness of nature difference between motion and static, which is integrated into initialization of DM-SLAM. Secondly, we design candidate map points selection mechanism based on neighborhood mutual exclusion to balance the accuracy of tracking camera pose and system robustness in motion scenes. Finally, we conduct experiments in the public dataset and compare DM-SLAM with ORB-SLAM. The experiments verify the superiority of the DM-SLAM.

A basic problem in all postulated pathways of prebiotic chemistry is the low concentration which generally is expected for interesting reactants in fluid environments. Even though compounds like nucleobases, sugars or peptides principally may form spontaneously under environmental conditions, they will always be rapidly diluted in an aqueous environment. In addition, any such reaction leads to side products which often exceed the desired compound and generally hamper the first steps of a subsequent molecular evolution. Therefore, a mechanism of selection and accumulation of relevant prebiotic compounds seems to be crucial for molecular evolution. A very efficient environment for selection and accumulation can be found in the fluid continuum circulating in tectonic fault zones. Vesicles which form spontaneously at a depth of approximately 1 km present a selective trap for amphiphilic molecules, especially for peptides composed of hydrophilic and hydrophobic amino acids in a suitable sequence. The accumulation effect is shown in a numeric simulation on a simplified model. Further, possible mechanisms of a molecular evolution in vesicle membranes are discussed. Altogether, the proposed scenario can be seen as an ideal environment for constant, undisturbed molecular evolution in and on cell-like compartments, the latter offering preferential starting conditions for a subsequent RNA world.

This paper represents a groundbreaking paradigm shift in network optimization. Departing from traditional static methodologies, this innovative approach harnesses the power of Generative Artificial Intelligence (AI) and Large Language Models (LLMs) to optimize cloud networks dynamically. By integrating advanced AI algorithms, this framework continuously adapts and evolves, ensuring optimal real-time performance. This dynamic optimization enhances efficiency and resilience, allowing cloud networks to adjust seamlessly to changing demands and conditions. Through the fusion of cutting-edge technology and adaptive intelligence, this approach heralds a new era in network optimization, empowering organizations to achieve unprecedent-ed levels of agility and scalability in their cloud infrastructures.

Given the persistence of microplastics in the environment and their potential toxicity to ecosystems, understanding of likely microplastic accumulation ‘hotspots’ in rivers is urgently needed. To contribute to this challenge, this paper reports results of a microplastic survey from a heavily urbanised catchment, the River Tame, which flows through the city of Birmingham, UK. All sediment sampled was found to contain microplastics with an average abundance of 165 particles kg-1. While urban areas generally have a greater abundance of microplastics as compared with rural, there is no simple relationship between microplastic numbers and population density or proximity to wastewater treatment sites. The greatest change in microplastic abundance was due to the presence of a lake along the course of the River Tame i.e. on entering the lake flow velocities are reduced which promotes the deposition of fine sediment and potentially microplastics. This suggests that the greatest concentrations of microplastics will not be found in-channel but rather on the floodplain and other low velocity environments such as meander cutoffs. We also identified a new mechanism of microplastic fixation in freshwater environments through ecological engineers, specifically caddisfly that incorporated microplastics into their casing. These results highlight the need to explore further hydrodynamic and ecological impacts on microplastics fate and transport in rivers.

Most neurodegenerative diseases, including Alzheimer's disease, ischemic stroke, subarachnoid hemorrhage, and intracerebral hemorrhage are associated with inflammation. Tumor necrosis factor (TNF) is a pleiotropic pro-inflammatory cytokine that regulates cerebral infarction in stroke pathology, and its action is influenced by the bioavailability of its membrane-bound receptors, TNFR1 and TNFR2, and microglial activation. During the initial onset of these diseases, the soluble variant of the cytokine presents with prolonged and excessive activation of TNFR1, resulting in cell death and long-term neurological impairments. Therapeutic interventions for neurodegenerative diseases have targeted TNF to limit the onset of neuroinflammation. First-generation therapeutics have been demonstrated to inhibit membrane-bound TNF to TNFR2 receptor binding, resulting in severe side effects such as infections and cancer. As such, second-generation drugs, including XPro1595, have been developed to selectively inhibit soluble TNF and impede the effects of TNFR1 while still allowing for TNFR2 activation. Early results in murine TBI models demonstrate reduced glial reactivity by 50%, reduced dendritic degeneration by 30%, increased plasticity by 15%, and improved functional outcomes by 20% post-TBI. This scoping review of TNF receptors in various neurodegenerative diseases seeks to evaluate current and future therapeutic strategies as well as highlight potential strategies to eliminate confounding variables present in the current literature.

Affinity reagents, or target-binding molecules, are quite versatile and are major workhorses in molecular biology and medicine. Antibodies are the most famous and frequently used type and they have been used for a wide range of applications, including laboratory techniques, diagnostics, and therapeutics. However, antibodies are not the only available affinity reagents and they do have significant drawbacks, including laborious and costly production. Aptamers are one potential alternative that have a variety of unique advantages. They are single stranded DNA or RNA molecules that can be selected for binding to many targets including proteins, carbohydrates, and small molecules – for which antibodies typically have low affinity. There are also a variety of cost-effective methods for producing and modifying nucleic acids in vitro without cells, whereas antibodies typically require cells or even whole animals. While there are also significant drawbacks to using aptamers in therapeutic applications, including low in vivo stability, aptamers have had success in clinical trials for treating a variety of diseases and two aptamer-based drugs have gained FDA approval. Aptamer development is still ongoing, which could lead to additional applications of aptamer therapeutics, including antitoxins, and combinatorial approaches with nanoparticles and other nucleic acid therapeutics that could improve efficacy.

Students in their first year of computer science (CS1) at universities typically struggle to grasp programming concepts. This paper covers research using a Java programming language-guided visual execution environment (VEE) to teach CS1 students about programming concepts. The topics covered include input and output, conditionals, loops, functions, arrays, recursion, and files, all of which are covered in an introductory programming course. The VEE walks beginner programmers through the fundamentals of programming, utilizing visual metaphors to explain and direct interactive Java tasks. The primary goal of this study is to determine whether a cohort of 105 CS1 students from four different groups who are enrolled in two universities—one in Madrid, Spain, and the other in Galway, Ireland—can advance their programming abilities under the guidance of the VEE. Second, does the improvement vary depending on the programming concept? The findings demonstrate that students' programming knowledge has greatly increased. This improvement is significant for all programming concepts, while it is more pronounced for some topics than others, such as operators, conditionals, and loops. Additionally, it demonstrates that students had little prior understanding of files and recursion. The most well-known concept to them was the sequence concept.

: The radar multi target tracking (MTT) technique requires prior knowledge of a number of parameters about the sensor, the target and backgrounds. The Integrated Track Splitting (ITS) is a fully automatic track-while-scan (TWS) target tracking algorithm capable of extracting and tracking a target in a dense clutter environment using quality false track discrimination (FTD) methodology. The computational complexity in ITS algorithm is limited, compared to other algorithms they use statistical methods to discriminate between false and true tracks, such as multiple hypothesis tracking (MHT), mainly due to the FTD performed. The paper provides an analysis of tracking parameters that allows determining the limit of the possibility of successful target tracking. Extensive experiments have confirmed that the recursive determination of the probability of the existence of a track during tracking can confirm a true track and reject a false track. The clutter density, number of random occurred targets, targets load during the maneuver and the target detection probability were varied. The results of experiments, carried out via Monte Carlo simulations, shown over representative confirmed true tracks (CTT) diagrams, root mean square error position and normalized tracking efficiency parametric diagrams allow the user to select optimal multi-target tracking parameters for different scenarios and clutter densities.

As we all know, many more dynamic objects appear almost continuously in real world, which are immensely able to impair the performance of the majority of vision-based SLAM systems that are based on the static-world assumption. In order to improve the robustness and accuracy of visual SLAM in the high dynamic environment, a real-time and robust stereo SLAM system for dynamic scenes was proposed. To weaken influences of dynamic content, the moving object detection method was put forward in our visual odometry, then the semantic segmentation network was combined into our stereo SLAM to extract pixel-level contours of dynamic objects. Then influences of dynamic objects were extremely weaken and the performance of our system was increased markedly in dynamic, complex and crowed city spaces. Experiment with both on KITTI Odometry dataset and in a real-life scene, the results show that our method can dramatically decrease the tracking error or drift, improve the robustness and stability of our stereo SLAM in high dynamic outdoor scenarios.

Purpose: This study aims to analyze the factors that affect the behavior of user-defined avatars in different virtual environments, and compare the differences in public self-awareness, self-expression, and emotional expression among customized avatars in multiple virtual contexts. Methods: Using a between-subjects experimental design, two random groups of participants were asked to customize avatars for themselves in two contexts, a multiplayer online social game (MOSG) and a virtual meeting (VM). i.e. a relaxed and a serious social environment. Results: When subjects perceived a more relaxed environment, the customized avatars had less self-similarity, and the subjects exhibited a stronger self-disclosure willingness and enhanced avatar wishful identification; nevertheless, public self-consciousness was not increased. When subjects perceived a more serious environment, the customized avatars exhibited a higher degree of self-similarity, and the subjects exhibited a greater self-presentation willingness, along with enhanced identification of avatar similarity, and increased public self-consciousness. Conclusions: Participants expressed positive emotions, suggesting that avatars play a positive role in various virtual contexts. The virtual context affects the self-similarity of user-customized avatars, and avatar self-similarity affects self-presentation and self-disclosure willingness, and these factors will affect the behavior of the user-customized avatar. This study contributes suggestions to the Metaverse avatar customization platform design.

Virtual Reality(VR) is an emerging technology with a broad range of application in training, entertainment, and business. To maximize the potentials of virtual reality as a medium, the unwelcome feeling of simulation sickness needs to be minimized. Even with advancements in VR, the usability concerns are barriers for a wide-spread acceptance. Several factors (hardware, software, human) play a part towards a pleasant VR experience. The reviewed scientific articles are mostly part of documents indexed in digital libraries. In this paper, we review the potential factors which cause simulation sickness and minimize the usability of virtual reality systems. We review the best practices from a developer’s perspective and some of the safety measures a user must follow while using the VR systems from existing research. Even after following some of the guidelines and best practices VR environments do not guarantee a pleasant experience for users. Limited research in VR environments towards requirement specification, design, and development for maximum usability and adaptability was the main motive for this work.

The increasing number of robots around us will soon create a demand for connecting these robots in order to achieve goal-driven teamwork in heterogeneous multi-robot systems. In this paper, we focus on robot teamwork specifically in dynamic environments. While the conceptual modeling of multi-agent teamwork has been studied extensively during the last two decades, related engineering concerns have not received the same degree of attention. Therefore, this paper makes two contributions. The analysis part discusses general design challenges that apply to robot teamwork in dynamic application domains. The constructive part presents a review of existing engineering approaches for challenges that arise with dynamically changing runtime conditions. An exhaustive survey of robot teamwork aspects would be beyond the scope of this paper. Instead, we aim at creating awareness for the manifold dimensions of the design space and highlight state-of-the-art technical solutions for dynamically adaptive teamwork, thus pointing at open research questions that need to be tackled in future work.

The non-contact patient monitoring paradigm moves patient care into their homes and enables long-term patient studies. The challenge, however, is to make the system non-intrusive, privacy-preserving, and low-cost. To this end, we describe an open-source edge computing and ambient data capture system, developed using low-cost and readily available hardware. We describe five applications of our ambient data capture system. Namely: (a) Estimating occupancy and human activity phenotyping; (b) Medical equipment alarm classification; (c) Geolocation of humans in a built environment; (d) Ambient light logging; and (e) Ambient temperature and humidity logging. We obtained an accuracy of 94% for estimating occupancy from video. We stress-tested the alarm note classification in the absence and presence of speech and obtained micro averaged F1 scores of 0.98 and 0.93, respectively. The geolocation tracking provided a room-level accuracy of 98.7%. The root mean square error in the temperature sensor validation task was 0.3°C and for the humidity sensor, it was 1% Relative Humidity. The low-cost edge computing system presented here demonstrated the ability to capture and analyze a wide range of activities in a privacy-preserving manner in clinical and home environments and is able to provide key insights into the healthcare practices and patient behaviors.

Due to the rapid growth of the Internet of Things (IoT), securing communications between a huge number of devices has become very difficult. Access controls and authentication secure the connection between IoT devices and protect sensitive data from unauthorized users or malicious attackers. In this paper, we provide a comprehensive review to emphasize the critical role of authentication and access control in securing IoT environments. This paper explores different types of access controls, like Attribute-Based Access Control and Role-Based Access Control. Furthermore, it demonstrates different authentication techniques, like passwords and biometrics. Based on the previous mechanisms, we discuss different IoT security challenges regarding authentication and access control mechanisms and highlight future directions. In addition, this paper investigates the integration between access control and authentication to safeguard IoT communications.

(1) Background: Since microplastics in the aquatic environment are difficult to prevent and can cause adverse physiological and biochemical reactions to various organisms, we aimed to analyze the effectiveness of an eco-friendly removal method using aquatic plants with high ornamental value and excellent water purification ability. (2) Methods: Iris pseudacorus and Lythrum anceps were planted in tap water contaminated with microplastics to analyze the removal rate and root adsorption of microplastics. (3) Results: The amount of microplastics in the planting boxes of Iris pseudacorus and Lythrum anceps was significantly reduced, and the adsorption of microplastics on the roots was confirmed. (4) Conclusions: It was found that the removal of microplastics in water by aquatic plants is effective and that microplastic pollution does not significantly affect plant growth. However, the removal of microplastics by adsorption on plant roots may be affected by various environmental factors, so it is necessary to consider various limitations.

Pycnodont fishes were a successful clade of neopterygian fishes that are predominantly found from shallow marine deposits. However, throughout their long 180 million years reign (Late Triassic - end Eocene), they have made multiple incursions into both brackish and freshwater environments. This fossil record mostly consists of fragmentary dental material but articulated specimens are known from Early Cretaceous lacustrine localities in Spain. This review article aims to document all non-marine occurrences of Pycnodontiformes throughout most of the Mesozoic and early Palaeogene. This review highlights two interesting trends in the history of non-marine habitat colonization by pycnodonts: (1) a huge spike in non-marine occurrences during the Cretaceous, (2) the most occurrences in non-marine localities occurred at the latest Cretaceous, the Maastrichtian. The high number of colonization events within the Cretaceous lines up with extreme climatic events such as high temperatures resulting in high sea levels which regularly flooded continental masses, allowing pycnodonts easier access to non-marine habitats. The increased presence of pycnodonts in brackish and freshwater habitats during the Maastrichtian might have played a role in their survival through the K/Pg extinction event. Freshwater habitats are not as vulnerable as marine ecosystems to environmental disturbance as the base of their food chain relies on detritus. Pycnodonts might have used such environments as a refuge and began to occupy marine waters after the K/Pg extinction event.

Ensuring safe and continuous autonomous navigation in long-term mobile robot applications is still challenging. To ensure a reliable representation of the current environment without the need for periodic re-mapping, updating the map is recommended. However, in case of incorrect estimation of robot pose, updating the map can lead to errors that prevent the robot localisation and jeopardize map accuracy. In this paper, we propose a safe LIDAR-based occupancy grid map updating algorithm for dynamic environments taking into account the uncertainties in the estimation of the robot’s pose. The proposed approach allows robust long-term operations as it can recover the robot’s pose, even when it gets lost, to continue the map update process providing a coherent map. Moreover, the approach is robust also to temporary changes in the map due to the presence of dynamic obstacles such as humans and other robots. Results highlighting map quality, localisation performance, and pose recovery, both in simulation and experiments, are reported.

Sustainable urban design or planning is not a LEGO-like assembly of prefabricated elements, but an embryo-like growth with persistent differentiation and adaptation towards a coherent whole. The coherent whole has a striking character – called living structure – that consists of far more small substructures than large ones. To detect the living structure, natural streets or axial lines have been previously adopted to be topologically represent an urban environment as a coherent whole. This paper develops a new approach to detecting the underlying living structure of urban environments. The approach takes an urban environment as a whole and recursively decomposes it into meaningful subwholes at different levels of hierarchy or scale ranging from the largest to the smallest. We compared the new approach to natural street and axial line approaches and demonstrated, through four case studies, that the new approach is better and more powerful. Based on the study, we further discuss how the new approach can be used not only for understanding, but also for effectively designing or planning the living structure of an urban environment to be more living or more livable.

Ecosystem surveillance monitoring is critical to managing natural resources and especially so under changing environments. Despite this importance, the design and implementation of monitoring programs across large temporal and spatial scales has been hampered by the lack of appropriately standardised methods and data streams. To address this gap, we outline a surveillance monitoring method based on permanent plots and voucher samples suited to rangeland environments around the world that is repeatable, cost-effective, appropriate for large-scale comparisons and adaptable to other global biomes. The method provides comprehensive data on vegetation composition and structure along with soil attributes relevant to plant growth, delivered as a combination of modules that can be targeted for different purposes or available resources. Plots are located in a stratified design across vegetation units, landforms and climates to enhance continental and global comparisons. Changes are investigated through revisits. Vegetation is measured to inform on composition, cover and structure. Samples of vegetation and soils are collected and tracked by barcode labels and stored long-term for subsequent analysis. Technology is used to enhance the accuracy of field methods, including differential GPS r plot locations, instrument based Leaf Area Index (LAI) measures, and three dimensional photo-panoramas for advanced analysis. A key feature of the method is the use of electronic field data collection to enhance data delivery into a publicly-accessible database.Our method is pragmatic, whilst still providing consistent data, information and samples on key vegetation and soil attributes. The method is operational and has been applied at more than 704 field locations across the Australian rangelands as part of the Ecosystem Surveillance program of the Terrestrial Ecosystem Research Network (TERN). The methodology enables continental analyses, and has been tested in communities broadly representative of rangelands globally, with components being applicable to other biomes. Here we also recommend the consultative process and guiding principles that drove the development of this method as an approach for development of the method into other biomes. The consistent, standardised and objective method enables continental, and potentially global analyses than were not previously possible with disparate programs and datasets.

This review discusses a broad range of recent advances (2013-2017) of chemical imaging using electrochemical methods, with a particular focus on techniques that have been applied to study cellular processes, or techniques that show promise for use in this field in the future. Non-scanning techniques such as microelectrode arrays (MEAs) offer high time-resolution (< 10 ms) imaging, however at reduced spatial resolution. In contrast, scanning electrochemical probe microscopies (SEPMs) offer higher spatial resolution (as low as a few nm per pixel) imaging, with images collected typically over many minutes. Recent significant research efforts to improve the spatial resolution of SEPMs using nanoscale probes, and to improve the temporal resolution using fast scanning have resulted in movie (multiple frame) imaging with frame rates as low as a few seconds per image. Many SEPM techniques lack chemical specificity or have poor selectivity (defined by the choice of applied potential for redox-active species). This can be improved using multifunctional probes, ion-selective electrodes and tip-integrated biosensors, although additional effort may be required to preserve sensor performance after miniaturization of these probes. We discuss advances to the field of electrochemical imaging, and technological developments which are anticipated to extend the range of processes that can be studied. This includes imaging cellular processes with increased sensor selectivity and at much improved spatiotemporal resolution than has been previously customary.

Intratumoral immune cytolytic activity (CYT), measured as the geometric mean of the expression of Granzyme-A (GZMA) and Perforin-1 (PRF1), has emerged as a critical factor in cancer immunotherapy, with significant implications for patient prognosis and treatment outcomes. Here, we review how different immune checkpoint pathways, the composition of Tumor Microenvironment (TME), antigen presentation and metabolic pathways, all regulate CYT. We also discuss the various methods through which CYT can be assessed. The detection and analysis of tumor-infiltrating lymphocytes using flow cytometry or immunohistochemistry provide important information on the immune cell populations within the TME. Gene expression profiling and spatial analysis techniques, such as multiplex immunofluorescence and imaging mass cytometry, allow researchers to study CYT in the context of the TME. We further report the significant clinical implications that CYT has, as its increased levels are associated with positive clinical outcomes and a favorable prognosis. Moreover, CYT can be used as a prognostic biomarker and aid in patient stratification. Measuring CYT through different methods offers promising paths for improving treatment responses. Overall, we highlight that the understanding and modulation of CYT levels is critical for improving cancer immunotherapy. Research into CYT and the factors that influence it has the potential to transform cancer treatment and improve patient outcomes.

Cordycepin has good antitumor activity, but its clinical application is limited due to the easy deamination of N6 in structure. In this study, a large lipopolysis group was introduced at the cordycepin N6 to improve the problem, Cordycepin derivatives(3a-4c) were synthesized, and biological evaluation of compounds were studied. In the study, the vitro antitumor activity of the compounds against MCF7 cells, HepG2 cells and SGC-7901 cells was evaluated by MTT assay. In the results, compound 4a showed the most obvious inhibitory effect on MCF7 cells with IC50 value of 27.566±0.52 μM, which was much lower than cordycepin. Compound 4a showed high selectivity between MCF7 and normal MCF-10A cells. Further biological evaluation showed that compound 4a promoted apoptosis and blocked the cell cycle in G0/G1 phase. Then, Western Blot was used to detect related apoptotic proteins. It was found that Compound 4a could down-regulate the expression of Bcl-2 protein and up-regulate the expression of p53, Bax, Caspase-3, and Caspase-9 proteins. The mitochondrial membrane potential decreased continuously and the positive expression rate decreased. It was speculated that compound 4a induced the apoptosis of MCF7 cells through the mitochondrial pathway.

The perturbation in water balance rather than any change in salt content is the main cause of hyponatremia, the most frequent electrolyte abnormality defined as serum sodium concentration <135 mEq/L. Hyponatremia may be divided as mild (Na>120 mEq/L) or severe (Na<120 mEq/L) hyponatremia, most frequently observed in elderly ICU hospitalized patients. Based on tonicity hyponatremia may be hypotonic (decreased concentration of solute), isotonic, and hypertonic (falsely low sodium). According to the volume of the extracellular fluid (ECF) hyponatremia is further divided as hypovolemic, euvolemic, or hypervolemic hyponatremia. Finally, hyponatremia may develop rapidly as acute (<48 h) with usually severe symptoms, or slowly as chronic hyponatremia, being usually asymptomatic or with mild symptoms. Patient’s medical history and clinical symptoms and signs could point to a certain diagnostic direction. Acute severe hyponatremia is presented with headaches, vomiting, nausea, fatigue, impaired cognition, gait with increased falls symptoms etc., while the severe symptomatology due to hyponatremic encephalopathy is presented as confusion, agitation, seizures, or even coma and death. Nevertheless, an urgent evaluation of the volume and neurological status is essential for prevention of neurological damages. The treatment of hyponatremia should of course be based on the underlying cause, the duration and degree of hyponatremia, the observed symptoms, and volume status of patient.

Since the 1980s, a growing interest in goat milk was noticed due to the nutritional values and health benefits of this milk, which resulted in increasing goat populations and milk production worldwide. This comprehensive review elaborates on goat milk composition compared to other types of milk. It is also an overview of goat milk production, properties, nourishment-value, applications in dairy products, and potential health benefits. Goat milk composition and its characteristics are slightly different from other types of milk and can be utilized to manufacture many dairy products. Fresh goat milk and goat milk products (e.g., yogurt and kefir were found to provide various potential health benefits, such as anti-inflammatory, prevent cardiovascular disease, anti-diabetic and antihypertensive, strengthen bones, boost immunity, and improve metabolism.

The concerning worldwide increase of obesity and chronic metabolic diseases such as T2D, dyslipidemia, and cardiovascular disease motivates further investigations into preventive and alternative therapeutic approaches. Over the past decade, there is growing evidence that the formation and activation of thermogenic adipocytes (brown and beige) may serve as therapy to treat obesity and its associated diseases owing to its capacity to increase energy expenditure and to modulate circulating lipids and glucose levels. Thus, understanding the molecular mechanism of brown and beige adipocytes formation and activation will facilitate the development of strategies to combat metabolic disorders. Here, we provide a comprehensive overview of pathways and players involved in the development of brown and beige fat as well as the role of thermogenic adipocytes in energy homeostasis and metabolism. Also, we discuss the alterations in brown and beige adipose tissue function during obesity and, explore the therapeutic potential of thermogenic activation to treat metabolic syndrome.

Obesity and chronic low-grade inflammation are becoming global epidemics. The dysbiosis has a specific role in the metabolism and energy stocks of the host. The discovery that a low-grade of inflammation could be directly connected to the intestinal microbiota metabolic endotoxemia (elevated levels of plasma lipopolysaccharides) has allowed the identification of novel mechanisms involved in the control of the intestinal barrier. In this review, it will analyze the latest news to explain how human symbiotic microorganisms participate in the growth of the fat reserves and promote insulin resistance as a low-grade inflammation. Besides, it will discuss new treatments with probiotics and prebiotics as a promising therapeutic approach to reverse the host's metabolic changes linked to dysbiosis observed in obesity.

Cancer being a multi-factorial disease, a multi-target approach is needed to treat it with minimal side-effects. Therefore, combined use of a proven herbal formula with chemo-therapy could be the better therapeutic. It may maintain homeostasis by synergistically targeting multiple signaling pathways involved in tumorigenesis, thus circumventing recurrence, resistance, and immunosuppression. Here we aim to determine the effectiveness and safety of an FDA-approved herbal formula, SR033 in combination with 5-fluorouracil (5FU) and paclitaxel (PTX). We report chemo-sensitization and chemo-synergy in HeLa and MCF-7 cell lines, immunomodulation of COX-2, PD-L1, VEGF and TGFβ and overall survival in-vitro and in-vivo via oral and topical delivery of SR033. In-vitro, SR033/5FU significantly reverses 5FU and PTX-resistance, lower COX-2, and PD-L1, resulting in TGFβ/ VEGF axis modulation. Furthermore, the study suggests that due to anti-oxidative potential of SR033, oral administration exerts chemo-preventive activity and restores cellular compartment in solid tumor and ascites-bearing mice models. Furthermore, the topical application, SR033L with low-dose 5FU increases survival rate, reduces tumor growth, and completely restores local and peripheral neutrophil-lymphocyte ratio in solid tumor mice model. The study indicates that SR033 could be a strong candidate in combination with low-dose 5FU and PTX for a holistic approach to cancer management.

Transdermal drug delivery systems (TDDS) are designed to administer a consistent and effective dose of medication through the patient's skin. These pharmaceutical preparations are self-contained, discrete dosage forms designed to be placed topically on intact skin to release the active component at a controlled rate by penetrating the skin barriers. This medication provides a continuous and prolonged administration of a substance at a consistent rate. TDDS, or transdermal drug delivery system, has gained significant attention as a non-invasive method of administering drugs to vulnerable patient populations, such as pediatric and geriatric patients. This approach is considered easy to administer and helps overcome bioavailability issues associated with conventional drug delivery, which can be hindered by poor absorption and metabolism. TDDS has various advantages compared to conventional methods of drug administration. It is less intrusive, more patient-friendly, and can circumvent first-pass metabolism and the corrosive acidic environment of the stomach that happens when medications are taken orally. Multiple methodologies have been devised to augment the transdermal permeability of diverse pharmaceutical substances. Recent advancements in transdermal drug delivery systems have facilitated the precise delivery of medications to the intended site of action by improving the penetration of drugs through the outermost layer of the skin, known as the stratum corneum, resulting in enhanced drug availability throughout the body. This review seeks to provide a concise overview of the several methods employed in the production of TDDS, as well as their evaluation, therapeutic uses, clinical considerations, and current advancements. These advancements have resulted in the development of intelligent, biodegradable, and highly efficient transdermal drug delivery systems.

Vascular cell adhesion molecule-1 (VCAM-1) is closely associated with tumor progression and metastasis. However, the relevance and role of VCAM-1 in lung cancer have not been clearly elucidated. In this study, we found that VCAM-1 was highly overexpressed in lung cancer tissue compared with that of normal lung, and high VCAM-1 expression correlated with poor survival of lung cancer patients. VCAM-1 knockdown reduced invasion in A549 human lung cancer cells, and competitive blocking experiments targeting the Ig-like domain 6 of VCAM-1 (VCAM-1-D6) demonstrated that the VCAM-1-D6 domain was critical for VCAM-1-mediated A549 cell invasion. Next, we developed a human monoclonal antibody specific to human and mouse VCAM-1-D6 (VCAM-1-D6 huMab), which was isolated from a human synthetic antibody library using phage display technology. Finally, we showed that VCAM-1-D6 huMab had a nanomolar affinity for VCAM-1-D6 and that it potently suppressed invasion in A549 and NCI-H1299 lung cancer cell lines. Taken together, these results suggest that VCAM-1-D6 is a novel therapeutic target in VCAM-1-mediated lung cancer invasion and that our newly developed VCAM-1-D6 huMab will be a useful tool for inhibiting VCAM-1-expressing lung cancer cell invasion.

Autonomous navigation of a mobile robot in dynamic environments presents a significant challenge in the field of robotics. The primary objective for mobile robot navigation is to ensure both smoothness and safety of movement. A path planning is applied to generate a trajectory that allows the robot to move smoothly while avoiding collisions with both stationary and moving obstacles. This study aims to introduce an Adaptive Neuro-Fuzzy Inference System (ANFIS)-based control strategy for a mobile robot navigating in dynamic environments, with a significant focus on ensuring collision-free path planning. The developed control strategy incorporates four ANFIS controllers, each regulating the robot's responsive behaviors. The experimental scene includes a mobile robot moving in an environment with static and dynamic obstacles without colliding with the obstacles. The experimental tests confirm the model's capability to facilitate collision-free motion, employing a path planning algorithm for determining the shortest route to the target destination. Simulations are conducted to show the effectiveness of the proposed algorithm, highlighting the mobile robot's efficiency in navigating without collisions while avoiding both stationary and moving obstacles using the integration of ultrasonic sensors.

For a mobile robot, navigation in a densely crowded space can be a challenging and sometimes impossible task, especially with traditional techniques. In this paper, we present a framework to train neural controllers for differential drive mobile robots which must safely navigate a crowded environment while trying to reach a target location. To learn the robot’s policy, we train a convolutional neural network using two reinforcement learning algorithms, Deep Q-Networks (DQN) and Asynchronous Advantage Actor Critic (A3C), and develop a training pipeline that allows to scale the process to several compute nodes. We show that the asynchronous training procedure in A3C can be leveraged to quickly train neural controllers and test them on a real robot in a crowded environment.

One of the problems, which make it difficult to solve the mystery of the origin of life, would be how life emerged in chemically complex messy environments on the primitive Earth. It is considered that three main points contributed to open the way to the emergence of life. (1) A characteristic inherent in [GADV]-amino acids, which are easily produced with prebiotic means. (2) Protein 0th-order structure or [GADV]-amino acid composition generating water-soluble globular protein with some flexibility, which can be produced even by random joining of [GADV]-amino acids. (3) Formation of versatile [GADV]-microspheres, which can grow, divide, proliferate even without genetic system, was the emergence of proto-life. (4) [GADV]-microspheres with a higher proliferation ability than others could be selected. The proto-Dawin evolution made it possible to proceed forward to creation of the core life system composed of (GNC)n gene, anticodon stem-loop tRNA or AntiC-SL tRNA (GNC genetic code) and [GADV]-protein. (5) Eventually, the first genuine life with the core life system emerged. Thus, the formation processes of [GADV]-protein and (GNC)n gene in chemically complex messy environments were the steps to the emergence of genuine life.

Fluid flow and chemokine gradients play a large part in not only regulating homeostatic processes in the brain, but also in pathologic conditions by directing cell migration. Tumor cells in particular are superior at invading into the brain resulting in tumor recurrence. One mechanism that governs cellular invasion is autologous chemotaxis, whereby pericellular chemokine gradients form due to interstitial fluid flow (IFF) leading cells to migrate up the gradient. Glioma cells have been shown to specifically use CXCL12 to increase their invasion under heightened interstitial flow. Computational modeling of this gradient offers better insight into the extent of its development around single cells, yet very few conditions have been modelled. In this paper, a computational model is developed to investigate how a CXCL12 gradient may form around a tumor cell and what conditions are necessary to affect its formation. Through finite element analysis using COMSOL and coupled convection-diffusion/mass transport equations, we show that velocity (IFF magnitude) has the largest parametric effect on gradient formation, multidirectional fluid flow causes gradient formation in the direction of the resultant which is governed by IFF magnitude, common treatments and flow patterns have a spatiotemporal effect on pericellular gradients, exogenous background concentrations can abrogate the autologous effect depending on how close the cell is to the source, that there is a minimal distance away from the tumor border required for a single cell to establish an autologous gradient, and finally that the development of a gradient formation is highly dependent on specific cell morphology.

We address the process of discounting in random environments which allows to value the far future in economic terms. We review several approaches to the problem regarding different well-established stochastic market dynamics in the continuous-time context and include the Feynman-Kac approach. We also review the relation between bond pricing theory and discount and introduce the market price of risk and the risk neutral measures from an intuitive point of view devoid of excessive formalism. We provide the discount for each economic model and discuss their key results. We finally present a summary of our previous empirical studies on several countries of the long-run discount problem.

This paper proposes a novel data processing framework dedicated to bedload monitoring in underwater environments. After calibration, by integration the total energy in the nominal bandwidth, the proposed experimental setup is able to accurately measure the mass of individual sediments hitting the aluminum plate. This require a priori knowledge of the vibration trasients in order to match a predefined dictionary. Based on unsupervised hierarchical agglomeration of complex vibration spectra, the proposed algorithms allow to accurately localize the transients corresponding to the shocks created by sediment impacts on a steel plate.

Intelligent systems are driven by the latest technological advances in so different areas as sensing, embedded systems, wireless communications or context recognition. This paper focuses on some of those areas. Concretely, the paper deals with wireless communications issues on embedded systems. More precisely, the paper combines the multi-hop networking with Bluetooth technology and a quality of service (QoS) metric, the latency. Bluetooth is a radio license free worldwide communication standard that makes low power multi-hop wireless networking available. It establishes piconets (point-to-point and point-to-multipoint links) and scatternets (multi-hop networks). As a result, many Bluetooth nodes can be interconnected to set up ambient intelligent networks. Then, this paper presents the results of the investigation on multi-hop latency with park and sniff Bluetooth low power modes conducted over the hardware test bench previously implemented. In addition, the empirical models to estimate the latency of multi-hop communications over Bluetooth Asynchronous Connectionless Links (ACL) in park and sniff mode are given. The designers of devices and networks for intelligent systems will benefit from the estimation of the latency in Bluetooth multi-hop communications that the models provide.

DKA represents an acute, severe complication of relative insulin deficiency and a common presentation of Type 1 Diabetes Mellitus (T1DM) primarily and, occasionally, T2DM in children and adolescents. It is characterized by the biochemical triad of hyperglycaemia, ketonaemia and/or ketonuria, and acidaemia. Clinical symptoms include dehydration, tachypnoea, gastrointestinal symptoms, and reduced level of consciousness, precipitated by a variably long period of polyuria, polydipsia and weight loss. The present review aims to summarize potential pitfalls in the diagnosis and management of DKA. A literature review was conducted using the Pubmed/Medline databases including articles published from 2000 onwards. Diagnostic challenges include differentiating between T1DM and T2DM, DKA and hyperosmolar hyperglycaemic state (HHS), or between DKA and alternative diagnoses presenting with overlapping symptoms, such as pneumonia, asthma exacerbation, urinary tract infection, gastroenteritis, acute abdomen and central nervous system infection. The mainstays of DKA management include careful fluid resuscitation, timely intravenous insulin administration and restoration of shifting electrolyte disorders and underlying precipitating factors. However, evidence suggests that optimal treatment remains a therapeutic challenge. Accurate and rapid diagnosis, prompt intervention and meticulous monitoring are of major importance to break the vicious cycle of life-threatening events and prevent severe complications during this potentially fatal medical emergency.

The purpose of this article is to present an IoT architecture implemented in an intelligent environment, focusing on the optimization of initial conditions and device management. A general control system was developed using an open-source platform, integrating aWi-Fi network and YAML coding to enable communication and control of the IoT architecture devices. The implementation includes actuators, sensors, and control devices that, through a graphical interface, allow the visualization of the historical record of activities and real-time measurements of connected devices. The design includes specific mechanisms and the analysis of materials through tensile tests on specimens, following the ASTM E8 standard, and deformation test simulations, in which PLA demonstrated better performance compared to materials like ABS and resin. The significance of the implemented IoT system lies in an energy saving of 58% compared to conventional structures. Additionally, the study of response times for network connections showed that using an Ethernet cable resulted in a response time of 1.21 seconds, representing a reduction of 1.65 seconds compared to the second lowest value obtained.

BACKGROUND: Thromboembolic disorders including Myocardial infarction[ MI] and stroke represent the leading causes of death worldwide. Fibrinolytic enzymes extracted from microbial sources showed high efficacy in the dissolution of different blood clots. AIM OF THE STUDY: Screening and the bacterial recombinant DNA manufacture of bacterial fibrinolytic enzymes from different soil environments in Egypt. METHODOLOGY: A total of 50 soil samples were screened for their fibrinolytic enzyme production. The potent fibrinolytic enzyme-producing bacterial isolates were evaluated for their thrombolytic activities using the plasma plate method. The characterization of the enzyme activity and thermostability were carried out; also, the determination of molecular mass using a mass spectrometer and western blot technique was performed. The purification of the fibrinolytic enzymes was done through the affinity chromatography technique. On the other hand, the production of the purified bacterial fibrinolytic enzyme was achieved via bacterial recombinant DNA technology. Formulation of fibrinolytic enzymes in different dosage forms was tried. RESULTS: In the present study, the purified bacterial fibrinolytic enzyme was approximately 83% pure through affinity chromatography and SDS-PAGE assay. The predominating bacterial isolate secreting fibrinolytic enzymes was found to be Bacillus cereus. The fibrinolytic enzyme activities of 50 soil samples were found to be in the range of 0.167-1.853 U/ ml. The fibrinolytic activity of the extracellular enzyme refined from the culture supernatant of Bacillus cereus was relatively stable over the PH range from 7.4-10 for 18 hours and also it showed stability with the highest productivity at a temperature of 43 0C for nearly 60 minutes. The enzyme was called fibrin-proteinase[ FP] in the present study. The FP degraded the fibrin clots via direct thrombolysis. The specific activity and the molecular mass of the FP were estimated to be nearly 40.71 Units/ mg protein and nearly 30 KDa respectively. Protease activity was noticed to be slightly increased in the presence of Fe+3; While it was inhibited in the presence of EDTA. On the other hand, the FP fibrinolytic activity was enhanced greatly after the addition of monovalent cations such as K+1 and Na +1. The enzyme was also active over the temperature range of 20- 65 0C with the highest activity at 55 0C. The optimum temperature and PH of protease production was at 35-43 0C and PH 8.0-10. Conclusion: During the present study, the thermostable fibrinolytic enzyme FP purified from Bacillus cereus in different soil environments in Egypt was a promising fibrinolytic enzyme because it showed a broader efficacious fibrinolytic activity as well as less adverse effects than the current fibrinolytic enzymes globally. It is recommended in the future advanced exploration of the optimization of suitable formulation of bacterial fibrinolytic enzymes to aid in the dissolution of various blood clots and as a consequence overcoming the high rate of mortality globally.

The COVID-19 pandemic has led to the growth of hybrid and online learning environments and the trend to introduce more technology into the classroom. One such change would be the use of smart synchronous hybrid learning environments (SSHLE), which are settings with both in-person and online students concurrently, and in which technology plays a key role in sensing, analyzing, and reacting throughout the teaching and learning process. These changing environments and the incorporation of new technologies can place a greater orchestration load on participants and a reduction in teacher agency. In this context, the aim of this paper is to analyse the orchestration load and teacher agency in different SSHLEs. The NASA-TLX model was used to measure the orchestration load in several scenarios. Questionnaires and interviews were used to measure teacher agency. The results obtained indicate that the orchestration load of the teacher tends to be high (between 60 and 70 points out of 100 of the NASA-TLX workload), especially when they lack experience in synchronous hybrid learning environments, and the orchestration load of the students tends to have average values (between 50 and 60) in the SSHLEs analysed. Meanwhile, the teacher agency does not appear to be altered but shows potential for improvement.

This paper presents Mathematical Formulation for Neutrino-Fission of a heavy nuclei in Neutrino-environments. It has been proposed that neutrino fission is a dynamic two-process reaction, where more than one neutrino can be captured by target nucleus. A quantity named Neutrino-Zeta with units of eV^-1 has been defined to represent Neutrino-environments. Neutrino-zeta with assumed excited energy states for heavy nuclei A∼230-270 is estimated to be 0.0212 MeV^-1, with the probability of fission Barrier energy state P(E_x,f)= 0.169064014 with E_x,f =6MeV. P(E_x,f)=0.222664 is highest at zeta=0.1MeV^-1 . It has been shown that probabilities of certain excitation energy states and their corresponding decay reactions at those excitation energies can be equal for two neutrino-zetas. Neutron induced fission for different neutrinos hypothesize that probability of symmetric fission channels is higher at low neutrino-zetas, which can be tested experimentally.

Neurofibromatosis type 2 (NF2) is a genetic syndrome characterized by the growth of benign tumors in the nervous system, particularly bilateral vestibular schwannomas, meningiomas, and ependymomas. This review consolidates the current knowledge on NF2 syndrome, emphasizing the molecular pathology associated with the mutations in the gene of the same name, the NF2 gene, and the subsequent dysfunction of its product, the Merlin protein. Merlin, a tumor suppressor, integrates multiple signaling pathways that regulate cell contact, proliferation, and motility, thereby influencing tumor growth. The loss of Merlin disrupts these pathways, leading to tumorigenesis. We discuss the roles of another two proteins potentially associated with NF2-deficiency as well as Merlin: Yes-associated protein 1 (YAP), which may promote tumor growth, and Raf kinase inhibitory protein (RKIP), which appears to suppress tumor development. Additionally, this review discusses the efficacy of various treatments, such as molecular therapies that target specific pathways or inhibit neomorphic protein-protein interaction caused by NF2-deficiency. This overview not only expands on the fundamental understanding of NF2 pathophysiology but also explores the potential of novel therapeutic targets that affect the clinical approach to NF2 syndrome.

Prostate cancer lung metastasis represents a clinical conundrum due to their implication of advanced disease progression and the complexities they introduce in treatment planning. As the disease progresses to distant sites such as the lung, the clinical management becomes increasingly intricate, requiring tailored therapeutic strategies to address the unique characteristics of metastatic lesions. This review seeks to synthesize the current state of knowledge surrounding prostate cancer metastasis to the lung, shedding light on the diverse array of clinical presentations encountered, ranging from subtle radiological findings to overt symptomatic manifestations. By examining the diagnostic modalities utilized in identifying this metastasis, including advanced imaging techniques and histopathological analyses, the review aims to provide insights into the diagnostic landscape and the challenges associated with accurately characterizing lung metastatic lesions in prostate cancer patients. Moreover, the review delves into the nuances of therapeutic interventions employed in managing prostate cancer lung metastasis, encompassing systemic treatments such as hormonal therapies and chemotherapy, as well as metastasis-directed therapies including surgery and radiotherapy.

Advances in gastric cancer screening and endoscopic technology have made it possible to detect and treat gastric cancer at an early stage. As a result, about 40% of all gastric cancers have now been resected by endoscopic treatment in Japan. In endoscopic diagnosis, magnifying endoscopic observation using band-limited light such as narrow band imaging (NBI) has significantly improved the accuracy of gastric cancer diagnosis. At the same time, in endoscopic treatment, endoscopic submucosal dissection (ESD) has contributed to increase explosively the number of gastric cancers which could be resected endoscopically. In recent years, the construction of algorism for endoscopic diagnosis and treatment with a view to personalized medicine has been explored, and endoscopic use for gastric cancer managements is expected to develop further in the future. Keywords (5 words):

Many of the potential immune therapeutic targets are similarly affected in adult-onset neurodegenerative diseases such as Alzheimer’s (AD) disease, Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD), but also in a seemingly distinct Niemann-Pick type C disease with primarily juvenile-onset. This strongly argues for an overlap in pathogenic mechanisms. The commonly researched immune targets include various immune cell subsets such as microglia, peripheral macrophages, or regulatory T cells (Tregs), the complement system, and other soluble factors. In this review, we will compare these neurodegenerative diseases from a clinical point of view and point out the common pathways and mechanisms of protein aggregation, neurodegeneration and/or neuroinflammation that could potentially lead to shared treatment strategies. We also describe the common therapeutic approaches in treating the immune dysfunctions in these disorders, moving from immunization to microbiome regulation and stem cell treatment.

Monoterpenes as natural products are the subject of increased attention in the search for new pharmacological agents because of their numerous biological activities including antifungal, antibacterial, antioxidant, anticancer, antispasmodic, hypotensive, vasodilating effects, etc. In vitro and in vivo studies reveal their antidepressant, anxiolytic, and memory-enhancing in experimental dementia and Parkinson’s disease effects. Chemical modification of natural substances by conjugation with various synthetic components is a modern method of obtaining new biologically active compounds. The discovery of new potential drugs among monoterpene derivatives is a progressive direction in experimental pharmacology and a promising approach to the therapy of various pathologies. Biologically active substances such as monoterpenes borneol, camphor, geraniol, pinene, and thymol, were used to synthesize compounds with different properties, including analgesic, anti-inflammatory, anticonvulsant, anti-depressant, anti-Alzheimer’s, anti-parkinsonian, antiviral and antibacterial (anti-tuberculosis). Myrtenal is a perspective monoterpenoid with therapeutic potential in various fields of medicine. Its chemical modifications often lead to new or more pronounced biological effects. As an example, conjugation of myrtenal with the known pharmacophore adamantane allows one to enhance some of its key properties. Myrtenal-adamantane derivatives exhibited a variety of beneficial properties – antimicrobial, antifungal, antiviral, anticancer, anxiolytic, and neuroprotective, which are worth examining in more detail and at length.

Organ transplantation remains the only treatment option for patients with end-stage organ dysfunction. However, there are numerous limitations that challenge its clinical application, including the shortage of organ donations, the quality of donated organs, injury during organ preservation and reperfusion, primary and chronic graft dysfunction, acute and chronic rejection, infection, and carcinogenesis in post-transplantation patients. Acute and chronic inflammation and cell death are two major underlying mechanisms for graft injury. Necroptosis is a type of programmed cell death involved in many diseases and has been studied in the setting of all major solid organ transplants, including the kidney, heart, liver, and lung. It is determined by the underlying donor organ conditions (e.g., age, alcohol consumption, fatty liver, hemorrhage shock, donation after circulatory death, etc.), preservation conditions and reperfusion, as well as allograft rejection. Specific molecular mechanisms of necroptosis have been uncovered in the organ transplantation setting, and potential targeting drugs have been identified. We hope this review article will promote more clinical research to determine the role of necroptosis and other types of programmed cell death in solid organ transplantation to alleviate the clinical burden of ischemia-reperfusion injury and graft rejection.

Characterized in biomedical terms, stretching exercises have been defined as movements applied by external and/or internal forces – to increase muscle and joint flexibility, decrease muscle stiffness, to elevate joint range of motion (ROM), to increase the length of the morpho-functional unit “muscle-tendon”, to improve joint, muscle and tendon movements, contraction and relaxa-tion. The present review examines and summarizes the initial and recent literature data related to the biomechanical, physiological and therapeutic effects of static stretching (SS) on flexibility and other physiological characteristics of the main structural and functional unit “joint-ligaments-tendon-muscle”. The healing and therapeutic effects of SS, soon combined with other rehabilitation techniques (massage, foam rolling – with and without vibrations; hot/cold therapy, etc.) are discussed in relationship to creation of individual (patient-specific) or group programs for treatment and prevention of joint injuries as well as for improving performance in sports. From a theoretical point of view, the role of SS as positively affecting the composition of the connective tissue matrix is pointed out: type I-III collagen synthesis, hyaluronic acid and glucosaminoglycans (GAGs) turnover – under influence of the transforming growth factor beta-1 (TGF-β-1). Different variables as collagen type, biochemistry, elongation and elasticity are used as molecular biomarkers. Recent studies evaluated that the static progressive stretching therapy could prevent/reduce the development of arthrogenic contractures, joint capsule fibrosis, muscle stiffness and need new clinical applications. Combined stretch techniques are proposed and ap-plied in medicine and sports, depending on their long- and short-term effects on variables such as ROM, EMG activity, muscle stiffness, etc. The results obtained are of theoretical and practical interest for development of new experimental, mathematical and computational models and creation of efficient therapeutic programs. The healing SS effects on the main structural and functional unit – “joint-ligament-tendon-muscle” need further investigations, which could clarify and evaluate benefits of SS in prophylaxis and treatment of joint injuries - in healthy and ill in-dividuals, in older adults, as compared to young, active and well-trained persons, as well as to professional athletes.

MicroRNAs (miRNAs) are single-stranded, noncoding RNA molecules that regulate gene expression post-transcriptionally by binding to messenger RNAs. miRNAs are important regulators of gene expression, and their dysregulation is implicated in many human and dog diseases. Most cancers tested, to date, have been shown to express altered miRNA levels, which indicates their potential importance in the oncogenic process. Based on this evidence, numerous miRNAs have been suggested as potential cancer biomarkers for both diagnosis and prognosis. miRNA-based therapies have also been tested in different cancers and have provided measurable clinical benefits to patients. In addition, understanding miRNA biogenesis and regulatory mechanisms in cancer can provide important knowledge about resistance to chemotherapies, leading to more personalized cancer treatment. In this review, we have comprehensively summarized the importance of miRNA in human and dog cancer research. We have discussed the current state of development and potential for miRNA as both a diagnostic marker and a therapeutic target.

Reinventing approved therapeutic proteins for a new dose, a new formulation, a new route of administration, an improved safety profile, a new indication, or a new conjugate with a drug or a radioactive source is a creative approach to benefit from the billions spent on developing new therapeutic proteins. These new opportunities were created only recently with the arrival of AI/ML tools and high throughput screening technologies. Furthermore, the complex nature of proteins offers mining opportunities that are not possible with chemical drugs; bringing in newer therapies without spending billions makes this path highly lucrative financially while serving the dire needs of humanity. This paper analyses several practical reinventing approaches and suggests regulatory strategies to reduce development costs significantly. This should enable the entry of hundreds of new therapies at affordable costs.

Transposable elements (TEs) ubiquitously exist in the human genome, and some have the ability to copy and paste themselves to other locations, resulting in new insertions. Organisms have evolved with mechanisms and machineries to repress such activity. TEs are also co-opted for beneficial functions by the host and are thus maintained in the genome. During the lifetime of humans, aberrant TE activity might cause or contribute towards diseases including neurological conditions such as Alzheimers Disease (AD) and cancer. While inflammatory pathways linked to TEs may be a part of the disease pathology, on the other hand altered TE activity involving inflammatory pathways could be recognised by disease suppression mechanisms. For this reason, TEs could be targeted for therapeutic applications aiming to prevent TE activity or reduce initial inflammatory pathways as well as to activate disease suppression mechanisms. In this review, we describe the contributory and potential preventative roles of TEs in neurological conditions and cancer from a molecular and evolutionary perspective. Evolutionary paradigms both at the unicellular and organismal level aid understanding the role of TEs in disease. These observations could pave the way for the development of novel therapeutic approaches targeting TEs.

Background: Immunologic and neuro-inflammatory pathways have been found to play a major role in the pathogenesis of many neurological disorders such as epilepsy, proposing the use of novel therapeutic strategies. In the era of personalized medicine and in the face of the exhaustion of anti-seizure therapeutic resources it is worth looking at the current or future possibilities that neuroimmunomodulator or anti-inflammatory therapy can offer us in the management of patients with epilepsy. Methods: We performed a narrative review on the recent advances on the basic epileptogenic mechanisms related to the activation of immunity or neuroinflammation with special attention to current and future opportunities for novel treatments in epilepsy. Results: Neuroinflammation can be considered a universal phenomenon and occurs in structural, infectious, post-traumatic, autoimmune, or even genetically based epilepsies. The emerging research developed in recent years has allowed us to identify the main molecular pathways in-volved in these processes. These molecular pathways could constitute future therapeutic targets for epilepsy. Conclusions: Different drugs current or in development have demonstrated their capacity to inhibit or modulate molecular pathways involved in the immunologic or neuroinflammatory mechanisms described in epilepsy. Some of them should be tested in the future as possible antiepileptic drugs.

Understanding of the molecular mechanisms of prostate cancer has led to development of therapeutic strategies targeting androgen receptor (AR). These androgen-receptor signaling inhibitors (ARSI) include androgen synthesis inhibitor- abiraterone and androgen receptor antagonists- enzalutamide, apalutamide, and darolutamide. Although these medications provide significant improvement in survival among men with prostate cancer, drug resistance develops in nearly all patients with time. This could be through androgen-dependent or androgen-independent mechanisms. Even weaker signals and non-canonical steroid ligands can activate AR in the presence of truncated AR-splice variants, AR overexpression, or activating mutations in AR. AR splice variant, AR-V7 is the most studied among these and is not targeted by available ARSIs. Non-androgen receptor dependent resistance mechanisms are mediated by activation of an alternative signaling pathway when AR is inhibited. DNA repair pathway, PI3K/AKT/mTOR pathway, BRAF-MAPK and Wnt signaling pathway and activation by glucocorticoid receptors can restore downstream signaling in prostate cancer by alternative proteins. Multiple clinical trials are underway exploring therapeutic strategies to overcome these resistance mechanisms.

Medicinal mushrooms have got much attention from biologists in the last decades. Leucocalocybe mongolica Imai remains one of the famous clinical and edible mushrooms used in traditional Chinese medicine and Mongolian medicine to treat various diseases. It also commonly consumes in Chinese and Mongolian daily dishes. Numerous biochemical components exist in L. mongolica, especially in the fruiting bodies include; polysaccharides, sterol, lectins, laccase, amino acids, terpenes, volatile compounds, and so on. These biomedical components possess a lot of medicinal properties and provide diverse therapeutical effects for human health, such as anti-tumor activity, antiproliferative activity, anti-diabetes properties, hypotensive effect, hepatoprotective effect, antioxidant activity, cardioprotective effect, and so on. However, this review's main objectives are to illustrate some basics about the bioactive components in L. mongolica and its pharmacological effects on the human body. In addition to giving forward some suggestions for future research on this medicinal mushroom.

The treatment of peptides has played an important role in clinical practice since the discovery of insulin therapy in the 1920s. Over 60 peptide drugs are approved in the United States (US and other regional mar-kets, and peptides continue to undergo drug discovery steadily. Peptide research and development has lev-eraged a wider range of structures known from other plant sources, via pharmacology and medicinal molecular biology, beyond its conventional focus on individual endogenous peptides. We build a comprehensive database of peptides that have met scientific studies with more than 150 constantly evolving peptides. Here we provide a simple overview of the peptide-based drug therapy environment, comprising evolutionary points of view, structural properties, operational thresholds, and explanation of the therapeutic area.