Presence of antibodies directed against certain red cell antigens in a solid organ transplant recipient can complicate transplant outcome if the donor is positive for those antigen(s). Therefore, these are immunohematological barriers that affect clinical decisions taken in such scenarios. Case A: A 43 year old woman who was a case of chronic kidney disease (CKD). She was on dialysis while awaiting a renal transplant. During her pre-transplant workup, she was found to have anti-Jka and anti-e antibodies making it a challenging scenario. She was listed as a prospective match for a cadaver kidney. Complement dependant Cytotoxicity (CDC) cross-match was negative. But an additional typing was requested for the donor. When found to be Jka-, the next concern arose for any possible blood requirement during the transplant due to her anti-e antibody. Since the required units would have to be Jka-e-, a rare phenotype, it was decided to not allocate the current organ, put her back on dialysis and suitably prepare for the transplant by taking the time to correct her anemia, decide on a suitable operative strategy to minimize blood loss and attempt to arrange antigen negative units for her before the surgery. Case B: A 64 year old female patient suffered from non-alcoholic steatohepatitis(NASH) and was being considered for liver transplant from her son. However routine immunohematological testing before the transplant showed she had anti- Fya antibodies and was Fya-. Her liver donor was Fya+, but all the anticipated required red cell units needed to be Fya-. A total of 56 units were cross-matched to find 5 compatible units. Her surgery was uneventful and she required 3 units of those PRBCs during it. Red cell antigen systems should be taken into consideration in transplantations, atleast on a case-to-case basis, if not routinely, especially in the context of peri-transplant transfusion needs.
The rhizospheric dynamics governing uptake-translocation-excretion processes of current-use pesticides (CUPs) under metal co-exposure remain mechanistically unexplored. This study investigated the sorption dynamic, xylem and phloem translocation, and root excretion of 16 CUPs when copper (Cu) was present within water-rice (Oryza sativa L.) system using hydroponic experiments. The sorption dynamic indicated that more moderately and highly hydrophobic CUPs were taken up by fresh and dead rice roots respectively, indicating that moderately and highly hydrophobic CUPs potentially being taken up via symplastic and apoplastic pathways, respectively. The presence of Cu was found to induce damage to root cell membranes of rice which has limited impact on the root absorption of CUPs indicated by the comparable root concentration factors between sole CUPs and CUPs-Cu treatments. However, the presence of Cu enhanced the acropetal translocation of highly hydrophobic CUPs from root to shoot, with significant higher translocation factors being observed. These findings necessitate revision of conventional hydrophobicitydriven theory that highly hydrophobic organic chemicals were preferentially restricted to roots. Furthermore, the root excretions of moderately hydrophobic CUPs from roots to external solutions via passive diffusion were promoted in the presence of Cu which have not been elucidated previously. The potential ecological risks associated with the translocation, accumulation, and excretion of CUPs by rice needs careful reconsideration in metals-CUPs co-contamination sites.
This review maps the development of Health Policy Analysis (HPA) in low- and middle-income countries (LMICs) since 2008, when Gilson and Raphaely (2008) published a review clarifying the state of the field and tracing its evolution. Subsequent years have seen some progress in capacity strengthening for HPA in LMICs, but the extent of development of the field has not been formally assessed since that time. We used a combination of bibliometric, thematic and narrative analysis to better understand the nature of the research being undertaken, identify weaknesses in the evidence base, and gauge maturation of the field. Despite the relatively restrictive focus of this review, we identified 629 articles reporting empirical studies of LMIC policy experiences, revealing substantial growth in the volume of published HPA since 2008. However, significant imbalances in knowledge production remain, with low-income country experiences, and those of North Africa and Central Asia still neglected, and with the dominance of HIC authors persisting despite efforts to strengthen the field in LMICs. At the same time, the review finds evidence of maturation, reflected in deeper theoretical engagement, greater methodological diversity, the use of comparative approaches to enable causal explanation and cross-context learning, and the emergence of robust bodies of work on specific health policy issues. Taken together, the findings point to a field that has grown in scale, scope and analytic sophistication, but still requires deliberate nurturing. Purposeful efforts by researchers, funders, and institutions are needed to ensure that HPA realises its full potential and contributes to progressive policy change. Improving domestic and regional funding, supporting LMIC institutions and researchers, deepening theoretical engagement, and encouraging analytical HPA that enables explanation and cross-context learning are essential to sustaining the development of the field and ensuring that it continues to generate rigorous, relevant insights and contributes to progressive policy change.
Plant virus-based vectors are gaining significant attention as bioreactors for recombinant protein production due to their broad host range, robust expression levels and cost-effectiveness; however, their practical utility is frequently constrained by severe viral pathogenicity. Notably, the utility of potato virus Y (PVY), the type member of the genus Potyvirus, is severely hampered by its elicitation of tobacco vein necrosis (TVN). Here, we demonstrate that a single synonymous substitution (AAA to AAG) at the K178 codon of P1 causes almost no TVN. Mechanistically, the P1-AAG mutation attenuates the synergistic RNA silencing suppression (RSS) activity typically mediated by the P1/HC-Pro complex. This functional impairment abrogates the virus-induced upregulation of specific host microRNAs (miR6020, miR6164 and miR6021). Using this non-necrotic PVY-P1-AAG vector, we engineered an optimised bioproduction platform. By integrating a GFP-HRV3C fusion tag system with affinity purification and subsequent proteolytic cleavage, we achieved the high-yield synthesis of recombinant human interferons (IFN-α1b and IFN-α2b) in Nicotiana benthamiana and Nicotiana tabacum 'Xanthi'. Codon optimisation of the cargo genes further enhanced protein accumulation, achieving yields of up to 55.2 μg/g fresh leaf weight. Taken together, these results provide new insights into how synonymous substitutions influence potyviral pathogenicity and validate the symptomless P1-AAG vector as a robust system for biomanufacturing value-added proteins.
Background: Segmental arterial mediolysis (SAM) is a rare, non-inflammatory, non-atherosclerotic, non-hereditary arteriopathy of unknown etiology that typically affects medium-sized visceral arteries. The absence of reliable diagnostic criteria poses a significant challenge. Consequently, the diagnosis of SAM should be considered in the setting of a distinctive combination of clinical features, angiographic findings, and histopathology. Renal artery involvement is uncommon, and its occurrence in the donor graft during kidney transplantation (KT) has not previously been reported. Case presentation: We report the case of a kidney graft from a deceased donor in her seventh decade of life, transplanted into a recipient in her seventh decade of life. Donor-recipient ABO compatibility was confirmed, and both complement-dependent cytotoxicity crossmatch and flow cytometry crossmatch were negative. Cold ischemia time was 14 h, and warm ischemia time was 20 min. Immediately after declamping, massive thrombosis of the graft renal artery was observed and confirmed using an intraoperative flowmeter. The arterial anastomosis was taken down, the thrombus was removed, the artery was flushed with heparin, and the anastomosis was reconstructed using interrupted sutures. Despite revision, no arterial flow was detected, and the graft was deemed unsalvageable and explanted. Histopathological examination showed thinning of the tunica media, reduced smooth muscle cells on desmin staining, medial-adventitial dissection, and occlusive thrombosis, findings considered likely attributable to SAM. Conclusions: This case suggests that occult donor arterial wall disease compatible with SAM may present catastrophically during KT and may lead to immediate graft loss despite standard surgical salvage attempts. Although no validated strategy currently exists to screen for or prevent occult SAM in asymptomatic donors, awareness of this entity may assist transplant surgeons and pathologists in the evaluation of unexplained early graft arterial thrombosis, donor-graft vascular pathology, and communication with centres receiving paired organs from the same donor.
This study examined how daily mindfulness relates to the situational sensitivity of emotion regulation-that is, the extent to which individuals adjust their use of cognitive reappraisal and situation modification to the perceived controllability of daily stressors. Drawing on a lifespan perspective, we hypothesized that daily fluctuations in mindfulness would more strongly predict situationally sensitive strategy use in older compared to younger adults. Over 28 days, younger (n = 133, Mage = 24.95) and older adults (n = 119, Mage = 69.50) reported daily mindfulness, their use of emotion regulation strategies in response to the most unpleasant stressor of the day, and their perceived controllability of the stressor. Preliminary analyses indicated that older adults reported higher average levels of mindfulness than younger adults and that daily fluctuations in mindfulness were related to fluctuations in the use of both situation modification and cognitive reappraisal strategies. Unexpectedly, higher daily mindfulness was associated with greater alignment between perceived controllability and strategy use among younger, but not older, adults. When statistically controlling for person-level characteristics (i.e., gender, education, life satisfaction, positive affect, and negative affect), this age-differential effect remained robust for situation modification but was attenuated for cognitive reappraisal. Taken together, these findings suggest that mindfulness supports flexible, context-sensitive emotion, particularly among younger individuals and with regard to the use of situation modification. However, these effects did not extend to older adults or to cognitive reappraisal. (PsycInfo Database Record (c) 2026 APA, all rights reserved).
Rheumatoid arthritis (RA) is a chronic inflammatory disorder associated with a substantially increased risk of cardiovascular (CV) disease, driven by both persistent systemic inflammation and a high burden of traditional cardiometabolic risk factors. In recent years, glucagon-like peptide-1 receptor agonists (GLP-1RAs), licensed for type 2 diabetes mellitus and obesity, have attracted attention for their broader metabolic and cardiovascular benefits, raising the question of their potential role in RA. This scoping review summarizes current evidence on the impact of GLP-1RAs on RA disease activity, CV comorbidities, and the underlying immuno-metabolic mechanisms. Experimental studies suggest that GLP-1RAs could modulate key inflammatory pathways in synovial cells, reducing pro-inflammatory cytokine production, oxidative stress, and tissue-degrading enzymes, while improving mitochondrial function. Although clinical data remains limited, observational studies report improvements in disease activity, inflammatory markers, and pain in patients with RA treated with GLP-1RAs in addition to immunosuppressive treatment. Extensive evidence from randomized trials in metabolic populations demonstrates that GLP-1RAs improve glycemic control, induce significant weight loss, and reduce modestly but consistently blood pressure and atherogenic lipids, ultimately lowering major CV events and mortality. Although this evidence cannot be directly translated to RA populations, early real-world data specific to the disease suggest similar favorable trends, including reductions in cardiometabolic risk factors and thromboembolic events. Taken together, these findings suggest that GLP-1RAs may offer dual benefits in RA by addressing both metabolic dysfunction and inflammation. However, the current evidence base is heterogeneous and largely non-randomized, underscoring the need for dedicated trials.
Background/Objectives: Respiratory syncytial virus (RSV), human metapneumovirus (hMPV), and parainfluenza virus type 3 (PIV3) are leading causes of acute respiratory infections in children and the elderly, yet no licensed T-cell vaccines are available. This study aimed to develop multivalent T-cell vaccine candidates against these pathogens using a live attenuated influenza virus (LAIV) vector platform. Methods: Conserved F, N, and M proteins of RSV, hMPV, and PIV3 were identified through multiple sequence alignments. Fragments enriched with experimentally confirmed and predicted T-cell epitopes were selected using the IEDB and NetMHCpan servers. These fragments were assembled into polyepitope immunogenic cassettes, and their selected order was determined by thermodynamic analysis of mRNA secondary structures using the RNAfold Web Server. The selected cassettes were cloned into the neuraminidase (NA) gene of a cold-adapted LAIV vector. Recombinant viruses were rescued by reverse genetics and assessed for replicative fitness in embryonated chicken eggs and MDCK cells, NA enzymatic activity and genetic stability upon serial passaging. Results: Four cassettes were designed for RSV, three for hMPV, and one for PIV3, all containing fragments with multiple T-cell epitopes. Three recombinant viruses of LAIV/RSV type and three of LAIV/hMPV type were successfully rescued, while attempts to recover the remaining recombinant viruses, i.e., LAIV/RSV and LAIV/PIV3, were not successful. All rescued recombinant viruses replicated to titers comparable to the parental LAIV strain and retained the full-length insert for at least eight passages in eggs. Importantly, NA enzymatic activity of the LAIV vector was not compromised by the insertion of the polyepitope T-cell cassettes. Conclusions: We developed a panel of recombinant T cell-based vaccine candidates against RSV and hMPV using the LAIV vector platform. These recombinant viruses encode conserved T-cell epitopes of the target viruses while retaining the biological properties of LAIV strains. Taken together, these characteristics warrant further evaluation of these recombinant viruses in appropriate relevant in vitro models to directly assess their immunogenicity in terms of stimulating a T-cell response against target pathogens.
Epizootic bovine abortion (EBA) is a devastating late-term abortion caused by Pajaroellobacter abortibovis that, until recently, could only be controlled through management practices. A live epizootic bovine abortion agent (EBAA) vaccine was developed and reported to be both safe and effective in controlled challenge studies. Here we examined vaccine performance with randomized and blinded study conducted under field conditions. The study was divided into phases: safety, breeding efficiency, early fetal loss, and efficacy. An equal number of heifers were inoculated with either placebo or EBAA vaccine, 95 days prior to breeding. No anaphylaxis was observed, and the only notable adverse reactions were mild swelling at the injection site. Heifer conception rates were higher in placebo controls compared to the vaccinates while placebo controls experienced a greater percentage of early fetal losses; neither were significant. Vaccine efficacy was measured by both calving outcomes and production of Pajaroellobacter abortibovis-specific antibody. EBAA vaccinated heifers produced a 10% higher calf crop as compared to controls, though the difference was not significant. Significant differences were found when comparing P. abortibovis-associated losses in vaccinates to controls. Ninety-eight percent of vaccinated heifers seroconverted following vaccination as compared to 0% in the placebo group. Concomitant administration of Brucella abortus Strain RB51 and Anavac® vaccines had little to no effect on EBAA vaccine efficacy. Taken together, data demonstrates vaccine safety and efficacy of EBAA vaccine PCN 1544.00 in the face of natural field exposure.
coexistence of anemia and undernutrition is a major public health concern among children in Mali. However, there is a lack of study looking into the relationship between undernutrition and anemia among children in Mali. Therefore, this study was conducted by using multilevel analysis to identify significant factors associated with the coexistence of anemia and undernutrition among children. A cross-sectional design was conducted from Mali Demographic and Health Survey data from 2023/24. STATA 17 was used for data summarization and analysis. The model was evaluated using the intra-class correlation coefficient (ICC), median odds ratio (MOR), likelihood ratio (LR), and deviance. Variables with a p-value less than 0.2 in the bi-variable logistic regression analysis were taken into account for the next multilevel analysis. In the multilevel analysis, significant factors were presented using the Adjusted Odds Ratio (AOR) along with the 95% Confidence Interval (CI). The prevalence of the coexistence of anemia and undernutrition among children was 26.3% (CI: 25.2%, 27.4%). According to the multilevel logistic regression result, mothers aged 25-34 years (AOR = 1.41; 95% CI: 1.01, 1.96), no education (AOR = 1.51; 95% CI: 1.19, 1.91), primary education (AOR = 1.39; CI: 1.05, 1.84), not covered by health insurance (AOR = 2.18; 95% CI: 1.05, 2.47), rural residents (AOR = 1.46; 95% CI: 1.16, 1.84), and short maternal stature (AOR = 1.83; 95% CI: 1.49, 2.27) were associated with an increased odds of the coexistence of anemia and undernutrition among children. In contrast, tall maternal stature (AOR = 0.29; 95% CI: 0.22, 0.36) and children aged 37-47 months (AOR = 0.70; 95% CI: 0.50, 0.96) were associated with decreasing the odds of the coexistence of anemia and undernutrition among children. In Mali, the coexistence of anemia and undernutrition contributes to mortality and related complications among children. The finding from this study revealed that children whose mothers were aged 25-34, mothers without formal education, mothers without primary education, mothers whose health was not covered by health insurance, children who lived in rural areas, and maternal short stature were associated with increased odds of the coexistence of anemia and undernutrition among children. In contrast, tall maternal stature and children aged 37-47 were associated with decreasing the odds of the coexistence of anemia and undernutrition among children.
To evaluate how often history taking and physical examination are omitted before MRI referral and whether their omission is associated with clinical reasoning quality and MRI diagnostic yield. In this prospective study, adults undergoing MRI at a tertiary academic hospital were surveyed before imaging to determine whether the referring clinician had taken their history and performed a physical examination. Multivariable regression was used to assess determinants of omission and associations with clinical reasoning quality (defined as agreement between the suspected diagnosis and MRI findings) and MRI positivity (defined as findings relevant to the indication). Among 275 patients (median age 61 years; 50.0% male), history taking was omitted in 18.2% of cases and physical examination was omitted in 70.9%. History taking was less likely during surveillance than during new/first visits (odds ratio (OR) 0.140, p < 0.001) and more likely when MRI was requested by residents rather than medical specialists (OR 4.645, p = 0.018). Physical examination was more likely when MRI was requested by residents (OR 3.174, p = 0.007) or nurse specialists/physician assistants (OR 3.145, p = 0.033), and less likely during follow-up visits (OR 0.183, p < 0.001) and surveillance visits (OR 0.061, p < 0.001). Omission of physical examination was not associated with clinical reasoning quality (p = 0.370). Neither omission of history taking nor omission of physical examination was associated with MRI positivity (p = 0.430 and p = 0.286, respectively). History taking and physical examination were often omitted before MRI referral. Although no statistically significant association was observed between omission of bedside assessment and clinical reasoning quality or MRI positivity, reduced bedside assessment may limit the clinical context informing referral and interpretation.
To increase cloud computing utilization and performance, efficient load balancing and resource distribution techniques are essential. Dynamic load balancing and resource allocation in cloud systems is necessary due to a number of reasons, but this is not an easy and straightforward task. The primary goal of dynamic load balancing of cloud systems is to optimize the workload and resource utilization. The Harris Hawks Optimization (HHO) algorithm is a dynamic method of allocating the workloads to the virtual machines (VMs) according to the workload distribution and the use of the resources. The comparison of experimental analysis and other load-balancing methods shows that the HHO algorithm can be used to control dynamic load balancing in a rather efficient and effective way. With such technical developments, there has been a decrease in time taken to respond as well as the use of resources. The suggested solution is a cost-effective and efficient solution to the load-balancing problem in dynamic conditions and is based on the collaborative hawks hunting behavior. The system converts the resource allocation scheme to the changeable cloud application requirements. This is achieved by a multiobjective fitness function which aims to maximize the efficiency of resources, minimize the response time and resource usage. The primary objective of the study is to ensure that the clouds services become effective and sustainable. The Harris Hawks discover the most optimal distribution techniques of activities by closely observing the space of solutions. They then apply positional updates and iterative interactions to adapt to changing workloads. The system dynamically assigns jobs to virtual machines (VMs) without compromising load balance and efficient resource use through the use of the cooperative search behavior of the hawks. The proposed solution effectively manages the cases when the task requirements are constantly changing. Applying a multiobjective fitness function greatly improves key performance metrics like overall performance, resource usage, and reaction time. This study demonstrates how the HHO algorithm increases the effectiveness and robustness of cloud-based services in dynamic operational environments.
Background and Importance Optic nerve gliomas (ONGs) are benign and slow-growing tumors with a variable clinical course that may result in significant morbidity. The variability in tumor burden, challenging anatomy, and associated symptomatology require an individualized and multidisciplinary approach. The relative paucity of cases and variation in surgical anatomy prompt the need for accrual of cases in literature to advance the understanding of surgical techniques to address this rare clinical entity. Clinical Presentation A 19-year-old patient presented with severe and globe-threatening left eye proptosis, negatively affecting quality of life, due to a sporadic intraorbital ONG that had been inexorably growing over the previous 9 years, despite chemotherapy. The patient was taken to the operating room for a single-stage globe-sparing transorbital resection of the intraorbital ONG. The surgical plan consisted of an endoscopic endonasal approach for medial and inferior orbital wall decompression combined with an open lateral orbitotomy, via a lateral canthal incision, for subtotal piecemeal tumor resection to relieve the proptosis, restore alignment of the globe, and yield tissue for molecular analysis. The patient experienced profound improvement in quality of life and opted for radiographic surveillance that has been stable at 5 years. Discussion and Conclusion Surgical approaches to intraorbital tumors have included both transcranial and/or transorbital routes, with the latter more recently encompassing endoscopic endonasal techniques. This report presents the use of a novel combination of transorbital techniques for resection of an intraorbital ONG with severe proptosis, including an endoscopic endonasal approach combined with an open lateral orbitotomy.
The stability and functionality of biomolecules in ionic liquid (IL) environments have garnered significant interest due to their potential applications in biocatalysis, pharmaceutical formulations, and, particularly, protein preservation. In this study, we systematically investigated the effect of three Bmim-based IL-water systems, [BmimAcO-water], [BmimDCA-water], and [BmimPF6-water], on the stability of cytochrome c (Cyt-C) using molecular simulation tools. Our study reveals a significant impact on the structural stability of cytochrome c in different ionic liquids. We show that [BmimAcO-water] is the most suitable solvent for Cyt-C, and it preserves its structural topology better than the other two ionic liquid complexes. In contrast, the [BmimPF6-water] system showed the highest destabilization, particularly near the heme cofactor. The [BmimDCA-water] system exhibited intermediate behavior, with structural stability metrics intermediate between those of the AcO- and PF6- systems. Taken together, these findings highlight the pivotal influence of IL composition on the protein structure and dynamics.
The popularity of simultaneously integrated cognitive training and exercise programs is increasingly adopted as a strategy to mitigate age-related declines in cognitive function and physical fitness, and these benefits may be further enhanced in a social context. However, the effects of integrated programs particularly when delivered as group activities on physical fitness and body composition have not been comprehensively investigated. Therefore, the purpose of this study is to evaluate and compare the effects of the Activ4Brain program on physical fitness and body composition with those of aerobic exercise alone. Seventy-four cognitively healthy older persons, with an average age of 65.5 ± 6.2 years, were assigned to control (n = 27) aerobic exercise (AE) (n = 23) and integrated cognitive and aerobic exercise (Activ4Brain) groups (n = 24). Physical fitness was assessed using a cardiopulmonary exercise test (CPET), timed up and go (TUG), 30 s chair stand, and hand grip strength tests. Body composition was assessed using bioimpedance (Inbody 770, Biospace). Evaluated parameters included body mass index (BMI), fat mass, fat percentage, muscle mass, fat to muscle ratio (FMR), and phase angle (PhA). Measurements were taken before and after the 24-session intervention period. Within-group comparison was done using paired t-test and Wilcoxon signed rank test. Between group comparison was done with one-way Anova or Kruskal Wallis tests by using mean differences for each group. Paired t-test results revealed significant increment in VO2 peak (p=.006), handgrip strength (p=.037), 30-s chair stand test (p=.004) for the AE group. Additionally, Paired t-tests results revealed a significant reduction in fat percentage (p=.019) and increment in hand grip strength (p = 0.019), 30-s chair stand test (p = 0.010), and PhA (p=.029) for the Activ4Brain group. Additionally, although no significant differences were observed in the within-group comparisons for the TUG test in any of the groups, the changes differed significantly between the control and aerobic exercise (AE) groups (p = .033), as indicated by the Kruskal-Wallis test. Both the AE and Activ4Brain interventions resulted in improvements in physical fitness suggesting that the inclusion of cognitive training in the Activ4Brain program did not compromise its ability to also improve physical function. Moreover, the Activ4Brain program also resulted in improvements in body composition by reducing fat percentage and increasing PhA. The Activ4Brain program was a useful strategy to improve physical fitness and maintain body composition in older persons, while also incorporating cognitive training.
Enterotoxigenic Bacteroides fragilis (ETBF), which secretes B. fragilis toxin (BFT) and has been associated with colorectal cancer, can be enriched in patients with gall bladder cancer (GBC). Whether and how ETBF contributes to GBC is unclear. Here we confirm, through analysis of patient samples, that ETBF is enriched in GBC tumours, while experiments in mice show that ETBF colonizes the gall bladder. In vitro and in patient-derived organoids, ETBF promoted GBC proliferation. ETBF also promoted tumour growth in a BFT-dependent manner in a mouse GBC allograft model. Mechanistically, the tumorigenic activity of BFT was dependent on the ETBF surface protein, membrane-bound lytic murein transglycosylase D (MltD), which interacts with the host receptor protein, transmembrane serine protease 13 (TMPRSS13). This interaction activated JAK2-STAT3 signalling to promote tumorigenesis. BFT also activated NF-κB signalling, which increased CXCL1 secretion, leading to myeloid-derived suppressor cell recruitment and angiogenesis in the tumour microenvironment. Taken together, these findings uncover mechanisms through which ETBF facilitates GBC development, with potential promise as therapeutic targets to limit GBC progression.
Background/Objectives: The unprecedented structural and binding data for antibodies to the SARS-CoV-2 virus taken together with the mutations for the spike protein allows for a broad simulation study of antibody-spike protein binding. This provides an understanding of the co-evolution of human immunity and viral immunity escape. Methods: We utilized the YASARA molecular dynamics program to generate initial structures and simulate to equilibration for six SARS-CoV-2 variants and ten different antibodies sampling two different binding regions to the receptor binding domain of the spike (especially for the Class I antibodies in the same part of the spike that attaches to the ACE2 receptor protein) and one to the N-terminal domain of the spike. Starting structures for antibody binding to variant spike protein domains are perturbatively achieved through point mutations and insertions/deletions in the YASARA program. We employed YASARA to measure interfacial hydrogen bound counts between antibodies and variant spike proteins and the HawkDock MMGBSA program to characterize trends in binding energies with mutation for four of the antibodies. We utilized the VMD program to analyze the time course of hydrogen bond populations. Results: As seen in previous studies, interfacial hydrogen bond counts serve as an excellent proxy for binding energies without the large systematic error inherent in the latter. We find that there is generally a decline in antibody binding strength, as measured by interfacial hydrogen bond counts, with viral evolution, but that a modest re-entrance of binding strength is present for most antibodies studied. Generically, the antibody heavy chain binds more strongly to the spike protein, though for approximately half the antibodies the light chain binding strength converges to the heavy chain strength with viral evolution. Conclusions: The key conclusion is that the identified re-entrant immunity, speculatively arising from a balancing of maintenance of ACE2-spike binding while escaping antibodies through mutation, allows for some maintenance and even strengthening of immunity for later viral strains from early infection or vaccination.
Face identity recognition (FIR) is a key function for human social interactions, supported by specialized neural mechanisms. Previous studies have reported remarkable resilience of FIR to large vertical (i.e., top to bottom) or horizontal (i.e., ear-to-ear) compression of images, generally taken as evidence that spatial (configural) cues may play a limited role in this function. However, resistance of FIR to single-axis image compression rests on limited evidence, i.e., behavioral accuracy rates obtained with repeated iconic familiar face images presented for extended response windows. Here we objectively quantify the impact of single-axis image compression on implicit neural markers of single glance FIR. Twenty-one participants were tested in a well-validated paradigm, viewing the same unfamiliar face presented 6 times per second at one of five horizontal compression levels (0%, 22%, 45%, 67%, 90%), with various identity changes occurring periodically every five faces. Robust electroencephalographic (EEG) FIR responses observed over the occipito-temporal cortex at 1.2 Hz harmonics were fully preserved at a low compression level (22%) but sharply declined with increasing compression levels, showing 40% amplitude reduction at 2/3 image compression and near-complete suppression at 90%. These observations provide original evidence against a widespread view that single-axis, in particular horizontal, image compression has little effect on human FIR. Impairment of FIR with horizontal image compression can be attributed to distortion of relative distances between features, but also to the shape of local features and of the overall face structure.
To assess prevalence and associations of localized thinnings of the interdigitation zone ("IZT") without adjacent drusen or reticular pseudodrusen in a general population, affected by age-related macular degeneration (AMD), or free of any other retinal disease. On optical coherence tomographic images, taken from the macula of participants of the population-based Beijing Eye Study, we searched for IZTs. The study population included 1271 eyes (mean age:64.7 ± 9.8 years; range:50-91 years). IZT prevalence increased from 2/442 (0.5%;95%CI:0.0,1.0) in the normal group to 49/543 (9.0%;95%CI:7.0,11.0), 90/275 (32.7%;95%CI:27.2,38.2), and 9/11 (81.8%;95%CI:55.0,100) in eyes with early, intermediate or late AMD (geographic atrophy), respectively. IZTs were spatially associated with ellipsoid zone (EZ) defects (114/150 (76.0%) eyes), external limiting membrane (ELM) defects (92/150 (61.3%) eyes), any intraretinal hyperreflective foci (iHRF) (143/150 (95.2%) eyes), iHRFs in the outer nuclear layer or beyond (111/150 (74.0%) eyes), macular hypopigmentation (76/150 (50.7%) eyes), and RPE hypertransmission (46/150 (30.7%) eyes), in addition to a non-spatial association with a higher prevalence of outer nuclear layer thinning (48/150 (32.0%) eyes). Higher IZT prevalence correlated (multivariable analysis) with higher AMD stage (OR:1.28;95%CI:1.08,1.51;P = 0.004), and higher prevalences of EZ defects (OR:7.97;95%CI:4.20,15.1;P < 0.001), iHRFs with a smoke-like appearance in the outer nuclear layer (OR:2.52;95%CI:1.32,4.82;P = 0.005), RPE hypertransmissions (OR:12.6;95%CI:2.92,54.7;P < 0.001), and outer nuclear layer thinning (OR:27.5;95%CI:6.12,123;P < 0.001). IZTs are a common feature of AMD including the early AMD stage. Their spatial association with defects in the overlying EZ, IHRFs and macular hypopigmentations may warrant further research of a potential involvement of an intraretinal RPE cell migration in the IZT etiology.
The innate immune response is a critical defense mechanism by which vertebrates recognize and eliminate invading pathogens. Pattern recognition receptors (PRRs) detect pathogen-associated molecular patterns and activate downstream signaling pathways. NOD1, a classic PRR of the NLR family, recruits the adaptor protein RIPK2 to initiate antibacterial signaling. In this study, we cloned and characterized the NOD1 gene from snakehead (Channa argus). Briefly, the full-length NOD1 cDNA is 2829 bp encoding 943 amino acids, showing high homology with Perciformes. The qPCR analysis revealed widespread NOD1 gene expression in various tissues, with significant upregulation in the gill (p < 0.05) and spleen (p < 0.05) following bacterial infection. Overexpression of the NOD1 gene activated the NF-κB signaling pathway in a dose- and time-dependent manner, and specifically responded to the bacterial ligand iE-DAP but not to other tested ligands. Furthermore, NOD1 synergized with the downstream adaptor RIPK2 to enhance NF-κB activity, and direct protein interaction between NOD1 and RIPK2 was confirmed by co-immunoprecipitation. Taken together, these findings demonstrate that snakehead NOD1 plays a critical role in the host antimicrobial immune response.