Nat Commun. 2024 Aug 9;15(1):6818. doi: 10.1038/s41467-024-50491-x.

ABSTRACT

More than two million people worldwide are affected by life-threatening, invasive fungal infections annually. Candida species are the most common cause of nosocomial, invasive fungal infections and are associated with mortality rates above 40%. Despite the increasing incidence of drug-resistance, the development of novel antifungal formulations has been limited. Here we investigate the antifungal mode of action and therapeutic potential of positively charged, synthetic peptide mimics to combat Candida albicans infections. Our data indicates that these synthetic polymers cause endoplasmic reticulum stress and affect protein glycosylation, a mode of action distinct from currently approved antifungal drugs. The most promising polymer composition damaged the mannan layer of the cell wall, with additional membrane-disrupting activity. The synergistic combination of the polymer with caspofungin prevented infection of human epithelial cells in vitro, improved fungal clearance by human macrophages, and significantly increased host survival in a Galleria mellonella model of systemic candidiasis. Additionally, prolonged exposure of C. albicans to the synergistic combination of polymer and caspofungin did not lead to the evolution of tolerant strains in vitro. Together, this work highlights the enormous potential of these synthetic peptide mimics to be used as novel antifungal formulations as well as adjunctive antifungal therapy.

PMID:39122699 | DOI:10.1038/s41467-024-50491-x

Aging Dis. 2024 Jul 27. doi: 10.14336/AD.2024.0456. Online ahead of print.

ABSTRACT

Alzheimer's disease (AD) is an intricate neurodegenerative disorder characterized by the accumulation of misfolded proteins, including beta-amyloid (Aβ) and tau, leading to cognitive decline. Despite decades of research, the precise mechanisms underlying its onset and progression remain elusive. Cathepsins are a family of lysosomal enzymes that play vital roles in cellular processes, including protein degradation and regulation of immune responses. Emerging evidence suggests that cathepsins may be involved in AD pathogenesis. Cathepsins can influence the activation of microglia and astrocytes, the resident immune cells in the brain. However, cathepsin dysfunction may lead to the accumulation of misfolded proteins, notably Aβ and tau. In addition, dysregulated cathepsin activity may induce an exaggerated immune response, promoting chronic inflammation and neuronal dysfunction in patients with AD. By unraveling the classification, functions, and roles of cathepsins in AD's pathogenesis, this review sheds light on their intricate involvement in this devastating disease. Targeting cathepsin activity could be a promising and novel approach for mitigating the pathological processes that contribute to AD, providing new avenues for its treatment and prevention.

PMID:39122455 | DOI:10.14336/AD.2024.0456

Ocul Surf. 2024 Aug 7:S1542-0124(24)00085-5. doi: 10.1016/j.jtos.2024.08.005. Online ahead of print.

ABSTRACT

PURPOSE: While meibomian gland dysfunction (MGD) is widely recognized as a major cause of evaporative dry eye disease, little is known about normal gland differentiation and lipid synthesis or the mechanism underlying gland atrophy and abnormal lipid secretion. The purpose of this study was to use single-cell and spatial transcriptomics to probe changes in cell composition, differentiation, and gene expression associated with two murine models of MGD: age-related gland atrophy in wild-type mice and altered meibum quality in acyl-CoA wax alcohol acyltransferase 2 (Awat2) knockout (KO) mice.

METHODS: Young (6 month) and old (22 month) wild type, C57Bl/6 mice and young (3 month) and old (13 month) Awat2 KO mice were used in these studies. For single-cell analysis, the tarsal plate was dissected from the upper and lower eyelids, and single cells isolated and submitted to the UCI Genomic Core, while for the spatial analysis frozen tissue sections were shipped to Resolve Biosciences on dry ice and sections probed in duplicate using a meibomian gland specific, 100 gene Molecular Chartography panel.

RESULTS: Analysis of gene expression patterns identified the stratified expression of lipogenic genes during meibocyte differentiation, which may control the progressive synthesis of meibum lipids; an age-related decrease in meibocytes; and increased immune cell infiltration. Additionally, we detected unique immune cell populations in the Awat2 KO mouse suggesting activation of psoriasis-like, inflammatory pathways perhaps caused by ductal dilation and hyperplasia.

CONCLUSION: Together these findings support novel mechanism controlling gland function and dysfunction.

PMID:39122180 | DOI:10.1016/j.jtos.2024.08.005

Heart Rhythm. 2024 Aug 7:S1547-5271(24)03120-5. doi: 10.1016/j.hrthm.2024.08.014. Online ahead of print.

ABSTRACT

BACKGROUND: Early postoperative AF (POAF) is common after cardiac surgery and is associated with late-POAF recurrences. However, little is known about the burden of POAF, and its potential impact on long-term outcomes after cardiac surgery, particularly on the risk for late-POAF recurrences.

OBJECTIVE: To establish the distribution of POAF burden and to determine the association between early-POAF burden and late-POAF recurrences during 2.5 years of continuous rhythm monitoring after cardiac surgery in patients with and without preoperative history of AF.

METHODS: Patients undergoing cardiac surgery were prospectively enrolled and postoperatively continuously monitored with an implantable loop recorder (ILR) for 2.5 years. All patients underwent extensive clinical assessment at baseline. During the follow-up all AF episodes were registered, and AF-associated metrics, such as burden, were calculated for different time intervals. Early-POAF was defined as AF within first 90 postoperative days and late-POAF as AF after this interval.

RESULTS: A total of 98 consecutive patients were included. POAF burden during the early postoperative phase was significantly higher as compared to the late postoperative phase (p<0.001). The longest individual POAF episode was strongly associated with increased POAF burden after adjusting for age, sex, and AF-history (standardized Beta: 0.91, p<0.001). Also, early-POAF burden was associated with late-POAF (re)occurrence after adjusting for age, sex, AF-history (adjusted Hazard Ratio=1.93, 95%CI: 1.42-2.62, p<0.001).

CONCLUSION: POAF burden was significantly associated with the longest individual POAF episode duration. Additionally, greater early-POAF burden was associated with increased late-POAF incidence, highlighting its potential in estimating the risk for long-term POAF recurrences.

PMID:39121980 | DOI:10.1016/j.hrthm.2024.08.014

Cell Rep Methods. 2024 Aug 2:100833. doi: 10.1016/j.crmeth.2024.100833. Online ahead of print.

ABSTRACT

The type I CRISPR system has recently emerged as a promising tool, especially for large-scale genomic modification, but its application to generate model animals by editing zygotes had not been established. In this study, we demonstrate genome editing in zygotes using the type I-E CRISPR-Cas3 system, which efficiently generates deletions of several thousand base pairs at targeted loci in mice with 40%-70% editing efficiency without off-target mutations. To overcome the difficulties associated with detecting the variable deletions, we used a newly long-read sequencing-based multiplex genotyping approach. Demonstrating remarkable versatility, our Cas3-based technique was successfully extended to rats as well as mice, even by zygote electroporation methods. Knockin for SNP exchange and genomic replacement with a donor plasmid were also achieved in mice. This pioneering work with the type I CRISPR zygote editing system offers increased flexibility and broader applications in genetic engineering across different species.

PMID:39121862 | DOI:10.1016/j.crmeth.2024.100833

Dev Cell. 2024 Aug 2:S1534-5807(24)00455-6. doi: 10.1016/j.devcel.2024.07.015. Online ahead of print.

ABSTRACT

Muscle stem cells (MuSCs) enable muscle growth and regeneration after exercise or injury, but how metabolism controls their regenerative potential is poorly understood. We describe that primary metabolic changes can determine murine MuSC fate decisions. We found that glutamine anaplerosis into the tricarboxylic acid (TCA) cycle decreases during MuSC differentiation and coincides with decreased expression of the mitochondrial glutamate deaminase GLUD1. Deletion of Glud1 in proliferating MuSCs resulted in precocious differentiation and fusion, combined with loss of self-renewal in vitro and in vivo. Mechanistically, deleting Glud1 caused mitochondrial glutamate accumulation and inhibited the malate-aspartate shuttle (MAS). The resulting defect in transporting NADH-reducing equivalents into the mitochondria induced compartment-specific NAD+/NADH ratio shifts. MAS activity restoration or directly altering NAD+/NADH ratios normalized myogenesis. In conclusion, GLUD1 prevents deleterious mitochondrial glutamate accumulation and inactivation of the MAS in proliferating MuSCs. It thereby acts as a compartment-specific metabolic brake on MuSC differentiation.

PMID:39121856 | DOI:10.1016/j.devcel.2024.07.015

Cell. 2024 Aug 8;187(16):4373-4388.e15. doi: 10.1016/j.cell.2024.06.036.

ABSTRACT

Relatlimab (rela; anti-LAG-3) plus nivolumab (nivo; anti-PD-1) is safe and effective for treatment of advanced melanoma. We designed a trial (NCT03743766) where advanced melanoma patients received rela, nivo, or rela+nivo to interrogate the immunologic mechanisms of rela+nivo. Analysis of biospecimens from this ongoing trial demonstrated that rela+nivo led to enhanced capacity for CD8+ T cell receptor signaling and altered CD8+ T cell differentiation, leading to heightened cytotoxicity despite the retention of an exhaustion profile. Co-expression of cytotoxic and exhaustion signatures was driven by PRDM1, BATF, ETV7, and TOX. Effector function was upregulated in clonally expanded CD8+ T cells that emerged after rela+nivo. A rela+nivo intratumoral CD8+ T cell signature was associated with a favorable prognosis. This intratumoral rela+nivo signature was validated in peripheral blood as an elevated frequency of CD38+TIM3+CD8+ T cells. Overall, we demonstrated that cytotoxicity can be enhanced despite the retention of exhaustion signatures, which will inform future therapeutic strategies.

PMID:39121849 | DOI:10.1016/j.cell.2024.06.036

Environ Int. 2024 Jul 25;190:108907. doi: 10.1016/j.envint.2024.108907. Online ahead of print.

ABSTRACT

Environmental exposures and gene-exposure interactions are the major causes of some diseases. Early-life exposome studies are needed to elucidate the role of environmental exposures and their complex interactions with biological mechanisms involved in childhood health. This study aimed to determine the contribution of early-life exposome to DNA damage and the modifying effect of genetic polymorphisms involved in air pollutants metabolism, antioxidant defense, and DNA repair. We conducted a cohort study in 416 Colombian children under five years. Blood samples at baseline were collected to measure DNA damage by the Comet assay and to determine GSTT1, GSTM1, CYP1A1, H2AX, OGG1, and SOD2 genetic polymorphisms. The exposome was estimated using geographic information systems, remote sensing, LUR models, and questionnaires. The association exposome-DNA damage was estimated using the Elastic Net linear regression with log link. Our results suggest that exposure to PM2.5 one year before the blood draw (BBD) (0.83, 95 %CI: 0.76; 0.91), soft drinks consumption (0.94, 0.89; 0.98), and GSTM1 null genotype (0.05, 0.01; 0.36) diminished the DNA damage, whereas exposure to PM2.5 one-week BBD (1.18, 1.06; 1.32), NO2 lag-5 days BBD (1.27, 1.18; 1.36), in-house cockroaches (1.10, 1.00; 1.21) at the recruitment, crowding at home (1.34, 1.08; 1.67) at the recruitment, cereal consumption (1.11, 1.04; 1.19) and H2AX (AG/GG vs. AA) (1.44, 1.11; 1.88) increased the DNA damage. The interactions between H2AX (AG/GG vs. AA) genotypes with crowding and PM2.5 one week BBD, GSTM1 (null vs. present) with humidity at the first year of life, and OGG1 (SC/CC vs. SS) with walkability at the first year of life were significant. The early-life exposome contributes to elucidating the effect of environmental exposures on DNA damage in Colombian children under five years old. The exposome-DNA damage effect appears to be modulated by genetic variants in DNA repair and antioxidant defense enzymes.

PMID:39121825 | DOI:10.1016/j.envint.2024.108907

Redox Biol. 2024 Aug 2;75:103298. doi: 10.1016/j.redox.2024.103298. Online ahead of print.

ABSTRACT

Benign prostatic hyperplasia (BPH), characterized by the non-malignant enlargement of the prostate, exhibits a pronounced association with inflammation resulting from androgen receptor (AR) deficiency. Ferroptosis, a cell death mechanism triggered by iron-dependent lipid peroxidation and closely linked to inflammation, has yet to be fully understood in the context of BPH. Using RNA sequencing, we observed a significant elevation of taurine-upregulated gene 1 (TUG1) long noncoding RNA (lncRNA) in BPH tissues compared to normal prostate tissue. High levels of TUG1 exhibited a discernible correlation with both prostate volume and the extent of inflammatory infiltration in BPH patients. The suppression of TUG1 not only led to a reduction in prostate size but also ameliorated AR-deficiency-induced prostatic hyperplasia. Mechanistically, a decrease in AR in prostate luminal cells prompted macrophage aggregation and the release of IL-1β, subsequently fostering the transcription of TUG1 via MYC. Induced TUG1, through competitive binding with miR-188-3p, facilitated the expression of GPX4, thereby diminishing intracellular ROS levels and impeding ferroptosis in prostate luminal cells. Notably, the ferroptosis inducer JKE-1674 alleviated inflammation-induced prostatic hyperplasia in vivo. Together, these findings suggest that AR deficiency crucially inhibits ferroptosis, promoting BPH via the TUG1/miR-188-3p/GPX4 signaling axis, and making ferroptosis induction a promising therapeutic strategy for BPH patients with AR deficiency.

PMID:39121689 | DOI:10.1016/j.redox.2024.103298

Sci Adv. 2024 Aug 9;10(32):eadp0860. doi: 10.1126/sciadv.adp0860. Epub 2024 Aug 9.

ABSTRACT

How complex 3D tissue shape emerges during animal development remains an important open question in biology and biophysics. Here, we discover a mechanism for 3D epithelial shape change based on active, in-plane cellular events that is analogous to inanimate "shape programmable" materials, which undergo blueprinted 3D shape transformations from in-plane gradients of spontaneous strains. We study eversion of the Drosophila wing disc pouch, when the epithelium transforms from a dome into a curved fold, quantifying 3D tissue shape changes and mapping spatial patterns of cellular behaviors on the evolving geometry using cellular topology. Using a physical model inspired by shape programming, we find that active cell rearrangements are the major contributor to pouch eversion and validate this conclusion using a knockdown of MyoVI, which reduces rearrangements and disrupts morphogenesis. This work shows that shape programming is a mechanism for animal tissue morphogenesis and suggests that patterns in nature could present design strategies for shape-programmable materials.

PMID:39121221 | DOI:10.1126/sciadv.adp0860

Sci Adv. 2024 Aug 9;10(32):eadp6182. doi: 10.1126/sciadv.adp6182. Epub 2024 Aug 9.

ABSTRACT

Endothelial cells (ECs) are highly plastic, capable of differentiating into various cell types. Endothelial-to-mesenchymal transition (EndMT) is crucial during embryonic development and contributes substantially to vascular dysfunction in many cardiovascular diseases (CVDs). While targeting EndMT holds therapeutic promise, understanding its mechanisms and modulating its pathways remain challenging. Using single-cell RNA sequencing on three in vitro EndMT models, we identified conserved gene signatures. We validated original regulators in vitro and in vivo during embryonic heart development and peripheral artery disease. EndMT induction led to global expression changes in all EC subtypes rather than in mesenchymal clusters. We identified mitochondrial calcium uptake as a key driver of EndMT; inhibiting mitochondrial calcium uniporter (MCU) prevented EndMT in vitro, and conditional Mcu deletion in ECs blocked mesenchymal activation in a hind limb ischemia model. Tissues from patients with critical limb ischemia with EndMT features exhibited significantly elevated endothelial MCU. These findings highlight MCU as a regulator of EndMT and a potential therapeutic target.

PMID:39121218 | DOI:10.1126/sciadv.adp6182

Plant J. 2024 Aug 9. doi: 10.1111/tpj.16959. Online ahead of print.

ABSTRACT

The bilateral-to-radial symmetry transition occurring during the development of the Arabidopsis thaliana female reproductive organ (gynoecium) is a crucial biological process linked to plant fertilization and seed production. Despite its significance, the cellular mechanisms governing the establishment and breaking of radial symmetry at the gynoecium apex (style) remain unknown. To fill this gap, we employed quantitative confocal imaging coupled with MorphoGraphX analysis, in vivo and in vitro transcriptional experiments, and genetic analysis encompassing mutants in two bHLH transcription factors necessary and sufficient to promote transition to radial symmetry, SPATULA (SPT) and INDEHISCENT (IND). Here, we show that defects in style morphogenesis correlate with defects in cell-division orientation and rate. We showed that the SPT-mediated accumulation of auxin in the medial-apical cells undergoing symmetry transition is required to maintain cell-division-oriented perpendicular to the direction of organ growth (anticlinal, transversal cell division). In addition, SPT and IND promote the expression of specific core cell-cycle regulators, CYCLIN-D1;1 (CYC-D1;1) and CYC-D3;3, to support progression through the G1 phase of the cell cycle. This transcriptional regulation is repressed by auxin, thus forming an incoherent feed-forward loop mechanism. We propose that this mechanism fine-tunes cell division rate and orientation with the morphogenic signal provided by auxin, during patterning of radial symmetry at the style.

PMID:39121182 | DOI:10.1111/tpj.16959

J Neuromuscul Dis. 2024 Aug 7. doi: 10.3233/JND-240050. Online ahead of print.

ABSTRACT

HNRNPA1 variants are known to cause degenerative motoneuron and muscle diseases which manifests in middle age or later. We report on a girl with early childhood onset, rapidly progressive generalized myopathy including ultrastructural findings in line with a proteinopathy. Proteomics of patient-derived muscle and combined screening of genomic data for copy number variations identified a HNRNPA1 de novo intragenic deletion as causative for the phenotype. Our report expands the spectrum of HNRNPA1-related diseases towards early-childhood onset and adds HNRNPA1 to the growing list of ALS and myopathy genes for which certain mutations may cause severe pediatric phenotypes.

PMID:39121134 | DOI:10.3233/JND-240050

Plant Cell. 2024 Aug 9:koae227. doi: 10.1093/plcell/koae227. Online ahead of print.

ABSTRACT

Following whole-genome duplication (WGD), duplicate gene pairs (homoeologs) can evolve varying degrees of expression divergence. However, the determinants influencing these relative expression level differences (RFPKM) between homoeologs remain elusive. Here, we analyzed the RFPKM between homoeologs in three angiosperms, Nymphaea colorata, Nelumbo nucifera, and Acorus tatarinowii, all having undergone a single WGD since the origin of angiosperms. Our results show significant positive correlations in RFPKM of homoeologs among tissues within the same species, and among orthologs across these three species, indicating convergent expression balance/bias between homoeologous gene copies following independent WGDs. We linked RFPKM between homoeologs to gene attributes associated with dosage balance constraints, such as protein-protein interactions, lethal-phenotype scores in Arabidopsis (Arabidopsis thaliana) orthologs, domain numbers, and expression breadth. Notably, homoeologs with lower RFPKM often had more interactions and higher lethal-phenotype scores, indicating selective pressures favoring balanced expression. Also, homoeologs with lower RFPKM were more likely to be retained after WGDs in angiosperms. Within Nelumbo, greater RFPKM between homoeologs correlated with increased cis- and trans-regulatory differentiation between species, highlighting the ongoing escalation of gene expression divergence. We further found that expression degeneration in one copy of homoeologs is inclined towards nonfunctionalization. Our research highlights the importance of balanced expression, shaped by dosage balance constraints, in the evolutionary retention of homoeologs in plants.

PMID:39121058 | DOI:10.1093/plcell/koae227

ACS Synth Biol. 2024 Aug 9. doi: 10.1021/acssynbio.3c00537. Online ahead of print.

ABSTRACT

Microorganisms are shown to actively partition their intracellular resources, such as proteins, for growth optimization. Recent experiments have begun to reveal molecular components unpinning the partition; however, quantitatively, it remains unclear how individual parts orchestrate to yield precise resource allocation that is both robust and dynamic. Here, we developed a coarse-grained mathematical framework that centers on guanosine pentaphosphate (ppGpp)-mediated regulation and used it to systematically uncover the design principles of proteome allocation in Escherichia coli. Our results showed that the cellular ability of resource partition lies in an ultrasensitive, negative feedback-controlling topology with the ultrasensitivity arising from zero-order amino acid kinetics and the negative feedback from ppGpp-controlled ribosome synthesis. In addition, together with the time-scale separation between slow ribosome kinetics and fast turnovers of ppGpp and amino acids, the network topology confers the organism an optimization mechanism that mimics sliding mode control, a nonlinear optimization strategy that is widely used in man-made systems. We further showed that such a controlling mechanism is robust against parameter variations and molecular fluctuations and is also efficient for biomass production over time. This work elucidates the fundamental controlling mechanism of E. coli proteome allocation, thereby providing insights into quantitative microbial physiology as well as the design of synthetic gene networks.

PMID:39120961 | DOI:10.1021/acssynbio.3c00537

J Evol Biol. 2024 Aug 9:voae098. doi: 10.1093/jeb/voae098. Online ahead of print.

ABSTRACT

The central dogma of molecular biology can be conceptualised as the division of labour between templates and catalysts, where templates transmit genetic in- formation, catalysts accelerate chemical reactions, and the information flows from templates to catalysts but not from catalysts to templates. How can the template- catalyst division evolve in primordial replicating systems? A previous study has shown that even if the template-catalyst division does not provide an immediate fit- ness benefit, it can evolve through symmetry breaking between replicating molecules when the molecules are compartmentalised into protocells. However, cellular com- partmentalisation may have been absent in primordial replicating systems. Here, we investigate whether cellular compartmentalisation is necessary for the evolution of the template-catalyst division via symmetry breaking using an individual-based model of replicators in a two-dimensional space. Our results show that replicators evolve the template-catalyst division via symmetry breaking when their diffusion constant is sufficiently high, a condition that results in low genetic relatedness between replicators. The evolution of the template-catalyst division reduces the risk of invasion by "cheaters," replicators that have no catalytic activities, encode no catalysts, but replicate to the detriment of local population growth. Our results suggest that the evolution of the template-catalyst division via symmetry breaking does not require cellular compartmentalization and is, instead, a general phenomenon in replicators with structured populations.

PMID:39120521 | DOI:10.1093/jeb/voae098

mBio. 2024 Aug 9:e0078124. doi: 10.1128/mbio.00781-24. Online ahead of print.

ABSTRACT

Archaea are widespread in the environment and play fundamental roles in diverse ecosystems; however, characterization of their unique biology requires advanced tools. This is particularly challenging when characterizing gene function. Here, we generate randomly barcoded transposon libraries in the model methanogenic archaeon Methanococcus maripaludis and use high-throughput growth methods to conduct fitness assays (RB-TnSeq) across over 100 unique growth conditions. Using our approach, we identified new genes involved in nutrient utilization and response to oxidative stress. We identified novel genes for the usage of diverse nitrogen sources in M. maripaludis including a putative regulator of alanine deamination and molybdate transporters important for nitrogen fixation. Furthermore, leveraging the fitness data, we inferred that M. maripaludis can utilize additional nitrogen sources including ʟ-glutamine, ᴅ-glucuronamide, and adenosine. Under autotrophic growth conditions, we identified a gene encoding a domain of unknown function (DUF166) that is important for fitness and hypothesize that it has an accessory role in carbon dioxide assimilation. Finally, comparing fitness costs of oxygen versus sulfite stress, we identified a previously uncharacterized class of dissimilatory sulfite reductase-like proteins (Dsr-LP; group IIId) that is important during growth in the presence of sulfite. When overexpressed, Dsr-LP conferred sulfite resistance and enabled use of sulfite as the sole sulfur source. The high-throughput approach employed here allowed for generation of a large-scale data set that can be used as a resource to further understand gene function and metabolism in the archaeal domain.IMPORTANCEArchaea are widespread in the environment, yet basic aspects of their biology remain underexplored. To address this, we apply randomly barcoded transposon libraries (RB-TnSeq) to the model archaeon Methanococcus maripaludis. RB-TnSeq coupled with high-throughput growth assays across over 100 unique conditions identified roles for previously uncharacterized genes, including several encoding proteins with domains of unknown function (DUFs). We also expand on our understanding of carbon and nitrogen metabolism and characterize a group IIId dissimilatory sulfite reductase-like protein as a functional sulfite reductase. This data set encompasses a wide range of additional conditions including stress, nitrogen fixation, amino acid supplementation, and autotrophy, thus providing an extensive data set for the archaeal community to mine for characterizing additional genes of unknown function.

PMID:39120137 | DOI:10.1128/mbio.00781-24

Elife. 2024 Aug 9;13:e86181. doi: 10.7554/eLife.86181. Online ahead of print.

ABSTRACT

B-cell repertoires are characterized by a diverse set of receptors of distinct specificities generated through two processes of somatic diversification: V(D)J recombination and somatic hypermutations. B cell clonal families stem from the same V(D)J recombination event, but differ in their hypermutations. Clonal families identification is key to understanding B-cell repertoire function, evolution and dynamics. We present HILARy (High-precision Inference of Lineages in Antibody Repertoires), an efficient, fast and precise method to identify clonal families from single- or paired-chain repertoire sequencing datasets. HILARy combines probabilistic models that capture the receptor generation and selection statistics with adapted clustering methods to achieve consistently high inference accuracy. It automatically leverages the phylogenetic signal of shared mutations in difficult repertoire subsets. Exploiting the high sensitivity of the method, we find the statistics of evolutionary properties such as the site frequency spectrum and &#x1D451;&#x1D441;∕&#x1D451;&#x1D446; ratio do not depend on the junction length. We also identify a broad range of selection pressures spanning two orders of magnitude.

PMID:39120133 | DOI:10.7554/eLife.86181

Plant Cell Physiol. 2024 Aug 9:pcae089. doi: 10.1093/pcp/pcae089. Online ahead of print.

ABSTRACT

Light affects almost every aspect of plant development. It is perceived by photoreceptors, among which phytochromes (PHY) are responsible for monitoring the red and far-red spectrum. Arabidopsis thaliana possesses five phytochrome genes (phyA-E). Whereas functions of phyA and phyB are extensively studied, our knowledge on other phytochromes is still rudimentary. To analyze phyD function we expressed it at high levels in different phytochrome-deficient genetic backgrounds. Overexpressed phyD-YFP can govern effective light signaling but only at low temperature and in cooperation with functional phyC. Under these conditions, phyD-YFP accumulates to high levels and opposite to phyB, this pool is stable in light. By comparing the photoconvertible phyD-YFP and phyB levels and their signaling in continuous and pulsed irradiation, we showed that phyD-YFP is a less efficient photoreceptor than phyB. This conclusion is supported by the facts that only a part of the phyD-YFP pool is photoconvertible and thermal reversion of phyD-YFP is faster than that of phyB. Our data suggest that the temperature-dependent function of phyD is based on the amount of phyD protein and not on its Pfr stability, as described for phyB. We also found that phyD-YFP and phyB-GFP associate with strongly overlapping genomic locations and mediate similar changes in gene expression, however the efficiency of phyD-YFP is lower. Based on these data we propose that under certain conditions, synergistic interaction of phyD and phyC can substitute phyB function in seedlings and in adult plants, thus increases the ability of plants to respond more flexibly to environmental changes.

PMID:39119682 | DOI:10.1093/pcp/pcae089

Front Genet. 2024 Jul 25;15:1394630. doi: 10.3389/fgene.2024.1394630. eCollection 2024.

ABSTRACT

Acute Stress Disorder (ASD) is a psychiatric condition that can develop shortly after trauma exposure. Although molecular studies of ASD are only beginning, groups of metabolites have been found to be significantly altered with acute stress phenotypes in various pre-clinical and clinical studies. ASD implicated metabolites include amino acids (β-hydroxybutyrate, glutamate, 5-aminovalerate, kynurenine and aspartate), ketone bodies (β-hydroxybutyrate), lipids (cortisol, palmitoylethanomide, and N-palmitoyl taurine) and carbohydrates (glucose and mannose). Network and pathway analysis with the most prominent metabolites shows that Extracellular signal-regulated kinases and c-AMP response element binding (CREB) protein can be crucial players. After highlighting main recent findings on the role of metabolites in ASD, we will discuss potential future directions and challenges that need to be tackled. Overall, we aim to showcase that metabolomics present a promising opportunity to advance our understanding of ASD pathophysiology as well as the development of novel biomarkers and therapeutic targets.

PMID:39119583 | PMC:PMC11306072 | DOI:10.3389/fgene.2024.1394630