bluuebunny/crossref_metadata_2025 huggingface dataset:
The transcription factor TCF21 is necessary for adoption of cell fates by Foxd1+ stromal progenitors during kidney development
Authors: Finer Gal , Khan Mohammad D. , Zhou Yalu , Gadhvi Gaurav , Yacu George S. , Park Joo-Seop , Gomez R. Ariel , Sequeira-Lopez Maria Luisa S. , Quaggin Susan E. , Winter Deborah R.
Published: August 2024

Normal kidney development requires the coordinated interactions between multiple progenitor cell lineages. Among these, Foxd1+ stromal progenitors are essential for nephrogenesis, giving rise to diverse cell types including the renal stroma, capsule, mesangial cells, renin cells, pericytes, and vascular smooth muscle cells (VSMCs). However, the molecular mechanisms governing their differentiation remain poorly understood. This study investigates the role of Tcf21, a mesoderm-specific bHLH transcription factor, in Foxd1+ cell fate determination.

Using single-cell RNA sequencing (scRNA-seq), we analyzed 32,461 GFP+ cells from embryonic day 14.5 (E14.5)Foxd1Cre/+;Rosa26mTmG;Tcf21f/fkidneys (Tcf21-cKO) and controls. Clustering identified a predominant stromal population, further divided into six subpopulations associated with healthy kidney development: nephrogenic zone-associated stroma, proliferating stroma, medullary/perivascular stroma, collecting duct-associated stroma, differentiating stroma, and ureteric stroma. Loss of Tcf21 resulted in marked depletion of medullary/perivascular stroma, collecting duct-associated stroma, proliferating stroma, and nephrogenic zone-associated stroma stromal subpopulations, confirmed by immunostaining, which revealed severe constriction of medullary and collecting duct stromal spaces.

Additionally, we identified a novel cluster unique toTcf21-cKOkidneys, characterized by high expression of Endomucin (Emcn), a vascular endothelial marker. These cells spanned across pseudotime trajectories and were distributed broadly across the mutant kidney. The emergence of Emcn-expressing cells inTcf21-cKOkidneys coincided with a reduction in Acta2-expressing medullary stromal cells, suggesting a population shift.

Our findings highlight the critical role of Tcf21 in directing Foxd1+ progenitor differentiation. Loss of Tcf21 disrupts stromal cell fates, leading to aberrant kidney development and providing new insights into the mechanisms underlying congenital kidney anomalies.

TRANSLATIONAL STATEMENT

This study reveals critical insights into kidney development and congenital anomalies by identifying the developmental origins of stromal heterogeneity and the key role of Tcf21 in stromal progenitor differentiation. These findings enhance our understanding of stromal cell fate decisions and their relevance to congenital disorders. Additionally, this work provides valuable information for improving the recapitulation of the stromal compartment ex vivo, a current challenge in kidney organoid models. The role of Tcf21 in stromal phenotypic modulation underscores its broader significance in tissue repair and fibrotic diseases, suggesting potential avenues for therapeutic intervention.
Large protein databases reveal structural complementarity and functional locality
Authors: Szczerbiak Paweł , Szydlowski Lukasz M. , Wydmański Witold , Renfrew P. Douglas , Koehler Leman Julia , Kosciolek Tomasz
Published: August 2024

Recent breakthroughs in protein structure prediction have led to an unprecedented surge in high-quality 3D models, highlighting the need for efficient computational solutions to manage and analyze this wealth of structural data. In our work, we comprehensively examine the structural clusters obtained from the AlphaFold Protein Structure Database (AFDB), a high-quality subset of ESMAtlas, and the Microbiome Immunity Project (MIP). We create a single cohesive low-dimensional representation of the resulting protein space. Our results show that, while each database occupies distinct regions within the protein structure space, they collectively exhibit significant overlap in their functional profiles. High-level biological functions tend to cluster in particular regions, revealing a shared functional landscape despite the diverse sources of data. To facilitate exploration and improve access to our data, we developed an open-access web server. Our findings lay the groundwork for more in-depth studies concerning protein sequence-structure-function relationships, where various biological questions can be asked about taxonomic assignments, environmental factors, or functional specificity.
Temporal and spatial niche partitioning in a retrotransposon community of the Drosophila genome
Authors: Varoqui Marion , Mohamed Mourdas , Mugat Bruno , Gourion Daniel , Lemoine Maëlys , Pélisson Alain , Grimaud Charlotte , Chambeyron Séverine
Published: August 2024

Transposable elements (TEs), widespread genetic parasites, pose potential threats to the stability of their host genomes. Hence, the interactions observed today between TEs and their host genomes, as well as among the different TE species coexisting in the same host, likely reflect those that did not lead to the extinction of either the host or the TEs. It is not clear to what extent the expression and integration steps of the TE replication cycles are involved in this ‘peaceful’ coexistence. Here, we show that four Drosophila LTR RetroTransposable Elements (LTR-RTEs), although sharing the same overall integration mechanism, preferentially integrate into distinct open chromatin domains of the host germline. Notably, the differential expressions of the gtwin and ZAM LTR-RTEs in ovarian and embryonic somatic tissues, respectively, result in differential integration timings and targeting of accessible chromatin landscapes that differ between early and late embryonic nuclei, highlighting connections between temporal and spatial LTR-RTEs niche partitionings.
WheresWalker: a pipeline for rapid mutation mapping using whole genome sequencing
Authors: Feltes McKenna , Zimin Aleksey V. , Angel Sofia , Pansari Nainika , Hensley Monica R. , Anderson Jennifer L. , Shen Meng-Chieh , Klemek Mackenzie , Shen Yi , Ginde Vighnesh S. , Truong Vivian P. , Kozan Hannah , Le Nhan V. , Wilson Meredith H , Salzberg Steven L. , Farber Steven A.
Published: August 2024

Forward genetic screening is a powerful approach to assign functions to genes and can be used to elucidate the many genes whose functions remain unknown. Chemical mutagenesis is an unbiased and efficient method for generating point mutations in the founding generation of animals in a forward genetic screening experiment. Missense and nonsense mutations induced by chemical mutagenesis can lead to the generation of partial function, gain-of-function, or null alleles that underlie compelling phenotypes, but positional cloning of the underlying causative single base pair changes can be laborious and time-consuming, especially in large polymorphic genomes. Current methods use a bioinformatic mapping-by-sequencing approach which often identifies large genomic regions which contain an intractable number of candidate genes for testing. Here, we describe WheresWalker, a modern mapping-by-sequencing algorithm that identifies a mutation-containing interval and then supports positional cloning to refine the interval which drastically reduces the number of potential candidates allowing for extremely rapid mutation identification. We validated this method using mutants from a forward genetic mutagenesis screen in zebrafish for modifiers of ApoB-lipoprotein metabolism. WheresWalker correctly maps and identifies novel zebrafish mutations in mttp, apobb.1, and mia2 genes, as well as a previously published mutation in maize. Further, we use WheresWalker to identify a previously unappreciated ApoB-lipoprotein metabolism-modifying locus, slc3a2a.
An epigenetic memory at theCYP1Agene in cancer-resistant, pollution-adapted killifish
Authors: Carrothers Samantha , Trevisan Rafael , Jayasundara Nishad , Pelletier Nicole , Weeks Emma , Meyer Joel N. , Di Giulio Richard , Weinhouse Caren
Published: August 2024

Human exposure to polycyclic aromatic hydrocarbons (PAH) is a significant and growing public health problem. Frequent, high dose exposures are likely to increase due to a warming climate and increased frequency of large-scale wildfires. Here, we characterize an epigenetic memory at thecytochrome P450 1A(CYP1A) gene in a population of wildFundulus heteroclitusthat has adapted to chronic, extreme PAH pollution. In wild-type fish,CYP1Ais highly induced by PAH. In PAH-tolerant fish,CYP1Ainduction is blunted. Since CYP1A metabolically activates PAH, this memory protects these fish from PAH-mediated cancer. However, PAH-tolerant fish reared in clean water recoverCYP1Ainducibility, indicating that blunted induction is a non-genetic memory of prior exposure. To explore this possibility, we bred depurated wild fish from PAH-sensitive and -tolerant populations, manually fertilized exposure-naïve embryos, and challenged them with PAH. We observed epigenetic control of the reversible memory of generational PAH stress in F1PAH-tolerant embryos. Specifically, we observed a bivalent domain in theCYP1Apromoter enhancer comprising both activating and repressive histone post-translational modifications. Activating modifications, relative to repressive ones, showed greater increases in response to PAH in sensitive embryos, relative to tolerant, consistent with greater gene activation. Also, PAH-tolerant adult fish showed persistent induction ofCYP1Along after exposure cessation, which is consistent with defectiveCYP1Ashutoff and recovery to baseline. SinceCYP1Aexpression is inversely correlated with cancer risk, these results indicate that PAH-tolerant fish have epigenetic protection against PAH-induced cancer in early life that degrades in response to continuous gene activation.

Significance

Epigenetic memory, or the inheritance across cell division within an organism or across generations, of environmental exposure response is a compelling phenomenon with limited understanding of mechanism. Here, we characterized an epigenetic memory at theCYP1Agene in pollution-adaptedFundulus heteroclitus. We found that theCYP1Apromoter enhancer contains a bivalent domain, comprising both active and repressive histone modifications, that shows reduced function correlating with reduced gene induction by its pollutant activator. In early life, this memory protects fish against pollution-induced cancer. However, this reduced function carries a cost; adult fish show defective transcriptional recovery ofCYP1A, which increases cancer risk later in life. These results provide an initial mechanism for a model epigenetic memory and highlight potential costs.
The First Large-Scale Wastewater Surveillance of AMR to inform Hyperlocal Antibiotic prescribing: A Study from Bengaluru, India
Authors: Roy Imon , Gowthami N , Shamsi Shoa , Unnikrishnan Nikhilesh , Shah Prerak , Prasad Ramakrishna , Satyaseela Maneesh Paul , Shridhar Varsha
Published: August 2024

Approximately 1.2 million people died in 2019 globally due to antimicrobial resistant infections making it one of the major public health issues of the 21st century. Community level antibiotic resistance data is needed for guiding antibiotic prescriptions at the local level, which national databases may be unable to provide. We hypothesized that wastewater could have potential to detect local AMR patterns cost-effectively on a real time and longitudinal basis.

Our objectives were to explore the potential of wastewater to detect local AMR patterns of specific Gram Negative bacteria against 4 key antimicrobial classes across Bengaluru city. Wastewater from 66 open storm drain sites within all eight administrative zones of Bengaluru city, in southern India, between March and April 2022 were plated on McConkey and Shigella-Salmonella agar plates. 2 colonies were randomly picked from each plate, identified using standard biochemical tests and then subcultured for antibiotic sensitivity profiles against 5 common antibiotics: ciprofloxacin (Fluoroquinolone), cefixime (3rd generation cephalosporin), piperacillin/tazobactam (TZP, beta lactam/beta lactamase inhibitor), ertapenem and meropenem (carbapenems) on Mueller-Hinton plates

Of the 160 isolates selected for deeper scrutiny, 82% (132) belonged to the Enterobacteriaceae family. Of these, 95% (126) were known to cause human infections. About 28% of the clinically relevant Enterobacteriaceae isolates were susceptible to all five antibiotics tested while 12% were resistant to all five antibiotics, and the remainder had a mixed resistance profile. Our results indicate: a) drug resistant bacteria are found in significant numbers in open drains b) there is geographical variation within a city in the patterns and burden of AMR c) Wastewater could be both a method for estimating community burden of AMR. This is the first city-wide wastewater based AMR profiling in India and indicates the potential of such surveillance to provide hyperlocal community level data to influence local antibiotic prescription practices by primary care physicians and on antibiotic purchase and allocation decisions by government drug purchase committees.
Urine complement proteins are associated with kidney disease progression of type 2 diabetes in Korean and American cohorts
Authors: Yun Donghwan , Bae Sohyun , Gao Yuqian , Lopez Lauren , Han Dohyun , Nicora Carrie D. , Kim Tae Youn , Moon Kyung Chul , Kim Dong Ki , Fillmore Thomas L. , Kim Yon Su , Rosenberg Avi Z. , Wang Weijie , Sarder Pinaki , Qian Wei-Jun , Afkarian Maryam , Han Seung Seok
Published: August 2024

Background

Mechanisms of progression of diabetic kidney disease (DKD) are not completely understood. This study uses untargeted and targeted mass spectrometry-based proteomics in two independent cohorts on two continents to decipher the mechanisms of DKD in patients with type 2 diabetes.

Methods

We conducted untargeted mass spectrometry on urine samples collected at the time of kidney biopsy from Korean patients with type 2 diabetes and biopsy-proven diabetic nephropathy at Seoul National University Hospital (SNUH-DN cohort; n = 64). These findings were validated using targeted mass spectrometry in urine samples from a Chronic Renal Insufficiency Cohort subgroup with type 2 diabetes and DKD (CRIC-T2D; n = 282). Urinary biomarkers/pathways associated with kidney disease progression (doubling of serum creatinine, ≥50% decrease in estimated glomerular filtration rates, or the development of end-stage kidney disease) were identified.

Results

SNUH-DN patients had an estimated glomerular filtration rate (eGFR) of 55 mL/min/1.73 m2(interquartile range [IQR], 44–75) and random urine protein-to-creatinine ratio of 3.1 g/g (IQR, 1.7–7.0). Urine proteins clustered into two groups, with cluster 2 having a 4.6-fold greater hazard (95% confidence interval [CI], 1.9–11.5) of disease progression than cluster 1 in multivariable-adjusted, time-to-event analyses. Proteins in cluster 2 mapped to 10 pathways, four of the top five of which were complement or complement-related. A high complement score, constructed from urine complement protein abundance, was strongly correlated to 4 of 5 histopathologic DN features and was associated with a 2.4-fold greater hazard (95% CI, 1.0–5.4) of disease progression than a low complement score. Targeted mass spectrometry of the CRIC-T2D participants, who had an eGFR of 42 mL/min/1.73 m2(IQR, 37–49) and 24-hr urine protein of 0.48 g (IQR, 0.10–1.87), showed that the complement score similarly segregated them into rapid and slow DKD progression groups. In both cohorts, the complement score had a linear association with disease progression.

Conclusions

Urinary proteomic profiling confirms the association between the complement pathway and rapid DKD progression in two independent cohorts. These results suggest a need to further investigate complement pathway inhibition as a novel treatment for DKD.
Ground nesting of soft eggs by extinct birds and a new parity mode switch hypothesis for the evolution of animal reproduction
Authors: Guimarães M. Jorge , Wang Junyou , Zhang Xuemin , Sun Qiang , Cerqueira M. Fátima , Chung Yi-Hsiu , Deng Richard , Guo Bin , Alpuim Pedro , Ma Feimin , Wang Xiaobing , Yen Tzu-Chen
Published: August 2024

Nearshore ground nesting of soft eggs by extinct birds is demonstrated here, providing a new explanation for the abundance of bird fossils in early Cretaceous lacustrine environments, where humidity conditions required for soft egg incubation would have been present. This reinforces recent findings of Archaeopteryx soft eggs near Jurassic marine environments, the possibility that wings and elongated feathers developed primarily in association with nest protection on the ground and only secondarily with flight, and the origin of flight from the ground up. Notably, soft eggs preceded rigid eggs in evolution, but both crocodiles, whose ancestors seem to have antedated bird precursors, and extant birds reproduce exclusively via hard-shelled eggs. Therefore, an explanation is in order for how reproduction via soft eggs could have occurred in the bird lineage in-between two evolutionary moments of reproduction via rigid eggs. In alternative to the commonly accepted convergent evolution of viviparity and rigid eggshells, a parity mode switch hypothesis is presented here. It postulates the existence, since the rise of animals, of an inherited ancestral parity mode switch between viviparity and oviparity. This switch would have evolved to embrace hard-shelled oviparity after rigid eggshells appeared in evolution. Commitment to a particular parity mode or eggshell type may have conditioned survival of entire animal groups, especially during major extinction events, explaining, among others, the extinction of all birds that reproduced via soft eggshells.
Excluding Large Grazers Dramatically Improves Survival of Outplanted Juvenile Corals
Authors: van der Steeg Eveline , Humanes Adriana , Bythell John C. , Craggs Jamie R. , Edwards Alasdair J. , Golbuu Yimnang , Lachs Liam , Miller Margaret W. , Randle Janna L. , Guest James R.
Published: August 2024

High mortality rates of juvenile corals hinder both the natural recovery of populations and the successful implementation of restoration efforts. Grazing is a significant cause of juvenile coral mortality, and grazer exclusion devices have been shown to increase juvenile coral survivorship. However, most experiments have used cages that typically alter water flow and light conditions and exclude grazers of most sizes, making it difficult to quantify the effects of large grazers alone. Here, we test whether deterring large grazers can increase the survival and growth of six-month-oldAcropora digitiferajuveniles outplanted to a shallow reef crest, using arrangements of two or four long or short masonry nails that selectively exclude larger grazers (e.g., parrotfish) while minimising abiotic changes. By the end of our study, colonies with deterrents had significantly larger planar area (almost tenfold for the most effective treatment), more branches, greater height, and enhanced survival than those without deterrents. A critical period is the first week after outplanting when colonies with deterrents had significantly less tissue loss from grazing than those without. Less tissue loss in the first week was associated with significantly higher survival over the following 14 months, with an almost threefold improvement for the most effective treatment. For heavily grazed systems, our study highlights the importance of incorporating grazing deterrents into outplant devices to counteract the negative impact of large grazers on outplanted juvenile coral survival and boost restoration success.
AMH regulates ovary size by counteracting ovarian follicle cluster effects.
Authors: Lim Carmen , Yiew Lynn , Anderson Nicholas J. , Smith Peter , Quirke Laurel , Carne Alan , Sarma Urooza , Rose Ryan , Nicholson Martha , Jasoni Christine L. , Liu Ping , Petrich Simone , Juengel Jenny , Pankhurst Michael W.
Published: August 2024

Serum anti-Mullerian hormone (AMH) is the primary clinical indicator of mature oocyte counts in the ovaries, but its biological role remains poorly understood. Mammalian ovaries have a finite lifetime of oocytes that are slowly depleted as the dormant follicles housing the oocytes initiate maturation. Less than 0.1% of these follicles will reach maturity and ovulate an oocyte. Recent studies suggest that AMH is a key regulator that removes most of these follicles at early stages of follicle maturation. Most AMH is secreted as an inactive precursor protein, and we show that the required activating-enzymes are largely present outside the follicle. We then measured AMH concentrations in ovarian stroma with microdialysis showing that activity is confined to a short range from the site of secretion. To examine short-range interactions between follicles, we reconstructed the ovarian follicle positions from sheep ovaries in 3D space. This showed that most early follicles develop in proximity to more advanced follicles. Active immunisation of sheep against AMH to inhibit signalling, greatly expanded early follicle numbers, but almost entirely in proximity to large follicles. Large follicle proximity appears to greatly enhance early follicle survival, and AMH appears to attenuate this effect to prevent follicle overgrowth beyond sustainable limits.
Origins ofde novochromosome rearrangements unveiled by coupled imaging and genomics
Authors: Cosenza Marco Raffaele , Gaiatto Alice , Erarslan Uysal Büşra , Andrades Delgado Álvaro , Sautter Nina Luisa , Jendrusch Michael Adrian , Zumalave Duro Sonia , Rausch Tobias , Halavatyi Aliaksandr , Geissen Eva-Maria , Hasenfeld Patrick , Cortes-Ciriano Isidro , Kulozik Andreas , Pepperkok Rainer , Korbel Jan O.
Published: August 2024

Chromosomal instability results in widespread structural and numerical chromosomal abnormalities (CAs) during cancer evolution1–3. While CAs have been linked to mitotic errors resulting in the emergence of nuclear atypias4–7, the underlying processes and basal rates of spontaneous CA formation in human cells remain under-explored. Here we introduce machine learning-assisted genomics-and-imaging convergence (MAGIC), an autonomously operated platform that integrates automated live-cell imaging of micronucleated cells, machine learning in real-time, and single-cell genomics to investigatede novoCA formation at scale. Applying MAGIC to near-diploid, non-transformed cell lines, we track CA events over successive cell cycles, highlighting the common role of dicentric chromosomes as an initiating event. We determine the baseline CA rate, which approximately doubles inTP53-deficient cells, and show that chromosome losses arise more rapidly than gains. The targeted induction of DNA double-strand breaks along chromosomes triggers distinct CA processes, revealing stable isochromosomes, amplification and coordinated segregation of isoacentric segments in multiples of two, and complex CA outcomes, depending on the break location. Our data contrastde novoCA spectra from somatic mutational landscapes after selection occurred. The large-scale experimentation enabled by MAGIC provides insights intode novoCA formation, paving the way to unravel fundamental determinants of chromosome instability.
Premature cleavage and polyadenylation in the minor intron of PTEN modulate its expression and generates a functional long non-coding RNA in breast cancer
Authors: Elesnawy Mariam , Elghandour Rim , Hasna Hana , Fakhroo Aisha , Al-Sulaiti Boshra , Younis Ihab
Published: August 2024

Minor introns constitute 0.4% of all introns in human cells, but they are unique in their ability to regulate the genes in which they are embedded such that their low splicing efficiency can be a rate limiting step in gene expression. The first intron of the tumor suppressor gene, PTEN, has been documented to be a minor intron, but very little is known about its regulation. Regulation of PTEN levels in cancer cells, especially breast cancer is tightly controlled as a very small reduction in its expression can lead to tumorigenesis. Indeed, many genetic, epigenetic, post-transcriptional and post-translational mechanisms are employed to reduce PTEN levels or activities, leading to cancer. Here, we uncover a previously unexplored mechanism for modulating PTEN expression utilizing its minor intron. The minor intron of PTEN minor intron has one of the lowest splicing efficacies in breast cancer cells, causing at least 50% of PTEN pre-mRNA to retain it, and thus not produce a functional protein. We also show that, unlike other minor introns, the retained intron in PTEN pre-mRNA is not used as a molecular switch that would be spliced out when needed but is rather processed by premature cleavage and polyadenylation into a long noncoding RNA (lncRNA) that we termed PINC. Exogenous expression of PINC caused significant alterations to cellular proliferation, including breast cancer cells that harbor a genetic mutation in the PTEN gene and do not produce a functional PTEN protein. This shows that this novel lncRNA functions independently of the encoded protein of the host gene.
Prediction of Oligomeric Status of Quaternary Protein Structure by using Sequential Minimal Optimization for Support Vector Machine
Authors: Kumar Suresh
Published: August 2024

The prediction of quaternary structure and its function is important in pharmaceutical applications, drug design, medical or engineering applications. With the drastic rise in the number of protein sequences presented to the public database, acquiring an understanding of possible quaternary structural characteristics of their interested proteins in a timely way is essential for structural genomics research. There is a need for a method to identify quaternary attributes based on its amino acid sequence. In this study, discrimination of hetero-oligomer from non hetero-oligomer was demonstrated using amino acid composition implemented using a support vector machine with a minimum sequential optimization technique.
EnteroBase in 2025: exploring the genomic epidemiology of bacterial pathogens
Authors: Dyer Nigel P. , Päuker Birgitta , Baxter Laura , Gupta Anshul , Bunk Boyke , Overmann Jörg , Diricks Margo , Dreyer Viola , Niemann Stefan , Holt Kathryn E. , Rahman Mohammed , Brown Paul E. , Stark Richard , Zhou Zhemin , Ott Sascha , Nübel Ulrich
Published: August 2024

This paper presents an update on the content, accessibility and analytical tools of the EnteroBase platform for web-based pathogen genome analysis. EnteroBase provides manually curated databases of genome sequence data and associated metadata from currently >1.1 million bacterial isolates, more recently includingStreptococcusspp. andMycobacterium tuberculosis. We have implemented the genome-based detection of antimicrobial resistance determinants and the new bubble plot graphical tool for visualising bacterial genomic population structures, based on pre-computed hierarchical clusters. Access to data and analysis tools is provided through an enhanced graphical user interface and a new application programming interface (RESTful API). EnteroBase is now being developed and operated by an international consortium, to accelerate the development of the platform and ensure the longevity of the resources built. EnteroBase can be accessed athttps://enterobase.warwick.ac.ukas well ashttps://enterobase.dsmz.de.

GRAPHICAL ABSTRACT
Phenotypic divergence associated with genomic changes suggest local adaptation in obligate asexuals
Authors: Karapli-Petritsopoulou Athina , Heckelmann Jasmin Josephine , Anderson N. John , Franzenburg Sören , Frisch Dagmar
Published: August 2024

Local adaptation is a key evolutionary process that generates global biodiversity and is promoted by environmental heterogeneity. Most of the existing knowledge on adaptive capacity is focused on sexual organisms, while the adaptation potential of asexually reproducing eukaryotes as well as their vulnerability to environmental change remains unclear. Cyclical parthenogens of the keystone freshwater grazerDaphniaare known to be locally adapted with genetic differentiation related to environmental conditions even between neighbouring ponds. Similar patterns have been found in obligate parthenogenetic congeners, however studies on their local adaptation potential are rare. Here, we use respiration rate and whole genome sequencing to test the local adaptation of Arctic asexual polyploidDaphniafrom lakes with contrasting oxygen environments. The genomic data revealed the presence of two genetic clusters which differed significantly in respiration rates, suggesting molecular evolution as an adaptive mechanism. Functional enrichment pointed to differences in metabolic processes between the two genetic clusters. Our results, combining phenotypic and whole genome sequencing data, suggest that these clones are locally adapted to low oxygen concentrations and provide support for local adaptation by evolution in an obligate parthenogen.
Dynein contributes to spindle elongation during anaphase inCandida albicans
Authors: Shoukat Irsa , Allingham John S.
Published: August 2024

Abstract

Budding yeast must position the mitotic spindle at the mother-bud junction during anaphase to ensure proper chromosome segregation. Pushing and pulling forces on astral microtubules from dynein motors in the cell cortex are crucial for spindle positioning. In some higher eukaryotes and filamentous fungi, dynein also accelerates spindle elongation during anaphase, but in yeast model systems spindle elongation primarily relies on intra-spindle pushing forces from kinesin-5 motors. The pathogenic yeastCandida albicansis unique because its spindle can elongate without a functional kinesin-5. Our study helps explainC. albicans’ diminished kinesin-5 requirement by showing that its dynein, Dyn1, collaborates with its kinesin-5, Kip1, to facilitate spindle elongation. Cells lacking Kip1 activity by eitherKIP1deletion or Kip1 inhibition have more Dyn1 and astral microtubules, indicating spindle elongation happens through enhanced pulling on spindle pole body-bound astral microtubules by cortical Dyn1. When Dyn1 activity is depleted, spindle elongation speed is normal, but anaphase spindles persist for extended periods, and the number and length of astral microtubules increases. Depletion of both motors prevents spindle elongation and is lethal. The significance of astral microtubules in cells lacking either motor is highlighted by the lethal effects of microtubule-destabilizing drugs and exposure to low temperatures (8°C) that compromise microtubule stability. These findings demonstrate thatC. albicansspindle elongation involves cooperative forces from Kip1 and Dyn1 to ensure chromosome separation during cell division and thatC. albicansadapts to changes in abundance of these motors through alterations in their astral microtubule content.
Impact of a defined bacterial community including and excludingMegamonas hypermegaleon broiler cecal microbiota and resistance toSalmonellainfection
Authors: Schultz Marcolla Camila , Ju Tingting , Ten Kimberlee , Sharma Usha Sivakumar , Moeun Leakhena , Willing Benjamin P.
Published: August 2024

Intensive broiler production practices impair the transmission of commensal microbes from hens to offspring, resulting in a lower abundance of non-spore-forming strict anaerobic bacteria. We evaluated the effects of colonization by a defined community (DC) of bacteria including and excludingMegamonas hypermegalein chicks challenged withSalmonella. Inoculation with DC resulted in higher phylogenetic diversity and the dominance of Bacteroidetes species in the cecal microbiota, with a decrease in the relative abundance ofSalmonellaandEscherichia/Shigella, as well as a lowerEnterobacteriaceaeload. Substantial shifts in microbiota composition were coupled with subtle changes in metabolites and host responses, including changes in interferon-γ, macrophage colony-stimulating factor, propionate, valerate, and isovalerate concentrations in the ceca. We identified bacterial species that were able to establish and persist after a single exposure, many of which were members of Bacteroidetes. Although co-culture withM. hypermegalereducedSalmonellacounts by 99.3%in vitro,in vivoinoculation ofM. hypermegaleincreased splenicSalmonellacounts in inoculated chicks. The use of DC containing bacteria isolates harvested from the cecal contents of mature chickens can recapitulate the changes in volatile fatty acid concentrations observed in birds colonized with complex communities, and the presence ofM. hypermegalespecifically enhances the production of propionate. Our findings suggest that the use of DC can be explored as a strategy to control disease occurrence in broiler production; however, further research is warranted to properly understand the role of individual species in the broiler cecal community aiding the formulation of appropriate DCs.

Importance

Intensive production practices can reduce beneficial gut bacteria in broiler chickens, potentially leading to higher disease risk. We investigated whether introducing a defined community (DC) of beneficial bacteria, along withM. hypermegale, could improve gut health and resistance toSalmonellain broiler chicks. Our findings show that DC increases microbial diversity and reduces the relative abundance of potential pathogens, likeSalmonellaandEscherichia/Shigella, which was coupled with subtle changes in the immune responses of the birds and higher concentration of volatile fatty acids in the ceca. This study suggests that using DC can enhance poultry health and reduce disease, providing a potential strategy to improve broiler production. However, further research is needed to understand the roles of individual bacteria and refine these bacterial communities for practical use in farming. This work holds promise for developing natural methods to enhance poultry health and safety.
Repeated shifts in sociality are associated with fine-tuning of highly conserved and lineage-specific enhancers in a socially flexible bee
Authors: Jones Beryl M , Webb Andrew E , Geib Scott M , Sim Sheina , Schweizer Rena M , Branstetter Michael G , Evans Jay D , Kocher Sarah D
Published: August 2024

Comparative genomic studies of social insects suggest that changes in gene regulation are associated with evolutionary transitions in social behavior, but the activity of predicted regulatory regions has not been tested empirically. We used STARR-seq, a high-throughput enhancer discovery tool, to identify and measure the activity of enhancers in the socially variable sweat bee,Lasioglossum albipes. We identified over 36,000 enhancers in theL. albipesgenome from three social and three solitary populations. Many enhancers were identified in only a subset ofL. albipespopulations, revealing rapid divergence in regulatory regions within this species. Population-specific enhancers were often proximal to the same genes across populations, suggesting compensatory gains and losses of regulatory regions may preserve gene activity. We also identified 1182 enhancers with significant differences in activity between social and solitary populations, some of which are conserved regulatory regions across species of bees. These results indicate that social trait variation inL. albipesis driven both by the fine-tuning of ancient enhancers as well as lineage-specific regulatory changes. Combining enhancer activity with population genetic data revealed variants associated with differences in enhancer activity and identified a subset of differential enhancers with signatures of selection associated with social behavior. Together, these results provide the first empirical map of enhancers in a socially flexible bee and highlight links between cis-regulatory variation and the evolution of social behavior.
Relationships of hematocrit concentration with dementia from a multiethnic population-based study
Authors: Roh David J , Liu Minghua , Strobino Kevin , Assuras Stephanie , Guzman Vanessa A. , Levin Bonnie , Spitalnik Steven , Rundek Tatjana , Wright Clinton B. , Elkind Mitchell S.V. , Gutierrez Jose
Published: August 2024

Objective: Red blood cell (RBC) concentration impacts cerebrovascular disease, yet it is unclear whether RBC concentrations relate to dementia risk, particularly in racially/ethnically diverse cohorts. We investigated whether RBC concentrations associate with incident dementia risk in a diverse population of stroke-free individuals and explored whether cerebral small vessel disease (CSVD) mediates this relationship. Methods: A longitudinal observational analysis was performed using a population-based cohort of stroke-free, older adult participants (>50 years) from the Northern Manhattan Study (NOMAS) enrolled between 2003-2008. Participants received baseline hematocrit testing, MRI neuroimaging, and cognitive assessments at baseline and long-term follow-up. Associations of baseline hematocrit as a categorical variable (low, normal [reference], and high based on laboratory reference levels) with incident dementia were assessed using Cox models adjusting for relevant covariates. Separate analyses investigated whether MRI CSVD mediated these relationships. Results: We studied 1207 NOMAS participants (mean age 71±9 years, 60% female, 66% Hispanic). Mean hematocrit was 41.2% (±3.8) with 16% of participants developing incident dementia. Lower hematocrit associated with increased dementia risk (adjusted hazard ratio 1.81 [1.01-3.23]) after adjusting for age, sex, race/ethnicity, education, APOE status, and comorbidities. High hematocrit was not associated with dementia risk. No interactions by sex or race/ethnicity were seen and baseline CSVD did not mediate relationships between hematocrit and dementia. Conclusions: Low hematocrit associated with dementia risk in our diverse population cohort. Further work is needed to assess mechanisms behind anemia's relationship with dementia to assess whether this can serve as a trackable, preventable/treatable risk factor for dementia.
Semaglutide Improves Myocardial Perfusion and Performance in a Large Animal Model of Coronary Artery Disease
Authors: Stone Christopher R. , Harris Dwight D. , Broadwin Mark , Kanuparthy Meghamsh , Nho Ju-Woo , Yalamanchili Keertana , Hamze Jad , Abid M. Ruhul , Sellke Frank W.
Published: August 2024

Objective

Coronary artery disease (CAD) is the leading cause of death worldwide. It imposes an enormous symptomatic burden on patients, leaving many with residual disease despite optimal procedural therapy, and up to 1/3 with debilitating angina amenable neither to procedures, nor to current pharmacologic options. Semaglutide, a glucagon-like peptide 1 agonist originally approved for management of diabetes, has garnered substantial attention for its capacity to attenuate cardiovascular risk. Although subgroup analyses in patients indicate promise, studies explicitly designed to isolate the impact of semaglutide on the sequelae of CAD, independently of comorbid diabetes or obesity, are lacking.

Approach and Results

Yorkshire swine (n=17) underwent placement of an ameroid constrictor around the left circumflex coronary artery to induce CAD. Oral semaglutide was initiated postoperatively at 1.5 mg and scaled up in 2 weeks to 3 mg in treatment animals (SEM, n=8) for a total of 5 weeks, while control animals (CON, n=9) received no drug. All then underwent myocardial harvest with acquisition of perfusion and functional data using microsphere injection and pressure-volume loop catheterization. Immunoblotting, immunohistochemistry, and immunofluorescence were performed on the most ischemic myocardial segments for mechanistic elucidation. SEM animals exhibited improved left ventricular ejection fraction, both at rest and during rapid myocardial pacing (both p<0.03), accompanied by increased perfusion to the most ischemic myocardial region at rest and during rapid pacing (both p<0.03); reduced perivascular and interstitial fibrosis (both p <0.03); and apoptosis (p=0.008). These changes were associated with increased activation of the endothelial-protective AMPK pathway (p=0.005), coupled with downstream increases in endothelial nitric oxide synthase (p=0.014).

Conclusion

This study is the first to reveal the capacity of oral semaglutide to augment cardiac function in the chronically ischemic heart in a highly translational large animal model, likely through AMPK-mediated improvement in endothelial function and perfusion to the ischemic myocardium.
Analysis of 3.6 million individuals yields minimal evidence of pairwise genetic interactions for height
Authors: Jabalameli M.Reza , Holmes Michael V , Hinds David ,   23andMe Research Team, Auton Adam , Fontanillas Pierre
Published: August 2024

Adult height is a highly heritable polygenic trait with heritability attributable to thousands of independent variants. Large-scale studies have been able to detect genetic variants with contributions to height in the range of approximately 1.2 millimetre per allele copy on average. Non-additive genetic interactions may, in part, account for the difference between broad-sense and narrow-sense heritability estimates. However, prior studies have failed to identify variants with non-additive effects, possibly due to the lack of statistical power. Leveraging 3.6M individuals of European genetic ancestry in the 23andMe research cohort, we performed a genome-wide analysis study (GWAS) to select 1,063 independent common SNPs associated with height (p-value < 5e-8), and then screened for evidence of non-additive effects by analysing 564,453 models including a pairwise SNP-SNP interaction term. We identified 69 pairwise models with suggestive evidence of SNP-SNP interaction (p-value < 1e-4) and, for each SNP pair, we evaluated a fully saturated model including additive, dominant, and epistatic (additive-by-additive, additive-by-dominance and dominance-by-dominance) terms. We tested for the presence of epistatic interactions by comparing models with and without epistatic terms using a likelihood ratio test. Assuming a strict Bonferroni-corrected threshold of 8.9e-8 (0.05/564,453), we found no evidence of epistatic interactions (Likelihood ratio test (LRT) p-value < 9e-07 for all models). Our analysis rules out the existence of epistatic interactions between alleles of >1% frequency with effect sizes larger than 2.42mm. Our large-scale analysis provides further evidence of the minimal contribution of non-additivity in the genetic architecture of adult human height.
Efficacy and Safety of Albendazole 400 mg for 30 Days in Adults Patients with LowLoa loaMicrofilaremia: A Non-Inferiority Randomized Controlled Trial Compared to Ivermectin
Authors: Akomezoghe Luccheri Ndong , M’Bondoukwé Noé Patrick , Mawili Mboumba Denise Patricia , Ndong Ngomo Jacques Mari , Bridy Chesli Moutombi Ditombi , Sibi Matotou Hadry Roger , Migueba Valentin , Bouyou Akotet Marielle Karine
Published: August 2024

Background

Loa loainfection is endemic in central African countries like Gabon and in West Africa. Treatment typically involves the use of ivermectin and albendazole, with albendazole often used to reduce microfilaremia in individuals with high microfilaremia before administering ivermectin. This study aims to evaluate the efficacy and safety of albendazole in patients with low microfilaremia.

Methodology and principal findings

The study was conducted from November 7 to April 1 across 31 villages in the Woleu-Ntem province of northern Gabon. Following a questionnaire, venous blood was collected in EDTA tubes forLoa loadiagnosis. Eligible individuals were randomized into two treatment groups and followed for 30 days. One group received daily albendazole tablets (400 mg), while the other received a single dose of ivermectin (200μg/kg). The study reported a 33.0% prevalence ofLoa loainfection in northern Gabon. In the per-protocol analysis, the mean microfilaremia decreased significantly by 82.3% and 90.4% in the ALB and IVM groups, respectively (p˂ 0.001). The risk difference between the treatments was 8.1% [95% CI: 16.8; −0.6%]. For the intention-to-treat analysis, the mean microfilaremia decreased significantly by 82.4% and 90.8% in the ALB and IVM groups, respectively (p˂ 0.001), with a risk difference of 8.4% [95% CI: 16.2; 0.6%]. Eosinophil rates decreased by day 30 in both groups, though not significantly different (p>0.05).

Conclusions/Significance

The prevalence ofLoa loainfection (33.05%) is notably high in northern Gabon. Albendazole demonstrated microfilaricidal activity in individuals with lowLoa loamicrofilaremia. However, its efficacy appears inferior to that of ivermectin and seems to diminish at very low microfilarial loads.

Author summary

Loa loainfection is endemic in central African countries, including Gabon, and across West Africa. Despite the absence of specific treatments developed forLoa loa, current therapeutic approaches predominantly rely on diethylcarbamazine (DEC), ivermectin (IVM), and albendazole (ALB). Although ALB is more readily available, it is typically reserved for patients with high microfilaremia due to potential severe adverse effects following treatment with IVM. This study aimed to evaluate the efficacy and safety of ALB as an alternative treatment for patients with low microfilaremia compared to IVM. The findings suggest that ALB could serve as a viable alternative for the treatment of microfilaremic loiasis. Moreover, ALB treatment demonstrated adequate clinical efficacy and safety comparable to that of IVM.