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Thomas, J.

Publications and source records attributed to Thomas, J..

At least 19 recordsLinked to original sources

`Q-niche': topology-preserving niche hypervolumes built using a quantum mechanics modelling analogue.

Hutchinson's n-dimensional niche hypervolume underlies many ecological analyses, yet estimating hypervolumes from finite occurrence data remains challenging, particularly when niches contain non-convex structure such as separated regions or internal holes. Here, we introduce Q-niche, a quantum-mechanics-inspired algorithm for ecological hypervolume estimation. Using an inverse Schrodinger formulation, Q-niche transforms an occurrence-derived Gaussian field into a potential surface whose low-potential regions define a hypervolume represented by a stochastic point cloud. We evaluated Q-niche against Gaussian kernel density estimation and one-class support vector machine hypervolume estimators using synthetic niches, virtual species and empirical Acacia occurrence data. Across controlled synthetic benchmarks, Q-niche preserved imposed topological features more consistently than either alternative and showed closer overall topological agreement with occurrence clouds. This preservation remained robust across the tested parameter settings. Virtual-species analyses showed that stronger preservation of environmental topology did not necessarily produce greater overlap with the known geographical distribution, showing that topology and geographical range are not necessarily coupled. The empirical Acacia dataset revealed that the inferred size and topology of a niche hypervolume is estimator-dependent, favouring the use of Q-niche when hypervolume topology is the focus of research due to its topology preservation performance. Overall, Q-niche provides a practical tool for reconstructing complex niche hypervolumes and investigating how their geometry and topology relate to potential geographical distributions.

ecology↗

Endogenous SMN Heterogeneity Defines Dynamic States of Motor Neuron Vulnerability and Resilience

Selective neuronal vulnerability, whereby some neurons degenerate while others remain resilient despite a shared genetic and disease context, is a defining feature of neurodegenerative diseases, yet the intrinsic mechanisms underlying these divergent fates remain poorly understood. Here, we identify naturally occurring heterogeneity in endogenous Survival Motor Neuron (SMN) protein abundance as a determinant of dynamic motor neuron (MN) vulnerability states that predict neuronal fate. Longitudinal live-cell imaging of human SMN-Clover reporter MNs shows that neurons with high endogenous SMN survive significantly longer than neighboring low-SMN neurons across healthy, spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS) genetic backgrounds. These vulnerability states are not fixed: a substantial proportion of MNs progressively increase endogenous SMN abundance, transitioning toward a more resilient state associated with enhanced survival. Low-SMN neurons also exhibit increased spontaneous activity, linking endogenous SMN abundance to neuronal physiology and survival. In vivo, selectively vulnerable MN populations display corresponding shifts in endogenous SMN abundance during disease progression, supporting the relevance of SMN-defined vulnerability states beyond in vitro models. Integrated transcriptomic and proteomic analyses reveal distinct molecular programs associated with resilient and vulnerable states, including RNA metabolism, proteostasis, cytoskeletal organization, neuronal activity and stress responses. Among conserved molecular differences, the anti-apoptotic regulator LMO3 emerged as a candidate mediator of resilience. LMO3 overexpression reduced expression of p53-responsive genes, increased MN survival and shifted neurons toward higher endogenous SMN states. Together, these findings establish endogenous protein heterogeneity as a determinant of dynamic neuronal vulnerability and reveal neuronal resilience as a plastic molecular state that can be identified and therapeutically reinforced.

neuroscience↗

Sleep spindles stabilize human thalamocortical networks, inhibiting pathological disruptions

The thalamus coordinates sleep-dependent brain function including memory consolidation, sensory gating, and network stability through spindle oscillations. Thalamocortical circuits are also affected in many neurological and neuropsychiatric disorders. Yet how human thalamocortical circuits respond to pathological disruptions remain poorly understood. Here, we leveraged interictal epileptiform discharges (IEDs) as spontaneous perturbations to probe spindle-generating circuits and thalamocortical dynamics in vivo. Using multi-night intracranial recordings spanning multiple thalamic nuclei and cortical regions in 55 individuals with epilepsy, we investigated interactions between sleep spindles and epileptic activity across timescales from milliseconds to days. Sleep spindles were associated with IED suppression, whereas IEDs increased subsequent spindle probability, revealing bidirectional interactions between physiological and pathological activity. Nights with lower IEDs corresponded to increased spindle occurrence, longer duration, and faster frequency, reflecting a more stable thalamocortical state. These findings propose sleep spindles as potential regulators of thalamocortical networks that actively respond to and regulate pathological activity.

neuroscience↗

Cfap410a and Cby work together with tissue-specific requirements to build Drosophila ciliary transition zones

Cilia and flagella perform essential physiological functions in eukaryotes, and defects in these organelles cause several human diseases, including cancer and ciliopathies. The architecture of cilia is highly organized. The ciliary compartment is separated from the cytoplasm by the transition zone (TZ). The severity of ciliopathies linked to TZ assembly defects highlights the TZ's critical role. Although several core conserved complexes are involved in TZ assembly, variations in TZ composition are associated with structurally and functionally diverse cilia. Here, we identify Cfap410a as a novel component of the ciliary TZ in the two Drosophila ciliated tissues, male germ cells and sensory neurons. Cfap410a is one of the two Drosophila paralogs (Cfap410a and Cfap410b) of human CFAP410, whose mutations are associated with axial spondylo-metaphyseal dysplasia, retinitis pigmentosa and amyotrophic lateral sclerosis. We show here that Cfap410a is a proximity partner of Cby and that they act cooperatively in the hierarchy of the TZ assembly program by bridging the CEP290 and MKS transition zone modules. Simultaneous loss of Cfap410a and Cby halts ciliary growth by disrupting TZ formation in multiple types of Drosophila ciliated cells, each of which exhibiting varying dependence on these two proteins. Interestingly, the function of Cfap410a and Cfap410b are not functionally redundant, indicating that the two proteins have evolved towards specific functions. In summary, our results propose a novel role for CFAP410a at the TZ and provide an explanation for how deregulation of conserved TZ components could lead to tissue-specific ciliopathies.

cell biology↗

Proteoform plasticity modulates the temperature response in circadian timekeeping

The molecular circadian clock optimally coordinates an organism's physiology with the light/dark cycle. One commonality among circadian molecular clock proteins is that they undergo alternative splicing, yielding multiple proteoforms. The isoform-specific sequences spliced into clock proteins contain intrinsically disordered regions (IDRs), suggesting that these regions might be intricately involved in cellular regulation. However, the functions of these isoform-specific IDRs in the clock remain poorly defined. Here, we use the core clock repressor FREQUENCY (FRQ) from the fungal circadian model system Neurospora crassa to test the hypothesis that alternative splicing of core clock IDRs yields multiple proteoforms that expand the functional regulatory capacity of FRQ. To do so, we biophysically characterized an IDR specific to the long isoform of the core clock repressor FRQ and identified motifs and molecular behaviors that regulate clock robustness in a temperature-dependent manner. We further compared the interactomes of two FRQ isoforms, identifying distinct functions and interacting proteins that could contribute to temperature regulation. Taken together, our data highlight that isoform-specific IDRs in clock-repressor proteins enhance and expand clock function in a context-dependent manner.

biochemistry↗

High-Dimensional Immunophenotyping Identifies Circulating Immune Signatures Associated with FeNO-Defined Asthma Phenotypes

Background: Asthma is a heterogeneous inflammatory airway disease traditionally classified into T2 high (eosinophilic) and T2 low inflammatory phenotypes. Fractional exhaled nitric oxide (FeNO) is commonly used as a biomarker of T2 inflammation, although nitric oxide also regulates monocyte maturation and T cell polarization. We hypothesized that FeNO identifies distinct systemic immune phenotypes in asthma. Methods: Peripheral immune cell subsets were characterized using OMIP - 69, a 40 - color high dimensional immunophenotyping panel encompassing innate and adaptive immune populations. Adults with asthma and healthy controls underwent peripheral blood immunophenotyping. FeNO was dichotomized at 25 ppb (FeNO - high [&ge;] 25 vs FeNO - low <25). Immune-cell subset proportions were summarized as medians (IQRs) and compared using the Wilcoxon rank-sum test. Logistic regression was used to evaluate associations between immune subsets and FeNO status. Results: Eighteen participants with asthma and seven healthy controls were enrolled. Asthmatic participants had higher BMI than healthy controls (median [IQR] asthma: 35.1 [28.9 - 37.7] vs healthy: 25.4 [22.6 - 26.7] kg/m2; p=0.003), although demographics were otherwise similar. Among asthmatics, 10 participants had FeNO - low asthma, and eight had FeNO - high asthma. FeNO - high asthma demonstrated increased classical monocytes (CD14++CD16 -) and compared with healthy controls (p=0.027), whereas FeNO - low asthma more closely resembled healthy controls. Intermediate monocytes (CD14++CD16+) were increased in FeNO - high versus FeNO - low (p= 0.08); a similar association was noted for classical monocytes (p = 0.13). In contrast, CCR7+ TCR; T - cells were significantly enriched in FeNO - low asthma (p=0.002). Logistic regression demonstrated positive associations between high - FeNO and classical monocytes (OR 16.06, 95% CI 1.56 - 1304.69; p=0.007) and intermediate monocytes (OR 4.19, 1.22 - 132.30; p=0.017), whereas CCR7+ {gamma} {delta} T - cells were negatively associated with high FeNO (OR 0.06, 0.00 - 0.47; p=0.001). Conclusions: Distinct systemic immune signatures identified by high-dimensional cytometry support the existence of biologically divergent FeNO - defined asthma endotypes and may inform future biomarker-driven approaches to patient stratification and precision therapy.

immunology↗

Identification of pre-existing ubiquitous neoantigen-reactive tumor-infiltrating T-cells in a patient with metastatic pancreatic neuroendocrine tumor

BackgroundMutation-derived neoantigens, typically identified in primary tumors, are emerging therapeutic targets for personalized cancer vaccines and adoptive T-cell therapies. However, clinical efficacy of neoantigen-directed therapies in patients with metastatic disease remains limited, partly due to inter-site genetic heterogeneity. We investigated whether ubiquitous neoantigens-derived from mutations shared across all tumor sites-could provide more effective, durable targets, particularly in patients undergoing resection of metastatic lesions. MethodsWhole-exome and RNA sequencing were performed on 14 tumor samples (primary and 13 synchronous nodal metastases) from a treatment-naive patient with pancreatic neuroendocrine tumor (PNET). Ubiquitous mutations were identified bioinformatically, and their immunogenicity assessed using in-vitro stimulation of autologous peripheral blood mononuclear cells followed by IFN-{gamma} ELISpot assay. Neoantigen-specific T-cell clonotypes were further identified by HLA-tetramer staining and single-cell RNA/TCR sequencing. Neoantigen-reactive clonotypes identified in peripheral blood were tracked across multiple metastatic sites using bulk TCR{beta} repertoire sequencing. ResultsAmong 1,195 non-synonymous mutations detected, eight were shared across all 14 tumor sites. Of these, one encoded a neoantigen that elicited a reproducible IFN-{gamma} ELISpot response in peripheral blood, confirming its immunogenicity. Further, we identified the corresponding neoantigen-reactive TCR clonotypes in blood. Comparison with bulk TCR{beta} repertoires from eight metastatic sites showed that these clonotypes were present in every site analyzed, with evidence of local clonal expansion. ConclusionThis study provides direct evidence that a single ubiquitous mutation-derived neoantigen can generate systemic T-cell responses and clonotype expansion across multiple metastatic sites in a TMB-low, TIL-low tumor. Our findings support incorporating mutation-sharing status across metastases as a key criterion for neoantigen selection in cancer vaccines and adoptive T-cell therapies. This approach could inform the design of neoantigen-directed immunotherapies in metastatic PNET and potentially other metastatic solid tumors. What is already known on this topicNeoantigen-directed therapies, such as personalized cancer vaccines or adoptive T-cell transfer, can induce anti-tumor responses but have shown limited success in metastatic disease. One major barrier is genetic heterogeneity between tumor sites, suggesting that targeting ubiquitous mutations-those shared across all tumor sites-may improve the efficacy of such therapies. What this study addsIn one patient with metastatic pancreatic neuroendocrine tumor involving 13 lymph nodes, we identified eight ubiquitous mutations, one of which generated a detectable neoantigen-specific T-cell response in blood. The corresponding T-cell clonotypes were found across all metastatic sites analyzed and showed evidence of clonal expansion, providing direct evidence of systemic and local recognition of a shared neoantigen in a TMB-low/TIL-low cancer. How this study might affect research, practice or policyThese findings support incorporating mutation sharing across metastases as a key criterion in neoantigen selection for cancer vaccines and adoptive T-cell therapies. This strategy could enhance the relevance and durability of neoantigen- directed approaches in patients with metastatic disease.

immunology↗

Confirmation of gamma irradiation mediated inactivation of a Vero adapted African swine fever virus Lisbon 60 strain for molecular assays

African swine fever virus (ASFV), the etiologic agent of African Swine Fever (ASF), is a high-consequence pathogen requiring experiments to be conducted in containment in non-endemic countries, thereby restricting diagnostic development, the creation of reference standards, and proficiency testing (PT). Safe and reliable inactivation methods are essential to expand diagnostic capacity while preserving nucleic acid integrity for molecular assays in unaffected countries. This study employed gamma irradiation to achieve complete inactivation of ASFV without compromising downstream molecular detection, as gamma irradiation offers deep penetration and uniform dose delivery. ASFV-cell culture supernatants were subjected to gamma irradiation doses ranging from 2 to 50 kGy. Viral replication was evaluated using TCID{square}{square} and serial passages, revealing a consistent dose{square}dependent reduction in infectivity across increasing irradiation dose levels and a complete loss of ASFV infectivity at 30 and 50 kGy. Molecular detection remained unaffected at all of the tested doses as confirmed by qPCR Ct values and sequence identity of the p72 gene. Whole genome sequencing demonstrated >99% genome coverage and consistent read depth profiles across irradiated and non-irradiated samples, indicating preservation of genomic integrity at all tested doses. These findings demonstrate that gamma irradiation at 50 kGy fully inactivates ASFV-cell supernatants while maintaining nucleic acid quality suitable for molecular diagnostics. The resulting inactivated material meets quality assurance requirements for molecular reference standards and PT panels and can be safely distributed to laboratories outside high containment facilities, supporting broader diagnostic readiness and harmonization of ASFV testing.

microbiology↗

Highly Stable Mn(V)-Nitrido and Nitrogen-Atom Transfer Reactivity within a De Novo Protein

High-valent metal-nitrido species are powerful nitrogen-atom transfer intermediates but remain difficult to access and control due to intrinsic instability and bimolecular N-N coupling pathways. Herein, we report the first formation of a high-valent Mn(V)-nitrido complex within a de novo designed protein scaffold and demonstrate that a reactive precursor to this species can be catalytically intercepted for enantioselective aziridination. A Mn(V){equiv}N unit derived from an abiological diphenyl porphyrin is confined within a designed helical bundle protein, where the protein environment suppresses bimolecular decay and enables detailed spectroscopic characterization. Electron paramagnetic resonance, resonance Raman, and circular dichroism spectroscopies confirm formation of a low-spin Mn(V)-nitrido species that is stable for weeks at room temperature and exhibits minimal perturbation of the Mn{equiv}N unit upon modulation of the axial histidine ligand, while catalytic activity and stereochemical outcome are sensitive to its presence. Mechanistic studies identify monochloramine (NH2Cl) as the operative nitrogen-atom donor and support the involvement of a transient Mn-bound N-transfer intermediate en route to nitrido formation. Under catalytic conditions, this intermediate is inter-cepted to perform aziridination with TON {approx} 180 and an enantiomeric ratio of 65:35. Together, these results establish de novo protein design as a platform for stabilizing high-valent metal-nitrido species and harnessing their reactivity for nitrogen-atom transfer chemistry beyond the limits of natural metalloenzymes and small-molecule catalysts.

biochemistry↗

Validation of a molecular workflow for Cochliomyia hominivorax (New World screwworm) identification in field samples

Cochliomyia hominivorax, New world Screwworm (NWS), has become a reemerging veterinary concern in the United States due to the recent northward expansion of fly detections as far as northern Mexico. Rapid, accurate and validated detection pipelines need to be developed in the case of an incursion into the United States. Confirmatory cases are evaluated by morphological identification with no paired test to verify identifications. With the frequency of submissions of non-ideal samples, particularly from fly traps, a molecular tool would be necessary for species identification. In this manuscript, we develop and assess a pipeline including three real-time PCR assays targeting the ribosomal RNA and five sets of Sanger primers targeting the mitochondrial genome that would be used as a paired tool with morphological identification. Two of the assessed real-time PCR assays are highly specific, sensitive and repeatable requiring <1 copy per reaction for detection. Four of the five Sanger primer sets were assessed, optimized and results evaluated for potential use in preliminary geographic analysis of specimens. This workflow will expedite screening of samples, provide a method to verify results using different tools and help understand genetic variations within the mitochondria for NWS outbreaks.

molecular biology↗

Thalamic Interictal Epileptic and Non-Epileptic Events during NREM Sleep in Patients with Focal Epilepsy: a Stereo-EEG Study

BackgroundThalamic recordings are increasingly incorporated into stereo-electroencephalography (SEEG) evaluations of drug-resistant focal epilepsy to guide neuromodulation targeting. Human thalamic electrophysiology, however, is poorly defined, limiting the distinction between pathological and physiological activity. Here, we characterized interictal epileptic and non-epileptic events during non-rapid eye movement (NREM) sleep across multiple thalamic nuclei and examined their relationship to seizure outcomes. MethodsWe analyzed NREM sleep SEEG recordings from 64 patients with drug-resistant focal epilepsy. Electrodes sampled four thalamic nuclei: centromedian (CM), pulvinar (Pu), ventral lateral (VL), and ventral posterolateral (VPL). Patients were classified into three outcome groups: favorable, unfavorable, and surgically non-remediable. Rates of thalamic spikes, high-frequency oscillations (HFOs), spike-fast activity, and sleep spindles were analyzed and compared across nuclei and outcomes. FindingsRecordings of the thalamus revealed both pathological and physiological interictal events. Interictal epileptic events were infrequent. Only [~]0.2% of seizure-onset zone spikes propagated to the thalamus. Thalamic spike-fast activity was indicative of unfavorable surgical outcomes (CM: p = 0.047, d = 0.46) or surgically non-remediable epilepsy (VL: p = 0.002, d = 0.84). In contrast, thalamic sleep spindles were ubiquitous but reduced in surgically non-remediable patients (CM: p = 0.031, d = -0.58; VL: p = 0.005, d = -0.79). Finally, unique thalamic SEEG patterns were identified, including spikes concomitant with spindles, isolated spikes, and physiological fast ripples. InterpretationThis study provides a comprehensive characterization of thalamic interictal events during NREM sleep, enriching our understanding of thalamic pathophysiology and highlighting the value of thalamic recordings in presurgical evaluation.

neuroscience↗

Sleep fragmentation drives local, network-specific epileptic activity in human epilepsy

Sleep has complex links with epileptic activity, yet the causal role of sleep instability in driving and modulating pathological discharges in the human brain remains incompletely understood. Here we directly examine this by characterising the fine-scale temporal coupling between experimentally induced sleep arousals and interictal epileptiform discharges (IEDs), using combined stereo-electroencephalography and polysomnography recordings in patients with epilepsy. Sleep arousals triggered rapid IED increases, with effects gated by anatomical region and sleep stage. Increases were confined to neocortical regions and occurred during both non-rapid eye movement stage 2 (N2) and stage 3 (N3) sleep, with a larger effect observed in N2. IED increases did not differ between the seizure-onset zone and surrounding regions. Despite elevating IED counts, arousals did not alter IED spatial propagation, indicating state-dependent enhancement of local cortical excitability without recruitment of broader epileptic networks. These findings establish a causal role for sleep instability in actively driving pathological activity on fine-grained spatiotemporal scales, and highlight sleep stabilisation as a promising therapeutic strategy to reduce epileptic burden and preserve cortical network function.

neuroscience↗

Isolation and characterization of broad-range Staphylococcus epidermidis sepunaviruses

Staphylococcus epidermidis is a major contributor to biofilm-associated infections, bacteraemia, and sepsis in humans. Additionally, it is an important veterinary pathogen. The spread of multi-drug resistant S. epidermidis (MRSE) poses an even greater challenge, requiring the development of antibiotic-alternative approaches. Here, we isolated four new broad-range phages capable of infecting a large panel of 65 clinical and veterinary isolates of S. epidermidis. Phages with the broadest host range produced plaques on 37% of the hosts tested and halos on an additional 40%. These phages belonged to the Sepunavirus genus, as supported by their morphology and genome analysis. A genome-wide association study identified a significant correlation between resistance to phage lysis and the presence of the sbcCD complex and the ica operon, highlighting the protective role of biofilms against the phages isolated in this study. Furthermore, distinct phage-encoded methyltransferases identified in the phage genomes may contribute to differences in host ranges. This study advances our knowledge on the diversity and characteristics of S. epidermidis phages, which could be considered as interesting tools for phage therapeutics. RepositoriesPhage genomes are available under Genbank accession numbers PV426907-PV426910. Bacterial genome sequences determined as part of this study, and all Bakta annotations, are available via Figshare (doi:10.6084/m9.figshare.29066417 and doi:10.6084/m9.figshare.29079968 respectively).

microbiology↗

Form Follows Function: A New Paradigm of Pancreatic Cancer Progression

Pancreatic ductal adenocarcinoma (PDAC) exhibits a distinctive propensity to invade nearby organs and infiltrate large blood vessels, even in the absence of distant metastasis. While the genetic and transcriptomic drivers of PDAC progression have been well studied, the mechanisms by which these molecular changes translate into functional, invasive behavior remain largely unknown. Here, we uncover a striking level of tissue organization, characterized by previously unrecognized spatial and geometric properties within and among tumor structures. Leveraging the first large-scale, AI-assisted, human-curated PDAC atlas from hematoxylin and eosin (H&E) images, we annotated, classified, and characterized 144,474 malignant and normal structures from treatment-naive (n=118) and neoadjuvant-treated PDAC patients (n=50). Additionally, we developed a new computational tool, SHAPE, to investigate PDAC aggressiveness through a comprehensive "geometrization" of cancer progression. Using traditional H&E-stained slides and three-dimensional (3D) tissue reconstruction experiments, we observed that invading tumor structures display an eccentric morphology with pronounced local angular coherence. These geometric and spatial properties revealed coherent architectural patterns, with invasive structures closely tracking vessels and nerves as they infiltrate surrounding tissue. Mechanistically, integration of morphological features from 39,045 annotated tumor structures with whole-genome and RNA sequencing data revealed that PDACs with numerous eccentric structures exhibit increased copy number alterations (CNAs), loss of heterozygosity (LoH) on the p-arm of chromosome 17, and a quasi-mesenchymal/basal-like molecular subtype. Spatial transcriptomic analysis of 1,650 tumor structures from six additional PDAC patients further confirmed upregulation of invasive cellular programs within highly eccentric structures, such as epithelial-to-mesenchymal transition (EMT), angiogenesis, coagulation, and complement pathways, underscoring their infiltrative nature. Finally, cross-validation of our AI-based method enabled a fully automated, highly interpretable computational approach to assist pathologists and clinicians in evaluating neoadjuvant chemotherapy response, predicting patient survival, and guiding chemotherapy in adjuvant settings. Collectively, these findings deepen our understanding of PDAC progression, identify a new hallmark of tumor architecture, and pave the way for full integration of AI-driven morphology-based approaches into clinical workflows to improve the management of PDAC patients.

cancer biology↗

Drug screen reveals new potent host-targeted antivirals against Mpox virus

Mpox virus (MPXV), a re-emerging zoonotic threat, has caused outbreaks in non-endemic regions through respiratory, sexual, and close-contact transmission. The increased transmissibility of Clade IIb fueled the 2022 global outbreak, with 2024 Clade Ib spread in the Democratic Republic of Congo further escalating concern. Both outbreaks were declared public health emergencies by the WHO. Although tecovirimat (TPOXX) has been used off-label for Mpox, its limited effectiveness highlights the critical need for newer antivirals for MPXV. We conducted high- throughput antiviral drug screening using a host-directed kinase inhibitor library composed of 2,750 compounds against 2022 Clade IIb MPXV. Our primary screen identified 138 compounds preventing MPXV cytopathic effects, including multiple inhibitors of EGFR, PI3K-mTOR, and Ras/Raf, as well as apoptosis and autophagy regulators. Secondary and tertiary screenings yielded a shortlist of potent, nontoxic antiviral compounds that inhibited MPXV replication. Three selected compounds, IRAK4-IN-6, SM-7368, and KRAS inhibitor-10, reduced MPXV-induced cell death in primary human epidermal keratinocytes. IRAK4-IN-6 and SM-7368 were also found to modulate NF-{kappa}B and STING signaling. Furthermore, these compounds were found effective in reducing skin lesions and viral burden in a mouse model of MPXV skin infection. Together, our study reveals new classes of antiviral compounds against MPXV, offering promising candidates for future clinical development.

microbiology↗

Phenotype-genotype discordance in antimicrobial resistance profiles of Gram-negative uropathogens recovered from catheter-associated urinary tract infections in Egypt

Catheter-associated urinary tract infections (CAUTIs) are among the most common healthcare-associated infections in low- and middle-income countries (LMICs). In this study, phenotypic (EUCAST AMR profiles) and genomic data were generated for 132 isolates (67 Escherichia coli, 14 Pseudomonas aeruginosa, 11 Klebsiella pneumoniae, 9 Proteus mirabilis, 8 Providencia spp., 5 Enterobacter hormaechei, and 18 rare uropathogens) recovered from CAUTIs in an Egyptian hospital. Among the Escherichia coli isolates, phylogroup B2 was most represented (53.7 %), followed by B1 (19.4 %), A (11.9 %), D (7.4 %), F (5.9 %) and C (1.4 %). Several (22/132, 16.6 %) isolates were multidrug-resistant, while almost half (62/132, 46.9 %) were extensively drug-resistant. Comparison of phenotypic data with genotypic data from three different AMR-profiling tools (ResFinder, CARD, AMRFinder) highlighted phenotype-genotype discordance as an important consideration in resistome studies in Egypt, with a total concordance of 91.1 %, 85.7 %, and 80.3 % for ResFinder, CARD and AMRFinder, respectively. Pseudomonas, at the species level, exhibited the greatest discordance. At the antimicrobial level, meropenem was subject to greatest discordance. In addition to the findings from our comparative analyses, new AMR variants are reported for Egypt for Pseudomonas (OXA-486, OXA-488, OXA-905, IMP-43, PDC-35, PDC-45, PDC-201) and Escherichia coli (TEM-176, TEM-190). In summary, we show that there is phenotype-genotype discordance in AMR profiling among CAUTI isolates, highlighting the need for comprehensive approaches in resistome studies. We also show the genomic diversity of Gram-negative uropathogens contributing to disease burden in a little-studied LMIC setting.

microbiology↗

Population and adaptation history of 739 Thlaspi arvense natural accessions

Pennycress (Thlaspi arvense) is a promising intermediate oilseed crop, producing oil suitable for conversion to biofuels--including aviation fuels. While domestication efforts are ongoing, a deeper understanding of the genetic architecture of traits is crucial for informing future breeding efforts. Here, we conducted the largest genomic and phenotypic survey of pennycress to date, analyzing 739 accessions collected across four continents. Leveraging whole-genome sequencing and field-collected phenotypes, we characterized the standing genetic variation underlying key agronomic traits and climate resilience. Our findings revealed multiple independent migration events to North America, with substantial genetic admixture. We identified homologs of Arabidopsis thaliana flowering-time genes that contribute to adaptation and demonstrated the agronomic benefits of winter-type pennycress. Furthermore, through multi-season field trials, we identified a genomic region containing a cluster of mTERF genes strongly associated with green canopy coverage, a critical trait for biomass retention and yield stability. These insights provide a genomic roadmap for accelerating pennycress domestication and improving its resilience to climate variability.

genomics↗

Swiprosin-1/EFhd2 promotes mitochondrial spare capacity in response to immobilized antigen in B cells via microtubule stabilization

B cells can recognize soluble and membrane bound antigens, enabling them to initiate and execute versatile immune responses. This study examines Swiprosin-1/EFhd2 (EFhd2) in regulating mitochondrial function and organization in B cells during B cell receptor (BCR) activation and immune synapse formation. Using EFhd2 knockout (KO) and wild-type (WT) murine B cells, we assessed mitochondrial abundance, membrane potential, and respiratory capacity using soluble anti-IgM and anti-CD40/IL-4 stimulation. EFhd2KO B cells exhibit more functional mitochondria and mitochondrial spare capacity selectively in activated but not in resting cells. This phenotype changed absolutely upon BCR synapse formation: While activated WT B cells enhance basal mitochondrial respiration, ATP production and maximal respiration, with large increments of spare capacity, EFhd2KO B cells fail completely to do so. Actin depolymerization and microtubule destabilization impair functional mitochondrial upregulation in WT but not in EFhd2KO B cells, while microtubule stabilization restores full spare capacity in EFhd2KO B cells at the BCR synapse. Live-cell imaging reveals that EFhd2KO B cells fail to organize mitochondria, microtubules, and BCRs symmetrically. Super-resolution 3D imaging shows that WT B cells condense mitochondria at the synapse, whereas EFhd2KO B cells display dispersed, unorganized mitochondria and BCR clusters. EFhd2 re-expression restores mitochondrial polarization in EFhd2KO B cells, confirming its role in coordinating mitochondrial positioning. These findings highlight EFhd2 as a key integrator of cytoskeletal and mitochondrial functions for optimal B cell responses to membrane bound antigens. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=174 HEIGHT=200 SRC="FIGDIR/small/637645v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@1844c37org.highwire.dtl.DTLVardef@a7b9eaorg.highwire.dtl.DTLVardef@19ec265org.highwire.dtl.DTLVardef@1eca7fb_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗