bluuebunny/crossref_metadata_2025 huggingface dataset:
Out-of-Anatolia: cultural and genetic interactions during the Neolithic expansion in the Aegean
Authors: Koptekin Dilek , Aydoğan Ayça , Karamurat Cansu , Altınışık N. Ezgi , Vural Kıvılcım Başak , Kazancı D. Deniz , Doğu Ayça Küçükakdağ , Kaptan Damla , Gemici Hasan Can , Yüncü Eren , Umurtak Gülsün , Duru Refik , Fidan Erkan , Çevik Özlem , Erdoğu Burçin , Korkut Taner , Knüsel Christopher J. , Haddow Scott , Larsen Clark Spencer , Özbal Rana , Gerritsen Fokke , Özdoğan Eylem , Usanmaz Uygar Ozan , Derici Yasin Cemre , Uçmazoğlu Mine , Jay Flora , Özdoğan Mehmet , Götherström Anders , Erdal Yılmaz Selim , Malaspinas Anna-Sapfo , Atakuman Çiğdem , Özer Füsun , Somel Mehmet
Published: June 2024

Western Anatolia has been a crucial yet elusive element in the Neolithic expansion from the Fertile Crescent to Europe. Using 30 new palaeogenomes from Anatolia c.8000-6000 BCE we describe the early Holocene genetic landscape of Western Anatolia, which reveals population continuity since the late Upper Pleistocene. Our findings indicate that the Neolithisation of Western Anatolia in the 7thmillennium BCE was a multifaceted process, characterised by the assimilation of Neolithic practices by indigenous groups and the influx of populations from the east, their admixed descendants eventually laying the foundations of Neolithic Southeast Europe. Intriguingly, the observed diversity in material culture among Aegean Early Neolithic communities correlates with their geographical distances but not their genetic differences, signifying a decoupling between cultural developments and genetic admixture processes.
A selective alternative pathway complement inhibitor for treatment of paroxysmal nocturnal hemoglobinuria
Authors: Sülzen Hagen , Tulmin Hanna , Hájek Miroslav , Čermák Jaroslav , Kadlecová Alžběta , Pompach Petr , Votrubová Jitka , Zoltner Martin , Zoll Sebastian
Published: June 2024

The complement system, a critical component of the human innate immune system, enhances the ability to clear microbes and damaged cells. Dysregulation of this system, particularly the alternative pathway (AP), can lead to several rare blood disorders such as paroxysmal nocturnal hemoglobinuria (PNH). This study introduces SH-01, a blood parasite-derived, novel recombinant protein which selectively inhibits the AP. We show that SH-01 effectively prevents the lysis of erythrocytes isolated from PNH patients. Unlike current treatments such as eculizumab, SH-01 targets the AP without impairing the classical or lectin pathways, reducing the risk of infections and extravascular hemolysis. SH-01 functions through a unique two-stage mechanism, preventing C3b deposition and inhibiting AP C5 convertase activity while maintaining the amplification loop’s functionality. Immunization studies in mice showed no significant immune response against SH-01, and the protein exhibited high stability and no acute toxicity. These findings suggest SH-01 as a promising candidate for treatment of PNH and other diseases characterized by AP hyperactivation, offering a more targeted therapeutic and thus safer approach.
A next generation neural mass model with neuromodulation
Authors: Depannemaecker Damien , Duprat Chloé , Casagrande Gabriele , Saggio Marisa , Athanasiadis Anastasios Polykarpos , Angiolelli Marianna , Carbonell Carola Sales , Wang Huifang , Petkoski Spase , Sorrentino Pierpaolo , McIntosh Anthony Randal , Sheheitli Hiba , Jirsa Viktor
Published: June 2024

The study of brain activity and its function requires the development of computational models alongside experimental investigations to explore different effects of multiple mechanisms at play in the central nervous system. Chemical neuromodulators, such as dopamine, play central roles in regulating the dynamics of neuronal populations. In this work, we propose a modular framework to capture the effects of neuromodulators at the neural mass level. Using this framework, we formulate a specific model for dopamine dynamics affecting D1-type receptors. We detail the dynamical repertoire associated with dopamine concentration evolution and characterize the transitions across qualitatively different oscillatory states as a function of relevant parameters, along with the variations in frequency of the emergent multi-scale oscillations.
Substance P receptor signaling contributes to host maladaptive responses during enteric bacterial infection
Authors: Cremin Michael , Ramirez Valerie T. , Sanchez Kristina , Tay Emmy , Murray Kaitlin , Brust-Mascher Ingrid , Reardon Colin
Published: June 2024

Immune responses in the intestine are intricately balanced to prevent pathogen entry without inducing immunopathology. The nervous system is well-established to interface with the immune system to fine-tune immunity in various organ systems including the gastrointestinal tract. Specialized sensory neurons can detect bacteria, bacterial products, and the resulting inflammation, to coordinate the immune response in the gastrointestinal tract. These sensory neurons release peptide neurotransmitters such as Substance P (SP), to induce both neuronal signaling and localized responses in non-neuronal cells. With this in mind, we assessed the immunoregulatory roles of SP receptor signaling during enteric bacterial infection with the non-invasive pathogenCitrobacter rodentium. Pharmacological antagonism of the SP receptor significantly reduced bacterial burden and prevented colonic crypt hyperplasia. Mice with SP receptor signaling blockade had significantly reduced inflammation and recruitment of T-cells in the colon. Reduced colonic T-cell recruitment is due to reduced expression of adhesion molecules on colonic endothelial cells in SP receptor antagonist-treated mice. Using SP receptor T-cell conditional knockout mice, we further confirmed SP receptor signaling enhanced select aspects of T-cell responses. Our data demonstrates that SP receptor signaling can significantly reduce inflammation and prevent host-maladaptive responses without impinging upon host protection.
Within and Across Species Variation in Plant Traits in Response to Long-Term Experimental Herbivore Exclusion in a Semi-Arid Shrubland
Authors: Fernández-Murillo María del Pilar , Alfaro Fernando Daniel , Kelt Douglas A. , Meserve Peter L. , Gutiérrez Julio R. , Troncoso Alejandra J. , Craven Dylan
Published: June 2024

1) Herbivores shape multiple facets of biodiversity patterns and ecosystem processes, yet are increasingly threatened by habitat loss and climate change. Here, we use a long-term experiment to examine how excluding herbivores, a proxy for biodiversity loss, restructures dominant plant ecological strategies within and across species.

2) We measured twelve functional traits of four dominant annual plant species in the semi-arid shrublands of Chile. We evaluated changes in trait distributions within and across species and changes in the coordination between above- and below-ground strategies in response to vertebrate herbivore exclusion.

3) Our study reveals three dominant ecological strategies characterizing trait variation within and across species, with an increase in the coordination between above- and below-ground strategies in the presence of herbivores. Our results show that herbivores induce shifts in ecological strategies, leading to conservative resource use, increased herbivore tolerance, reduced collaboration with soil microorganisms, and greater intraspecific diversity, facilitating species coexistence.

4) We empirically demonstrate how herbivores shape ecological strategies within and across species, and demonstrate that the absence of herbivores alters the diversity of adaptation strategies of plants and leads to a decoupling of resource acquisition strategies above- and below-ground. These results advance understanding of annual plant responses to herbivore loss.
Interannual changes in nutrient and phytoplankton dynamics in the Eastern Mediterranean Sea (EMS) predict the consequences of climate change; results from the Sdot-Yam Time-series station 2018-2022
Authors: Ben-Ezra Tal , Blachinsky Alon , Gozali Shiran , Tsemel Anat , Fadida Yotam , Tchernov Dan , Lehahn Yoav , Tsagaraki Tatiana Margo , Berman-Frank Ilana , Krom Michael
Published: June 2024

Global climate change is predicted to reduce nutrient fluxes into the photic zone, particularly in tropical and subtropical ocean gyres, while the occasional major storms will result in increased nutrient pulses. In this study the nutrient and phytoplankton dynamics have been determined at a new time-series station in the southeastern Levantine basin of the Eastern Mediterranean Sea (EMS) over 4.5 years (2017-2022). In 2018 and 2019, there was a moderate concentration of residual nitrate and nitrite (N+N) in the photic zone (280-410nM) in winter, resulting in phytoplankton dynamics dominated by cyanobacteria with relatively few picoeukaryotes (280± 90 μgC m−2). Winter storm driven mixing was much reduced in 2020 and particularly in 2021, resulting in a lower concentration of N+N in the photic zone, which decreased during summer stratification, such that by August 2021, the N+N was highly depleted (<60 nM) resulting in an integrated phytoplankton biomass of 23 μgC m−2. A major storm in December 2021 (Storm Carmel) injected high N+N (750 nM; max = 1090 nM) in the upper 100 m, which stimulated pico and nanophytoplankton biomass (∼2400 μgC m−2) and probably increased eukaryotes (diatoms). The pattern of measured silica reinforced our conclusion that we sampled 3 different nutrient and ecosystem states. Phosphate was always at or close to LoD because of rapid uptake by cyanobacteria into their periplasm. These results predict that climate change in the EMS will result in periods of nutrient and phytoplankton depletion (Famine) interrupted by short periods of Mesotrophy (Feast) caused by major storms.

Highlights

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Nutrient dynamics from 4 years of Time-series station in the S.E. Levantine basin

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Defined ecosystem status of normal, depleted and temporarily mesotrophic which are predicted status’ caused by climate change

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Winters with low deep mixing resulted in severely nutrient depleted conditions subsequently

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Major storm and relatively shallow nutricline resulted in temporary mesotrophic status
Mutant scaling laws reveal that accelerated evolution via gene amplification requires spatially structured population growth
Authors: Komarova Natalia L. , Pritchard Justin , Wodarz Dominik
Published: June 2024

Principles of evolution in spatially structured expanding populations have recently received much attention, but more work remains to be performed, especially for complex, multi-step evolutionary processes, where mutations are accumulated in an expanding population. A key limitation is that the simulation of spatially explicit stochastic computational models is essential, but not feasible for larger population sizes characteristic of prokaryotic and eukaryotic cell populations. We describe a methodological advance by deriving scaling laws that allow the straightforward prediction of the number of single-hit, double-hit and multi-hit mutants as a function of wild-type population size in spatially expanding populations. While this is a versatile tool to address a range of cutting-edge evolutionary questions, here we apply this methodology to reconcile apparently contradicting data from experimental evolution studies regarding the role of gene amplifications for the emergence of point mutations in bacteria. Applying the scaling laws, we demonstrate that in populations that expand in a 2D or a 3D spatial setting, gene amplifications can significantly promote mutant emergence, and that this is not possible in well-mixed populations. In support of the predictions, experiments that do show accelerated mutant evolution through gene amplifications grew bacteria in spatially restricted lawns, while those that failed to show an effect grew bacteria in non-spatial liquid media.
The evolution of sequence specificity in a DNA binding protein family
Authors: Nandy Meghna , Sharda Mohak , Seshasayee Aswin Sai Narain
Published: June 2024

Transcriptional regulation enables bacteria to adjust to its environment. This is driven by transcription factors (TFs), which display DNA site recognition specificity with some flexibility built-in. TFs however are not considered essential to a minimal cellular life. How do they evolve? It has been hypothesised that TFs evolve by gaining specificity (and other functions) on a background of non-specific chromosome structuring proteins. We used the IHF/HU family of DNA binding proteins, in which IHF binds DNA in a sequence specific manner whereas HU binds more indiscriminately, to test this hypothesis. We show that neither protein was present in the last common bacterial ancestor, and that HU evolved first in early-branching clades. By reconstructing ancestral sequencesin-silicoon a rooted phylogeny of IHF/HU we show that the common ancestor of this family was probably HU-like and therefore non-specific in binding DNA. Various residues characteristic of IHF and shown to be involved in specific sequence recognition (at least inE. coli) evolved gradually with several gains and losses along the phylogeny. Finally, we suggest that the evolution of the IHF/HU from a HU-like ancestor to IHF, and by inference the evolution of DNA site specificity in this family, was driven by selection.
Distinct dopaminergic spike-timing-dependent plasticity rules are suited to different functional roles
Authors: Sosis Baram , Rubin Jonathan E.
Published: June 2024

Various mathematical models have been formulated to describe the changes in synaptic strengths resulting from spike-timing-dependent plasticity (STDP). A subset of these models include a third factor, dopamine, which interacts with spike timing to contribute to plasticity at specific synapses, notably those from cortex to striatum at the input layer of the basal ganglia. Theoretical work to analyze these plasticity models has largely focused on abstract issues, such as the conditions under which they may promote synchronization and the weight distributions induced by inputs with simple correlation structures, rather than on scenarios associated with specific tasks, and has generally not considered dopamine-dependent forms of STDP. In this paper we introduce three forms of dopamine-modulated STDP adapted from previously proposed plasticity rules. We then analyze, mathematically and with simulations, their performance in three biologically relevant scenarios. We test the ability of each of the three models to maintain its weights in the face of noise and to complete simple reward prediction and action selection tasks, studying the learned weight distributions and corresponding task performance in each setting. Interestingly, we find that each plasticity rule is well suited to a subset of the scenarios studied but falls short in others. Different tasks may therefore require different forms of synaptic plasticity, yielding the prediction that the precise form of the STDP mechanism present may vary across regions of the striatum, and other brain areas impacted by dopamine, that are involved in distinct computational functions.
MAGMa: Your Comprehensive Tool for Differential Expression Analysis in Mass-Spectrometry Proteomic Data
Authors: Gupta Shagun , Kang Jin Joo , Sun Yu , Kumar Yugandhar , Wagner Mateusz , Comstock Will , Booth James , Smolka Marcus , Yu Haiyuan
Published: June 2024

Proteomics, the study of proteins and their functions, plays a vital role in understanding biological processes. In this study, we sought to address the challenges in analyzing complex proteomic datasets, where subtle changes in protein abundance are difficult to detect. Utilizing a newly developed tool,MaximalAggregation ofGood protein signal fromMass spectrometric data (MAGMa), we demonstrated its superior performance in accurately identifying true signals while effectively filtering out noise. Here we show that MAGMa strikes a balance between sensitivity and specificity on benchmarking datasets, offering a robust solution for analyzing various quantitative proteomic datasets. These findings advance the field by providing researchers with a powerful tool to uncover subtle changes in protein abundance, contributing to our understanding of complex biological systems and potentially facilitating the discovery of new therapeutic targets.
Just add water: A simple floral bud injection method for stableAgrobacterium-mediated transformation in two ecotypes ofMimulus guttatus
Authors: Stanley Lauren E. , Lowry David B.
Published: June 2024

Stable transformation is the biggest challenge for studying gene function in plants. In most plant species, stable transformation requires the development of arduous tissue culture and regeneration methods that often fail and can cause undesirable genetic changes. Floral transformation methods bypass these challenges by infiltratingAgrobacteriumdirectly into the ovules of developing flowers. However, this method has had limited success outside of a handful of plant species and genotypes within those species. Here, we demonstrate that the floral infiltration method is effective for some, but not all genotypes of the yellow monkeyflower,Mimulus guttatus, a model system for studies of ecology and evolution. To conduct transformation in genotypes where infiltration failed, we developed a novel floral injection method. Beyond expanding the number of genotypes that can be transformed, the floral injection method has other advantages, such as allowing plants to be infiltrated multiple times and a reduction in floral abscission and male sterility. Through a combination of floral infiltration and injection methods, we were able to transform both coastal perennial and inland annual genotypes ofM. guttatus, which sets the stage for understanding the molecular genetic underpinnings of local adaptation to the divergent habitats occupied by these distinctive ecotypes. Overall, the development of these efficient transformation methods will open up a wide range of new research avenues in theM. guttatusspecies complex.
NKp30 and NKG2D contribute to natural killer recognition of HIV-infected cells
Authors: Zhao Nancy Q. , Pi Ruoxi , Nguyen David N. , Ranganath Thanmayi , Seiler Christof , Holmes Susan , Marson Alexander , Blish Catherine A.
Published: June 2024

Natural killer (NK) cells respond rapidly in early HIV-1 infection. HIV-1 prevention and control strategies harnessing NK cells could be enabled by mechanistic understanding of how NK cells recognize HIV-infected T cells. Here, we profiled the phenotype of human primary NK cells responsive to autologous HIV-1-infected CD4+T cells in vitro. We characterized the patterns of NK cell ligand expression on CD4+T cells at baseline and after infection with a panel of transmitted/founder HIV-1 strains to identify key receptor-ligand pairings. CRISPR editing of CD4+T cells to knockout the NKp30 ligand B7-H6, or the NKG2D ligands MICB or ULBP2 reduced NK cell responses to HIV-infected cells in some donors. In contrast, overexpression of NKp30 or NKG2D in NK cells enhanced their targeting of HIV-infected cells. Collectively, we identified receptor-ligand pairs including NKp30:B7-H6 and NKG2D:MICB/ULBP2 that contribute to NK cell recognition of HIV-infected cells.
Broad-spectrum RNA antiviral inspired by ISG15-/-deficiency
Authors: Akalu Yemsratch T. , Patel Roosheel S. , Taft Justin , Canas-Arranz Rodrigo , Richardson Ashley , Buta Sofija , Martin-Fernandez Marta , Sazeides Christos , Pearl Rebecca L. , Mainkar Gayatri , Kurland Andrew P. , Geltman Rachel , Rosberger Haylen , Kang Diana D. , Kurian Ann Anu , Kaur Keerat , Altman Jennie , Dong Yizhou , Johnson Jeffrey R. , Zhangi Lior , Lim Jean K. , Albrecht Randy A. , García-Sastre Adolfo , Rosenberg Brad R. , Bogunovic Dusan
Published: June 2024

Type I interferons (IFN-I) are cytokines with potent antiviral and inflammatory capacities. IFN-I signaling drives the expression of hundreds of IFN-I stimulated genes (ISGs), whose aggregate function results in the control of viral infection. A few of these ISGs are tasked with negatively regulating the IFN-I response to prevent overt inflammation. ISG15 is a negative regulator whose absence leads to persistent, low-grade elevation of ISG expression and concurrent, self-resolving mild autoinflammation. The limited breadth and low-grade persistence of ISGs expressed in ISG15 deficiency are sufficient to confer broad-spectrum antiviral resistance. Inspired by ISG15 deficiency, we have identified a nominal collection of 10 ISGs that recapitulate the broad antiviral potential of the IFN-I system. The expression of the 10 ISG collection in an IFN-I non-responsive cell line increased cellular resistance to Zika, Vesicular Stomatitis, Influenza A (IAV), and SARS-CoV-2 viruses. A deliverable prophylactic formulation of this syndicate of 10 ISGs significantly inhibited IAV PR8 replicationin vivoin mice and protected hamsters against a lethal SARS-CoV-2 challenge, suggesting its potential as a broad-spectrum antiviral against many current and future emerging viral pathogens.

One-Sentence Summary

Human inborn error of immunity-guided discovery and development of a broad-spectrum RNA antiviral therapy
Destabilized host-parasite dynamics in newly founded populations
Authors: Bolnick Daniel I. , Barrett Rowan D.H. , Choi Emma , Eckert Lucas , Hendry Andrew P. , Kerns Emily V. , Lind Åsa J. , Milligan-McClellan Kathryn , Peichel Catherine L. , Sasser Kristofer , Thornton Alice R , Wolf Cole , Steinel Natalie C. , Weber Jesse N.
Published: June 2024

When species disperse into previously unoccupied habitats, new populations encounter unfamiliar species interactions such as altered parasite loads. Theory predicts that newly founded populations should exhibit destabilized eco-evolutionary fluctuations in infection rates and immune traits. However, to understand founder effects biologists typically rely on retrospective studies of range expansions, missing early-generation infection dynamics. To remedy this, we experimentally founded whole-lake populations of threespine stickleback. Infection rates were temporally stable in native source lakes. In contrast, newly founded populations exhibit destabilized host-parasite dynamics: high starting infection rates led to increases in a heritable immune trait (peritoneal fibrosis), suppressing infection rates. The resulting temporal auto-correlation between infection and immunity suggest that newly founded populations can exhibit rapid host-parasite eco-evolutionary dynamics.
Bilingual language processing relies on shared semantic representations that are modulated by each language
Authors: Chen Catherine , Gong Xue L. , Tseng Christine , Klein Daniel L. , Gallant Jack L. , Deniz Fatma
Published: June 2024

Billions of people throughout the world are bilingual and can extract meaning from multiple languages. While some evidence suggests that there is a shared system in the human brain for processing semantic information from native and non-native languages, other evidence suggests that semantic processing is language-specific. We conducted a study to determine how semantic representations in the brains of bilinguals can support both shared and language-specific processing for different languages. Functional magnetic resonance imaging (fMRI) was used to record brain responses while participants read several hours of natural narratives in their native (Chinese) and non-native (English) languages. These data were then used to specifically and comprehensively compare semantic representations between the two languages. First, we show that semantic representations are largely shared between languages. Second, we show that there are finer-grained differences that systematically alter how the same meaning is represented between different languages. Our results suggest that for bilinguals, semantic representations in the brain are shared across languages but modulated by each language. These results reconcile current competing theories of bilingual language processing.
Chromosome-scale genome assembly and gene annotation of the hydrothermal vent annelidAlvinella pompejanayield insight into animal evolution in extreme environments
Authors: El Hilali Sami , Dru Philippe , Le Moan Alan , Li Yang I , Huynen Martijn A. , Hoelz André , Robinson Robert C. , Martín-Durán José M. , Jollivet Didier , Claridge-Chang Adam , Copley Richard R.
Published: June 2024

The types of genomic change needed for environmental adaptation are of great interest. Annelid worms are a large phylum found in a rich diversity of habitats, giving opportunities to explore this issue. We report the chromosome level genome sequence of the Pompeii worm, the annelidAlvinella pompejana, an inhabitant of an extreme deep-sea hydrothermal vent environment. We find strong but heterogeneously distributed genetic divergence between populations taken from either side of the equator. Using transcript data, we produced a set of gene models and analysed the predicted protein set in the light of past hypotheses about the thermotolerance ofAlvinella, and compared it to other recently sequenced annelid vent worms. We do not find evidence of a more extreme genome wide amino acid composition than other species, neither do we find evidence for rapid genome evolution in the form of disrupted synteny. We discount the hypothesis of loss of amino acid biosynthesis genes associated with obligate symbioses reported in siboglinid annelids. We do find evidence of a parallel increase in the number of globin encoding genes and loss of light sensitive opsins and cryptochromes.Alvinellaencodes several respiratory enzymes unusual for bilaterian animals, suggesting an ability to better tolerate hypoxic environments.
A functional network model for body column neural connectivity inHydra
Authors: Braun Wilhelm , Jenderny Sebastian , Giez Christoph , Pavleska Dijana , Klimovich Alexander , Bosch Thomas C. G. , Ochs Karlheinz , Hövel Philipp , Hilgetag Claus C.
Published: June 2024

Hydrais a non-senescent animal with a relatively small number of cell types and overall low structural complexity, but a surprisingly rich behavioral repertoire. The main drivers ofHydra’s behavior are neurons that are arranged in two nerve nets comprising several distinct neuronal populations. Among these populations is the ectodermal nerve net N3 which is located throughout the animal. It has been shown that N3 is necessary and sufficient for the complex behavior of somersaulting and is also involved inHydrafeeding behavior. Despite being a behavioral jack-of-all-trades, there is insufficient knowledge on the coupling structure of neurons in N3, its connectome, and its role in activity propagation and function. We construct a model connectome for the part of N3 located on the body column. Using experimental data on the placement of neuronal somata and the spatial dimensions of the body column, we show that a generative network model combining non-random placement of neuronal somata and the preferred orientation of primary neurites yields good agreement with experimentally observed distributions of connection distances, connection angles, and the number of primary neurites per neuron. Having validated the N3 connectome model in this fashion, we place a simple excitable dynamical model on each node of the body column network and show that it generates directed, short-lived, fast propagating patterns of activity. In addition, by slightly changing the parameters of the dynamical model, the same structural network can also generate persistent activity. Finally, we use a neuromorphic circuit based on the Morris-Lecar model to show that the same structural connectome can, in addition to through-conductance with biologically plausible time scales, also host a dynamical pattern related to the complex behavioral pattern of somersaulting. We speculate that such different dynamical regimes act as dynamical substrates for the different functional roles of N3, allowingHydrato exhibit behavioral complexity with a relatively simple nervous system that does not possess modules or hubs.
Oldest attested languages in the Near East reveal deep transformations in the distribution of linguistic features
Authors: Efrat-Kowalsky Nour , Ranacher Peter , Neureiter Nico , Widmer Paul , Bickel Balthasar
Published: June 2024

It is an unresolved question to what extent the current frequency distributions of linguistic features inform us about what is representative of the language faculty and does not instead result from historical contingencies. We probe this question by leveraging unique data from the oldest attested languages, those preserved through writing from up to 5,000 years ago in the Ancient Near East. We examine 70 grammatical features for which there is sufficient evidence in the available records. After controlling for relatedness we find robust deviations of two of the oldest languages, Hurrian and Sumerian from both the ancient languages and the modern distribution. The spatial and temporal placement of these two languages reveal a divergent distribution of features in the region in prehistory, suggesting massive transformations of the linguistic distributions in the past few millennia. This challenges inferences about general characteristics of language based on modern distributions.
Meta-Analysis of Urinary Metabolite GWAS Studies Identifies Three Novel Genome-Wide Significant Loci
Authors: Zaki Jihan K. , Tomasik Jakub , McCune Jade , Scherman Oren , Bahn Sabine
Published: June 2024

Genome-wide association studies (GWAS) have substantially enhanced the understanding of genetic influences on phenotypic outcomes; however, realizing their full potential requires an aggregate analysis of numerous studies. Here we represent the first comprehensive meta-analysis of urinary metabolite GWAS studies, aiming to consolidate existing data on metabolite-SNP associations, evaluate consistency across studies, and unravel novel genetic links. Following an extensive literature review and data collection through the EMBL-EBI GWAS Catalog, PubMed, and metabolomix.com, we employed a sample size-based meta-analytic approach to evaluate the significance of previously reported GWAS associations. Our results showed that 1226 SNPs are significantly associated with urinary metabolite levels, including 48 lead SNPs correlated with 14 analytes: alanine, 3-aminoisobutyrate, betaine, creatine, creatinine, formate, glycine, glycolate, histidine, 2-hydroxybutyrate, lysine, threonine, trimethylamine, and tyrosine. Notably, the results revealed three previously unknown associations: rs4594899 with tyrosine (P = 6.6 × 10-9, N = 5447), rs1755609 with glycine (P = 3.3 × 10-10, N = 5447), and rs79053399 with 3-aminoisobutyrate (P = 6.9 × 10-10, N = 4656). These findings underscore the potential of urinary metabolite GWAS meta-analyses in revealing novel genetic factors that may aid in the understanding of disease processes, and highlight the necessity for larger and more comprehensive future studies.

Author summary

In this extensive study, we’ve meta-analysed data from various genome-wide association studies to better understand the genetic determinants of urinary metabolite levels. These metabolites are small molecules found in urine that reflect our body’s biochemical activities and can indicate states of health or disease. By combining results from previous research, we’ve identified 48 significant independent associations between single nucleotide polymorphisms (SNPs) and the levels of 14 metabolites in urine. Among these, we highlight three novel SNP-metabolite associations that offer new insights into the genetic architecture underlying metabolite regulation.

Our findings contribute to the growing body of evidence that demonstrates the value of large-scale genetic meta-analyses. The significant SNP-metabolite links uncovered may serve as biomarkers for complex biological processes and disease mechanisms. This work takes us a step closer to a more nuanced understanding of the genetic factors that influence metabolic pathways and holds promise for improving diagnostic and therapeutic strategies through precision medicine. However, the complexity of genetic contributions to metabolite variations calls for continued research, underscoring the need for larger and more comprehensive studies in the future.
Zebrafish do not have calprotectin
Authors: Orlandi Kona N. , Harms Michael J.
Published: June 2024

The protein heterodimer calprotectin and its component proteins, S100A8 and S100A9, play important antibacterial and proinflammatory roles in the mammalian innate immune response. Gaining mechanistic insights into the regulation and biological function of calprotectin will help facilitate patient diagnostics and therapy and further our understanding of the host-microbe interface. Recent literature has identified zebrafish s100a10b as zebrafish calprotectin based on sequence similarity, genomic context, and transcriptional upregulation during the immune response to bacterial infections. The field would benefit from expanding the breadth of calprotectin studies into a zebrafish innate immunity model. Here, we carefully evaluated the possibility that zebrafish possess a calprotectin. We found that zebrafish do not possess an ortholog of mammalian S100A8 or S100A9. We then identified four zebrafish s100 proteins— including s100a10b—that are expressed in immune cells and upregulated during the immune response. We recombinantly expressed and purified these proteins and measured the antimicrobial and proinflammatory characteristics. We found that none of the zebrafish proteins exhibited activity comparable to mammalian calprotectin. Our work demonstrates conclusively that zebrafish have no ortholog of calprotectin, and the most plausible candidate proteins have not convergently evolved similar functions.
KNOWLEDGE, ATTITUDE AND PRACTICE OF YOUNG WOMEN (AGE 18-25) IN BANGALORE CITY WITH REGARDS TO SELF-BREAST EXAMINATION
Authors: Pandita Swastik
Published: June 2024

Introduction: Breast cancer is a global health concern and a leading cause of morbidity and mortality. Breast self examination (BSE) is a commonly recommended screening method for breast cancer. This study intends to assess the knowledge of breast cancer and its screening in women aged 18-25 in Bangalore city and to assess the knowledge, attitude and practice of women aged 18-25 in Bangalore city with regards to breast self examination among the female college students studying non medical courses in Bangalore City, Karnataka, India. Materials and methods: A questionnaire‑based study was conducted among women aged 18-25 in Bangalore city and their scores in the fields of knowledge, attitude, and practice were calculated.Independent sample t-test and one-way analysis of variance (ANOVA) test of significance were used to examine the relation between the demographic characteristics and scores. Results: The mean knowledge score was 3.05 (SD:1.37, range:0-6). Knowledge scores significantly differed across family income per month (P<0.05), age groups (P<0.001), and level of education of father (P<0.05). The mean attitude score was 3.95 ( SD:1.78, range:1-8). The mean practice score was 0.83 (SD: 0.954, range:0-3).Practice scores varied significantly across age groups (P<0.05) , level of education of mother (P<0.05) and occupation of father (P<0.001).The correlation coefficients are 0.484 and 0.257 respectively (p<0.05). Conclusion: Breast Self Exam (BSE) is an easy method of early detection of breast cancer. There is a need to develop and adopt culturally appropriate and proven interventions to inform and train women about BSE in a diverse country like India. The study can be used as a basis to help raise awareness about BSE and its benefits among the same.
Complement 3a Receptor 1 on Macrophages and Kupffer cells is not required for the Pathogenesis of Metabolic Dysfunction-Associated Steatotic Liver Disease
Authors: Homan Edwin A. , Gilani Ankit , Rubio-Navarro Alfonso , Johnson Maya A. , Schaepkens Odin M. , Cortada Eric , Pereira de Lima Renan , Stoll Lisa , Lo James C.
Published: June 2024

Together with obesity and type 2 diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global epidemic. Activation of the complement system and infiltration of macrophages has been linked to progression of metabolic liver disease. The role of complement receptors in macrophage activation and recruitment in MASLD remains poorly understood. In human and mouse,C3AR1in the liver is expressed primarily in Kupffer cells, but is downregulated in humans with MASLD compared to obese controls. To test the role of complement 3a receptor (C3aR1) on macrophages and liver resident macrophages in MASLD, we generated mice deficient in C3aR1 on all macrophages (C3aR1-MjKO) or specifically in liver Kupffer cells (C3aR1-KpKO) and subjected them to a model of metabolic steatotic liver disease. We show that macrophages account for the vast majority ofC3ar1expression in the liver. Overall, C3aR1-MjKO and C3aR1-KpKO mice have similar body weight gain without significant alterations in glucose homeostasis, hepatic steatosis and fibrosis, compared to controls on a MASLD-inducing diet. This study demonstrates that C3aR1 deletion in macrophages or Kupffer cells, the predominant liver cell type expressingC3aR1, has no significant effect on liver steatosis, inflammation or fibrosis in a dietary MASLD model.
Targeted sequencing ofEnterobacteralesbacteria using CRISPR-Cas9 enrichment and Oxford Nanopore Technologies
Authors: Cottingham Hugh , Judd Louise M. , Wisniewski Jessica A. , Wick Ryan R. , Stanton Thomas D. , Vezina Ben , Macesic Nenad , Peleg Anton Y. , Okeke Iruka N. , Holt Kathryn E. , Hawkey Jane
Published: June 2024

Sequencing DNA directly from patient samples enables faster pathogen characterisation compared to traditional culture-based approaches, but often yields insufficient sequence data for effective downstream analysis. CRISPR-Cas9 enrichment is designed to improve yield of low abundance sequences but has not been thoroughly explored with Oxford Nanopore Technologies (ONT) for use in clinical bacterial epidemiology. We designed CRISPR-Cas9 guide RNAs to enrich for the human pathogenKlebsiella pneumoniae, by targeting multi-locus sequence type (MLST) and transfer RNA (tRNA) genes, as well as common antimicrobial resistance (AMR) genes and the resistance-associated integron geneintI1. We validated enrichment performance in bacterial isolates before comparing enriched and unenriched sequencing of three human faecal samples spiked withK. pneumoniaeat varying abundance. Enriched sequencing generated 56x and 11.3x the number of AMR and MLST reads respectively compared to unenriched sequencing and required approximately one third of the computational storage space. Targeting theintI1gene often led to detection of 10-20 proximal resistance genes due to the long reads produced by ONT sequencing. We demonstrated that CRISPR-Cas9 enrichment combined with ONT sequencing enabled improved genomic characterisation outcomes over unenriched sequencing of patient samples. This method could be used to inform infection control strategies by identifying patients colonised with high-risk strains.
Integrated forward and reverse degradomics uncovers the proteolytic landscape of aortic aneurysms and the roles of MMP9 and mast cell chymase
Authors: Bhutada Sumit , Martin Daniel R. , Cikach Frank , da Silva Emidio Germano , Willard Belinda B. , Ramkhelawon Bhama , Chung Mina K. , Dahal Satakshi , Ramamurthi Anand , Joshi Jayadev P. , Blankenburg Daniel , Barnard John , Blackstone Eugene H. , Roselli Eric E. , Apte Suneel S.
Published: June 2024

Background

Dysregulated proteolysis is implicated in thoracic (TAA) and abdominal aortic aneurysm (AAA) pathogenesis, but the proteolytic landscapes (degradomes) of aneurysmal and normal aorta, and contributions of individual proteases remain undefined. Here, a proteome-wide approach was used to uncover TAA and AAA degradomes, compare them quantitatively and define the specific role in aortic remodeling of two proteases consistently identified in the aneurysms, mast cell chymase (CMA1) and matrix metalloprotease 9 (MMP9).

Methods

The mass spectrometry-based N-terminomics strategyTerminalAmine IsotopicLabeling ofSubstrates (TAILS) was applied to Marfan syndrome TAAs (n=5), AAAs (n=16) and corresponding non-diseased aorta (TAs, n=4, and AAs, n=8) as a forward degradomics application, i.e., to define substrate and protease degradomes, and 8-plex iTRAQ-TAILS was used for quantitative comparison. Cleavage sites of CMA1 and MMP9 were sought by reverse degradomics, i.e., digestion of aortic proteins with these proteases, followed by 6-plex iTRAQ-TAILS. CMA1 and MMP9 proteolysis of biglycan was investigated usingAmino-TerminalOrientedMass spectrometry ofSubstrates (ATOMS).

Results

We experimentally annotated 16,923 proteolytically derived peptides (substrate degradome) and 90 proteases (protease degradome) in the aorta. Quantitative substrate degradome comparisons identified specific differentially modulated pathways and networks in TAA and AAA. Reverse degradomics elucidated > 300 CMA1 and MMP9 substrate cleavage sites, of which, many, including orthogonally validated biglycan cleavage, occurred in the disease degradomes.

Conclusions

Unbiased, proteome-wide forward degradomics of the aortic wall from TAA, AAA and non-diseased tissue generated the first systems biology view of vascular wall breakdown and public resource for the hitherto occult proteolytic landscape, demonstrating widespread extracellular matrix remodeling. The findings provide insights on aortic aneurysm pathways and potential disease biomarkers. Mapping of specific contributions of CMA1 and MMP9 on the aortic forward substrate degradome using reverse degradomics provides a strategy for defining the activities of all proteases involved in aortic disease.
Vitamin a deficiency causes apoptosis in the mammary gland of rats
Authors: Vasquez-Gomez M. , Filippa V. , Acosta M. , Mohamed F. , Campo Verde F. , Ferrari C. , Jahn G.A. , Giménez M.S. , Ramirez D.C. , Gomez Mejiba S.E.
Published: June 2024

Subchronic dietary vitamin A deficiency (VAD) causes severe abnormalities, including dysfunction of the epithelia of the mammary gland. However, the underlying mechanism of this process is partially known. Therefore, herein, we used a nulliparous-rat experimental model of dietary VAD for a total dieting regime of 3 and 6 months and intervened (refeed) with a vitamin A sufficient (VAS) diet for 0.5 or 1 month before the end of the diet regime and investigated the underlying molecular mechanism of mammary tissue dysfunction. Dietary vitamin A deficiency for 3 and 6 months caused increased inflammatory cell infiltration in the mammary gland parenchyma and glandular cells, with increased inflammation and apoptosis and reduced cell proliferation. These changes can be reversed with a VAS diet. Mammary gland dysfunction after a subchronic VAD is caused by an imbalance between NFκB and retinoic acid-triggered signaling. Inflammation, apoptosis, and impaired proliferation lead to dysfunction of the epithelia of the mammary gland of nulliparous rats fed a VAD diet.
Unveil the mechanism of Jinzhen Oral Liquid combined with Azithromycin in the treatment of Mycoplasma pneumoniae pneumonia based on Network pharmacology and clinical trials
Authors: Zhong Chengliang , Guo Shengxuan , Liu Qingyuan , Sun Deyang , Wang Boyang , Hu Siyuan , Li Xinmin , Ding Ying , Yuan Bin , Liu Jing , Xiang Long , Li Nan , Xue Zheng , Li Yan , Teng Yiqun , Yi Rongsong , Li Shao , Ma Rong
Published: June 2024

Mycoplasma pneumoniae pneumonia (MPP) is a common type of pneumonia among school-aged children and adolescents. Jinzhen Oral Liquid (JZOL) and Azithromycin (AZ) are commonly used treatment options in traditional Chinese medicine (TCM) and Western medicine, respectively. There are several clinical and basic research reports on their solo effect against MPP, enabling their combined treatment to become possible. However, the mechanisms and specific pharmacodynamics of their combined therapy remain unclear. In this study, we conducted a mechanistic analysis of the combination of JZOL and AZ based on network target, elucidating their modular network regulatory mechanisms. The modular mechanisms involve four modules, including hormone response, cell differentiation and migration, signal transduction, oxygen and hypoxia response, centered by TNF signaling pathway-mediated regulation. Under the instruction of computational analysis, we conducted a randomized, double-blind, three-armed, parallel-controlled, multicenter clinical study of different doses of JZOL combined with AZ for the treatment of MPP in children. At the study endpoint, the median time to clinical recovery showed statistically significant differences, which were also observed between groups for time to complete fever remission, time to relief of cough/phlegm, effective rate of chest X-ray improvement, and rate of healing of TCM symptoms. During the treatment period, there were no statistically significant differences in the rates of adverse events, serious adverse events, or adverse reactions between the groups. Different doses of JZOL combined with AZ in the treatment of MPP in children have shown the effects of shortening the course of the disease, relieving the symptoms, and improving the prognosis. The research program composed of computational prediction and clinical trials can significantly accelerate the research and development process and identify more effective treatment with good safety, which is worthy of clinical promotion.