Objective: Type I interferon receptor (IFNAR) signaling contributes to several autoimmune and vascular diseases such as atherosclerosis and stroke. The purpose of this study was to assess the influence of IFNAR1 deficiency on the formation and progression of experimental abdominal aortic aneurysms (AAAs). Methods: AAAs were induced in type I interferon receptor subunit 1 (IFNAR1) deficient and wild type control male mice via intra-infrarenal aortic infusion of porcine pancreatic elastase. Immunostaining for IFNAR1 was evaluated in experimental and clinical aneurysms. The initiation and progression of experimental AAAs was assessed via ultrasound imaging prior to (day 0) and 3-, 7-, and 14-days following elastase infusion. Aneurysmal histopathology was analyzed at sacrifice. Results: Increased aortic medial and adventitial IFNAR1 expression was present in both clinical AAAs harvested at surgery and experimental AAAs. Following AAA initiation, wild type mice experienced progressive, time-dependent infrarenal aortic enlargement. This progression was substantially attenuated in IFNAR1 deficient mice. On histological analyses, medial elastin degradation, smooth muscle cell depletion, leukocyte accumulation and neoangiogenesis were markedly diminished in IFNAR1 deficient as compared to wild type mice. Conclusion: IFNAR1 deficiency limited experimental AAA progression in response to intra-aortic elastase infusion. Combined with clinical observations, these results suggest a regulatory role for IFNAR1 activity in AAA pathogenesis.

Orthohepadnavirus causes chronic hepatitis in a broad range of mammals, including primates, cats, woodchucks, and bats. Hepatitis B virus (HBV) X protein inhibits type-I interferon (IFN) signaling, promoting HBV escape from the innate immune system to establish persistent infection. However, whether X proteins of Orthohepadnavirus viruses in the other species have similar inhibitory activity remains unknown. Here, we investigated the anti-IFN activity of 17 Orthohepadnavirus X proteins derived from various hosts. We observed conserved activity of Orthohepadnavirus X proteins in inhibiting TIR-domain-containing adaptor protein inducing IFN-β (TRIF)-mediated IFN-β signaling pathway through TRIF degradation. X proteins from domestic cat hepadnavirus (DCH), a novel member of Orthohepadnavirus, inhibited mitochondrial antiviral signaling protein (MAVS)-mediated IFNβ signaling pathway comparable with HBV X. These results indicate that inhibition of IFN signaling is conserved in Orthohepadnavirus X proteins.

Coronavirus disease 2019 (COVID-19) continues to cause morbidity and mortality worldwide; therefore, effective treatments remain crucial to controlling it. As interferon-alpha (IFN-α) and -beta (β) have been proposed as COVID-19 treatments, we sought to assess their effectiveness on respiratory, cardiovascular, neurological, and psychiatric signs and symptoms, as well as PASC and death, in hospitalized COVID-19 patients without multiple sclerosis (MS). Using a federated data research network (TriNetX), we performed a retrospective cohort study of hospitalized COVID-19 patients without MS who received IFN-α or -β treatment, comparing them to a similar cohort who did not receive treatment. Following propensity score-matched analyses, we demonstrate that hospitalized COVID-19 patients who were treated with IFN-α or -β had significantly higher odds of death. In contrast, there was no significant difference in any other outcomes between 1-30 days or 1 day to anytime afterward. Overall, hospitalized COVID-19 patients without MS who were treated with IFN-α or -β had similar short- and long-term sequelae (except for mortality) as those who did not receive treatment. The potential benefits of utilizing IFN-α or -β treatment as therapeutics remain to be realized, and our research highlights the need to explore repurposing drugs for COVID-19 using real-world evidence.

Corrosive burns lead to progressive esophageal stricture and dysphagia. There are many trials to prevent Esophageal stricture formation after corrosive burn. This study aimed to access the effects of EW-7197 on prevention for esophageal stricture formation after corrosive esophageal burn. animal study were classified divided into three groups: a healthy group, a control group (corrosive burn without EW-7197), and a treatment group (corrosive burn with EW-7197). Corrosive esophageal burns were produced using 30% NaOH on the lower esophagus. For 3 weeks, the control group received vehicle and the treatment group received 20 mg/kg/day EW-7197. Treatment efficacy was assessed by measuring the stenosis ratio by esophagogram with contrast media on day 21. histologic staining was performed to evaluate the fibrosis area ratio, and western blotting was performed to evaluate fibrotic markers. Among 20 rats that underwent surgery, 14 survived. Three in the treatment group died because of esophageal perforation, and three in the control group died due to their debilitating status. The esophageal stenosis ratio was significantly lower in the treatment group than in the control group (12.1 ± 9.5% and 42.2 ± 8.3%, respectively; p = 0.001). The histologic fibrosis area ratio was also significantly lower in the treatment group (12.5 ± 3.0% and 21.6 ± 2.1%, respectively; p = 0.001). The treatment group showed lower expressions of profibrogenic proteins such as TGF-β1, pSmad3, and α-SMA. EW-7197 may be a good alternative for the prevention esophageal stricture formation after corrosive burn.

Protein tyrosine phosphatase receptor type E (PTPRE) is a member of the “classical” protein tyrosine phosphatase subfamily and regulates a variety of cellular processes in a tissue-specific manner by antagonizing the function of protein tyrosine kinases. PTPRE plays a tumorigenic role in different human cancer cells, but its role in retinoblastoma (RB), the most common malignant eye cancer in children, remains to be elucidated. Etoposide resistant RB cell lines and RB patients display significant higher PTPRE expression levels compared to chemosensitive counterparts and the healthy human retina, respectively. PTPRE promotor methylation analyses revealed that PTPRE expression in RB is not regulated via this mechanism. Lentiviral PTPRE knockdown (KD) induced a significant decrease in growth kinetics, cell viability, and anchorage independent growth of etoposide resistant Y79 and WERI RB cells. Caspase-dependent apoptosis rates were significantly increased and a re-sensitization for etoposide could be observed after PTPRE depletion. In vivo chicken chorioallantoic membrane (CAM) assays revealed decreased tumor formation capacity as well as reduced tumor size and weight following PTPRE KD. Expression levels of miR631 were significantly downregulated in etoposide resistant RB cells and patients. Transient miR631 overexpression resulted in significantly decreased PTPRE levels and concomitantly decreased proliferation and increased apoptosis levels in etoposide resistant RB cells, impacts mirroring PTPRE KD effects and indicating PTPRE regulation via this miR. Additionally, PTPRE KD led to altered phosphorylation of protein kinase SGK3 and - dependent on the cell line - also AKT and ERK1/2, suggesting potential PTPRE downstream signaling pathways. In summary, these results indicate an oncogenic role of PTPRE in chemoresistant retinoblastoma.

Spinocerebellar ataxia type 3 is a neurodegenerative disease caused by an abnormal expansion of CAG repeats in the disease gene ATXN3, leading to prolonged polyglutamine (polyQ) tracts in the respective protein ataxin-3. The polyQ-expanded protein forms polyQ-containing aggregates in several brain regions which leads to neuronal cell loss. Autophagy is thought to play a significant role in clearing these polyQ-containing protein aggregates. Therefore, the autophagy mechanism was investigated in SCA3 with focus on the autophagic protein p62/sequestosome-1. Human and mouse RNA sequencing data were analyzed to determine RNA expression level of autophagic genes. Additionally, autophagy was studied in the SCA3 304Q knock-in mouse model and through several cell culture experiments using HEK-293T cells transfected with ATXN3 of differ-ent polyQ lengths. For cell culture experiments, autophagy was induced with rapamycin treat-ment, proteasomal degradation was blocked with MG132 and degradation of autophagic pro-teins was investigated using cycloheximide treatment. Here, we report an increased autophagy impairment with SCA3 disease progression seen in HEK-293T cells transfected with ATXN3 plasmid with expanded polyQ tracts, higher aged 304Q-knock-in mice, or human post-mortem brain material. Furthermore, co-localized aggregation of the autophagic protein p62 and the dis-ease protein ATXN3 was observed in the course of SCA3 disease. Therefore, we suggest a signifi-cant role for p62 in aggregate formation seen in the neurodegenerative disease SCA3.

Hepatitis E virus (HEV) is responsible for large waterborne epidemics of hepatitis in endemic countries and is an emerging zoonotic pathogen worldwide. In endemic regions, HEV-1 or HEV-2 genotypes are frequently associated with fulminant hepatitis in pregnant women, while with zoonotic HEV (HEV-3 and HEV-4), chronic cases of hepatitis and severe neurological disorders are reported. Hence, it is important to characterize the interactions between HEV and its host. Here, we investigated the ability of the non-structural polyprotein encoded by the first open reading frame (ORF1) of HEV to modulate the host early antiviral response and in particular the type I interferon (IFN-I) system. We found that the amino-terminal region of HEV-3 ORF1 (MetPCP), containing a putative methyltransferase (Met) and a papain-like cysteine protease (PCP) functional domain, inhibited IFN-stimulated response element (ISRE) promoter activation and the expression of several IFN-stimulated genes (ISGs) in response to IFN-I. We showed that the MetPCP domain interfered with the Janus kinase (JAK)/signal transducer and activator of transcription protein (STAT) signalling pathway by inhibiting STAT1 nuclear translocation and phosphorylation after IFN-I treatment. By contrast, MetPCP had no effect on STAT2 phosphorylation and a limited impact on the activation of the JAK/STAT pathway after IFN-II stimulation. This inhibitory function seemed to be genotype-dependent as MetPCP from HEV-1 had no significant effect on the JAK/STAT pathway. Overall, this study provides evidence that the predicted MetPCP domain of HEV ORF1 antagonises STAT1 activation to modulate the IFN response.

The sexual reproduction of ascomycetes is controlled by the mating-type(MAT) locus. (Pseudo)homothallic reproduction has been hypothesized based on genetic data from Hirsutella sinensis (Genotype #1 of Ophiocordyceps sinensis). In this study, the differential occurrence of the mating-type genes in the MAT1-1 and MAT1-2 idiomorphs, which constitute the genetic control of O. sinensis reproduction, was analyzed in 237 strains and 5 genomes of H. sinensis. The mating-type genes were differentially transcribed in H. sinensis Strain L0106, and the MAT1-2-1 transcript in H. sinensis Strain 1229 was alternatively spliced, with an unspliced intron I containing stop codons; these findings constitute O. sinensis reproduction controls at the transcriptional and coupled transcriptional-translational levels. The occurrence of the mating-type genes and a-/α-pheromone receptor genes differed among the 5 H. sinensis genomes. The differential occurrence and transcription of these genes are inconsistent with self-fertilization under (pseudo)homothallism but suggest self-sterility of H. sinensis, which therefore needs a mating partner to achieve sexual outcrossing under heterothallism or hybridization. Consistent occurrence and transcription of the mating-type genes of both the MAT1-1 and MAT1-2 idiomorphs have been reported in natural and cultivated Cordyceps sinensis, but these findings are insufficient to determine the reproduction mode(s) because of the co-occurrence of >90 fungal species and multiple genomically independent genotypes of O. sinensis. The mutant MAT1-1-1 and α-pheromone receptor transcripts in natural C. sinensis result in the N-terminus or middle-truncated proteins, with changes in hydrophobicity and secondary structures of the proteins, suggesting heterogeneous fungal source(s) of the proteins and hybridization reproduction.

Background Homologous recombination deficiency (HRD) evolved into a major diagnostic marker in high grade ovarian cancer (HGOC) predicting the response to poly (Adenosine diphosphate-ribose) polymerase inhibitors (PARPi) and also platinum-based therapy. In addition to HRD, the type of peritoneal tumor spread influences treatment response and patient survival; miliary type tumor spread has poorer predicted outcome than non-miliary type tumor spread. Methods Known methods for HRD assessment were adapted for our technical requirements and the Predictive-value Integrated Genomic Instability Score (PIGIS) for HRD assessment evolved as an outcome. PIGIS was validated in HGOC samples from 122 patients. We used PIGIS to analyze whether the type of tumor spread correlated with HRD status and whether this had an impact on survival. Results We demonstrated that PIGIS can discriminate HRD positive from HRD negative samples. Tumors with miliary tumor spread are HRD negative and have a very bad prognosis with a progression free survival (PFS) of 15.6 months and an overall survival (OS) of 3.9 years. However, HRD negative non-miliary spreading tumors in our cohort had a much better prognosis (PFS 35.4 months, OS 8.9 years), similar to HRD positive tumors (PFS 34.7 months, OS 8.9 years). Conclusions Our results indicate that in a predominantly PARPi naïve cohort the type of tumor spread might be a better predictor of response to platinum sensitivity than HRD. It remains to be determined, whether this also applies for sensitivity to PARPi.

The severe acquired respiratory coronavirus–2 (SARS–CoV-2) infection has initiated both acute and chronic COVID–19 disease between 2020 and 2022, currently evolving with other homologous prior coronavirus strains of the Nidoviridae order, which encompasses other prevalent alpha/ beta coronaviruses, but also the Middle East Respiratory Syndrome (MERS-CoV) and SARS-CoV-1, with recent SARS–CoV–2 variants, increasing demands for effective immunogens and therapeutic approaches that will reduce global disease burden and further infection from SARS–CoV-2 affected individuals that may experience post acute sequelae (PASC) or “Long COVID”. Following a worldwide programme of prophylactic vaccination, there is still a dilemma in the efforts to find prophylactic and early therapeutic approaches that would treat novel SARS-CoV-2 variants and prevent future epidemics or pandemics within host human and animal populations, where zoonotic or cross species transfer naturally occurs. Concerns about viral immune escape intersect at a specific point; a gained evolutionary ability of several viruses to co–infect and compete against previous scientific advances since 1796 that remain undetected or asymptomatic during the early stages of infection progressing to symptomatic and severe disease through capping of the 5' end of DNA and RNA genomes respectively, which is performed by the activated viral 2’ - O - Methyltransferase (MTase) enzyme, which is a complex of two viral non-structural proteins (NSPs) joined together through an activation process (NSP10/16). Moreover, it was discovered that certain polymorphic viruses translate NSP1, which prevents the activation of various Pattern Recognition Receptors (PRRs), directly silences important interferon-stimulated genes (ISGs), is signalled in a paracrine manner to neighbouring cells, and that induces the apoptosis of host cells, inducing an effect of “trace erase” effect and making the viral infection as immunologically “invisible” as possible during the initial, key stages of viral replication and distribution, all such mechanisms occurring independently of the viruses in cause. Other viral NSPs share a role with NSP1 in directly suppressing the activation of PRRs and ISGs, and all such viral proteins help the virus in its process of self-camouflaging against first- and second-line immunity, thereby often severely impacting the quality of the produced adaptive immune responses. The outcome of all such phenomena is the sharp decrease in the host Type I and Type III interferons' (IFNs) rate of synthesis by the host cells, that would usually occur and affect homeostatic cellular pathways, resulting in further viral replication and induced apoptosis. Nonetheless, effects of microbial immune evasion during the development of other viral or carcinogenic pathologies are not widely known. In short, polymorphic viruses developed a proportionate evolutionary response against developed adaptive immune responses, by currently relying on gaps mostly situated in the natural immune system in their process of molecular self-camouflaging. Scientists developed numerous approaches of early treatment that generally showed good success rates and fewer risks of adverse events, and the still early present stages of COVID-19 research should also be taken into consideration whilst filtering for the most appropriate solutions. For example, the administration of recombinant human interferons I and III into the nasal mucosa cellular layer, as key mediators of anti–viral activity, can simulate intracellular infection and stimulate cellular activity in a timely manner, training the innate and adaptive immune system cells to develop and appropriately stimulate an adequate immune response through B and T cells. Another example could involve the treatment of natural and adaptive lymphocytes with a low dose of IFNs I and possibly III, prior to their insertion into the host lymphatic system, possibly alongside additional recruitment of plasmacytoid dendritic cells (pDCs) as further interferon “factories”, all with the purpose of early infection management. It might be that focusing on directly offering the immune system the information about the genetics and protein structure of the pathogen, rather than training its first-line mechanisms to develop faster, excessively increases its specificity, making it reach a level that brings the virus the opportunity to evolve and escape previously-developed host immune mechanisms. It is until the scientific community realises this potentially crucial aspect that large proportions of the world population will probably continue to face serious epidemics and pandemics of respiratory diseases over the coming several decades, evidenced with dengue fever and more recently, monkeypox and possibly avian flu. Of note, it has been indicated that IFN I and / or III display significant immunising, early therapeutic and clinical disease onset-attenuating effects for many other microbial evoked diseases, as well as for a number of oncological diseases.

PHA synthases (PhaC) are grouped into four classes based on the kinetics and mechanisms of reaction. The grouping of PhaC enzymes into four classes is dependent on substrate specificity, according to the preference in forming short chain length (scl) or medium chain length (mcl) polymers: class I, class III, and class IV produce scl-PHAs depending on propionate, butyrate, valerate and hexanoate precursors, while class II phaC synthesize mcl-PHAs based on the alkane (C6 to C14) precursors. PHA synthases of class I, in particular PhaC_Cs from Chromobacterium USM2 and PhaC_Cn/RePhaC1 from Cupriavidus necator/R. eutropha, have been analysed and the crystal structures of the C-domains have been determined. PhaC_Cn/RePhaC1 was also studied by small angle X-ray scattering (SAXS) analysis. Models have been proposed for dimerization, catalysis mechanism, substrate recognition and affinity, product formation and product egress route. The assays based on amino acid substitution by mutagenesis have been useful to validate the hypothesis on the role of amino acids in catalysis and in accommodation of bulky substrates, for the synthesis of PHB co-polymers and medium chain length-PHA polymers with optimized chemical properties.

The vomeronasal system serves as a pivotal element in mammalian sensory biology, allowing the perception of chemical signals essential for social communication via the activation of two main receptor families, V1R and V2R. The expression of V1Rs and V2Rs is linked with that of the G-protein alpha-subunits, Gαi2 and Gαo, respectively. The exploration of the evolutionary pathways of V1Rs and V2Rs across all mammalian species remains a main challenge, juxtaposing available genomic data against emerging immunohistochemical evidence. However, recent investigations, in contrast to what is predicted by the currently annotated genomic sequences, have revealed the expression of Gαo in the vomeronasal neuroepithelium of wild canids, including wolves and foxes. In the present study, the employment of a specific antibody raised against the mouse V2R2, member of the C-family of vomeronasal receptors, V2Rs, has confirmed the expression of this receptor in the fox and wolf, but it has revealed the lack of expression in the dog. This may reflect the impact of domestication on the regression of the VNS in this species, in contrast to their wild counterparts, and underscores the effects of artificial selection on sensory functions. Thus, these findings suggest a more refined chemical detection capability in wild species.

The kinetics and efficacy profiles of photoinitiated polymerization are theoretically presented. For the same dose, lower light intensity achieves a higher steady-state-efficacy (SSE) in type-I; in contrast, type-II has an equal SSE. Higher light intensity has a faster rising efficacy, due to faster depletion of photoinitiator (PS) concentration. However, type-II process is also affected by the available oxygen. Higher light intensity produces more efficient singlet oxygen, resulting a higher transient efficacy, in which all intensities reach the same SSE when oxygen is completely depleted. With external oxygen, type-II efficacy increases with time, otherwise, it is governed only by the light dose, i.e., same dose achieves same efficacy. Moreover, type-II has an efficacy follows Bunsen Roscoe law (BRL), whereas type-I follows non-BRL. The measured type-I efficacy and gelation profile are analyzed by our analytic formulas. Schematics of the photocrosslinking stage defined by the availability of oxygen is developed, where both type-I and –II coexist until the oxygen is depleted. The overall efficacy may be enhanced by resupply of PS or oxygen during the light exposure. The roles of light dose and PS concentration on the efficacy of photoinitiated polymerization should be are governed a new concept of a volume efficacy (Ve), defined by the product of the crosslink (or gelation) depth (CD) and local [efficacy].

Type III interferon (IFN-λs) exhibit potent antiviral activity and immunomodulatory effects in specific cells. Nucleotide fragements of bovine ifn-λ (boifn-λ) gene was synthetized after codon optimization. The boifn-λ gene was then amplified by splicing by overlap extension PCR (SOE PCR), resulting in serendipitous acquisition of the mutated boIFN-λ3V18M. Recombinant plasmids pPICZαA-boIFN-λ3/λ3V18M were constructed and the corresponding proteins were expressed in Pichia pastoris with high-level extracellular soluble form. Dominant expression strains of boIFN-λ3/λ3V18M were selected by Western blot and ELISA, cultured on a large scale, and the recombinant proteins purified by ammonium sulphate precipitation and ion exchange chromatography, yielding 1.5g/L and 0.3 g/L, with 85% and 92% purity, respectively. The antiviral activities of boIFN-λ3/λ3V18M exceeded 106 U/mg, were neutralized with IFN-λ3 polyclonal antibodies, were susceptible to trypsin, and retained stability within defined pH and temperature ranges. Furthermore, boIFN-λ3/λ3V18M exerted antiproliferative effects on MDBK cells without cytotoxicity at 104 U/mL. Overall, boIFN-λ3 and boIFN-λ3V18M did not differ substantially in biological activity, except for reduced glycosylation of the latter. Development of boIFN-λ3 and comparative evaluation with the mutant provide theoretical insights into antiviral mechanisms of boIFN-λs and provide material for therapeutic development.

The p53 tumor suppressor protein shows antiviral activity. The replication of viruses is also antagonized by interferons (IFNs) – cytokines, which control immunity genes by the STAT transcription factors. The best studied interferons belong to type I (e.g. IFNα) and type II (IFNγ) groups. IFNα and IFNγ both induce activating phosphorylation of STAT1 on Tyr701. Previously, we noticed that p53 activates SOCS1, which is a negative regulator of STAT1 phosphorylation. Thus, we hypothesized that p53 by activating SOCS1 expression reduces phosphorylation of STAT1 and attenuates activation of genes stimulated either by IFNα or IFNγ. To test this hypothesis, we exposed p53-proficient and p53-deficient cells to strong p53 activators, and either to IFNα or IFNγ. Subsequently, we estimated the phosphorylation status of STAT1 and the expression of genes regulated by either of these cytokines. Strong activation of p53 reduced the phosphorylation of STAT1 on Tyr701, however surprisingly it did not lead to reduced expression of most tested interferon-stimulated genes. On contrary, p53 and IFNγ synergized in the activation of CASP1, IFIT1 and IFIT3 genes. We conclude that the interactions between p53 and interferon-activated pathways are more complicated than initially expected, but the apparent cooperation between p53 and IFNγ deserves further studies.

Sixteen crossbred rabbits (New Zealand white x Thai native breed) were randomly divided into two groups of eight to determine the effects of daily oral administration of crude extracts from the butterfly pea (Clitoria ternatea L.) from weaning (at 35 days) to slaughter (at 90 days). Effects on phagocytic activity of blood polymorphoneuclear leukocytes, serum biochemistry, meat quality, muscular lipid peroxidation, apparent digestibility, and gut histology were studied. The results revealed that the phagocytic function of circulating leukocytes (75 and 90 days) and alveolar macrophages (90 days) did not differ between the two groups. At slaughter, treated rabbits had lower blood urea nitrogen concentrations and higher liver weight than control rabbits (p < 0.05). After chilling at 4°C for 24 hours, lower meat pH and alteration of meat color (a brighter, less yellow, Hue angle and color saturation) were observed in the treated group (p < 0.05). Furthermore, lipid peroxidation (measured at 3, 5 and 7 storage days) in the meat of treated rabbits was lower than in controls (p < 0.05). Apparent digestibility (analyzed at 46 days for four days) revealed improved organic matter and ether extracts in the treated group (p < 0.05), whereas gut histology was unaffected. In conclusion, butterfly pea extract supplementation did not affect phagocytic function but led to a modification in meat color, delayed lipid peroxidation, and improved digestibility.

Nanocrystalline silicon oxide (nc-SiOx:H) is a multipurpose material with its varied application in solar cells as a transparent front contact, intermediate reflector, back reflector layer and even tunnel layer for passivating contacts, owing to easy tailoring of its optical properties. In this work, we systematically investigate the influence of gas mixture (SiH4, CO2, PH3 and H2), RF power and process pressure on the optical, structural and passivation properties of thin n-type nc-SiOx:H films prepared in an industrial, high throughput, plasma-enhanced chemical vapor deposition (PECVD) reactor. We provide a detailed description of the n-type nc-SiOx:H material develop-ment using various characterization techniques (SEM, EDX, Raman spectroscopy, and spectro-scopic ellipsometry) with a focus on the relationship between the material properties and the pas-sivation they provide to n-type c-Si wafers characterized by their effective carrier lifetime (τeff). Further, we also outline the parameters to be kept in mind while developing different n-type nc-SiOx:H layers for different solar cell applications. We report a tunable optical gap (1.8 – 2.3 eV) for our n-type nc-SiOx:H films as well as excellent passivation properties with τeff up to 3.5 ms (iVoc ~ 715 mV) before annealing. Oxygen content plays an important role in determining the crystallinity and hence passivation quality of the deposited nanocrystalline silicon oxide films.

Abstract: Viremia in coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is often only discussed in passing and there are very few references detailing its structural mechanisms. In addition to viremia in the classic closed cardiovascular system, the lymphatic system is discussed in relation to a possible “lympho-viremia”. The cells that comprise each of these separate but interacting systems will be examined and include endothelial cells, erythrocytes, leukocytes (monocytes/monocyte-derived macrophages and resident tissue macrophages) (lymphocytes) (neutrophils) and thrombocytes -platelets. The SARS-CoV-2 virus has been identified in multiple extrapulmonary target organs at autopsy in those with severe COVID-19 requiring intensive care. Vulnerable COVID-19 patients may suffer from multiple storms including viral/virion storm, redox storm, cytokine storm and thrombo-embolic storm. Therefore, it is important that the possible mechanisms of viremia be explored in greater detail and how these mechanisms might affect intravascular blood components, extracellular tissue interstitium and organ structural remodeling and function. While the co-morbidity of T2DM does not increase the risk of acquiring COVID-19, it is commonly accepted that T2DM increases the risk for COVID-19 admissions to hospitals, assisted ventilation, morbidity and mortality. Importantly, the co-existence of T2DM and COVID-19 may have synergistic detrimental outcomes.

This is the fourth part of [6] on the existence of K¨ahler Einstein metrics of the general type I almost homogeneous manifolds of cohomogeneity one. We actually carry out all the results in [8] to the type I cases. In part II [14], we obtained a lot of new K¨ahler-Einstein manifolds as well as Fano manifolds without K¨ahler-Einstein metrics. In particular, by applying Theorem 15 therein, we have complete results in the Theorems 3 and 4 in that paper. However, we only have some partial results in Theorem 5 there. In this note, we shall give a report of recent progress on the Fano manifolds Nn,m when n > 15 and N′n,m when n > 4. We actually give two nice pictures for these two classes of manifolds. See our Theorems 1 and 2 in the last section. Moreover, we post two conjectures. Once we could solve these two conjectures, the question for these two classes of manifolds would be completely solved. With applying our results to the canonical circle bundles we also obtain Sasakian manifolds with or without Sasakian-Einstein metrics. That also give some open Calabi-Yau manifolds.

The field of nephrology has recently directed a considerable amount of attention towards the stimulator of interferon genes (STING) molecule since it appears to be a potent driver of chronic kidney disease (CKD). STING and its activator, the cyclic GMP-AMP synthase (cGAS) are among the most relevant inducers that promote the expression of type I interferons (IFN-Is). These cytokines have been long recognized as part of the mechanism used by the innate immune system to battle viral infections; however, their involvement in sterile inflammation remains unclear. Mounting evidence pointing to the involvement of the IFN-I pathway in sterile kidney inflammation provides potential insights into the complex interplay between the innate immune system and damage to the most sensitive segment of the nephron, the glomerulus. The STING pathway is often cited as the cause of renal disease originating from non-infection related caused by the induction of IFN-I expression. However, other receptors have been implicated in this process, mainly by recognizing host-derived nucleic acids. This review explores the main endogenous inducers of IFN-I in glomerular cells, discusses what exposure to the main autocrine and paracrine cytokines has on these cells, and identifies the pathways that are implicated in the development of glomerular damage.

Retroaortic left renal veins are an often overlooked, but no so rare anatomic anomaly that might cause a few aspecific symptoms and signs, especially flank or inguinal pain, microscopic or even gross hematuria; in the vast majority of cases it is, thought, totally asymptomatic. The nutcracker syndrome that might arise in the case of RLRV is mainly due to the re- duced space between aorta and the vertebral body and the consequent compression on the venal rein; this might in turn cause upstream hypertension, hematuria, varicocele, pain. The compression of RLRV leads to hematuria because of renal venous hypertension, consequent left renal congestion. This upstream venous congestion might result, in some cases, in left-sided varicocele in men and pelvic congestion syndrome in women. From a radiologic point of view, the presence of RLRV and the precise reporting its subtypes is mandatory.

We propose the Hamiltonian formalism of Bianchi type 1 cosmological model for perfect fluid. We have considered both the equation of state parameter ω and the cosmological constant Λ as the function of volume V(t) which is defined by the product of three scale factors of the Bianchi type 1 line element. We propose a Lagrangian for the anisotropic Bianchi type-1 model in view of a variable mass moving in a variable potential . We can decompose the anisotropic expansion in terms of expansion and shearing motion by Lagrangian mechanism. We have considered a canonical transformation from expanding scale factor to scalar field ø which helps us to give the proper classical definition of that scalar field in terms of scale factors of the mentioned model. This definition helps us to explain the cosmological inflation. We have used large anisotropy(as in the cases of Bianchi models) and proved that cosmic inflation is not possible in such large anisotropy. Therefore we can conclude that the extent of anisotropy is less in case of our universe. Otherwise the inflation theory which explained the limitations of Big Bang cannot be resolved.Part II is contained with some analysis of the lagrangian ; derived in Part I ; on the quintessence model.

In this paper we will consider the cosmic fluid to be dissipating i.e it has both bulk and shearing viscosity. We propose the Hamiltonian formalism of Bianchi type 1 cosmological model for cosmic fluid which is dissipating i.e it has both shearing and bulk viscosity. We have considered both the equation of state parameter ω and the cosmological constant Λ as the function of volume V(t) which is defined by the product of three scale factors of the Bianchi type 1 line element. We propose a Lagrangian for the anisotropic Bianchi type-1 model in view of a variable mass moving in a variable potential . We can decompose the anisotropic expansion of Bianchi type 1 in terms of expansion and shearing motion by Lagrangian mechanism. We have considered a canonical transformation from expanding scale factor to scalar field ø which helps us to give the proper classical definition of that scalar field in terms of scale factors of the mentioned model. By this transformation we can express the mass to be moving in a scalar potential field. This definition helps us to explain the nature of expansion of universe during cosmological inflation. We have used large anisotropy(as in the cases of Bianchi models) and proved that cosmic inflation is not possible in such large anisotropy. Therefore we can conclude that the extent of anisotropy is less in case of our universe. Otherwise the inflation theory which explained the limitations of Big Bang cannot be resolved. In the case of bulk and shearing viscous fluid we get the solution of damped harmonic oscillator after the cosmological inflation.Part I contains the calculations of bulk viscous fluids and Part II contains the calculations of bulk and shearing viscous fluid.At the end we have also provided the relation of shearing and expansion.Part III will give the approximation of low viscosity to solve the viscous fluid problem.

Type 2 Diabetes Mellitus and Alzheimer's disease are two diseases with a high incidence today that share similar pathophysiological mechanisms suggesting a potential causal relationship between them. In fact, Alzheimer-associated Mellitus Diabetes is also known as Type 3 Diabetes Mellitus and constitutes a diabetes intricately linked to Alzheimer's disease. Central to this association is insulin resistance, a key factor leading to decreased insulin sensitivity, hyperglycemia, and impaired glucose uptake. Because of this, the brain is altered resulting in energy deficits and neuronal damage associated with neurodegenerative disorder characteristic of Alzheimer's disease. Both diseases exhibit common biochemical and physiological characteristics such as inflammation, mitochondrial dysfunction, oxidative stress, and the formation of advanced glycation end products. Understanding the complex pathophysiology of Type 3 Mellitus Diabetes and identifying common features shared with Diabetes and Alzheimer's disease are essential steps towards potential therapeutic interventions targeting the insulin resistance pathway. The authors of this review on the relationships between type 2 diabetes and Alzheimer's disease have developed two works. In the first (Relationships between Type 2 Diabetes Mellitus and Alzheimer's Disease. I. Common pathogenic mechanisms), authors explore the shared (physiological, genetics and molecular) pathological changes occurring in Type 2 Mellitus Diabetes and Alzheimer's disease as well as pathways such as AMPK, PPARγ, cAMP, and PI3K/Akt as potential targets for managing Type 3 Diabetes Mellitus. By exploring these intricate mechanisms, the goal is to uncover their interdependencies and facilitate the discovery of innovative pharmacological and nutritional (epigenetics) strategies. In the second paper (Relationships between Type 2 Diabetes Mellitus and Alzheimer's Disease. II Potential therapies) we describe possible nutritional intervention, particularly dietary patterns and phytochemicals that can enhance the effects of pharmaceutical drugs designed against pathological mechanisms involved in the complex dual disease Type 2 Diabetes Mellitus and Alzheimer's disease (or in Type 3 Diabetes Mellitus as other authors consider).

A study of Bianchi Type I cosmological model is undertaken in the framework of creation of particles. To accommodate the creation of new particles, the universe is regarded as an Open thermodynamical system. The energy conservation equation is modified with the incorporation of a creation pressure in the energy momentum tensor. Exact solutions of the field equations are obtained (i) for a particular choice of the particle creation function and (ii) by considering the deceleration parameter to be constant. In the first model the behavior of the solution at late times is investigated. The physical aspects of the model have also been discussed. In the case of the second model we have restricted our analysis to the power law behaviour for the average scale factor. This leads to a particular form for the particle creation function. The behavior of the solution is investigated and the physical aspects of the model have also been discussed for the matter dominated era.

(1) Background: Little research is done on the link of diabetic kidney disease (DKD) progression and diabetic gastroenteropathy in type 1 diabetes (T1D). (2) Methods. We performed a cross-sectional study with 100 T1D patients, 27 of them had progressive DKD, defined as estimated glomerular filtration rate (eGFR) decline≥3 ml/min/year or increased albuminuria stage over the mean follow-up time of 5.89±1.73 years. Newly developed score with 17 questions on gastrointestinal (GI) symptoms was used. Faecal calprotectin was measured by ELISA. Lower GI endoscopies were performed in 21 patients. (3) Results: Gastrointestinal symptom score demonstrated high reliability (Cronbach's α=0.78). Patients with progressive DKD had higher GI symptom scores compared to those with stable DKD (p=0.019). The former group demonstrated more frequent bowel movement disorders (p=0.04). The scores correlated negatively with eGFR (r = -0.335; p = 0.001), positively with albuminuria (r=0.245; p=0.015), Hba1c (r=0.305, p=0.002), diabetes duration (r=0.251, p=0.012). Faecal calprotectin levels did not differ between DKD groups significantly. The most commonly reported histopathological findings of enteric mucosa were infiltration with eosinophils, lymphocytes, plasmacytes, presence of lymphoid follicles and lymphoid aggregates. Conclusion: progression of DKD positively correlated with gastrointestinal symptoms, but more research is needed to clarify the causal relationships of the gut-kidney axis in T1D.

Type 2 diabetes has been linked to the expression of Human Leukocyte Antigens, principally to the major Histocompatibility Complex Class II and only scarce reports to Major Histocompatibility Complex class I in specific populations. The objective of the present work was to explore the presence of polymorphisms in the MHC class I related to Type 2 diabetes in the Mexican population using the GWAS SIGMA database. This database contains information of 3,848 Mexican individuals with type 2 diabetes and 4,366 control individuals from the same population without clinical or hereditary history of the disease. The searching criteria considered a P value < 0.005 and odds ratio, OR > 1.0. Ten novel statistically significant nucleotide variants were identified: four polymorphisms associated with HLA-A (A*03:01:01:01), and six with HLA-C (C*01:02:01:01). These alleles have a high prevalence in Latin American populations and could potentially be associated with autoimmunity mechanisms related with the development of Type 2 diabetes complications.

This study aimed to assess the prognostic significance of total leukocyte count (TLC) and hemoglobin (Hb) levels upon admission for patients with acute pulmonary embolism (PE), considering the European Society of Cardiology (ESC) model for mortality risk. 1622 patients from a regional PE registry were included. Decision tree statistics were employed to evaluate TLC and Hb's prognostic value, both independently and in conjunction with the ESC model. Results indicated all-cause and PE-related in-hospital mortality rates of 10.7% and 6.5% respectively. Subgrouping patients based on TLC cutoff values (≤11.2, 11.2-16.84, &gt;16.84 x10^9/L) revealed increasing all-cause mortality risks (7.0%, 11.8%, 30.2%). Incorporating Hb levels (≤126 g/L or above) further stratified the lowest risk group into two strata with all-cause mortality rates of 10.1% and 4.7%. Similar trends were observed for PE-related mortality. Notably, TLC improved risk assessment for intermediate-high risk patients within the ESC model, while Hb levels enhanced mortality risk stratification for lower risk PE patients in the ESC model for all-cause mortality. In conclusion, TLC and Hb levels upon admission can refine the ESC model's mortality risk classification for patients with acute PE, providing valuable insights for improved patient management.

Background: Signaling by toll like receptors (TLRs) initiates important immune responses against viral infection. The role of TLRs in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections is not well elucidated. Thus, we investigated the interaction of TLRs agonists and SARS-COV-2 antigens with immune cells in vitro. Material & methods: 30 coronavirus disease 2019 (COVID-19) patients (15 severe and 15 moderate) and 10 age and sex matched control (HC) were enrolled. Peripheral blood mononuclear cells (PBMCs) were isolated and activated with TLR3, 7, 8 and 9 agonists, the spike protein (SP) of SARS-CoV-2 and the Receptor Binding Domain (RBD) unit of SP. Frequencies of CD3⁺IFN-β⁺ T cells, and CD3⁺IFN-g⁺ T cells was evaluated by flow cytometry. Interferon (IFN)-b gene expression was assessed by qRT-PCR. Results: The frequency of CD3+IFN-β+ T cells was higher in moderate and severe patients at baseline in comparison with HCs. Stimulation of PBMCs from moderate patients with SP and TLR8 agonist significantly upregulated the frequency of CD3+IFN-β+ T cells (P=0.0005 and 0.0024, respectively) when compared to non-stimulated (NS) samples. The greatest increase in CD3⁺IFN-b⁺ T cell frequency in PBMCs from severe patients was seen with TLR8 and TLR7 agonists when compared to NS (P= 0.003 and 0.0167, respectively). TLR stimulation did not significantly enhance the frequency of CD3+IFN-g+ T cells generated from PBMCs from moderate and severe patients compared with unstimulated controls. However, the frequency of CD3+IFN-ɣ+ T cells in PBMCs from moderate patients was upregulated by agonists of TLR3, 8 and 9, SP and RBD when compared with NS samples from HCs. The expression of the IFN-β gene after stimulation of CD3⁺T cells with the TLR8 agonist was also up-regulated in moderate than severe patients (moderate vs. severe: p=0.0006). In addition, stimulation of CD3⁺ T cells with SP, up-regulated the expression of IFN-β gene expression in cells from patients with moderate disease (moderate vs. severe: p=0.01). Conclusion: Stimulation of PBMCs from COVID-19 patients with a TLR8 agonist and with SP enhanced IFN-b protein and gene levels. This may potentiate immune responses against SARS-CoV-2 infection and prevent viral replication and spread.

The instability of traveling pulses in nonlinear diffusion problems is inspected on the example of Gunn domains in semiconductors. Mathematically the problem is reduced to the calculation of the "energy" of the ground state in Schrödinger equation with a complicated potential. A general method to obtain the bottom-part spectrum of such equations based on the approximation of the potential by square wells is proposed and applied. Possible generalization of the approach to other types of nonlinear diffusion equations is discussed.

Abstract: The effect of collagen type 1 (Col I) oxidation on Adipose Tissue-Derived Mesenchymal Stem Cells (ADMSCs) remodeling is described as a model for acute oxidative stress. Morphologically, remodeling was presented by a mechanical rearrangement of adsorbed FITC-Col I and a trend for its organization in a fibril-like pattern - a process strongly abrogated in oxidized samples, but without visible changes in cell morphology. The cellular proteolytic activity was quantified in multiple samples utilizing fluorescence de-quenching (FRET effect). In the presence of ADMSCs a significant increase of native FITC-Col I fluorescence was observed, almost absent in the oxidized samples. Parallel studies in cell-free systems confirmed the enzymatic de-quenching of native FITC-Col I by Clostridial collagenase, again showing significant inhibition in oxidized samples. The structural changes in the oxidized Col I was further studied by Differential Scanning Calorimetry: an additional endotherm at 33.6°C along with the typical for native Col I at 40.5°C with sustained enthalpy (∆H) was observed in oxidized samples. Collectively, it has been evidenced that remodeling of Col I by ADMSCs is altered upon oxidation due to the intrinsic changes in the protein structure, thus presenting a novel mechanism for the control of stem cells' behavior toward collagen.

Anti-interferon (IFN)-γ autoantibodies are linked to varicella-zoster virus (VZV) infection. Given the elevated risks of herpes zoster (HZ) in rheumatoid arthritis (RA) patients treated with Janus kinase inhibitors (JAKi), we aimed to examine the relationship between anti-IFN-γ autoantibodies with HZ development in JAKi-treated patients. In twenty-four RA patients with new-onset HZ and forty-two without HZ, serum titers of anti-IFN-γ autoantibodies, plasma levels of IFN-γ, monocyte chemoattractant protein-1 (MCP-1), and IFN-γ inducible protein-10 (IP-10) were measured by ELISA. Significantly lower MCP-1 levels were observed in patients with HZ compared to those without (median, 98.21pg/ml, interquartile range (IQR) 77.63-150.30pg/ml versus 142.3pg/ml, IQR 106.7-175.6pg/ml, p&lt;0.05). There was no significant difference in anti-IFN-γ titers, IFN-γ levels, or IP-10 levels between patients with and without HZ. Three of 24 patients with HZ had severe HZ with multi-dermatomal involvement. Anti-IFN-γ titers were significantly higher in patients with severe HZ than in those with non-severe HZ (median 24.8ng/ml, IQR 21.0-38.2ng/ml versus 10.5ng/ml, IQR 9.9-15.0ng/ml, p&lt;0.005). In conclusion, patients with HZ had significantly lower MCP-1 levels than those without HZ, and patients with severe HZ had significantly higher titers of anti-IFN-γ than those with non-severe HZ. Given small sample size, our results need further validation in future studies.

(1) Background Diabetic Retinopathy (DR) is the primary cause of poor vision in young adults. Screening for DR is important but many patients do not attend; (2) Methods: We validated an algorithm for predicting DR and its progression by conducting a retrospective study of 11 children in a population of 120,389 T2DM (3) Results: By applying the algorithm to the population showed an AUC of 0.93 (95% CI, 0.92–0.94) for any-DR and 0.90 (95% CI, 0.89–0.91) for referable-DR(4) Conclusions: The algorithm is useful for predicting patients who could develop referable forms of DR and also for any-DR. This would allow a personalized screening plan to be drawn up for each patient.

The receptor-type protein tyrosine phosphatases (RPTPs) are involved in a wide variety of physiological functions which are mediated via their diverse extracellular regions. They play key roles in cell-cell contacts, bind various ligands and are regulated by dimerization and other processes. Depending on the subgroup they have been described as everything from ‘rigid rods’ to ‘floppy tentacles’. Here we review current experimental structural knowledge on the extracellular region of RPTPs and draw on AlphaFold structural predictions to provide further insights into structure and function of these cellular signalling molecules.

Life-threatening inflammatory conditions such as acute respiratory distress syndrome or sepsis often go hand in hand with severe vascular leakage. During inflammation, endothelial cell integrity and intact barrier function are crucial to limit leukocyte and plasma extravasation. Prostaglandin D₂ (PGD₂) is a potent inflammatory lipid mediator with vasoactive properties. It has been suggested that PGD^­₂ is involved in the regulation of endothelial barrier function; however, it is unclear whether this is also true for primary human pulmonary microvascular endothelial cells. Furthermore, as PGD₂ is a highly promiscuous ligand, we set out to determine which receptors are important in human pulmonary endothelial cells. In the current study, we found that PGD₂ and the DP1 agonist BW245c potently strengthened pulmonary and dermal microvascular endothelial cell barrier function and protected against thrombin-induced barrier disruption. Yet surprisingly, these effects were mediated only to a negligible extent via DP1 receptor activation. In contrast, we observed that the EP4 receptor was most important and mediated the barrier enhancement by PGD₂ and BW245c. These data demonstrate a novel mechanism by which PGD₂ may modulate inflammation and emphasizes the role of EP4 receptors in human endothelial cell function.

Collagen is the most abundant protein in the animal kingdom. Industrial collagen is mainly bovine and porcine origin. However, due to religious beliefs, allergic issues, and infectious diseases, alternative sources of collagen as marine are gaining increasing interest. In this work, the acid-soluble collagen (ASC) were extracted from salt-cured Atlantic cod (Gadus morhua) skin and characterized. The extraction yield was about 2.0%, equivalent to the extraction yield reported for other fish skins. The electrophoretic pattern showed the typical type I structure (α, β and γ chains). UV-VIS and FTIR absorbance spectra suggested a very pure ASC with an intact triple helical structure. The integrity and the adequate porosity required for different applications were then confirmed by electron micrograph. Our findings allow us to say that, for the first time, we extracted acid-soluble type I collagen from salt-cured Atlantic cod skin, with characteristics suitable for application in various fields, such as biomedical.

This paper aims to provide an adaptation of the TL-moments method to censored data. The present study concentrates on Type-I censored data. The idea of using TL-moments with censored data may seem conflicting. But our perspective in that, we may use data censored from one side and trimmed from the other side. This study is applied to estimate the two unknown parameters of the Weibull distribution. The suggested point is compared with Direct L-moments and ML methods. A Monte Carlo simulation study is carried out to compare these method in terms of estimate average, root of mean square error (RMSE) and relative absolute biases (RAB).

To conduct high-precision and high-resolution numerical simulation of complex flow structures in turbomachinery, a high-order finite volume weighted essentially non-oscillatory (WENO) scheme for the large eddy simulation (LES) is improved and embedded into the three-dimensional viscous unsteady CFD solver NUAA-Turbo. Firstly, the spectral characteristics and unsteady convergence of the improved WENO scheme are studied. Compared with the classical WENO scheme, the improved WENO scheme has better dissipation and dispersion characteristics and faster convergence speed. Then, the coefficient CW of the Wall-Adapting Local Eddy-viscosity (WALE) model is calibrated by decaying homogeneous isotropic turbulence (DHIT) test case. Finally, the scheme is applied to conduct high-precision LES calculations of turbulent boundary layer flow, supersonic compression corner flow, and low-pressure turbine cascade separation flow. The numerical simulation results show that this WENO scheme has excellent shock wave capture ability and turbulence resolution and can capture more flow field details with less mesh size, greatly reducing the computational cost and laying a foundation for large-scale engineering application of LES.

The building envelope has the most significant contribution in the reduction of the building energy consumption. Application of new, alternative and improved materials and systems has an important impact on the buildings performances. This paper is focused on the thermal transmittance, as an indicator of the thermal conductance of the construction element. It includes comparisons of the U-values, calculated by software, with those measured in situ on three representative façade walls. The walls have been constructed with the new wall system Fragmat NZ-1, a new product in Macedonian buildings. This research provides basic information on the thermal transmittance of the system. The results of the analysis show that the in situ measuring is a useful tool in validation of the precision of analytically calculated values, since it was difficult to obtain precise results from the analytical calculations only, especially when the layers are with non-uniform thickness.

This paper concentrates on the general birth-death processes with two different types of catastrophes. The Laplace transform of transition probability function for birth-death processes with two-type catastrophes are is successfully expressed with the Laplace transform of transition probability function of the birth-death processes without catastrophe. The first effective catastrophe occurrence time is considered. The Laplace transform of its probability density function, expectation and variance are obtained.

Groove pancreatitis represents a chronic focal form of pancreatitis affecting the zone between the pancreatic head and the duodenal „C” loop, known as the groove area. This is a rare condition that affects the pancreatic periampullary part, including the duodenum and the common bile duct, associated usually with long-term alcohol and tobacco misuse and being more frequent in men than in women. The most common clinical symptoms of groove pancreatitis include weight loss, acute abdominal pain, nausea, and jaundice. This report is about a 66 year old woman with a history of heavy smoking, presenting with weight loss, nausea, and upper abdominal pain. Contrast enhanced computed tomography revealed the existence of a chronic pancreatitis as well as the dilatation of the main pancreatic duct, a cyst of the pancreatic head and enlargement of the biliary tract. Conservatory treatment was initiated but with no improvement of symptoms. Since there was no indication for endoscopic retrograde cholangiopancreatography, we decided to perform a pancreatoduodenectomy, as surgery appears to be the single effective treatment.

Introduction: Mucopolysaccharidosis type I (MPSI) is an autosomal recessive lysosomal storage disorder characterized by deficient or absent α-L-iduronidase (IDUA) enzyme activity due to pathogenic variants in IDUA gene. Early treatment with hematopoietic stem cell transplantation and/or enzyme replacement therapy is associated with improved outcomes in this progressive multisystem disease. The diagnosis is usually delayed due to late presentation and nonspecific symptoms resulting in high morbidity and mortality. The incidence of MPSI in US is estimated to be 0.26:100,000, however, it is unknown in Kuwait. This pilot study was undertaken to screen MPSI in all Kuwaiti neonates born at Farwaniya Hospital over a period of 12-months. This study examined the incidence of MPSI in a major center in Kuwait for inclusion in the national newborn screening program to enable its early detection and adequate treatment. Methods: All Kuwaiti neonates born at Farwaniya Hospital, Kuwait from December 2021 to December 2022, were screened for MPSI. The screening consisted of determining IDUA enzyme activity in dried blood spots (DBS)-derived samples by Tandem Mass Spectrometry. A follow-up genetic analysis of IDUA gene is planned to screen the cases with diminished IDUA enzyme activity as second-tier testing. Results: A total of 618 newborns, including 331 (54%) males and 287 (46%) females, were screened. Twenty of them had deficient IDUA enzyme activity but showed negative genetic testing for IDUA. However, we have diagnosed one additional female baby with MPSI, who belonged to Farwaniya Hospital, but the parents chose to deliver in a private hospital. She presented at age three months with recurrent upper airway infections, snoring and extensive Mongolian spots. The molecular study revealed previously reported pathogenic nonsense variant in IDUA c.1882C>T; p.(Arg628Ter), associated with severe phenotype. That being included, MPSI is estimated to be about 0.3% among tested females and 0.2% of all screened cases in Kuwait. Conclusion: Our study is the first to evaluate the incidence of MPSI in Kuwait. Given the single center, small number of screened babies and the short study duration thus far, it is premature to calculate the incidence of MPSI. It is anticipated that as the study continues and more infants are examined, we would be able to estimate the incidence of this disease in our population correctly. Further studies including screening newborns in all maternity hospitals in Kuwait are needed to calculate the actual incidence of MPSI. Our data supports including MPSI in national newborn screening program to allow early initiation of treatment and thus improve disease outcome.

The level of technological development of any civilization can be gaged in large part by the amount of energy they produce for their use, but also encompasses that civilization’s stewardship of their home world. Following the Kardashev definition, a Type I civilization is able to store and use all the energy available on its planet. In this study, we develop a model based on Carl Sagan’s K formula and use this model to analyze the consumption and energy supply of the three most important energy sources: fossil fuels (e.g., coal, oil, natural gas, crude, NGL and feedstocks), nuclear energy and renewable energy. We also consider environmental limitations suggested by United Nations Framework Convention on Climate Change, the International Energy Agency, and those specific to our calculations to predict when humanity will reach the level of a Kardashev scale Type I civilization.

In this paper, a new axial-type magnetic gear with auxiliary flux-enhancing structure (AFS-AMG) is proposed. Compared to conventional AFS-AMG, it has the higher torque density and higher permanent magnet (PM) utilization factor. Firstly, the design rules and operating principles of proposed AFS-AMG are elaborated. Then, the mapping relation between the radial-type magnetic gears (RMGs) and AMGs are elucidated. Compared to its counterpart in RMGs, AFS-AMGs achieve small size. Then, the geometrical parameters of AFS-AMGs are optimized to obtain the better electromagnetic performances, where the torque density per volume and per PM volume is adopted as the evaluation standard. Finally, three different AMG topologies are constructed in finite element analysis (FEA) software for comparison. It is proven that the AFS-AMG has the largest torque density per volume and per PM volume.

A good management of diabetes requires at the same time self-regulation behaviour and a balanced involvement of family components. This study’s aims were: understanding fear of injections and perceptions of family conflicts in preadolescents and adolescents with type 1 diabetes mellitus and their mothers, comparing their perceptions, and identifying the risk factors impacting patients’ quality of life. Participants were one hundred and two patients (Mean age = 14.63, SD = 2.43; age range = 10-19 years; Females = 52) and their mothers (Mean age = 46.94, SD = 6.2, age range = 27-63 years), who filled in self and proxy-report questionnaires. Twenty % of patients and 14.7% of their mothers reported clinical score for fear of self-injection and blood testing. Mothers reported higher fear of injecting and family conflicts compared with the patients. Age, fear of injecting and family conflicts impacted significantly on patients’ quality of life perceptions. Clinical consideration and recommendations are given basing on the empirical results.

The article presents several innovative systems developed through student laboratory projects, including two autonomous vehicles, a four-legged walking robot, an active ankle-foot orthosis, a ball on beam balancing mechanism, a ball on plate system, and a manipulator arm—all powered by pneumatic artificial muscles (PAMs). Fluidic muscles offer significant potential in various mechatronic systems, robots, and manipulators due to their flexible, lightweight nature and compliance. Their ability to produce smooth and adaptable motions is particularly beneficial in applications requiring natural and human-like movement, such as rehabilitation and assistive devices. Although PAMs powered control systems face challenges with nonlinear phenomena, their biologically inspired design holds promise for future applications across various industries. These may include innovative applicability in industrial, automotive, and aerospace sectors, as well as use in sports, medical aids, entertainment, and animatronics. Incorporating self-made laboratory systems actuated by PAMs into control systems education offers a comprehensive learning opportunity that combines theoretical concepts with hands-on experience. This approach develops the necessary skills of future engineers, expanding their understanding of technical principles and preparing them for future challenges in engineering practice.

Dysregulation of the angiotensin-II Type-I receptor (AT1R) and its pathway was reported to associate with poor-prognosis in several malignancies, including colorectal-cancer (CRC). We have explored the therapeutic-potential of targeting AT1R using valsartan, and its pharmacological-interaction with Fluorouracil (5-FU) in CRC. Anti-proliferative function was evaluated in 2-/3-dimensional cells and in vivo models. Anti-proliferative, anti-migratory, apoptotic function and effect on cell-cycle was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), wound-healing test, and Fluorescence-activated cell sorting (FACS), respectively, while gene-expression was determined at mRNA/protein levels. By histogical analysis and measuring of oxidative/antioxidant markers, we evaluated the anti-inflammatory properties of valsartan. Valsartan suppressed cell-growth and impacted the anti-tumor-activities of 5-FU by apoptosis-induction. Valsartan inhibited the cells migration by perturbation of Matrix metalloproteinase (MMP1). Furthermore, valsartan inhibited tumor-growth and metastasis, and this was more notable in valsartan/5-FU combination-treated-group. The mechanism was plausible to be via the induction of Reactive-oxygen-species (ROS) and down-regulation of Superoxide-dismutase (SOD), thiol/catalase (CAT) as well as Vascular endothelial growth factor (VEGF) and Transforming growth factor beta (TGF-β). Valsartan may protect cells against intestinal fibrosis by modulation of pro-fibrotic and pro-inflammatory components include fibronectin, Interleukin) IL-1β (, Tumor necrosis factor alpha) TNF-α (, Interferon gamma) INF-γ (, and Monocyte Chemotactic Protein 1 (MCP-1). Our findings demonstrated that targeting the AT1R receptor may inhibit tumor-growth and ameliorate fibrosis and inflammation associated with CRC via modulation of AT1 and TGF-β pathways.

In this paper, we study the well-posedness and asymptotics of a one-dimensional thermoelastic laminated beam system either with or without structural damping, where the heat conduction is given by Fourier's law effective in the rotation angle displacements. We show that the system is well-posed by using Lumer-Philips theorem, and prove that the system is exponentially stable if and only if the wave speeds are equal, by using the perturbed energy method and Gearhart-Herbst-Prüss-Huang theorem. Furthermore, we show that the system with structural damping is polynomially stable provided that the wave speeds are not equal, by using the second-order energy method.

High hopes were associated with the new anti-angiogenic medicament, bevacizumab, which due to the possibility of binding to isoform A of vascular endothelial growth factor (VEGF), inhibited the creation of new blood vessels. However, not only blood vessels are responsible for the tumor cells' spread. During the process of tumor growth, lymphangiogenesis is mediated by other isoforms of the VEGF family, specifically VEGF-C and VEGF-D, which are independent of the bevacizumab action. Therefore, based on the mechanism of bevacizumab action and the processes of angio- and lymphangiogenesis, we formed three hypotheses: 1) if the lymph nodes in the primary ovarian cancers are metastatic, the outcome of bevacizumab treatment is worsened; 2) concerning the second-line treatment, bevacizumab will act in a weakened manner if the recurrence occurs in lymph nodes compared to local recurrences; 3) patients treated by bevacizumab are more likely to have recurrences in lymph nodes. These hypotheses raise the issue of the existing gap of knowledge, which concerns the effect of bevacizumab on the metastatic lymph nodes.

This present study was designed to find out whether the acankoreagenin showed the antidiabetic and renoprotective effects in streptozotocin (STZ)-induced diabetic nephropathy (DN) rats. Type I diabetes was induced by a single intraperitoneal injection of STZ (70 mg/kg). At the end of the experiment, rats were euthanized and serum/plasma was separated for the determination of glucose, insulin, glycated hemoglobin A1c (HbA1c), C-peptide, biochemical parameters, and kidney function. One kidney was used for determining glutathione, superoxide dismutas, malondialdehyde, and tumor necrosis factor-alpha levels. The other kidney and pancreas were used for histopathological studies and immunohistochemical measurement of transforming growth factor beta (TGF-β) or NF-κB. Acankoreagenin (2 mg/kg) treatments led to a significant reduction in blood glucose assessed via oral glucose tolerance test (OGTT) in diabetic rats at 2 h. The treatment also resulted in improved body weight, decreased HbA1c, restored lipid profile, and renal oxidative stress. By inhibiting NF-κB, the release of proinflammatory cytokines was suppressed and by inhibiting TGF-β, the renal fibrosis was suppressed in STZ-induced diabetic rat model. Histopathological injury was also observed in pancreatic and renal tissues. These findings support the beneficial effect of acankoreagenin treatment in DN, which could be attributed to its antidiabetic and renoprotective effects.

Human influenza A viruses (IAVs) cause global pandemics and epidemics, which remain serious threats to public health because of the shortage of effective means of control. To combat the surge of viral outbreaks, new treatments are urgently needed. Developing new virus control modalities requires better understanding of virus-host interactions. Here we describe how IAV infection triggers cellular apoptosis, and how this process can be exploited towards development of new therapeutics, which might be more effective than the currently available anti-influenza drugs.

The assortment of low-cost 3D printers for “in-practice” use, e.g., for clear aligner therapies, is ever increasing. To address concerns about the accuracy of orthodontic models produced on such printers when cost efficient modes of 3D printing are employed, this study examined the effect of print model body type and print angulation on accuracy. Six printing-configuration groups were included: 2 model types (solid or hollow shell) combined with 3 print angles (0°, 70°, or 90°) with 10 models/group; all models were printed with 100-µm layer thickness using a digital light processing-based 3-dimensional printer. Eleven selected structures and distances were measured on the printed models with a digital microscope and compared to the same measures on a digitized master model. The clinically-acceptability range was set at ±0.25 mm difference from the master model for single tooth measurements (intra-tooth) and ±0.5 mm for cross-arch measurements (inter-tooth). For individual measurements across all models, 98% fell within clinical acceptability. For mean measurements within each model group, only canine height for the shell-0° model had a mean difference (0.26 mm ± 0.03) outside the clinically acceptable range for intra-tooth measurements. Standard deviations for all intra-tooth measurements were within 0.07 mm. While none of the mean inter-tooth measurements exceeded the acceptability range, the standard deviations were larger (0.04 to 0.30 mm). Accuracy of orthodontic models for clear aligner therapies was not impacted beyond the clinically acceptable range when altering model body type and print angulation to improve efficiency of 3D printing. These findings suggest greater flexibility of the practitioner to alter print settings to address time and cost efficiency in various clinical scenarios and still maintain clinically acceptable model accuracy.

The androgen/androgen receptor (AR)-signaling axis plays a central role in the development and growth of prostate cancer (PCa) cells. Upon androgen-binding the AR dimerizes with another AR, translocates into the nucleus where the AR-dimer activates/inactivates androgen-dependent genes. In consequence treatments for locally advanced or metastatic PCa are commonly based on androgen deprivation therapies (ADT). Unfortunately, the clinical benefits of ADT are only transitory and most tumors develop mechanisms allowing the AR to bypass its need for physiological levels of circulating androgens. In the clinic failure of ADT is often characterized by the synthesis of a C-terminally truncated, constitutively active AR splice variant, termed AR-V7. In contrast to AR, the constitutively active AR-V7 does no longer need androgenic stimuli for nuclear entry and/or dimerization. The goal of the present study was to mechanistically decipher the interaction between full-length AR (AR-FL) and AR-V7 in AR-null HEK-293 cells using the NanoLuc Binary Technology (NanoBiT) structural complementation assay under androgen stimulation and deprivation conditions. Our data point toward a hypothesis that AR-FL/AR-FL homodimers form in the cytoplasm, whereas AR-V7/AR-V7 localize in the nucleus. However, after 15 min of androgen stimulation, all AR-FL/AR-FL, AR-FL/AR-V7 and AR-V7/AR-V7 dimers localized in the nucleus. In this way, we can show an androgen-regulated interaction between AR-FL and AR-V7 at forming heterodimers that localize in the nucleus, whereas AR-V7/AR-V7 dimers were found to localize in the absence of androgens in the nucleus. Treatment with enzalutamide diminished the luminescence of AR-FL homodimers and AR-FL/AR-V7 heterodimers but not AR-V7/AR-V7 homodimers.

The involvement of the angiotensin II type 1 receptor in the Frank-Starling Law of the Heart, where the various activations are very limited, allows simple analysis of the kinase systems involved and thence extrapolation of the mechanism to that of angiotensin control of activation of cardiac and skeletal muscle contraction. The involvement of phosphorylation of the myosin light chain in the control of contraction is accepted but not fully understood. The involvement of troponin-I phosphorylation is also indicated but of unknown mechanism. There is no known signal for activation of myosin light chain kinase or Protein Kinase C-βII other than Ca²⁺/calmodulin but the former is constitutively active and thus has to be under control of a regulated inhibitor, the latter kinase may also be the same. Ca²⁺/calmodulin is not activated in Frank-Starling, i.e. there are no diastolic or systolic [Ca²⁺] changes. I suggest here that that the regulated inhibition is by myosin light chain phosphatase and/or β-arrestin. Angiotensin activation is by translocation of the β-arrestin from the sarcoplasm to the PM thus reducing its kinase inhibition action in the sarcoplasm, this reduced inhibition has been wrongly attributed to a mythical downstream agonist property of β-arrestin.

The theory of heavy ion double charge exchange (DCE) reactions proceeding by effective rank–2 isotensor interactions is presented. Virtual pion–nucleon charge exchange interactions are investigated as the source for induced isotensor interactions, giving rise to the Majorana DCE (MDCE) reaction mechanism. MDCE is of a generic character, proceeding through pairs of complementary (π±,π∓) reactions in the projectile and target nucleus. The dynamics of the elementary processes is discussed where the excitation of pion–nucleon resonances are of central importance. Investigations of initial and final state ion–ion interactions show that these effects are acting as vertex renormalizations. In closure approximation, well justified by the finite pion mass, the second order transition matrix elements reduce to pion potentials and effective two–body isotensor DCE interactions, giving rise also to two–body correlations in either of the participating nuclei. Connections to neutrinoless Majorana double beta decay (MDBD) are elucidated at various levels of dynamics, from the underlying fundamental electro–weak and QCD scales to the physical scales of nuclear MDBD and MDCE physics. It is pointed out that heavy ion MDCE reactions may also proceed by competing electro–weak charge exchange processes, leading to lepton MDCE by electrons, positrons, and neutrinos.

Daridorexant, as the first Dual Orexin Receptor Antagonist (DORA) marketed in Europe, offers a novel therapeutic approach to insomnia. However, data regarding its real-world safety are scarce. Thus, the aim of this study was to assess its safety profile using a large-scale pharma-covigilance database. Daridorexant-related Adverse Drug Reaction (ADR) reports from the FDA Adverse Event Reporting System were scrutinized, and ADRs were selected using reporting odds ratio (ROR) as a measure of disproportionality. Frequencies of events related to daridorexant were compared to all other drugs (reference group, RG1) and only to other DORAs (RG2). Only significant disproportionalities to both RGs were evaluated in-depth. A total of 845 dari-dorexant-related reports were selected; nightmares (n = 146; Dari vs. RG1: ROR = 113.74; 95%CI[95.13, 136]; Dari vs. RG2: ROR = 2.35; 95CI%[1.93, 2.85]), depression (n = 22; Dari vs. RG1: 2.13; [1.39, 3.25]; Dari vs. RG2: ROR = 2.31; 95CI%[1.45, 3.67]), and hangover (n = 20; Dari vs. RG1: ROR = 127.92; 95CI%[81.98, 199.62]; Dari vs. RG2: 3.38; [2.04, 5.61]) were considered as safety signals. These data provide valuable insights into the real-world safety profile of dari-dorexant, supporting the existence of safety signals related to nightmares, depression, and hang-over.

Despite chronic fibrosis and associated excess extracellular matrix (ECM) deposition and crosslinking occurring in many pathological conditions, few in vitro studies examine how fibrosis-induced ECM stiffening impacts lymphatic endothelial cells (LEC) behavior and subsequent new lymphatic vessel growth and function. This study examined the stiffening profile of PhotoCol®—commercially available methacrylated type I collagen—photo-crosslinked with photoinitiators Lithium phenyl-2,4,6-trimethylbenzoylphosphinate (LAP), Irgacure 2959 (IRG), and Ruthenium/Sodium Persulfate (Ru/SPS) prior to evaluating PhotoCol® permeability and LEC response to PhotoCol® at low and high stiffness levels representing normal and fibrotic ECM stiffness. Ru/SPS produced the highest maximum stiffness for photo-crosslinked PhotoCol® hydrogels. While Ru/SPS stiffness values did not differ significantly with increased light exposure, permeability decreased significantly with increasing light exposure for 40 kDa dextran. Finally, LECs on softer PhotoCol® appeared smaller with less prominent VE-Cadherin (cell-cell junction) and F-actin expression compared to cells on stiffer PhotoCol®. Overall, PhotoCol® with Ru/SPS photoinitiator provides the fibrillar microstructure and dynamic stiffness range that enables systematic study of LEC stiffness responses relevant to the stiffened ECM observed in pathologies with significant fibrotic activity. Therefore, this study demonstrates the utility of PhotoCol® with Ru/SPS for disease modeling applications, particularly modeling lymphatic vascular growth and function during fibrosis.

Autoantibodies against type 1 interferons (IFN-I) are highly specific marker for type 1 autoimmune polyglandular syndrome (APS-1). Moreover, determination of antibodies to IFN-ω and IFN-α2 allows a short-term diagnosis in patients with isolated and atypical forms of APS-1. In this study, a comparison of three different methods, namely, multiplex microarray-based, cell-based and enzyme-linked immunosorbent assays for detection of antibodies against omega-interferon and alpha2-interferon was carried out. A total of 206 serum samples from adult patients with APS-1, APS-2, isolated autoimmune endocrine pathologies, non-autoimmune endocrine disorders and healthy individuals were analyzed. In the APS-1 patient cohort (n=18), there was good agreement between the results of anti- IFN-I antibody tests performed by three methods, with 100% specificity and sensitivity for microarray-based assay. Although only the cell-based assay can determine the neutralizing activity of autoantibodies, the microarray-based assay can serve as a highly specific and sensitive screening test to identify anti- IFN-I antibody positive patients.

Managing the multisystemic symptoms of type I Gaucher Disease (GD) requires a multidisciplinary team approach that includes disease-specific treatments, as well as supportive care. This involves a range of medical specialists, general practitioners, supportive care providers, and patients. Phenotype classification and the setting of treatment goals are important for optimizing the management of type I GD, and providing personalized care. The ability to classify disease severity using validated measurement tools allows the standardization of patient monitoring, and the measurement of disease progression and treatment response. Defining treatment goals is useful to provide a benchmark for assessing treatment response, and managing the expectations of patients and their families. Although treatment goals will vary depending on disease severity, they include the stabilization, improvement or reversal (if possible) of clinical manifestations. Enzyme replacement therapy (ERT) is the standard care for patients with type I GD, but a novel substrate reduction therapy (SRT), Eliglustat has demonstrated safety and efficacy in selected patients. To ensure that treatment goals are being achieved, regular, comprehensive follow up is necessary.

Resistance training increases myofiber hypertrophy, but the morphological adaptations that occur within myofibers remain largely unresolved. Fifteen males with minimal training experience (24±4 years, 17.9±1.4 kg/m2 lean body mass index) performed 10 weeks of conventional, full-body resistance training (2x weekly). Body composition, the radiological density of the vastus lateralis muscle using peripheral quantitative computed tomography (pQCT), and vastus lateralis muscle biopsies were obtained one week prior to and 72 hours following the last training bout. Fiber typing and the quantification of myofibril and mitochondrial areas per fiber were performed using histology/immunohistochemistry (IHC) techniques. Relative myosin heavy chain and actin protein abundances per wet muscle weight as well as citrate synthase (CS) activity assays were also obtained on tissue lysates. Training increased whole-body lean mass, mid-thigh muscle cross-sectional area, various strength metrics, and mean and type II fiber cross sectional areas (fCSA) (p<0.05). Myofibril areas in type I or II fibers were not altered with training, suggesting a proportional expansion with fCSA increases. Relative myosin heavy chain and actin protein abundances also did not change with training. IHC indicated training increased mitochondrial areas in both fiber types (p=0.018). However, CS activity levels remained unaltered with training. Interestingly, although pQCT-derived muscle density increased with training (p=0.036), suggestive of myofibril packing, a positive association existed between training-induced changes in this metric and changes in type I+II myofibril areas (r=0.600, p=0.018). Shorter-term resistance training seemingly involves a proportional expansion of myofibrils and an accelerated expansion of mitochondria in type I and II fibers. Additionally, histological and biochemical techniques should be viewed independently from one another given the lack of agreement between the variables assessed herein. Finally, the pQCT may be a viable tool to non-invasively track morphological changes in muscle tissue.

The Chagas disease (CD) is an endemic infectious disease in a large part of Latin America. This disease is characterized by the fact of being caused by the parasite Trypanosoma cruzi. Some symptoms of this disease are cardiopathies and gastrointestinal problems. Therefore, the commonly used treatment consists of nitro drugs such as benznidazole and nifurtimox, which target the nitroreductase enzyme that docks to the coenzyme flavin mononucleotide (FMN) and an oxidation-reduction reaction is generated. From this reaction, the nitro chemical function of benznidazole and nifurtimox is reduced to amine. This amine in turn interacts with the parasite´s DNA. In vitro tests experimentally help in the study of the parasite resistance to the drug benznidazole. This fact could explain how nonsynonymous mutations in the nitroreductase (NTR) enzyme do not allow the anchorage of the FMN coenzyme and as a consequence the parasite susceptibility to benznidazole decreases as the drug cannot be reduced. The structural relations from the hybrid Quantum Mechanics-Molecular Mechanics (QM/MM) allow to detect the small changes generated in the system, considering a charge distribution associated with the structure, angle changes, interaction distances, potential surface calculations between the wildtype enzyme and the mutation found.

The Upper Hunter Valley is a major coal mining area containing approximately 40% of the currently identified total coal reserves in New South Wales (NSW), Australia. Due to the ongoing increase of mining activities, PM10 (air-borne particle with an aerodynamic diameter less than 10 micrometres) pollution has become a major air quality concern in local communities. This paper summarises the spatial and temporal variability modes of PM10 pollution in the region, based on long-term multi-site monitoring data and the application of the rotated principal component analysis (RPCA) and wavelet analysis techniques. RPCA identified two distinct air quality clusters/subregions in the valley, one in the west/northwest, the other in the southeast. Wavelet analysis revealed the annual cycle to be most persistent temporal mode of PM10 variability in both subregions, with intermittent signals observed at time scales of around 120, 30~90 and under 30 days. How these variation modes are related to the effects of local PM10 emissions and the influence of meteorology at different time scales deserves further attention in future work. The findings will be used in air quality reporting and forecasting in NSW. The methodology and results can also be useful for air quality research in similar regions elsewhere.

Members of the Ebolavirus genus demonstrate a marked differences in pathogenicity in humans with Ebola (EBOV) being the most pathogenic, Bundibugyo (BDBV) less pathogenic and Reston (RESTV) causing no severe disease in humans. The VP24 protein encoded by members of the Ebolavirus genus blocks type I interferon (IFN-I) signaling through interaction with host karyopherin alpha nuclear transporters, potentially contributing to virulence. Previously we demonstrated that BDBV VP24 (bVP24) binds with lower affinities to karyopherin alpha proteins relative to EBOV VP24 (eVP24), and this correlated with reduced inhibition of IFN-I signaling. We hypothesized that modification of eVP24-karyopherin alpha interface to make it similar to bVP24 would attenuate the ability to antagonize IFN-I response. We generated a panel of recombinant EBOVs containing single or combinations of point mutations in the eVP24-karyopherin alpha interface. Most of the viruses appeared to be attenuated in both IFN-I-competent 769-P and IFN-I-deficient Vero-E6 cells in the presence of IFNs. However, the R140A mutant grew at reduced levels even in the absence of IFNs in both cell lines, as well as in U3A STAT1 knockout cells. Both the R140A mutation and its combination with the N135A mutation caused almost complete inhibition of genome replication and transcription suggesting the role of these mutations in an IFN-I-independent attenuation. Additionally, we found that unlike eVP24, bVP24 does not inhibit interferon lambda 1 (IFN-λ1), which potentially explains the lower pathogenicity of BDBV relative to EBOV. Thus, the VP24 residues binding karyopherin alpha affect ebolavirus pathogenicity by IFN-I-dependent and independent mechanisms.

In this article, we establish some new generalized inequalities of Hilbert-type on time scales delta calculus which considered as similar formulas for inequalities of Hilbert type proved by Chang-Jian, Lian-Ying and Cheung [7]. These inequalities will proved by applying Hölder’s inequality, chain rule on time scales and the mean inequality. As special cases of our results (when T = N and T = R), we get the discrete and continuous inequalities. Also, we can obtain other inequalities in different time scale, like T = q^Z, q > 1.

Neuronal cell fate is predominantly controlled by the effects of growth factors, such as neurotrophins, and the activation of a variety of signaling pathways acting through neurotrophin receptors, namely Trk and p75 (p75NTR). Despite their beneficial effects on brain function, their therapeutic use is compromised, due to their polypeptidic nature and blood–brain-barrier impermeability. To overcome these limitations, our previous studies have proven that DHEA-derived synthetic analogs can act like neurotrophins, lacking endocrine side effects. The present study focuses on the biological characterization of a newly synthesized analog, ENT-A044, and its role on inducing cell specific functions of p75NTR. We show that ENT-A044 can induce cell death and phosphorylation of JNK protein by activating p75NTR. Additionally, ENT-A044 can induce the phosphorylation of TrkB receptor, indicating that our molecule can activate both neurotrophin receptors, leading towards the protection of neuronal populations that express both receptors. Furthermore, the present study demonstrates for the first time the expression of p75NTR in human induced Pluripotent Stem Cells - derived Neural Progenitor Cells (hiPSCs - derived NPCs) and receptor-dependent cell death induced by ENT-A044 treatment. In conclusion, ENT-A044 could be proven a lead molecule for the development of novel pharmacological agents, aiming on new therapeutic approaches and research tools, by controlling p75NTR actions.

The broad emission bump in the electromagnetic spectra observed following the detection of gravitational waves created during the kilonova event of merger of two neutron stars in August 2017, GW170817, has been linked to the heavy elements of lanthanides (Z=57-71), and a new understanding of creation of heavy elements in the r-process. The initial spectral emission bump has a wavelength range of 3000 - 7000 \AA, thus covering the region of ultraviolet (UV) to optical (O) wavelengths, and is similar to those seen for lanthanides. Most lanthanides have large number of closely lying energy levels which introduce extensive sets of radiative transitions which often form broad region of lines of significant strength. The current study explores these broad features through photoabsorption spectroscopy of 25 lanthanides ions, Ho I-III, Er I-IV, Tm I-V, Yb I-VI and Lu I-VII. With excitations only to a few orbitals up beyond the ground configurations, we find most of these ions cover large number of bound levels with open $4f$ orbital and produce tens to about hundred thousands lines that may form one or multiple broad features in X-ray to UV, O, and infrared (IR) regions. Spectrum of each of 25 ions is presented indicating presence, shape and wavelength region of the features. Accuracy of atomic data to interpret the merger spectra has been a outstanding problem. The present study aims at providing improved atomic data for energies and transition parameters obtained using relativistic Breit-Pauli approximation implemented in the atomic structure code SUPERSTRUCTURE. The present data have been benchmarked with available experimental data for energies and transition parameters. The study finds that number of ions under the present study are possible contributors of the emission bump of GW170817. All atomic data will be made available online at NORAD-Atomic-Data database.

Our recent study detected the expression of a tissue Renin-Angiotensin System (tRAS) in human intervertebral discs (IVDs). The present study sought to investigate the impact of angiotensin II receptor type 1 (AGTR1) antagonist losartan on human nucleus pulposus (NP) cell inflammation and degeneration induced by tumor necrosis factor-α (TNF-α). Human NP cells (4 donors, Pfirrmann grade 2-3, 30-37 years old, male) were isolated and expanded. TNF-α (10 ng/mL) was used to induce inflammation and degeneration. We examined the impact of losartan supplementation and measured gene expression of tRAS, anabolic, catabolic, and inflammatory markers in NP cells after 24 h and 72 h of exposure, respectively. T0070907, a PPAR-gamma antagonist, was applied to examine the regulatory pathway of losartan. Losartan (1 mM) significantly impaired TNF-α induced increase of pro-inflammatory (nitric oxide and TNF-α), catabolic (matrix metalloproteinases), and tRAS (AGTR1a and Angiotensin Converting Enzyme) markers. Further, losartan maintained the NP cell phenotype by upregulating aggrecan and downregulating collagen type I expression. In summary, losartan showed anti-inflammatory, anti-catabolic, and positive phenotype modulating effects on human NP cells. These results indicate that tRAS signaling plays an important role in IVD degeneration, and tRAS modulation with losartan could represent a novel therapeutic approach.

Concrete is more stable than filler as a false roof in a downward approach type infill quarry, but the mechanical model of a concrete false roof is not clear. As a result, there has been limited application. Therefore, it is necessary to establish the mechanical model of a concrete artificial false roof to enhance the stability of the downward approach infill quarry. This paper combines theoretical analysis, model derivation, finite element analysis and field application methods. Firstly, the basic assumptions of thin plate theory and elasticity mechanics are used as the premise to establish the differential equations of the deflection curve of the concrete thin plate false roof. Then, the three types of bending moment generation of the concrete thin plate false roof are explored. Secondly, the relationship between the location of dangerous surface and dangerous point in hard-supported weak-slab structure and soft-supported weak-slab structure is analyzed, and the type of uniform load and calculation model of concrete thin-slab false roof are improved. Finally, according to the established mechanical model of thin slab false roof, finite element analysis and field application were carried out. The results show that there are three types of deflection curve differential equations in the concrete thin slab false roof perpendicular to the strike, and three extreme points exist in the middle section of the thin slab and on both sides of the surrounding rock. The hazardous surface of the hard-supported weak-slab structure is present at the intersection of the encircling rock and the thin-slab fake ceiling, with the perilous point situated on the top of this surface. The hazardous surface of the soft-supported weak-slab structure can be found in the centre section of the thin-slab fake ceiling, with the perilous point being located at the bottom of this surface. Moreover, the damage mode for both structures is that of maximum tensile stress damage. Upon conducting a finite element analysis, the results indicate that the concrete's maximum tensile stress is significantly high.

The study of the impact of polyQ expansion driven proteotoxicity on cell metabolism has evi-denced NAD molecule as a central player in regulating metabolic response and cell repair in neurodegeneration. The decline in NAD intracellular levels represents a hallmark of ageing aris-ing from a dysregulation between NAD-consuming and biosynthetic enzymatic reactions in which NMNAT plays a key role. By an integrated bioanalytical and proteomic experimental design, the derangement of NAD metabolism deriving from the accumulation of polyQ-Htt protein has been analysed in Saccha-romices cerevisiae harbouring a 103Q-Htt and compared with wild-type Htt, in absence and in presence of a phenolic extract from EVOO, as a source of antioxidant bioactive compounds. Quantification of NAD and its precursors and proteomic analysis of the differential protein ex-pression has been performed by LC-DAD-MS. Chronological lifespan and NAD homeostasis was strongly impaired by proteotoxic polyQ-Htt, eliciting a depletion of NAD levels and accumulation of NaMN. In parallel a downregulation of Sirt2 expression levels has been observed. Phenolic extract administration had no meaningful ef-fects on NAD replenishment to prevent proteotoxicity. NaMN can represent a biomarker of accel-erated aging, and/or a signaling molecule for cell repair.

Pain is unpleasant sensory and emotional experience accompanied by tissue injury. Often an indi-vidual experience, it can be influenced by different physiological, psychological, and social factors. Fibromyalgia, one of the most difficult-to-treat types of pain, is characterized by general muscle pain accompanied by obesity, fatigue, sleep, and memory and psychological concerns. Fibromyal-gia has increased nociceptive sensations via central sensitization in the brain and spinal cord level. We used intermittent cold stress to create a mouse fibromyalgia pain model (Day 0: 3.69  0.14 g; Day 5: 2.13  0.12 g). Mechanical pain could be reversed by eicosapentaenoic acid (EPA) admin-istration (Day 0: 3.72  0.14 g; Day 5: 3.69  0.13 g). A similar trend could be also observed for thermal hyperalgesia. The levels of elements in the transient receptor potential V1 (TRPV1) sig-naling pathway were increased in the ascending pain pathway, including the thalamus, medial prefrontal cortex, somatosensory cortex, anterior cingulate cortex, and cerebellum. EPA intake significantly attenuated this overexpression. Novel chemogenetics method was used to indeed in-hibit SSC to ACC activity presented an analgesic effect through TRPV1 downstream pathway. The present results provide insights as to the role of TRPV1 signaling pathway as in fibromyalgia and its potential as a clinical target.

LR004 is a novel chimeric (human/mouse) monoclonal antibody developed for the treatment of advanced colorectal carcinoma with detectable epidermal growth factor receptor (EGFR) expression. We aimed to investigate the preclinical pharmacokinetics (PK) and in vivo biodistribution of LR004. The PK profiles of LR004 were initially established in rhesus monkeys. Subsequently, 125I radionuclide-labeled LR004 was developed and its binding activity to the EGFR antigen were evaluated. Furthermore, the biodistribution, autoradiography, and NanoSPECT/CT of 125I-LR004 in xenograft mice bearing A431 tumors were examined. The PK data revealed a prolonged half-life and nonlinear PK characteristics of LR004 within the dose range of 6–54 mg/kg. The radiochemical purity of 125I-LR004 was approximately 98.54%, and iodination of LR004 did not affect its specific binding activity to the EGFR antigen. In a classical biodistribution study, 125I-LR004 exhibited higher uptake in highly perfused organs than in poorly perfused organs. Prolonged retention properties of 125I-LR004 in tumors were observed at 4 and 10 days. Autoradiography and NanoSPECT/CT confirmed the significant accumulation and sustained retention of 125I-LR004 at the tumor site in xenograft mice. These findings demonstrated the adequate tumor targeting capabilities of 125I-LR004 in EGFR-positive tumors, which may improve dosing strategies and future drug development.

Crystalline silver thin layers were obtained by high-energy pulsed laser ablation without heating of the deposition substrate. The fluid Plateau-Rayleigh (PRI), Rayleigh – Taylor (RTI) and Richtmyer – Meshkov (RMI) instabilities, as well as crown splash induced during pulsed laser deposition (PLD) in high energy regime, resulting in ring and pearl shaped structures, offer the benefit of increased sorption surface. These morphological structures obtained for the silver thin layers make them of interest for catalytic applications. The study presented with this work addresses both the fundamental and applied issues on the morphological structures obtained for the silver thin layer and their catalytic function in organic processes. In this sense, the catalytic action of the thin silver layer was highlighted by modifications of the Reactive Blue 21 dye (C.I.) in aqueous solution with sodium bicarbonate. Specific investigations and analyzes were carried out by electron microscopy and elemental analysis (SEM-EDX), atomic force microscopy (AFM) and profilometry, mass spectrometry, ablation plasma diagnosis, diffractograms (XRD), as well as IR spectroscopy (FTIR). In addition to the experimental investigation and analyzes, simulation of the ionization energy threshold was conducted in COMSOL for complementary evaluation on the involved processes and phenomena.

We developed an ovarian cancer-targeted drug delivery system based on a follicle-stimulating hormone receptor (FSHR) peptide. The lipophilic chemotherapeutic drug SN38 and the photosensitizer IR820 were loaded into the phospholipid bilayer of liposomes. Near-infrared laser irradiation stimulated the generation of reactive oxygen species, causing short-term reactive molecular species and spatial-temporal restricted photodamage to the biological targets. The reactive molecular species and spatial-temporal restricted photodamage enhanced the release and uptake of chemotherapy drugs and increased the sensitivity to chemotherapy drugs in ovarian cancer cells. FSH liposomes loaded with SN38 and IR820 (SN38/IR820-Lipo@FSH) were prepared using thin-film hydration-sonication. FSH peptide binding was analyzed using 1H NMR spectrum and Maldi-Tof. The average size and zeta potential of SN38/IR820-Lipo@FSH were 105.1 ± 1.15 nm (PDI: 0.204 ± 0.03) and −27.8 ± 0.42 mV, respectively. SN38/IR820-Lipo@FSH exhibited good drug-loading properties and the in vitro release was slow. FSH significantly increased the uptake of liposomes, inhibited cell proliferation, and induced apoptosis in A2780 cells. Moreover, SN38/IR820-Lipo@FSH exhibited good tumor-targeting ability and anti-ovarian cancer activity in vivo. The SN38/IR820-Lipo@FSH exhibited specific targeting to A2780 ovarian cancer cells. The combination of chemotherapy and photodynamic treatment based on an FSH peptide-targeted delivery system may be an effective approach to treating ovarian cancer.

An active power dispatch method for a microgrid (MG) with multi-type loads, renewable energy sources (RESs) and distributed energy storage devices (DESDs) is the focus of this paper. The MG operates in a grid-connected model, and distributed power sources contribute to the service for load demands. The outputs of multiple DESDs are controlled to optimize the active power dispatch. Our goal with optimization is to reduce the economic cost under time-of-use (TOU) price, and to adjust the excessively high or low load rate of distributed transformers (DTs) caused by the peak-valley demand and load uncertainties. To simulate a practical environment, the stochastic characteristics of multi-type loads are formulated. The transition matrix of system state is provided. Then, a finite-horizon Markov decision process (FHMDP) model is established to describe the dispatch optimization problem. A learning-based technique is adopted to search the optimal joint control policy of multiple DESDs. Finally, simulation experiments are performed to validate the effectiveness of the proposed method, and the fuzzification analysis of the method is presented.

Suppressors of cytokine signaling (SOCS) genes are essential negative regulators that modulate cytokine signaling and play key roles in numerous biological processes, including immune responses. In this study, we cloned the complementary DNA (cDNA) sequences of two SOCS genes, designated as LvSOCS6 and LvSOCS7, from the white-leg shrimp, Litopenaeus vannamei. LvSOCS6 encoded a polypeptide of 463 amino acids (aa), spanning 1,392 base pairs (bp), while LvSOCS7 encodes a significantly larger polypeptide of 955 aa, encompassing 2,868 bp. Both LvSOCS proteins exhibited conserved domains associated with SOCS, including a centralized Src homology 2 (SH2) domain and a C-terminal SOCS box. Phylogenetic analysis revealed that the deduced aa sequences of LvSOCS6 and LvSOCS7 cluster within the invertebrate type I SOCS family, indicating their evolutionary relatedness. Tissue distribution analysis demonstrated ubiquitous expression of both LvSOCS genes across all examined tissues, with LvSOCS6 showing heightened expression in the gills and LvSOCS7 exhibiting a remarkable preference for the gills and stomach. Notably, mRNA expression patterns of LvSOCS genes following LPS and poly (I:C) stimulations exhibit significant upregulations, while PGN stimulation yields incongruous results across the experimented tissues. Interestingly, concurrent with the diminished expression of LvSOCS6 and LvSOCS7, there is a significant elevation in mRNA expression levels of LvSTAT, a vital component of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. These findings shed light on the potential involvement of the newly discovered type I SOCS genes in regulating the JAK/STAT pathway and assuming pivotal roles in orchestrating the innate immune responses in L. vannamei defense mechanisms.

“Pecorino” is a typical semi-hard cheese obtained with raw or heat-treated sheep milk using procedures to valorize the raw material's chemical and microbiological properties. In the present study, using a high throughput method of 16S rRNA gene sequencing, we assessed the evolution of the microbiome composition from milk to Pecorino cheese in artisanal processes using milk from Comisana and Lacaune sheep breeds. The comparative analysis of the bacterial com-munity composition revealed significant differences in the presence and abundance of specific taxa in the milk microbiome of the Comisana and Lacaune breeds. NGS analysis also revealed differences in the curd microbiome related to dairy farming practices, which have a relevant effect on the final structure of the Pecorino-cheese microbiome.

Motivated by empirical observations, we propose a possible extension of Gibrat's law. By applying it into the random growth theory of income distribution (Gabaix, 2009), we find that the income distribution is described by a generalized Pareto-type distribution (GPD) with three parameters. We observe that there is a parameter /elta in the GPD that plays a key role in determining the shape of income distribution. By using the Kolmogorov-Smirnov test, we empirically show that, for typical market-economy countries, /elta is close to 0 significantly, such that the income distribution is characterized by a two-class pattern in which the bottom 90% of the population is approximated by an exponential distribution and the richest 1%~3% is approximated by an asymptotic power law. However, we empirically find that, for China both in planned economy period and in early stages of market reformation (from 1978 to 1990), /elta is significantly deviated from 0, such that the bottom of the population no longer conforms to an exponential distribution.

Background: Coronavirus disease 2019 (COVID-19) has emerged as a global threat to human health and disease risk increases with advancing age. The regulation of the ACE2 gene that codes for COVID-19 host receptor ACE2 has been shown to be under epigenetic regulation. Here, we examined whether intensive DNA methylation profiling of the ACE2 gene differed by human host tissue and cell type, gender, and age. Results: Accessing four public datasets, we observed unique human cell-type-specific ACE2 DNA methylation patterns. In human lung tissues, gender differences in DNA methylation at 2 sites related to the ACE2 gene were identified. Further, in freshly isolated airway epithelial cells, DNA methylation near the transcription start site of the ACE2 gene associated with biological age. Conclusion: Epigenetic profiling of host tissue may permit discovery of age and gender-related potential risk factors for COVID-19. How perturbations in ACE2 methylation relate to clinical severity across the ages and gender needs to be determined to guide screening tools and potential epigenetic modification targeting to alleviate COVID-19 morbidity in the elderly.

Using data from the Swedish National Diabetes Register, this study examines the gender disparity among patients with type I diabetes who have experienced a specific cardiovascular complication, while exploring the association between weight variability, age group, and gender. Fourteen cardiovascular complications have been considered. This analysis is conducted by using three-way correspondence analysis (CA) which allows for the partitioning and decomposition of Pearson’s three-way chi-squared statistic. The dataset comprises of information organized in a data cube, detailing how weight variability among these patients correlates with a cardiovascular complication, age group and gender. The three-way CA method presented in this paper allows for one to assess the statistical significance of the association between these variables and to visualize this association, highlighting the gender gap among these patients. It is worth noting that the association between weight variability, age group, and gender varies among different types of cardiovascular complications.

Existing research indicates that mineralization of Carlin-type gold deposit is related to geological structures, but current studies mostly focus on the qualitative association, and lack quantitative analysis of the relationship between mineralization and structural features, which limits the potential for predictive mineral exploration. In this study, the Nibao Carlin-type gold deposit was selected as the research area to conduct three-dimensional geological modeling, spatial analysis, and three-dimensional prospectivity modeling. Spatial analysis revealed that the majority of gold ore bodies are situated near the main fault, with gold mineralization primarily occurring within a spatial range of approximately -80 meters to 20 meters from the main fault plane. This spatial distribution predominantly aligns in a SW-NE direction. Spatial characteristic extraction of fault slope indicators suggests that the slope angles are conducive to the migration and accumulation of ore-forming hydrothermal fluids, with ore body metal content rapidly increasing within an angle range of approximately 20° to 60°. The shape analysis of the mainfault indicates that the principal spaces of mineralization enrichment are within -10m to 20m of the fault plane undulations, where gold resources are concentrated in a relatively flat area. However, the degree of mineralization is more pronounced in the protruding sections than in the depressed areas. The areas with significant dip changes in faults display higher variations in orebody attitudes, with mineralization noticeably weaker in areas where the fault steepness changes markedly. Ore-bearing units exhibit significantly higher grades within the -17° to 3° interval of fault steepness transition. This interval also sees a rapid accumulation of gold resources. The Nibao gold mine's mineralization is derived from deep, ore-bearing hydrothermal fluids ascending along major fractures, precipitating, and accumulating in favorable ore-hosting spaces (faults, anticline cores) and lithological combinations (sedimentary tuffs, tuffs). Three deep potential gold targets were identified, highlighting the deep western edge of the F1 fault and the deep southeast-trending lower plate as prospective areas for future exploration. This study underscores the effectiveness of 3D prospective modeling as an indispensable tool for elucidating the spatial distribution of fault-controlled Carlin-type gold deposits and their tectonic determinants.

DIEP-based breast reconstruction necessitates wide undermining at the abdominal donor-site, creating large wound areas. Flap harvesting is usually conducted using electrosurgical dissection devices. This study sought to compare the clinical outcomes in patients after using the PEAK PlasmaBlade (PPB) versus monopolar electrocautery (MPE). This retrospective cohort study included 128 patients with DIEP-based breast reconstruction. Patient characteristics as well as information on the postoperative course were collected and a comparative evaluation was conducted. The MPE group exhibited significantly (p* = 0.0324) higher abdominal drainage volume (351.11 ± 185.96 ml) compared to the PPB group (279.38 ± 183.38 ml). Subgroup analysis demonstrated that PPB significantly reduced postoperative wound fluid in patients with BMI > 30 kg/m² (p* = 0.0284), without prior neoadjuvant chemotherapy (p** = 0.0041), and among non-smokers (p = 0.0046). Furthermore, postoperative pain was significantly (p**** < 0.0001) lower in the PPB cohort. This study confirms the non-inferiority of the PEAK PlasmaBlade to conventional electrocautery for abdominal flap harvesting. The PPB demonstrated advantages, notably reduced drainage volume and lower postoperative pain levels. Recognizing patient subsets that benefit more from the PPB highlights the importance of personalized device selection based on patient characteristics.

Interactions between receptors and ligands of the tumor necrosis factor superfamily (TNFSF) provide costimulatory signals that control the survival, proliferation, differentiation, and effector function of immune cells. All components of the TNF superfamily are associated with NF-kB functions that are not limited to cell death and may promote survival in the face of adipose tissue inflammation in obesity. Inflammation and pro-inflammatory dysfunction of mitochondria are key factors associated with insulin resistance in obesity. The aim of the study was to analyze the relationship of soluble forms of receptors and ligands of the TNF superfam-ily in blood plasma with mitochondrial dynamics in adipose tissue (greater omentum (GO) and subcutaneous adipose tissue (Sat)) of obese patients with and without type 2 diabetes mellitus (T2DM). Increased plasma sTNF-R1, sTNF-R2, sTNFRSF8 receptors and ligands TNFSF12, TNFSF13, TNFSF13B are characteristic of obese patients without T2DM. Increases in TNFSF12, TNFSF13B, and sTNF-R1 levels are associated with decreased glucose concentration and decreased BMI in obese patients. The gene expression levels responsible for regulating mitochondrial dynamics were increased in obese patients without T2DM and were unbalanced in patients with obesity and T2DM.

In this paper, we have established Hermite-Hadamard inequalities for r-preinvex functions via fractional integrals.

Drosophila melanogaster serves as a important research model both for genetic investigations and for the study of metal toxicity, facilitating the elucidation of physiological mechanisms comparable to those of human organisms. In our research, we evaluated the toxicity effect resulting from exposure to various concentrations of lead and copper on the prolificity rates throughout the life cycle (egg-adult) of four genotypes of Drosophila melanogaster: wild-type (control), white, brown, and white-vestigial. During our study, the prolificity rates were examined across three repetitions under the impact of exposure to concentrations of 0.50, 1.00, 2.00, and 4.00 mM of copper (CuSO₄) and lead (Pb(C₂H₃O₂₎₂). Prolificity rates throughout the life cycle exhibited variations as a direct consequence of genetic factors, the concentration of exposure, and the specific type of metal, either copper or lead. The mutant white-vestigial genotype revealed an IC₅₀ concentration for prolificity inhibition at lower doses of 2.00 mM for copper and 4.00 mM for lead, in contrast to the control genotype (wild-type), which exhibited an inhibition concentration rate >IC₅₀ of 4.00 mM only in the case of copper. Our results concluded that the (i) dose influences the prolificity rate in a directly proportional manner, (ii) comparative analyses between copper and lead revealed that copper displayed toxicity across all genotypes within the concentration range of 0.50 mM to 2.00 mM. In contrast, lead exhibited toxicity within the concentration range of 1.00 mM to 4.00 mM, highlighting a (iii) more acute toxicity characteristic in the case of copper. Thus, the results of this research reflect the importance of using Drosophila melanogaster as a genetic model in the comparative study of the interaction between genetic factors and the toxicity of metals, offering significant insights into monitoring their impact and defining the maximum permissible doses on organisms.

Background and Objectives Neurofibromatosis 1 (NF1 MIM # 162200), also known as von Recklinghausen disease, is among the most common autosomal dominantly transmitted disorders characterized mainly by neurocutaneous manifestations such as café au lait spots, intertriginous freckling, various types of neurofibromas (cutaneous neurofibromas or plexiform tumors), neurological manifestations, and bone abnormalities. It occurs with an incidence of 1:3000–1:4000 cases. Cone-rod dystrophies belong to the large group of retinal dystrophies, a highly heterogeneous group of disorders clinically manifested mainly by damage to cone and rod cells and have a broad spectrum of clinical manifestations. Many genes are involved in their etiology, with more than 100 currently identified, including the CRX gene responsible for the autosomal dominant form of cone-rod dystrophy (ad CORD). Materials and Methods: The authors present an intriguing case of a patient diagnosed with Neurofibromatosis type 1 (NF1) as an infant and ocular involvement (myopia and astigmatism onset at age 15), which yielded a surprising molecular testing result. Results: Molecular DNA analysis identified a rare occurrence of two mutational variants, including a pathogenic variant in the NF1 gene, c.3871-2A, and a likely pathogenic variant in the CRX gene c.119G>A. Conclusions: The authors present this case to highlight the surprises offered by molecular testing in a condition where the diagnosis is usually based on clinical criteria, thus providing patients with competent genetic advice.

Stimulation of the alpha 7 nicotinic acetylcholine receptor (α7nAChR) has shown beneficial effects in several acute inflammatory disease models. This study aims to examine whether treatment with the selective α7nAChR agonist PHA 568487 can dampen inflammation and thereby improve cardiac function after myocardial infarction in mice. The possible anti-inflammatory properties of α7nAChR agonist PHA 568487 were tested in vivo using the air pouch model and in a permanent occlusion model of acute myocardial infarction in mice. Hematology parameters and cytokine levels were determined. Infarct size and cardiac function were assessed via echocardiography 24 h and one week after the infarction. Treatment with α7nAChR agonist PHA 568487 decreased 12 (CCL27, CXCL5, IL6, CXCL10, CXCL11, CXCL1, CCL2, MIP1a, MIP2, CXCL16, CXCL12 and CCL25) out of 33 cytokines in the air pouch model of acute inflammation. However, α7nAChR agonist PHA 568487 did not alter infarct size, ejection fraction, cardiac output or stroke volume at 24 h nor at 7 days after the myocardial infarction compared with control mice. In conclusion, despite promising immunomodulatory effects in the acute inflammatory air pouch model, α7nAChR agonist PHA 568487 did not affect infarct size or cardiac function after a permanent occlusion model of acute myocardial infarction in mice. Consequently, this study does not strengthen the hypothesis that stimulation of the α7nAChR is a future treatment strategy for acute myocardial infarction when reperfusion is lacking. However, whether other agonists of the α7nAChR can have different effects remains to be investigated.

In this paper, we establish the generalized Qi-type inequality involving conformable fractional integrals. The results presented here would provide extensions of those given in earlier works.

A single type I RC (Fe-S type, ferredoxin reducing) is found in several of the phyla of anoxygenic phototrophic bacteria. They include the heliobacteria (HB), the green sulfur bacteria (GSB) and the chloroacidobacteria (CAB), for which high-resolution homodimeric RC-PS structures have recently appeared [1-4]. The 2.2-Å Xray structure of the RC-PS of Heliomicrobium modesticaldum [1] revealed that the core PshA apoprotein (PshA1 and PshA2 homodimeric pair) exhibits a structurally conserved PSI arrangement comprised of five C-terminal transmembrane helices (TMHs) forming the RC domain and six N-terminal TMHs coordinating the light-harvesting (LH) pigments. The Hm. modesticaldum structure lacked quinones, indicating that electrons were transferred directly from the A0 (81-OH-chlorophyl (Chl) a) primary acceptor to the FX [4Fe4S] component, serving as the terminal RC acceptor. A pair of additional TMHs designated as Psh X were found, that function as a low-energy antennae. The 2.5Å resolution cryo-electron microscopy (cryo-EM) structure for the RC-PS of the GSB Chlorobaculum tepidum [2] included two Fenna-Matthews-Olson protein (FMO) antennae, which transfer excitations from the chlorosomes to the RC-PS (PscA1 and PscA2) core. Two cytochromes c (PscC) molecules were revealed, which act in series as electron donors to the photooxidized RC BChl a’ special pair, as well as PscB, housing the [4Fe-4S] cluster FA and FB, and the associated PscD protein [3]. Although their FMO components were missing from the 2.6-Å cyro-EM structure of the Zn-BChl a’ special pair containing RC-PS of Chloroacidobacterium thermophilum [4], a unique architecture was revealed that consisted of seven additional subunits including PscZ in place of PscD, the PscX and PscY cytochrome c serial electron donors and four low mol. wt. subunits of unknown function. Overall, these diverse structures have revealed that: (i) the HB RC-PS is the simplest light-energy transducing complex yet isolated, and represents the closest known homolog to a common homodimeric RC-PS ancestor; (ii) the symmetrically localized Ca2+binding sites found in each of the Type I homodimeric RC-PSs likely gave rise to the analogously positioned Mn4CaO5 cluster of the PSII RC and the TyrZ RC donor site; (iii) a close relationship between the GSB RC-PS and Chl protein (CP)43 and CP47 of PSII was demonstrated by the strongly conserved locations of their LH-(B)Chls; (iv) LH-BChls of the GSB-RC-PS are also localized in the conserved RC-associated positions of the PSII ChlZ-D1 and ChlZ-D2 sites; (v) glycosylated carotenoids of the GSB RC-PS are located in the homologous carotenoid-containing positions of PSII, reflecting an O2-tolerance mechanism capable of sustaining early stages in the evolution of oxygenic photosynthesis. In addition to the close relationships found between the homodimeric RC-PS and PSII, duplication of the gene encoding the ancestral Type I RC apoprotein, followed by genetic divergence my well account for the appearance of the heterodimeric Type I and Type II RC found in extant oxygenic phototrophs. Accordingly, the long-held view that PSII arose from the anoxygenic Type II RC is now supplanted by the new evidence provided by Type I RC-PS homodimer structures, indicating that the evolutionary origins of anoxygenic Type II RCs along with their distinct antenna rings are likely to have occured later than the events which gave rise to their oxygenic counterparts.

Brain arteriovenous malformations (BAVMs) are a critical concern in hereditary hemorrhagic telangiectasia (HHT) patients, carrying the risk of life-threatening intracranial hemorrhage. While traditionally seen as congenital, the debate continues due to documented de novo cases. Our primary goal was to identify the precise postnatal window in which deletion of the HHT gene Endoglin (Eng) triggers BAVM development. We employed SclCreER(+);Eng2f/2f mice, enabling timed Eng gene deletion in endothelial cells via tamoxifen. Tamoxifen was given at four postnatal periods: P1-3, P8-10, P15-17, and P22-24. BAVM development was assessed at 2-3 months using latex dye perfusion. We examined angiogenic activity by assessing vascular endothelial growth factor receptor 2 (VEGFR2) expression via Western blotting and Flk1-LacZ reporter mice. Longitudinal magnetic resonance angiography (MRA) was conducted up to 9 months. BAVMs emerged in 88% (P1-3), 86% (P8-10), and 55% (P15-17) of cases, with varying localization. Notably, the P22-24 group did not develop BAVMs but exhibited skin AVMs. VEGFR2 expression peaked in the initial 2 postnatal weeks, coinciding with BAVM onset. These findings support the “second hit” theory, highlighting the role of early postnatal angiogenesis, in initiating BAVM development in HHT type I mice.

Objective: to retrospectively evaluate the incidence rate (IR) of echocardiographic signs suspected for pulmonary hypertension (PH) in Systemic sclerosis (SSc) patients after the introduction of a combination therapy with bosentan and sildenafil for treatment or prevention of digital ulcers. Methods: patients attending the Scleroderma Unit of the Universital Hospital of Careggi from July 2010 to July 2023 were enrolled. Patients older than 18 years old, with an history of digital ulcers, treated with bosentan and sildenafil in combination for at least 12 months were included. Patients with a diagnosis of PH preceding the introduction of the therapy were excluded. Demographical data, disease duration, laboratoristic and instrumental data (pulmonary function tests, echocardiographic estimation of pulmonary artery pressure (PAPs) and ultrasonographic value of renal resistive index) were collected. The IR of echocardiographic signs suspected for pulmonary hypertension and their 95% confidence interval were calculated in events/1000 patients-years.Results: forty-seven patients were enrolled; mean disease duration was 12,14 years (SD 5,87). Mean duration of the combination treatment was 78.33 (SD 41.37) months and total at-risk time was 3525 months. Two patients (4,2%) presented echocardiographic signs of PH (sPAP 50 mmHg and 40 mmHg); the IR was calculated to be 6.8/1000 patients-years (95% CI 6,02-7,7). In one of the 2 patients RHC excluded PAH, while the other patient refused to undergo to RHC and PAH could not be confirmed/excluded. A stability of PFTs and echocardiografic PAPs was observed during the observation time. Conclusions: the results of this retrospective study suggest that combination therapy with endothelin receptor antagonist and Phosphodiesterase-5 (PDE5) inhibitors could help in preventing PAH in SSc; prospective case-control studies on larger population are needed to improve knowledge in this field.

Background: Skin is exposed to ultraviolet radiation (UV) and air pollution and recent works demonstrated these factors have additive effects in the disturbance of skin homeostasis. Nuclear factor erythroid 2-related factor 2 (Nrf2) and aryl hydrocarbon receptor (AHR) appears appropriate targets in the management of combined environmental stressors. The protective effects of Silymarin (SM), an antioxidant and anti-inflammatory complex of flavonoids, were evaluated. Methods: Reactive oxygen species (ROS) and interleukin 1-alpha (IL-1a) were quantified in UV+urban dust stressed reconstructed human epidermis (RHE) treated with SM. Gene expression study was conducted on targets related to AHR and Nrf2. SM agonistic activity on cannabinoid receptor type 2 (CB2R) was evaluated on mast cells. Clinical study quantified the performance of SM and cannabidiol (CBD), in skin exposed to solar radiation and air pollution. Results: SM decreased morphological alterations, ROS and IL-1a in UV+urban dust stressed RHE. AHR and Nrf2 related genes were upregulated that control antioxidant effector and barrier function. Interleukin 8 gene expression was decreased. Clinical study confirmed SM to improve homogeneity and perceived well-being of urban skins exposed to UV, outperforming CBD. SM activated CB2R and release of β-endorphin from mast cells. Conclusions: SM provides protection of skin from oxidative stress and inflammation caused by two major factors of exposome and appears mediated by AHR-Nrf2. SM activation of CB2R opens a new understanding of SM anti-inflammatory properties.

Aims:To update analytic formulas for the overall efficacy of corneal collagen crosslinking (CXL) including both type-I and oxygen-mediated type-II mechanisms, the role of oxygen and the initiator regeneration. Study Design:modeling the kinetics of CXL in UV light and using riboflavin as the photosensitizer.Place and Duration of Study:New Taipei City, Taiwan, between June, 2021 and July, 2021.Methodology:Coupled kinetic equations are derived under the quasi-steady state condition for the 2-pathway mechanisms of CXL. For type-I CXL, the riboflavin (RF) triplet state [T] may interact directly with the stroma collagen substrate [A] to form radical (R) and regenerate initiator. For type-II process, [T] interacts with oxygen to form a singlet oxygen [¹O₂]. Both reactive radical (R) and [¹O₂], can relax to their ground state, or interact with the substrate [A]) for crosslinking. Based on a safety dose, the minimum corneal thickness formula is derived. Results:Our updated theory/modeling showed that oxygen plays a limited and transient role in the process, in consistent with that of Kamave [2]. In contrary, Kling et al [3] believed that type-II is the predominant mechanism, which however conflicting with the epi-on CXL results. For both type-I and type-II, a transient state conversion (crosslink) efficacy in an increasing function of light intensity (or dose), whereas, its steady state efficacy is a deceasing function of light intensity. RF depletion in type-I is compensated by the RF regeneration term (RGE) which is a decreasing function of oxygen. For the case of perfect regeneration case (or when oxygen=0), RF is a constant due to the catalytic cycle. Unlike the conventional Dresden rule of 400 um thickness, thin cornea CXL is still safe as far as the dose is under a threshold dose (E*), based on our minimum thickness formula (Z*). Our formula for thin cornea is also clinically shown by Hafez et al forultra thin (214 nm) CXL. Conclusion: For both type-I and type-II, a transient state conversion (crosslink) efficacy in an increasing function of light intensity (or dose), whereas, its steady state efficacy is a deceasing function of light intensity. Ultra thin cornea is still safe as far as it is under a threshold dose (E*), based on our minimum thickness formula.

This paper is devoted to the study of multi-dimensional integral transform with Fox H-function in the kernel in weighted spaces integrable functions in the domain R+n with positive coordinates. Mapping properties such as the boundedness, the range, the representations of the considered transformation are established.

The C-type lectin-like receptor 2 (CLEC-2) is expressed on platelets and mediates binding to podoplanin (PDPN) on various cell types. The binding to circulating tumor cells (CTCs) leads to platelet activation and promote metastatic spread. The increased level of soluble CLEC-2 (sCLEC-2), presumably, released from activated platelets was shown in patients with thromboinflammatory and malignant disease. However, the functional role of sCLEC-2 and the mechanism of sCLEC-2 release is not known. In this study, we focused on the effect of platelet activation on CLEC-2 expression and the sCLEC-2 plasma level in cancer patients. First, citrated blood from healthy volunteer donors (n=20) was used to measure the effect of platelet stimulation by classical agonists and PDPN on aggregation, CLEC-2 expression on platelets by flow cytometry, sCLEC-2 release to the plasma by ELISA and total CLEC-2 expression by Western blot analysis. Second, sCLEC-2 was determined in plasma samples from healthy donors (285) and patients with colorectal carcinoma (CRC; 194), melanoma (160), breast cancer (BC; 99) or glioblastoma (49). PDPN caused a significant increase of the aggregation response induced by classical agonists. ADP or PDPN stimulation of platelets caused a significant decrease of CLEC-2 on platelets and sCLEC-2 in the plasma, whereas, total CLEC-2 in platelet lysates remained the same. Thus, the increased plasma level of sCLEC-2 is not a suitable biomarker of platelet activation. In patients with CRC (median 0.9 ng/mL), melanoma (0.9 ng/mL) or BC (0.7 ng/mL) we found significantly lower sCLEC-2 levels (p&lt;0.0001), whereas, glioblastoma patients displayed higher levels (2.6 ng/mL; p=0.0233) compared to healthy controls (2.1 ng/mL). The low sCLEC-2 plasma level observed in most of the tumor entities of our study, presumably, results from the internalization of sCLEC-2 by activated platelets or binding of sCLEC-2 to CTC.

Pre-eclampsia is a hypertension disorder during pregnancy, significantly affects maternal morbidity and mortality worldwide. A Case-control research was done on 100 pregnant mothers as respondents: 50 case (pre-eclampsia) and 50 control groups (healthy pregnant mothers). Selected case the following characteristics: were patients that visited the Syamrabu Bangkalan Public Hospital; were third-generation Madura natives; aged between 20-40 years old; had a gestational age of over 20mgg; had blood pressure above 140/90mmHg; and single pregnancies. Control had the following characteristics: were healthy pregnant women without pre-eclampsia or chronic hypertension; were third-generation Madura natives; had a gestational age of over 20mgg; aged between 20-40 years; and without pregnancy complications. The results showed of those with PE, 45 had the AA genotype (homozygote) (90%), five had AC (heterozygote) (8%) and one had CC (homozygote) (2%). As for those without PE, 33 had the AA genotype (homozygote) (73.3%), 11 had AC (heterozygote) (26.7%), none had CC (homozygote) (0%). PE and non-PE cases mostly had the AA genotype (homozygote) and A alleles. AT1R 1166 A/C polymorphism was found to be a significant risk factor for pre-eclampsia, while potassium level had no significant effect on it. Meaning further research is needed on different ethnicities and races.

Introduction- Chiari malformation type 1 (CM-1) is defined by the caudal displacement of cerebellar tonsils through the foramen magnum (cut off of 5 mm from McRae line.) In Chiari malformation type 1.5 (CM-1.5) both cerebellar tonsils and brainstem result herniated. Patient with CM may exhibit a variety of symptoms: the most common are headache and cervical pain. Associated anomalies such as syringomyelia (67-80%), hydrocephalus (10 %), craniosynostosis or tethered spinal cord may be present. Surgical treatment is not performed in asymptomatic patients, while the presence of syringomyelia represents an indication for surgical decompression. In this paper we report our experience with the use of intra-operative ultrasonography in orienting surgical decompression with or without dural opening. Methods- We retrospectively examined and selected pediatric patients with CM-1/ CM-1.5 who were managed between 2006-2020 at Giannina Gaslini Hospital. Exclusion criteria were the association with achondroplasia and with spina bifida. Results- A total of 211 pediatric patients were identified for evaluation: CM-1 accounted for 83.9% of patients and CM-1.5 for 16.1%. Syringomyelia was associated in 28.4% of cases and hydrocephalus in 8%. According to findings at the intra-operative ultrasonography, a bony and ligamentous decompression alone was sufficient in 59.8% patients, a simple opening of dura mater was performed in 3% and a duraplasty in 27.1%. Seven patients experience post-operative complications, and 3 patients needed a second surgical operation for insufficient decompression, found at follow-up. Discussion and conclusion- The standard surgical treatment of CM-1/ CM-1.5 consists in decompression of posterior cranial fossa. Whether to perform a simple bony decompression or to associate the opening of the dura mater with duraplasty has always been controversial in pediatric population. Our case series, where good radiological findings were achieved with a limited number of reoperations, shows how intra-operative ultrasound may be a real-time helpful tool in orienting the surgical strategy, if we consider as surgical endpoint the restoration of cerebrospinal fluid (CSF) flux. However, there is the need to standardize this method, using quantitative variables.

Survival following Ebola virus (EBOV) infection correlates with the ability to mount an early and robust interferon (IFN) response. The host IFN-induced proteins that contribute to controlling EBOV replication are not fully known. Among the top genes with the strongest early increases in expression after infection in vivo is IFN-induced HERC5. Using a transcription- and replication-competent VLP system, we showed that HERC5 inhibits EBOV virus-like particle (VLP) replication by depleting EBOV mRNAs. The HERC5 RCC1-like domain was necessary and sufficient for this inhibition and did not require zinc finger antiviral protein (ZAP). Moreover, we showed that EBOV (Zaire) glycoprotein (GP) but not Marburg virus GP antagonized HERC5 early during infection. Our data identifies a novel ‘protagonist-antagonistic’ relationship between HERC5 and GP in the early stages of EBOV infection that could be exploited for the development of novel antiviral therapeutics.

An azaphenothiazine derivative, 6-chloroethylureidoethyldiquino[3,2-b;2’,3’-e][1,4]thiazine (DQT) has recently been shown to exhibit immunosuppressive activities in mouse models. It also inhibited the expression of CXCL10 at the protein level, at non-toxic concentrations, in the culture of KERTr cells treated with double-stranded RNA, poly(I:C). In this report, we demonstrated that DQT inhibits the transcription of the CXCL10 gene. Although CXCL10 is an IFNγ-inducible protein, we found that the CXCL10 protein was induced without the detectable release of IFNγ or IκB degradation. Hence, we concluded that IFNγ or NFκB were not involved in the regulation of the CXCL10 gene in KERTr cells transfected with poly(I:C) as well as in the inhibitory activity of DQT. On the other hand, we found that IFNβ was induced under the same conditions and its expression was inhibited by DQT. Kinetic analysis showed that an increase in IFNβ concentrations occurred 4-8 h after poly(I:C) treatment, while the concentration of CXCL10 was undetectable at that time and started to increase later, when IFNβ reached high levels. Therefore, DQT may be regarded as a new promising inhibitor of IFNβ expression and IFNβ-dependent downstream genes and proteins, e.g., CXCL10 chemokine, which is implicated in pathogenesis of autoimmune diseases.

Abstract: Kiwifruit, a perennial horticultural crop known for its nutritional value, faces significant challenges due to biotic and abiotic stresses, affecting its yield and quality. Leucine-rich repeat receptor-like proteins (LRR-RLPs), a major group of receptor-like proteins in plants, have diverse functions in plant physiology, including growth, development, signal transduction, and stress responses. Despite their importance, the specific roles of kiwifruit LRR-RLPs in response to biotic and abiotic stresses remain poorly understood. In this study, we investigated the expression patterns of kiwifruit LRR-RLPs under various stress conditions, including pathogen stress, heat stress, waterlogging stress, and copper stress. Through genome and transcriptome analyses, we identified a total of 101, 164, and 105 LRR-RLPs in Actinidia Chinensis 'Hongyang', Actinidia eriantha 'Huate', and Actinidia chinensis 'Red5' kiwifruit, respectively, classified into 9 subgroups based on phylogenetic relationships. Synteny analysis revealed that the expansion of kiwifruit LRR-RLPs was primarily attributed to segmental duplication events. Using RNA-seq data from pathogen-infected kiwifruits, we identified specific LRR-RLP genes potentially involved in different stages of pathogen infection. Additionally, we observed the potential involvement of kiwifruit LRR-RLPs in abiotic stress responses, with upstream transcription factors possibly regulating their expression. Furthermore, protein interaction network analysis unveiled the participation of kiwifruit LRR-RLP genes in the regulatory network of abiotic stress responses. These findings highlight the crucial roles of LRR-RLPs in mediating both biotic and abiotic stress responses in kiwifruit, offering valuable insights for the breeding of stress-resistant kiwifruit varieties.

The present study aimed at investigating the in vitro and in vivo susceptibility of malaria parasites to crude extracts and fractions from Polyalthia suaveolens, Uvaria angolensis, and Monodora tenuifolia. The ethanolic extracts were prepared by maceration, and were further partitioned using water, dichloromethane, hexane, and methanol. The most promising fraction was subjected to column chromatography and the sub-fractions tested for activity in vitro. The antiplasmodial effect of extracts and fractions was tested against the Chloroquine resistant (PfK1) strain in 96 wells microtiter plate format using SYBR green florescence assay. The promising fraction was further assessed for cytotoxicity and acute toxicity in Swiss albino mice and subsequently against the rodent malaria parasite, P. berghei. Qualitative phytochemical screening was also performed on the promising fraction. The methanol fractions exerted the overall better effect with that of the twigs of P. suaveolens (PStw(Ace)) showing the highest potency with a IC50 value of 3.24 µg/mL followed by the fractions of leaf of M. tenuifolia (MoTel(Ace), IC50= 3.84 µg/ml) and stem bark of P. suaveolens (IC50= 4.90 µg/ml). The phytochemical screening showed the presence of alkaloids, lactones, and phenols in the more active fraction of P. suaveolens (PStw(Ace)). The chromatographic fractionation of this fraction led to 12 sub-fractions with PS8 sub-fraction being the most active (IC50= 4.42 µg/mL). In vivo, oral administration of 2000 mg/kg b.w of fraction PStw(Ace) in mice showed no signs of toxicity. Also, fraction PStw(Ace) at 400 mg/kg b.w exerted the highest suppressive effect against P. berghei strain B throughout the 4 days experiment (% parasitaemia below 5.2%). Overall, the results achieved supported the use of the three plants in the traditional treatment of malaria in Cameroon. More interestingly, the methanolic fraction of the twigs extract from P. suaveolens might be of interest in future development of an antimalarial phytodrug.