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Abstract Vaccines to the Plasmodium falciparum reticulocyte binding-like protein homologue 5 (PfRH5) target the blood-stage of the parasite life cycle. PfRH5 has the potential to trigger the production of strain-transcendent antibodies and has proven its efficacy both in pre-clinical and early clinical studies. Vaccine-induced monoclonal antibodies (mAbs) to PfRH5 showed promising outcomes against cultured P. falciparum laboratory strains from distinct geographic areas. Here, we assessed the functional impact of vaccine-induced anti-PfRH5 mAbs on more genetically diverse P. falciparum clinical isolates. We used mAbs previously isolated from single B cells of UK adult PfRH5 vaccinees and used ex-vivo growth inhibition activity (GIA) assays to assess their efficacy against P. falciparum clinical isolates. Next-generation sequencing (NGS) was used to assess the breadth of genetic diversity in P. falciparum clinical isolates and to infer the genotype/phenotype relationship involved in antibody susceptibility. We showed a dose-dependent inhibition of clinical isolates with three main GIA groups: high, medium and low. Except for one isolate, our data show no significant differences in the mAb GIA profile between P. falciparum clinical isolates and the 3D7 reference strain, which harbors the vaccine allele. We also observed an additive relationship for mAb combinations, whereby the combination of GIA-low and GIA-medium antibodies resulted in increased GIA, having important implications for the contribution of specific clones within polyclonal IgG responses. While our NGS analysis showed the occurrence of novel mutations in the pfrh5 gene, these mutations were predicted to have little or no functional impact on the antigen structure or recognition by known mAbs. Our present findings complement earlier reports on the strain transcendent potential of anti-PfRH5 mAbs and constitute, to our knowledge, the first report on the susceptibility of P. falciparum clinical isolates from natural infections to vaccine-induced human mAbs to PfRH5.

Abstract Background The World Health Organization predicted 10.6 million new tuberculosis cases and 1.5 million deaths in 2022. Tuberculous meningitis, affecting 1% of active TB cases, is challenging to diagnose due to sudden onset, vague symptoms, and limited laboratory tests. Nanopore-targeted sequencing (NTS) is an emerging third-generation sequencing technology known for its sequencing capabilities. We compared its detection efficiency with Xpert, MTB culture, PCR, and AFB smear in cerebrospinal fluid samples to highlight the substantial potential of NTS in detecting intracranial tuberculosis. Methods This study included 122 patients suspected of having intracranial tuberculosis at the Second Hospital of Nanjing in Jiangsu Province, China, between January 2021 and January 2024. The Univariate logistic regression and random forest regression identified risk factors and clinical markers. A chi-square test evaluated diagnostic accuracy for different image types of intracranial tuberculosis. Results The research involved 100 patients with intracranial tuberculosis. Among them, 41 had tuberculous meningitis, 27 had cerebral parenchymal tuberculosis, and 32 had mixed intracranial tuberculosis. Besides, 22 patients were diagnosed with other brain conditions. In diagnosing intracranial tuberculosis, NTS demonstrated a sensitivity of 60.0% (95% CI: 49.7-69.5%) and a specificity of 95.5% (95% CI:75.1-99.8%), with an AUC value of 0.78 (95% CI: 0.71 to 0.84), whose overall performance was significantly better than other detection methods. There was no notable difference (P > 0.05) in diagnostic accuracy between NTS and the final diagnosis for intracranial tuberculosis patients with varying imaging types. Furthermore, patients who tested positive had a 31.500 (95% CI: 6.205-575.913) times higher risk of having intracranial tuberculosis compared to those with negative results. Conclusion Due to its convenience, efficiency, quick turnaround time, and real-time sequencing analysis, NTS might become a promising and reliable method for providing microbiological diagnoses for patients with intracranial tuberculosis and for screening populations at risk.

Summary: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-neutralizing antibodies are substantially expanded 1 month after a shot of XBB.1.5 monovalent mRNA vaccine (XBB.1.5 MV) booster, but the durability of this response remains unknown. Here, we address this question by performing neutralization assays on four viral variants (D614G, BA.5, XBB.1.5, and JN.1) using sera from participants obtained at ∼1 month, ∼3 months, and ∼6 months post an XBB.1.5 MV booster. Our findings indicate that the resulting neutralizing antibody titers are robust and generally remain at stable levels for the study period, similar to those following XBB infection. Importantly, this durability of neutralizing antibody titers contrasts with the decline observed after a booster of the original monovalent or BA.5 bivalent mRNA vaccine. Our results are in line with the recent national data from the Centers for Disease Control and Prevention, showing that the efficacy against symptomatic SARS-CoV-2 infection is sustained for up to 4 months after an XBB.1.5 MV booster.

Abstract The successful reprogramming of impaired wound healing presents ongoing challenges due to the impaired tissue microenvironment caused by severe bacterial infection, excessive oxidative stress, as well as the inappropriate dosage timing during different stages of the healing process. Herein, a dual-layer hydrogel with sodium alginate (SA)-loaded zinc oxide (ZnO) nanoparticles and poly(N-isopropylacrylamide) (PNIPAM)-loaded Cu5.4O ultrasmall nanozymes (named programmed time-released multifunctional hydrogel, PTMH) was designed to dynamically regulate the wound inflammatory microenvironment based on different phases of wound repairing. PTMH combated bacteria at the early phase of infection by generating reactive oxygen species through ZnO under visible-light irradiation with gradual degradation of the lower layer. Subsequently, when the upper layer was in direct contact with the wound tissue, Cu5.4O ultrasmall nanozymes were released to scavenge excessive reactive oxygen species. This neutralized a range of inflammatory factors and facilitated the transition from the inflammatory phase to the proliferative phase. Furthermore, the utilization of Cu5.4O ultrasmall nanozymes enhanced angiogenesis, thereby facilitating the delivery of oxygen and nutrients to the impaired tissue. Our experimental findings indicate that PTMHs promote the healing process of diabetic wounds with bacterial infection in mice, exhibiting notable antibacterial and anti-inflammatory properties over a specific period of time.

The recently dominant SARS-CoV-2 Omicron JN.1 has evolved into multiple sublineages, with recurrent spike mutations R346T, F456L, and T572I, some of which exhibit growth advantages, such as KP.2 and KP.3. We investigated these mutations in JN.1, examining their individual and combined effects on immune evasion, ACE2 receptor affinity, and in vitro infectivity. F456L increased resistance to neutralization by human sera, including those after JN.1 breakthrough infections, and by RBD class-1 monoclonal antibodies, significantly altering JN.1 antigenicity. R346T enhanced ACE2-binding affinity and modestly boosted the infectivity of JN.1 pseudovirus, without a discernible effect on serum neutralization, while T572I slightly bolstered evasion of SD1-directed mAbs against JN.1's ancestor, BA.2, possibly by altering SD1 conformation. Importantly, expanding sublineages such as KP.2 containing R346T, F456L, and V1104L, showed similar neutralization resistance as JN.1 with R346T and F456L, suggesting V1104L does not appreciably affect antibody evasion. Furthermore, the hallmark mutation Q493E in KP.3 significantly reduced ACE2-binding affinity and viral infectivity, without noticeably impacting serum neutralization. Our findings illustrate how certain JN.1 mutations confer growth advantages in the population and could inform the design of the next COVID-19 vaccine booster.

As SARS-CoV-2 continues to spread and mutate, tracking the viral evolutionary trajectory and understanding the functional consequences of its mutations remain crucial. Here, we characterized the antibody evasion, ACE2 receptor engagement, and viral infectivity of the highly mutated SARS-CoV-2 Omicron subvariant BA.2.87.1. Compared with other Omicron subvariants, including EG.5.1 and the current predominant JN.1, BA.2.87.1 exhibits less immune evasion, reduced viral receptor engagement, and comparable infectivity in Calu-3 lung cells. Intriguingly, two large deletions (Δ15-26 and Δ136-146) in the N-terminal domain (NTD) of the spike protein facilitate subtly increased antibody evasion but significantly diminish viral infectivity. Collectively, our data support the announcement by the USA CDC that the public health risk posed by BA.2.87.1 appears to be low.

ObjectiveDiagnosing tuberculosis (TB) can be particularly challenging in the absence of sputum for pulmonary tuberculosis cases and extrapulmonary TB (EPTB). This study evaluated the utility of nanopore-based targeted next-generation sequencing (tNGS) for diagnosing TB in tissue samples, and compared its efficacy with other established diagnostic methods.MethodsA total of 110 tissue samples from clinical cases were examined. The sensitivity and specificity of tNGS were benchmarked against a range of existing diagnostic approaches including hematoxylin and eosin (HE) staining in conjunction with acid-fast bacilli (AFB) detection, HE staining combined with PCR, HE staining paired with immunohistochemistry (IHC) using anti-MPT64, and the Xpert Mycobacterium tuberculosis (MTB)/rifampicin (RIF) assay.ResultsThe sensitivity and specificity of tNGS were 88.2 and 94.1%, respectively. The respective sensitivities for HE staining combined with AFB, HE staining combined with PCR, HE staining combined with IHC using anti-MPT64, and Xpert MTB/RIF were 30.1, 49.5, 47.3, and 59.1%. The specificities for these methods were 82.4, 88.2, 94.1, and 94.1%, respectively. Analysis of drug resistance based on tNGS results indicated that 10 of 93 TB patients (10.75%) had potential drug resistance.ConclusionTargeted next-generation sequencing achieved higher accuracy than other established diagnostic methods, and can play a crucial role in the rapid and accurate diagnosis of TB, including drug-resistant TB.

The modulation classification technology for radar intra-pulse signals is important in the electronic countermeasures field. As the high quality labeled radar signals are difficult to be captured in the real applications, the signal modulation classification base on the limited number of labeled samples is playing a more and more important role. To relieve the requirement of the labeled samples, many self-supervised learning (SeSL) models exist. However, as they cannot fully explore the information of the labeled samples and rely significantly on the unlabeled samples, highly time-consuming processing of the pseudo-labels of the unlabeled samples is caused. To solve these problems, a supervised learning (SL) model, using the contrastive learning (CL) method (SL-CL), is proposed in this paper, which achieves a high classification accuracy, even adopting limited number of labeled training samples. The SL-CL model uses a two-stage training structure, in which the CL method is used in the first stage to effectively capture the features of samples, then the multilayer perceptron is applied in the second stage for the classification. Especially, the supervised contrastive loss is constructed to fully exploring the label information, which efficiently increases the classification accuracy. In the experiments, the SL-CL outperforms the comparison models in the situation of limited number of labeled samples available, which reaches 94% classification accuracy using 50 samples per class at 5 dB SNR.

Spiral arms are one of the most important features used to classify the morphology of local galaxies. The cosmic epoch when spiral arms first appeared contains essential clues to the evolution of disk galaxies. In this Letter, we used James Webb Space Telescope images from the Cosmic Evolution Early Release Science Survey to visually identify spiral galaxies with redshift 0.5 ≤ z ≤ 4 and stellar mass ≥10 ^10 M _⊙ . Out of 873 galaxies, 216 were found to have a spiral structure. The spiral galaxies in our sample have higher star formation rates and larger sizes than nonspiral galaxies. We found the observed spiral fraction decreases from 48% at z ∼ 0.75 to 8% at z ∼ 2.75. These fractions are higher than the fractions observed with the Hubble Space Telescope. We even detect possible spiral-like features at redshifts z > 3. We artificially redshifted low-redshift galaxies to high redshifts and reinspected them to evaluate observational effects. By varying the input spiral fraction of the redshifted sample, we found that the input fraction of ∼35% matches the observed fraction at z = 2–3 the best. We are able to rule out spiral fractions being

ABSTRACTThe SARS-CoV-2 Omicron subvariants have dominated the pandemic due to their high transmissibility and immune evasion conferred by the spike mutations. The Omicron subvariants can spread by cell-free virus infection and cell–cell fusion, the latter of which is more effective but has not been extensively investigated. In this study, we developed a simple and high-throughput assay that provides a rapid readout to quantify cell–cell fusion mediated by the SARS-CoV-2 spike proteins without using live or pseudotyped virus. This assay can be used to identify variants of concern and to screen for prophylactic and therapeutic agents. We further evaluated a panel of monoclonal antibodies (mAbs) and vaccinee sera against D614G and Omicron subvariants, finding that cell–cell fusion is substantially more resistant to mAb and serum inhibition than cell-free virus infection. Such results have important implications for the development of vaccines and antiviral antibody drugs against cell–cell fusion induced by SARS-CoV-2 spikes.

Summary: SARS-CoV-2 Omicron BA.2.75 has diversified into multiple subvariants with additional spike mutations and several are expanding in prevalence, particularly CH.1.1 and BN.1. Here, we investigated the viral receptor affinities and neutralization evasion properties of major BA.2.75 subvariants actively circulating in different regions worldwide. We found two distinct evolutionary pathways and three newly identified mutations that shaped the virological features of these subvariants. One phenotypic group exhibited a discernible decrease in viral receptor affinities, but a noteworthy increase in resistance to antibody neutralization, as exemplified by CH.1.1, which is apparently as resistant as XBB.1.5. In contrast, a second group demonstrated a substantial increase in viral receptor affinity but only a moderate increase in antibody evasion, as exemplified by BN.1. We also observed that all prevalent SARS-CoV-2 variants in the circulation presently, except for BN.1, exhibit profound levels of antibody evasion, suggesting this is the dominant determinant of virus transmissibility today.

Abstract Background Cell therapy is a key technology to prevent sacrificing normal skin. Although some studies have shown the promise of human epidermal stem cells (EpiSCs), the efficacy, biosafety and quality control of EpiSC therapy have not been systematically reported. Methods The biosafety, stemness maintenance and wound repair of EpiSC were systematically verified by in vitro and in vivo experiments. EpiSC were prepared from the foreskin using a collagen type IV rapid adherence method. The EpiSCs were identified by flow cytometry, immunofluorescence staining and cell morphology. The well-growing passage 1 (P1) EpiSCs were used to determine the proliferation curve (counting method). EpiSC clone formation assay was performed by Giemsa staining. Nude mice were used to prepare a full-thickness skin defect wound model to detect the repair effect of EpiSCs. The biosafety of EpiSCs was double tested in vitro and in vivo. Results The results showed that the expression of specific markers and clone formation efficiency was stable when passage 1 (P1) to P8 cells were cultured, and the stemness rate of P8 cells was close to 85.1%. EpiSCs were expanded in vitro for 25 days, the number of cells reached 2.5 × 108, and the transplantable area was approximately 75% of the total body surface area (TBSA). At 45 days, the total number of cells was approximately 30 billion, and the transplantable area was approximately the size of a volleyball court. A nude mouse wound model indicated that EpiSCs could rapidly close a wound. On postinjury day 7, the wound epithelialization rate in the cell transplantation group was significantly higher than that in the NaCl group (P

The repeated emergence of highly pathogenic human coronaviruses as well as their evolving variants highlight the need to develop potent and broad-spectrum antiviral therapeutics and vaccines. By screening monoclonal antibodies (mAbs) isolated from COVID-19-convalescent patients, we found one mAb, 2-36, with cross-neutralizing activity against SARS-CoV. We solved the cryo-EM structure of 2–36 in complex with SARS-CoV-2 or SARS-CoV spike, revealing a highly conserved epitope in the receptor-binding domain (RBD). Antibody 2–36 neutralized not only all current circulating SARS-CoV-2 variants and SARS-COV, but also a panel of bat and pangolin sarbecoviruses that can use human angiotensin-converting enzyme 2 (ACE2) as a receptor. We selected 2-36-escape viruses in vitro and confirmed that K378 T in SARS-CoV-2 RBD led to viral resistance. Taken together, 2–36 represents a strategic reserve drug candidate for the prevention and treatment of possible diseases caused by pre-emergent SARS-related coronaviruses. Its epitope defines a promising target for the development of a pan-sarbecovirus vaccine.

Abstract The recent stall in the global reduction of malaria deaths has made the development of a highly effective vaccine essential. A major challenge to developing an efficacious vaccine is the extensive diversity of Plasmodium falciparum antigens. While genetic diversity plays a major role in immune evasion and is a barrier to the development of both natural and vaccine-induced protective immunity, it has been under-prioritized in the evaluation of malaria vaccine candidates. This study uses genomic approaches to evaluate genetic diversity in next generation malaria vaccine candidate PfRh5. We used targeted deep amplicon sequencing to identify non-synonymous Single Nucleotide Polymorphisms (SNPs) in PfRh5 (Reticulocyte-Binding Protein Homologue 5) in 189 P. falciparum positive samples from Southern Senegal and identified 74 novel SNPs. We evaluated the population prevalence of these SNPs as well as the frequency in individual samples and found that only a single SNP, C203Y, was present at every site. Many SNPs were unique to the individual sampled, with over 90% of SNPs being found in just one infected individual. In addition to population prevalence, we assessed individual level SNP frequencies which revealed that some SNPs were dominant (frequency of greater than 25% in a polygenomic sample) whereas most were rare, present at 2% or less of total reads mapped to the reference at the given position. Structural modeling uncovered 3 novel SNPs occurring under epitopes bound by inhibitory monoclonal antibodies, potentially impacting immune evasion, while other SNPs were predicted to impact PfRh5 structure or interactions with the receptor or binding partners. Our data demonstrate that PfRh5 exhibits greater genetic diversity than previously described, with the caveat that most of the uncovered SNPs are at a low overall frequency in the individual and prevalence in the population. The structural studies reveal that novel SNPs could have functional implications on PfRh5 receptor binding, complex formation, or immune evasion, supporting continued efforts to validate PfRh5 as an effective malaria vaccine target and development of a PfRh5 vaccine.

The UltraViolet imaging of the Cosmic Assembly Near-infrared Deep Extragalactic Legacy Survey Fields (UVCANDELS) program provides deep Hubble Space Telescope (HST) F275W and F435W imaging over four CANDELS fields (GOODS-N, GOODS-S, COSMOS, and Extended Groth Strip). We combine this newly acquired UV imaging with existing HST imaging from CANDELS as well as existing ancillary data to obtain robust photometric redshifts and reliable estimates for galaxy physical properties for over 150,000 galaxies in the ∼430 arcmin ^2 UVCANDELS area. Here, we leverage the power of the new UV photometry to not only improve the photometric redshift measurements in these fields, but also constrain the full redshift probability distribution combining multiple redshift-fitting tools. Furthermore, using the full UV-to-IR photometric data set, we measure the galaxy physical properties by fitting templates from population synthesis models with two different parameterizations (flexible and fixed form) of the star formation histories (SFHs). Compared to the flexible SFH parameterization, we find that the fixed-form SFHs systematically underestimate the galaxy stellar masses, both at the low-mass (≲10 ^9 M _⊙ ) and high-mass (≳10 ^10 M _⊙ ) end, by as much as ∼0.5 dex. This underestimation is primarily due the limited ability of fixed-form SFH parameterization to simultaneously capture the chaotic nature of star formation in these galaxies.

UVCANDELS is a Hubble Space Telescope Cycle-26 Treasury Program awarded 164 orbits of primary ultraviolet (UV) F275W imaging and coordinated parallel optical F435W imaging in four CANDELS fields—GOODS-N, GOODS-S, EGS, and COSMOS—covering a total area of ∼426 arcmin ^2 . This is ∼2.7 times larger than the area covered by previous deep-field space UV data combined, reaching a depth of about 27 and 28 ABmag (5 σ in 0.”2 apertures) for F275W and F435W, respectively. Along with new photometric catalogs, we present an analysis of the rest-frame UV luminosity function (LF), relying on our UV-optimized aperture photometry method, yielding a factor of 1.5 increase over H-isophot aperture photometry in the signal-to-noise ratios of galaxies in our F275W imaging. Using well-tested photometric redshift measurements, we identify 5810 galaxies at redshifts 0.6 < z < 1, down to an absolute magnitude of M _UV = −14.2. In order to minimize the effect of uncertainties in estimating the completeness function, especially at the faint end, we restrict our analysis to sources above 30% completeness, which provides a final sample of 4726 galaxies at −21.5 < M _UV < −15.5. We performed a maximum likelihood estimate to derive the best-fit parameters of the UV LF. We report a best-fit faint-end slope of $\alpha =-{1.359}_{-0.041}^{+0.041}$ at z ∼ 0.8. Creating subsamples at z ∼ 0.7 and z ∼ 0.9, we observe a possible evolution of α with redshift. The unobscured UV luminosity density at M _UV < −10 is derived as ${\rho }_{{\rm{U}}{\rm{V}}}={1.339}_{-0.030}^{+0.027}\,(\times {10}^{26}\,{\rm{e}}{\rm{r}}{\rm{g}}\,{{\rm{s}}}^{-1}\,{{\rm{H}}{\rm{z}}}^{-1}\,{{\rm{M}}{\rm{p}}{\rm{c}}}^{-3})$ using our best-fit LF parameters. The new F275W and F435 photometric catalogs from UVCANDELS have been made publicly available on the Barbara A. Mikulski Archive for Space Telescopes.

We use the Ultraviolet Imaging of the Cosmic Assembly Near-infrared Deep Extragalactic Legacy Survey fields (UVCANDELS) to measure half-light radii in the rest-frame far-UV for ∼16,000 disk-like galaxies over 0.5 ≤ z ≤ 3. We compare these results to rest-frame optical sizes that we measure in a self-consistent way and find that the stellar mass–size relation of disk galaxies is steeper in the rest-frame UV than in the optical across our entire redshift range. We show that this is mainly driven by massive galaxies (≳10 ^10 M _⊙ ), which we find to also be among the most dusty. Our results are consistent with the literature and have commonly been interpreted as evidence of inside-out growth wherein galaxies form their central structures first. However, they could also suggest that the centers of massive galaxies are more heavily attenuated than their outskirts. We distinguish between these scenarios by modeling and selecting galaxies at z = 2 from the VELA simulation suite in a way that is consistent with UVCANDELS. We show that the effects of dust alone can account for the size differences we measure at z = 2. This indicates that, at different wavelengths, size differences and the different slopes of the stellar mass–size relation do not constitute evidence for inside-out growth.

Accurate identification of beneficial mutations is central to antibody design. Many knowledge-based (KB) computational approaches have been developed to predict beneficial mutations, but their accuracy leaves room for improvement. Thermodynamic integration (TI) is an alchemical free energy algorithm that offers an alternative technique for identifying beneficial mutations, but its performance has not been evaluated. In this study, we developed an efficient TI protocol with high accuracy for predicting binding free energy changes of antibody mutations. The improved TI method outperforms KB methods at identifying both beneficial and deleterious mutations. We observed that KB methods have higher accuracies in predicting deleterious mutations than beneficial mutations. A pipeline using KB methods to efficiently exclude deleterious mutations and TI to accurately identify beneficial mutations was developed for high-throughput mutation scanning. The pipeline was applied to optimize the binding affinity of a broadly sarbecovirus neutralizing antibody 10-40 against the circulating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) omicron variant. Three identified beneficial mutations show strong synergy and improve both binding affinity and neutralization potency of antibody 10-40. Molecular dynamics simulation revealed that the three mutations improve the binding affinity of antibody 10-40 through the stabilization of an altered binding mode with increased polar and hydrophobic interactions. Above all, this study presents an accurate and efficient TI-based approach for optimizing antibodies and other biomolecules.

Summary: A better understanding of the durability and breadth of serum-neutralizing antibody responses against multiple severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants elicited by COVID-19 vaccines is crucial in addressing the current pandemic. In this study, we quantified the decay of serum neutralization antibodies (nAbs) after second and third doses of the original COVID-19 mRNA vaccine. Using an authentic virus-neutralization assay, we found that decay half-lives of WA1- and Delta-nAbs were both ∼60 days after second and third vaccine dose. Unexpectedly, the durability of serum antibodies that neutralize three different Omicron subvariants (BA.1.1, BA.5, BA.2.12.1) was substantially better, with half-lives of ≥6 months. A booster dose of the original COVID-19 vaccine was also found to broaden antibody responses against SARS-CoV and four other sarbecoviruses, in addition to multiple SARS-CoV-2 strains. These findings suggest that repeated vaccinations with the COVID-19 vaccine may confer a degree of protection against future spillover of sarbecoviruses from animal reservoirs.

We present measurements of [Ne iii ] λ 3869 emission in z ∼ 1 low-mass galaxies taken from the Keck/DEIMOS spectroscopic surveys HALO7D and DEEPwinds. We identify 167 individual galaxies with significant [Ne iii ] emission lines, including 112 “dwarf” galaxies with $\mathrm{log}({M}_{\star }/{M}_{\odot })\lt \,9.5$ , with 0.3 < z < 1.4. We also measure [Ne iii ] emission from composite spectra derived from all [O ii ] λλ 3727,3729 line emitters in this range. This provides a unique sample of [Ne iii ] emitters between well-studied emitters at z = 0 and 2 < z < 3. To study evolution in ionization conditions in the interstellar medium (ISM) over this time, we analyze the log([Ne iii ] λ 3869/[O ii ] λλ 3727,3729) ratio (Ne3O2) as a function of the stellar mass and of the log([O iii ] λλ 4959,5007/[O ii ] λλ 3727,3729) ratio (O32). We find that the typical star-forming dwarf galaxy at this redshift, as measured from the composite spectra, shares the Ne3O2– M _⋆ relation with local galaxies but has higher O32 at a given Ne3O2. This finding implies that the ionization and metallicity characteristics of the z ∼ 1 dwarf population do not evolve substantially from z ∼ 1 to z = 0, suggesting that the known evolution in those parameters from z ∼ 2 has largely taken place by z ∼ 1. Individual [Ne iii ]-detected galaxies have emission characteristics situated between local and z ∼ 2 galaxies, with elevated Ne3O2 and O32 emission potentially explained by variations in stellar and nebular metallicity. We also compare our dwarf sample to similarly low-mass z > 7 galaxies identified in JWST Early Release Observations, finding four HALO7D dwarfs with similar size, metallicity, and star formation properties.

Background: SARS-CoV-2 antigen-based tests are well-calibrated to infectiousness and have a critical role to play in the COVID-19 public health response. We report the development and performance of a unique lateral flow immunoassay (LFA). Methods: Combinations of several monoclonal antibodies targeting multiple antigenic sites on the SARS-CoV-2 nucleocapsid protein (NP) were isolated, evaluated, and chosen for the development of a LFA termed CoV-SCAN (BioMedomics, Inc.). Clinical point-of-care studies in symptomatic and asymptomatic individuals were conducted to evaluate positive predictive agreement (PPA) and negative predictive agreement (NPA) with RT-PCR as comparator. Results: In laboratory testing, CoV-SCAN detected 14 recombinant N-proteins of SARS-CoV-2 variants with sensitivity in the range of 0.2–3.2 ng/mL, and 10 authentic SARS-CoV-2 variants with sensitivity in the range of 1.6–12.5 TCID50/swab. No cross reactivity was observed with other human coronaviruses or other respiratory pathogens. In clinical point-of-care testing on 148 individuals over age 2 with symptoms of ≤5 days, PPA was 87.2% (CI 95: 78.3–94.8%) and NPA was 100% (CI 95: 94.2–100%). In another 884 asymptomatic individuals, PPA was 85.7% (CI 95: 42.1–99.6%) and 99.7% (99.0–99.9%). Overall, CoV-SCAN detected over 97.2% of specimens with CT values

Summary: The recently emerged B.1.1.529 (Omicron) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant has a highly divergent spike (S) glycoprotein. We compared the functional properties of B.1.1.529 BA.1 S with those of previous globally prevalent SARS-CoV-2 variants, D614G and B.1.617.2. Relative to these variants, B.1.1.529 S exhibits decreases in processing, syncytium formation, virion incorporation, and ability to mediate infection of cells with high TMPRSS2 expression. B.1.1.529 and B.1.617.2 S glycoproteins bind ACE2 with higher affinity than D614G S. The unliganded B.1.1.529 S trimer is less stable at low temperatures than the other SARS-CoV-2 Ss, a property related to its more “open” S conformation. Upon ACE2 binding, the B.1.1.529 S trimer sheds S1 at 37°C, but not at 0°C. B.1.1.529 pseudoviruses are relatively resistant to neutralization by sera from patients with coronavirus disease 2019 (COVID-19) and vaccinees. These properties of the B.1.1.529 S glycoprotein likely influence the transmission, cytopathic effects, and immune evasion of this emerging variant.

Abstract Background Pulmonary arterial hypertension (PAH) is a lethal vasculopathy characterized by pathogenic remodeling of pulmonary arterioles leading to increased pulmonary pressures, right ventricular hypertrophy, and heart failure. PAH can be associated with other diseases (APAH: connective tissue diseases, congenital heart disease, and others) but often the etiology is idiopathic (IPAH). Mutations in bone morphogenetic protein receptor 2 (BMPR2) are the cause of most heritable cases but the vast majority of other cases are genetically undefined. Methods To identify new risk genes, we utilized an international consortium of 4241 PAH cases with exome or genome sequencing data from the National Biological Sample and Data Repository for PAH, Columbia University Irving Medical Center, and the UK NIHR BioResource – Rare Diseases Study. The strength of this combined cohort is a doubling of the number of IPAH cases compared to either national cohort alone. We identified protein-coding variants and performed rare variant association analyses in unrelated participants of European ancestry, including 1647 IPAH cases and 18,819 controls. We also analyzed de novo variants in 124 pediatric trios enriched for IPAH and APAH-CHD. Results Seven genes with rare deleterious variants were associated with IPAH with false discovery rate smaller than 0.1: three known genes (BMPR2, GDF2, and TBX4), two recently identified candidate genes (SOX17, KDR), and two new candidate genes (fibulin 2, FBLN2; platelet-derived growth factor D, PDGFD). The new genes were identified based solely on rare deleterious missense variants, a variant type that could not be adequately assessed in either cohort alone. The candidate genes exhibit expression patterns in lung and heart similar to that of known PAH risk genes, and most variants occur in conserved protein domains. For pediatric PAH, predicted deleterious de novo variants exhibited a significant burden compared to the background mutation rate (2.45×, p = 2.5e−5). At least eight novel pediatric candidate genes carrying de novo variants have plausible roles in lung/heart development. Conclusions Rare variant analysis of a large international consortium identified two new candidate genes—FBLN2 and PDGFD. The new genes have known functions in vasculogenesis and remodeling. Trio analysis predicted that ~ 15% of pediatric IPAH may be explained by de novo variants.

Abstract Objective Epidermal stem cells (EpSCs) can self-renew, which are responsible for the long-term maintenance of the skin, and it also plays a critical role in wound re-epithelization, but the mechanism underlying EpSCs proliferation is unclear. GDF-5, also known as BMP-14, is a member of the BMP family and can be used as a self-renewal supporter. Here, we studied the effects of GDF-5 on mouse EpSCs proliferation mechanism in wound healing. Methods Firstly, the effects of GDF-5 on EpSCs proliferation was tested by using CCK8 reagent and PCNA expression was analyzed by Western blotting. Secondly, we screened genes that promote EpSCs proliferation in the FOX and cyclin family by qPCR, and then the protein expression level of the selected genes was further analyzed by Western blotting. Thirdly, siRNA plasmids and pAdEasy adenovirus were transfected or infected, respectively, into mouse EpSCs to detect the effect of target genes on GDF-5-induced cell proliferation. Furthermore, we injected GDF-5 to a deep partial thickness burn mouse model for finding out whether EpSCs proliferation can be detected by immunohistochemical. Finally, the relevant target genes were analyzed by qPCR, immunoblotting, and dual-luciferase reporter gene detection. Results We discovered that 100 ng/ml recombinant mouse GDF-5 was the optimal concentration for promoting mouse EpSCs proliferation. Through preliminary screened by qPCR, we found that Foxg1 and cyclin D1 could be the downstream molecules of GDF-5, and the results were confirmed by Western blotting. And the effect of GDF-5 on mouse EpSCs proliferation was adjusted by Foxg1/cyclin D1 in vitro and in vivo. Besides, GDF-5-induced transcription of cyclin D1 was regulated by Foxg1-mediated cyclin D1 promoter activity. Conclusion This paper showed that GDF-5 promotes mouse EpSCs proliferation via Foxg1-cyclin D1 signal pathway. It is suggested that GDF-5 may be a new approach to make EpSCs proliferation which can be used in wound healing.

Accumulation of somatic hypermutation (SHM) is the primary mechanism to enhance the binding affinity of antibodies to antigens in vivo. However, the structural basis of the effects of many SHMs remains elusive. Here, we integrated atomistic molecular dynamics (MD) simulation and data mining to build a high-throughput structural bioinformatics pipeline to study the effects of individual and combination SHMs on antibody conformation, flexibility, stability, and affinity. By applying this pipeline, we characterized a common mechanism of modulation of heavy-light pairing orientation by frequent SHMs at framework positions 39H, 91H, 38L, and 87L through disruption of a conserved hydrogen-bond network. Q39LH alone and in combination with light chain framework 4 (FWR4L) insertions further modulated the elbow angle between variable and constant domains of many antibodies, resulting in improved binding affinity for a subset of anti-HIV-1 antibodies. Q39LH also alleviated aggregation induced by FWR4L insertion, suggesting remote epistasis between these SHMs. Altogether, this study provides tools and insights for understanding antibody affinity maturation and for engineering functionally improved antibodies.

We present gas-phase metallicity measurements for 583 emission line galaxies at 0.3 < z < 0.85, including 388 dwarf galaxies with $\mathrm{log}({M}_{\star }/{M}_{\odot })\lt 9.5$ , and explore the dependence of the metallicity on the stellar mass and star formation (SF) properties of the galaxies. Metallicities are determined through the measurement of emission lines in very deep (∼7 hr exposure) Keck/DEIMOS spectra taken primarily from the HALO7D survey. We measure metallicity with three strong-line calibrations (O3H β , R23, and O3O2) for the overall sample, as well as with the faint [Ne iii ] λ 3869 and [O iii ] λ 4363 emission lines for 112 and 17 galaxies where robust detections were possible. We construct mass–metallicity relations (MZR) for each calibration method, finding MZRs consistent with other strong-line results at comparable redshift, as well as with z ∼ 0 galaxies. We quantify the intrinsic scatter in the MZR as a function of mass, finding it increases with lower stellar mass. We also measure a weak but significant correlation between increased MZR scatter and higher specific star formation rate (SFR). We find a weak influence of SFR in the fundamental metallicity relation as well, with an SFR coefficient of α = 0.21. Finally, we use the flux ratios of the [O ii ] λ λ 3727,3729 doublet to calculate gas electron density in ∼1000 galaxies with $\mathrm{log}({M}_{\star }/{M}_{\odot })\lt 10.5$ as a function of redshift. We measure low electron densities ( n _e ∼ 25 cm ^−3 ) for z < 1 galaxies, again consistent with z ≈ 0 conditions, but measure higher densities ( n _e ∼ 100 cm ^−3 ) at z > 1. These results all suggest that there is little evolution in star-forming interstellar medium conditions from z ∼ 1 to z = 0, confirmed with a more complete sample of low-mass galaxies than has previously been available in this redshift range.

Giant star-forming clumps are a prominent feature of star-forming galaxies (SFGs) and contain important clues on galaxy formation and evolution. However, the basic demographics of clumps and their host galaxies remain uncertain. Using the Hubble Space Telescope/Wide Field Camera 3 F275W images from the Ultraviolet Imaging of the Cosmic Assembly Near-infrared Deep Extragalactic Legacy Survey, we detect and analyze giant star-forming clumps in galaxies at 0.5 ≤ z ≤ 1, connecting two epochs when clumps are common (at cosmic high noon, z ∼ 2) and rare (in the local Universe). We construct a clump sample whose rest-frame 1600 Å luminosity is 3 times higher than the most luminous local H ii regions ( M _UV ≤ −16 AB). In our sample, 35% ± 3% of low-mass galaxies (log[ M _∗ / M _⊙ ] < 10) are clumpy (i.e., containing at least one off-center clump). This fraction changes to 22% ± 3% and 22% ± 4% for intermediate (10 ≤ log[ M _∗ / M _⊙ ] ≤ 10.5) and high-mass (log[ M _∗ / M _⊙ ] > 10.5) galaxies, in agreement with previous studies. When compared to similar-mass nonclumpy SFGs, low- and intermediate-mass clumpy SFGs tend to have higher star formation rates (SFRs) and bluer rest-frame U − V colors, while high-mass clumpy SFGs tend to be larger than nonclumpy SFGs. However, clumpy and nonclumpy SFGs have similar Sérsic index, indicating a similar underlying density profile. Furthermore, we investigate how the UV luminosity of star-forming regions correlates with the physical properties of host galaxies. On average, more luminous star-forming regions reside in more luminous, smaller, and/or higher specific SFR galaxies and are found closer to their hosts’ galactic centers.

The UltraViolet imaging of the Cosmic Assembly Near-infrared Deep Extragalactic Legacy Survey Fields (UVCANDELS) program provides Hubble Space Telescope (HST)/UVIS F275W imaging for four CANDELS fields. We combine this UV imaging with existing HST/near-IR grism spectroscopy from 3D-HST+AGHAST to directly compare the resolved rest-frame UV and H α emission for a sample of 979 galaxies at 0.7 < z < 1.5, spanning a range in stellar mass of 10 ^8−11.5 M _⊙ . Using a stacking analysis, we perform a resolved comparison between homogenized maps of rest-UV and H α to compute the average UV-to-H α luminosity ratio (an indicator of burstiness in star formation) as a function of galactocentric radius. We find that galaxies below stellar mass of ∼10 ^9.5 M _⊙ , at all radii, have a UV-to-H α ratio higher than the equilibrium value expected from constant star formation, indicating a significant contribution from bursty star formation. Even for galaxies with stellar mass ≳10 ^9.5 M _⊙ , the UV-to-H α ratio is elevated toward their outskirts ( R / R _eff > 1.5), suggesting that bursty star formation is likely prevalent in the outskirts of even the most massive galaxies, but is likely overshadowed by their brighter cores. Furthermore, we present the UV-to-H α ratio as a function of galaxy surface brightness, a proxy for stellar mass surface density, and find that regions below ∼10 ^7.5 M _⊙ kpc ^−2 are consistent with bursty star formation, regardless of their galaxy stellar mass, potentially suggesting that local star formation is independent of global galaxy properties at the smallest scales. Last, we find galaxies at z > 1.1 to have bursty star formation, regardless of radius or surface brightness.

High-resolution imaging of galaxies in rest-frame UV has revealed the existence of giant star-forming clumps prevalent in high-redshift galaxies. Studying these substructures provides important information about their formation and evolution and informs theoretical galaxy evolution models. We present a new method to identify clumps in galaxies’ high-resolution rest-frame UV images. Using imaging data from CANDELS and UVCANDELS, we identify star-forming clumps in an HST/F160W ≤ 25 AB mag sample of 6767 galaxies at 0.5 ≤ z ≤ 3 in four fields, GOODS-N, GOODS-S, EGS, and COSMOS. We use a low-passband filter in Fourier space to reconstruct the background image of a galaxy and detect small-scale features (clumps) on the background-subtracted image. Clumpy galaxies are defined as those having at least one off-center clump that contributes a minimum of 10% of the galaxy’s total rest-frame UV flux. We measure the fraction of clumpy galaxies ( f _clumpy ) as a function of stellar mass, redshift, and galaxy environment. Our results indicate that f _clumpy increases with redshift, reaching ∼65% at z ∼ 1.5. We also find that f _clumpy in low-mass galaxies ( $9.5\leqslant \mathrm{log}({M}_{* }/{M}_{\odot })\leqslant 10$ ) is 10% higher compared to that of their high-mass counterparts ( $\mathrm{log}({M}_{* }/{M}_{\odot })\gt 10.5$ ). Moreover, we find no evidence of significant environmental dependence of f _clumpy for galaxies at the redshift range of this study. Our results suggest that the fragmentation of gas clouds under violent disk instability remains the primary driving mechanism for clump formation, and incidents common in dense environments, such as mergers, are not the dominant processes.

The study of galaxy evolution hinges on our ability to interpret multiwavelength galaxy observations in terms of their physical properties. To do this, we rely on spectral energy distribution (SED) models, which allow us to infer physical parameters from spectrophotometric data. In recent years, thanks to wide and deep multiwave band galaxy surveys, the volume of high-quality data have significantly increased. Alongside the increased data, algorithms performing SED fitting have improved, including better modeling prescriptions, newer templates, and more extensive sampling in wavelength space. We present a comprehensive analysis of different SED-fitting codes including their methods and output with the aim of measuring the uncertainties caused by the modeling assumptions. We apply 14 of the most commonly used SED-fitting codes on samples from the CANDELS photometric catalogs at z ∼ 1 and z ∼ 3. We find agreement on the stellar mass, while we observe some discrepancies in the star formation rate (SFR) and dust-attenuation results. To explore the differences and biases among the codes, we explore the impact of the various modeling assumptions as they are set in the codes (e.g., star formation histories, nebular, dust and active galactic nucleus models) on the derived stellar masses, SFRs, and A _V values. We then assess the difference among the codes on the SFR–stellar mass relation and we measure the contribution to the uncertainties by the modeling choices (i.e., the modeling uncertainties) in stellar mass (∼0.1 dex), SFR (∼0.3 dex), and dust attenuation (∼0.3 mag). Finally, we present some resources summarizing best practices in SED fitting.

Summary: Antibodies that potently neutralize SARS-CoV-2 target mainly the receptor-binding domain or the N-terminal domain (NTD). Over a dozen potently neutralizing NTD-directed antibodies have been studied structurally, and all target a single antigenic supersite in NTD (site 1). Here, we report the cryo-EM structure of a potent NTD-directed neutralizing antibody 5-7, which recognizes a site distinct from other potently neutralizing antibodies, inserting a binding loop into an exposed hydrophobic pocket between the two sheets of the NTD β sandwich. Interestingly, this pocket was previously identified as the binding site for hydrophobic molecules, including heme metabolites, but we observe that their presence does not substantially impede 5-7 recognition. Mirroring its distinctive binding, antibody 5-7 retains neutralization potency with many variants of concern (VOCs). Overall, we reveal that a hydrophobic pocket in NTD proposed for immune evasion can be used by the immune system for recognition.

Summary: Antibodies with heavy chains that derive from the VH1-2 gene constitute some of the most potent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-neutralizing antibodies yet identified. To provide insight into whether these genetic similarities inform common modes of recognition, we determine the structures of the SARS-CoV-2 spike in complex with three VH1-2-derived antibodies: 2-15, 2-43, and H4. All three use VH1-2-encoded motifs to recognize the receptor-binding domain (RBD), with heavy-chain N53I-enhancing binding and light-chain tyrosines recognizing F486RBD. Despite these similarities, class members bind both RBD-up and -down conformations of the spike, with a subset of antibodies using elongated CDRH3s to recognize glycan N343 on a neighboring RBD—a quaternary interaction accommodated by an increase in RBD separation of up to 12 Å. The VH1-2 antibody class, thus, uses modular recognition encoded by modular genetic elements to effect potent neutralization, with the VH-gene component specifying recognition of RBD and the CDRH3 component specifying quaternary interactions.

The diversity of B cell receptors provides a basis for recognizing numerous pathogens. Antibody repertoire sequencing has revealed relationships between B cell receptor sequences, their diversity, and their function in infection, vaccination, and disease. However, many repertoire datasets have been deposited without annotation or quality control, limiting their utility. To accelerate investigations of B cell immunoglobulin sequence repertoires and to facilitate development of algorithms for their analysis, we constructed a comprehensive public database of curated human B cell immunoglobulin sequence repertoires, cAb-Rep (https://cab-rep.c2b2.columbia.edu), which currently includes 306 immunoglobulin repertoires from 121 human donors, who were healthy, vaccinated, or had autoimmune disease. The database contains a total of 267.9 million V(D)J heavy chain and 72.9 million VJ light chain transcripts. These transcripts are full-length or near full-length, have been annotated with gene origin, antibody isotype, somatic hypermutations, and other biological characteristics, and are stored in FASTA format to facilitate their direct use by most current repertoire-analysis programs. We describe a website to search cAb-Rep for similar antibodies along with methods for analysis of the prevalence of antibodies with specific genetic signatures, for estimation of reproducibility of somatic hypermutation patterns of interest, and for delineating frequencies of somatically introduced N-glycosylation. cAb-Rep should be useful for investigating attributes of B cell sequence repertoires, for understanding characteristics of affinity maturation, and for identifying potential barriers to the elicitation of effective neutralizing antibodies in infection or by vaccination.

Congenital diaphragmatic hernia (CDH) is a severe birth defect that is often accompanied by other congenital anomalies. Previous exome sequencing studies for CDH have supported a role of de novo damaging variants but did not identify any recurrently mutated genes. To investigate further the genetics of CDH, we analyzed de novo coding variants in 362 proband-parent trios including 271 new trios reported in this study. We identified four unrelated individuals with damaging de novo variants in MYRF (P = 5.3x10(-8)), including one likely gene-disrupting (LGD) and three deleterious missense (D-mis) variants. Eight additional individuals with de novo LGD or missense variants were identified from our other genetic studies or from the literature. Common phenotypes of MYRF de novo variant carriers include CDH, congenital heart disease and genitourinary abnormalities, suggesting that it represents a novel syndrome. MYRF is a membrane associated transcriptional factor highly expressed in developing diaphragm and is depleted of LGD variants in the general population. All de novo missense variants aggregated in two functional protein domains. Analyzing the transcriptome of patient-derived diaphragm fibroblast cells suggest that disease associated variants abolish the transcription factor activity. Furthermore, we showed that the remaining genes with damaging variants in CDH significantly overlap with genes implicated in other developmental disorders. Gene expression patterns and patient phenotypes support pleiotropic effects of damaging variants in these genes on CDH and other developmental disorders. Finally, functional enrichment analysis implicates the disruption of regulation of gene expression, kinase activities, intra-cellular signaling, and cytoskeleton organization as pathogenic mechanisms in CDH.

Influenza B virus (IBV) is a respiratory pathogen that infects humans and causes seasonal influenza epidemics. However, cellular response to IBV infection in humans and mechanisms of host-mediated restriction of IBV replication are not thoroughly understood. In this study, we used next-generation sequencing (NGS) to perform transcriptome profiling of IBV-infected human lung epithelial A549 cells at 0, 6, 12, and 24 h post infection (hpi) and characterized the cellular gene expression dynamics. We observed that more than 4000 host genes were differentially regulated during the study period, which included up regulation of genes encoding proteins, having a role in the innate antiviral immune responses, immune activation, cellular metabolism, autophagy, and apoptosis, as well as down regulation of genes involved in mitosis and cell proliferation. Further analysis of RNA-Seq data coupled with RT-qPCR validation collectively showed that double-strand RNA recognition pathways, including retinoic acid-inducible gene I (RIG-I) and Toll-like receptor 3 (TLR3), were substantially activated following IBV infection. Taken together, these results provide important initial insights into the intimate interaction between IBV and lung epithelial cells, which can be further explored towards elucidation of the cellular mechanisms in restriction or elimination of IBV infections in humans.

Based on Abaqus software, the temperature profiles during laser heating CFRP materials in different fiber directions was investigated in this research. The 3D temperature distribution and temperature history of laminates with different ply directions were analyzed and compared through the homogenous model. It is found that the focusing characteristics of laser causes a large temperature gradient. Meanwhile, the temperature field of CFRP laminate extends toward the direction of fibers because of the large axial thermal conductivity of carbon fibers. The thermal conduction in the thickness direction is poor, so the lower layer will not reach the melting temperature. In order to verify the validity of the model, a real-time temperature field measurement device consisting of thermal imager and thermocouples was built. The results show that the model can effectively simulate the temperature field of composite materials irradiated by laser.

The macro-mesoscopic joint fatigue model containing hardening particles and crystal characteristics is established to study the effect of the hardening particles and the grain orientation on fatigue properties of an aluminum alloy friction stir welding (FSW) joint. The macroscopic model is composed of the weld nugget zone, thermo-mechanically affected zone, heat-affected zone, and base material, according to the metallurgical morphology and hardness distribution of the joint. Cyclic stress and strain data are used to determine the material properties. The fatigue parameters used in the calculation of cyclic stresses and strains are obtained with the four-point correlation method. The mesoscopic models of different zones are inserted into the joint macroscopic model as submodules. The models containing the information of hardening particles and grain orientation are established with crystal plasticity theory for the grains and isotropic hardening rule for the hardening particles. The effects of hardening particles and grain orientation on the stress and strain responses are discussed. The simulation results show that high-angle misorientation of adjacent grains hinders the stress transfer. The particle cluster or cracked particles intensify the stress and strain concentrations.

Body size is one of the most important attributes of a species, but the basic question of why and how each species reaches a different “right size„ is still largely unknown. Herein, three phylogenetically closely related catfishes from Sisoridae, including one extraordinarily large-sized Bagarius yarrelli and two average-sized Glyptothorax macromaculatus and Oreoglanis setiger, were comparatively studied using RNA-Seq. Approximately 17,000 protein-coding genes were annotated for each of the three fishes, and 9509 genes were identified as high-confidence orthologous gene pairs. Comparative expressions uncovered a similar functional cluster about ribosome biogenesis was enriched in different tissues of the upregulated genes of Bagarius yarrelli. Moreover, differentially expressed genes and positively selected genes revealed that the glycolysis/pyruvate metabolism and cell cycle pathways have also greatly enhanced in this large-sized species. In total, 20 size-related candidate genes (including two growth modulators: the serine/threonine-protein kinases 3 (AKT3) and adaptor protein 1 (SH2B1), and a crucial pyruvate kinase (PKM2A)) were identified by multiplying comparative analyses along with gene functional screening, which would play major roles in enabling the large body size associated with Bagarius yarrelli and provide new insights into body size evolution. In conjunction with field observations and morphological comparisons, we hypothesize that habitat preferences promote size divergence of sisorids.

This study addresses a critical gap in the literature on variable importance ranking algorithms, particularly in the context of traffic safety, an area of profound public interest with significant economic, health, and environmental implications. Utilizing a comprehensive national crash database, fourteen distinct ranking algorithms are examined for their ability to rank twenty-eight variables influencing crash injury severity. Key findings indicate disparate results across algorithms, emphasizing the need for rigorous evaluation before method selection. Some variables demonstrate consistent rankings with low standard deviations across methods. Interestingly, two identical variables in the filtered dataset display divergent rankings in some decision tree-based and neural network algorithms, pointing to training variability and algorithmic stochasticity. A consensus ranking identifies the top five factors influencing crash severity: the number injured in a crash, first harmful event, lighting condition, speed limit, and ejection. Correlation analyses show general agreement among methods, albeit with some exceptions. Hierarchical clustering reveals four distinct clusters of ranking algorithms. While the study further advances our understanding of variable importance rankings, limitations exist, warranting further research. This study serves not just as a methodological guide but also as an urgent call for a more nuanced approach to improving road safety. [ABSTRACT FROM AUTHOR]