bluuebunny/crossref_metadata_2025 huggingface dataset:
Gut microbiota-mediated conversion of mangiferin to norathyriol alters short chain fatty acid and urate metabolism
Authors: Bunt Daan , Schwalbe Markus , El Aidy Sahar
Published: January 2025

Mangiferin (MAN), a natural C-glycosylxanthone, is recognized for its health-promoting effects in traditional medicinal preparations. However, its poor bioavailability and limited intestinal permeability restrict its direct biological activity in vivo. Previous studies have suggested a potential bacterial breakdown of MAN into norathyriol (NOR), an aglycone with significantly higher bioavailability and absorption. Yet, the prevalence of MAN-metabolizing microbes, the presence of MAN or NOR within the gut microbial community, and their effects on the composition and metabolic activity of the gut microbiome remain unclear. In this study, fecal samples from healthy adult volunteers treated with MAN revealed its conversion to NOR, with interindividual variation attributed to the uncultured bacterial strain CAKRHR01 sp934339005. While MAN had minimal impact on microbial composition and metabolic activity, NOR treatment significantly increased pH, reduced overall bacterial cell counts, and selectively suppressed short-chain fatty acid-producing bacteria, including Faecalibacterium prausnitzii as well as urate consumers, such as Enterocloster bolteae. These findings underscore the potential of NOR to modulate gut microbial activity and highlight the importance of understanding microbiome-mediated metabolism when assessing the health implications of phytochemicals.
Genome-wide association analyses in dairy heifers highlight genes overlapping with mouse and human fertility and human health traits
Authors: Marrella Mackenzie A. , Schettini Gustavo P. , Morozyuk Michael , Walsh Allison , Cockrum Rebecca , Biase Fernando H.
Published: January 2025

Heifer Infertility and disease are important challenges in dairy cattle production. We investigated genetic differences between Holstein heifers with varying fertility potential and health. We carried out a genome-wide association analysis comparing heifers that conceived at first insemination against those requiring multiple attempts or failing to become pregnant, as well as heifers culled due to health issues. There were 12 significant SNPs (P<5x10-5) associated with fertility and 35 SNPs associated with health traits. There were 166 significant SNPs when infertile, sub-fertile and animals culled due to health issues were grouped. Two SNPs identified in the analysis of infertility were found nearNUFIP1and withinTENM4genes, both genes are linked to embryonic lethality in mouse knockouts. Follow-up CRISPR-Cas9 mediated disruption ofNUFIP1significantly (P<0.05) reducedin vitroblastocyst development in cattle embryos, whileTENM4editing did not alterin vitroblastocyst development. Additionally, SNPs overlapped with previously identified reproduction-related QTL (CNTN4,DLG2,PARP10,PRICKLE,TMEM150B) or health-related QTL (FAM162A,PARP10). We also identified genes within or near genes previously associated with age at menarche (CADM2, DLG2,FHIT,LSAMPandTENM4) or lung function or pulmonary diseases (ASCC2,BCAS3,BTBD9,CADM2,CNTN4,CPEB4,CTNNA2,DEUP1,DGKH,DLG2,ENOX1,EPHB1,ERC2,ERGIC1,EYA2,FAM162A,FGF18,FHIT,GRID1, KCNIP4,LINGO2,LRMDA,MALRD1,NEBL,PLA2G6,PLXDC2,PRPF18,SLC8A1,TEAD4,TSPAN9) in humans. These results further support genetic components of fertility and health in cattle. The findings also show overlapping genetic architecture between fertility and health traits, with a degree of conservation across mammals.

Summary sentence

Several genetic variants that influence female fertility and health in cattle were identified, and many genes harboring or near significant polymorphisms are common to equivalent phenotypes in mice and humans.
Spatial Transcriptomics Reveals Expression Gradients in Developing Wheat Inflorescences at Cellular Resolution
Authors: Long Katie A. , Lister Ashleigh , Jones Maximillian R. W. , Adamski Nikolai M. , Ellis Rob E. , Chedid Carole , Carpenter Sophie J. , Liu Xuemei , Backhaus Anna E. , Goldson Andrew , Knitlhoffer Vanda , Pei Yuanrong , Vickers Martin , Steuernagel Burkhard , Kaithakottil Gemy G. , Xiao Jun , Haerty Wilfried , Macaulay Iain C. , Uauy Cristobal
Published: January 2025

The diversity of plant inflorescence architectures is specified by gene expression patterns. In wheat (Triticum aestivum), the lanceolate-shaped inflorescence (spike) is defined by rudimentary spikelets at the base which initiate first but subsequently lag in development compared with central spikelets. While previous studies identified gene expression differences between central and basal inflorescence sections, the spatio-temporal dynamics and gradients along the apical-basal axis remain poorly resolved due to bulk tissue-level techniques. Here, using spatial transcriptomics, we profiled 200 genes across four stages of wheat inflorescence development to cellular resolution. Cell segmentation and unsupervised clustering identified 18 expression domains and their enriched genes, revealing dynamic spatio-temporal organisation along the apical-basal axis of the inflorescence. Along this axis, we uncovered distinct and spatially coordinated gene expression gradients patterning meristems prior to the visible delay in basal spikelet development. This study demonstrates the potential for spatial transcriptomics time-series to advance plant developmental biology.
Theory of axo-axonic inhibition
Authors: Brette Romain
Published: January 2025

The axon initial segment of principal cells of the cortex and hippocampus is contacted by GABAergic interneurons called chandelier cells. The anatomy, as well as alterations in neurological diseases such as epilepsy, suggest that chandelier cells exert an important inhibitory control on action potential initiation. However, their functional role remains unclear, including whether their effect is indeed inhibitory or excitatory. One reason is that there is a relative gap in electrophysiological theory about the electrical effect of axo-axonic synapses. This contribution uses resistive coupling theory, a simplification of cable theory based on the observation that the small initial segment is resistively coupled to the large cell body acting as a current sink, to fill this gap. The main theoretical finding is that a synaptic input at the proximal axon shifts the action potential threshold by an amount equal to the product of synaptic conductance, driving force at threshold, and axial axonal resistance between the soma and either the synapse or of the middle of the initial segment, whichever is closer. The theory produces quantitative estimates useful to interpret experimental observations, and supports the idea that axo-axonic cells can potentially exert powerful inhibitory control on action potential initiation.

Significance statement

Chandelier cells form GABAergic synapses on the initial segment of pyramidal cells of the cortex and hippocampus. Despite their striking morphology and alterations in neurological diseases such as epilepsy, their functional role remains unclear. This study develops a quantitative theory to precisely assess the electrical impact of a synaptic input at the proximal axon. It shows that axo-axonic inhibition acts by shifting the action potential threshold proportionally to the synaptic conductance. This work underlines the role of chandelier cells in controlling action potential initiation and provides a quantitative tool to interpret experimental observations.
PHACE: Phylogeny-Aware Co-Evolution
Authors: Kuru Nurdan , Adebali Ogun
Published: January 2025

The co-evolution trends of amino acids within or between genes offer valuable insights into protein structure and function. Existing tools for uncovering co-evolutionary signals primarily rely on multiple sequence alignments (MSAs), often neglecting considerations of phylogenetic relatedness and shared evolutionary history. Here, we present a novel approach based on the substitution mapping of amino acid changes onto the phylogenetic tree. We categorize amino acids into two groups: ‘tolerable’ and ‘intolerable,’ and assign them to each position based on the position dynamics concerning the observed amino acids. Amino acids deemed ‘tolerable’ are those observed phylogenetically independently and multiple times at a specific position, signifying the position’s tolerance to that alteration. Gaps are regarded as a third character type, and we only consider phylogenetically independent altered gap characters. Our algorithm is based on a tree traversal process through the nodes and computes the total amount of substitution per branch based on the probability differences of two groups of amino acids and gaps between neighboring nodes. We employ an MSA-masking approach to mitigate misleading artifacts from poorly aligned regions. When compared to tools utilizing phylogeny (CAPS and CoMap) and state-of-the-art MSA-based approaches (DCA, GaussDCA, PSICOV, and MIp), our method exhibits significantly superior accuracy in identifying co-evolving position pairs, as measured by statistical metrics including MCC, AUC, and F1 score. PHACE’s success arises from its ability to consider the frequently neglected phylogenetic dependency.
Hydralazine inhibits cysteamine dioxygenase to treat preeclampsia and senesce glioblastoma
Authors: Shishikura Kyosuke , Li Jiasong , Chen Yiming , McKnight Nate R. , Bustin Katelyn A. , Barr Eric W. , Chilkamari Snehil R. , Ayub Mahaa , Kim Sun Woo , Lin Zongtao , Hu Ren-Ming , Hicks Kelly , Wang Xie , O’Rourke Donald M. , Bollinger J. Martin , Binder Zev A. , Parsons William H. , Martemyanov Kirill A. , Liu Aimin , Matthews Megan L.
Published: January 2025

The vasodilator hydralazine (HYZ) has been used clinically for ∼ 70 years and remains on the World Health Organization’s List of Essential Medicines as a therapy for preeclampsia. Despite its longstanding use and the concomitant progress toward a general understanding of vasodilation, the target and mechanism of HYZ have remained unknown. We show that HYZ selectively targets 2-aminoethanethiol dioxygenase (ADO) by chelating its metal cofactor and alkylating one of its ligands. This covalent inactivation slows entry of proteins into the Cys/N-degron pathway that ADO initiates. HYZ’s capacity to stabilize regulators of G-protein signaling (RGS4/5) normally marked for degradation by ADO explains its effect on blood vessel tension and comports with prior associations of insufficient RGS levels with human preeclampsia and analogous symptoms in mice. The established importance of ADO in glioblastoma led us to test HYZ in these cell types. Indeed, a single treatment induced senescence, suggesting a potential new HYZ-based therapy for this deadly brain cancer.
Targeted-SMN insufficiency in Skeletal Muscle Stem Cells mediates non-cell autonomous loss of motor neurons at long term
Authors: Mecca Jordan , Mignot Julien , Gervais Marianne , Ozturk Teoman , Astord Stéphanie , Berthier Juliette , Bauché Stéphanie , Messéant Julien , Biferi Maria-Grazia , Rouard Hélène , Barkats Martine , Relaix Frédéric , Didier Nathalie
Published: January 2025

Spinal Muscular Atrophy (SMA) is due to a deficit in SMN protein encoded by the SMN1 gene. SMN-targeted disease modifying treatments have greatly improved the clinical outcomes of this neuromuscular disease. However, uncertainties remain regarding their long-term efficacy and non-neuronal tissue involvement in disease progression. We found that SMA type II patient muscles display a reduced number of quiescent PAX7+ Muscle Stem Cells (MuSC). In SMA mice, we showed that SMN is an important regulator of myogenic progenitor fate during early postnatal growth. In Pax7 Cre-driven conditional knockout mouse models, we demonstrated that high levels of SMN are required to ensure the maintenance of the quiescent MuSC pool in adult muscle. We further established that depletion of SMN-deficient MuSC yielded neuromuscular junctions remodeling followed by a non-cell autonomous loss of motor neurons in the long term. Overall, our findings demonstrate that MuSC are a crucial therapeutic target for SMA treatment.
Phosphorylation of α-synuclein fibrils at S129 changes DNAJB1 binding as probed by solid-state NMR
Authors: Pacheco Sayuri , Reselammal Dhanya S. , Zhang Qingya , Siemer Ansgar B.
Published: January 2025

Amyloid fibrils composed of the protein α-synuclein (aSyn) are implicated in the pathogenesis of synucleinopathies. These pathological fibrils, characterized by their rigid amyloid cores, also feature flexible intrinsically disordered regions (IDRs) that interact with various cellular components. Due to their solvent exposure and flexibility, the N- and C-termini, IDRs of aSyn fibrils, have been used as targets for immunotherapies and serve as binding sites for many chaperones. Chaperones are known to play a vital role in preventing and reversing amyloid formation in neurodegenerative diseases, but how they recognize misfolded proteins is often poorly understood. DNAJB1 is a co-chaperone that is part of a larger complex formed with Hsp70 and Apg2, which collectively disaggregate amyloid fibrils such as those formed by aSyn, tau, or huntingtin. Although the entire chaperone and co-chaperone complex are required for aggregate disassembly, DNAJB1 directly recognizes these amyloid fibrils. More specifically, DNAJB1 preferentially binds to the C-terminus of wild-type aSyn. However, over 90% of aSyn fibrils in Lewy bodies are phosphorylated at S129. Here, we determine the effect of S129 phosphorylation on DNAJB1-aSyn fibril binding using biochemical assays and solid-state NMR. We show that DNAJB1 preferentially binds aSyn pS129 fibrils and that the aSyn binding site of pS129 and wild-type fibrils is different. These results suggest that pS129 might influence chaperone-mediated degradation efficiency.
Learning a Pairwise Epigenomic and Transcription Factor Binding Association Score Across the Human Genome
Authors: Kwon Soo Bin , Ernst Jason
Published: January 2025

Identifying pairwise associations between genomic loci is an important challenge for which large and diverse collections of epigenomic and transcription factor (TF) binding data can potentially be informative. We therefore developed Learning Evidence of Pairwise Association from Epigenomic and TF binding data (LEPAE). LEPAE uses neural networks to quantify evidence of association for pairs of genomic windows from large-scale epigenomic and TF binding data along with distance information. We applied LEPAE using thousands of human datasets. We present evidence using additional data that LEPAE captures biologically meaningful pairwise relationships between genomic loci and expect LEPAE scores to be a resource.
NIRDuino: A modular, Bluetooth-enabled, Android®-configurable fNIRS system with dual-intensity mode built on Arduino®
Authors: Kumar Anupam , Crawford Seth , Le Tiffany-Chau , Jounghani Ali Rahimpour , Carbonell Laura Moreno , Capps Alexandra Sargent , Walter Alec B. , Liu Daniel , Sullivan Reed , Jansen E. Duco , Hosseini SM Hadi , Bowden Audrey K.
Published: January 2025

Significance

We present NIRDuino: an Open-source Android®-configurable, modular, and Bluetooth-enabled fNIRS system that allows researchers to perform neuroimaging studies with up to eight emitters and 16 detectors. The complete system (including Android tablet) can be assembled for less than $1000, and the emitters and detectors can be arranged in any configuration to achieve the desired short and long channels required for their study.

Aim

The system has been designed with non-engineers in mind, and the researcher only needs to design the wearable interfaces to attach the emitters and detectors to the body appropriate for their intended application.

Approach

The system consists of a battery-powered, wireless controller built on the Arduino® Nano ESP32 platform, a dongle with sockets for each of the eight emitters and detectors that can be connected, and individual wired probes for emitters and detectors. In accompaniment, Arduino®-based firmware and an Android®application have also been developed and provided. The selected emitters and detectors can be arranged in any desired configuration, and the emitters can be configured to output light with both regular intensities and low intensities to collect data for “long channels” with sufficient signal quality and “short channels” without saturation. This paper details the system’s design and characterization on phantom and two physiological experiences on a human.

Results

The easy-to-configure hardware/software system demonstrated stability in fNIRS measurements using a single emitter-detector pair placed on a phantom, and reproduced previously published outcomes for arterial cuff measurements on the forearm and a arithmetic experiment on the forehead.

Conclusion

The NIRDuino circuitry and software demonstrated modularity and usability for NIRS experiments, and this low-cost platform will provide researchers globally with an affordable fNIRS system to easily adopt and adapt for their unique experimental needs.
Does Precision Grip Research Extend to Unconstrained, Multidigit Grasping?
Authors: Lepori Fabrizio , Hartmann Frieder , Dehn Kira , Chessa Manuela , Fleming Roland W , Maiello Guido
Published: January 2025

Most daily tasks require using our hands. Whether taking a sip from a glass or throwing a ball, we effortlessly select appropriate grasps. Yet, despite many possible hand configurations, most grasping research has focused on the finger-and-thumb ‘precision grip’. We thus questioned whether findings on precision grip hold under unconstrained grasping conditions. To test this, we compared how participants grasped 3D objects made of brass and wood, with both precision grip and unconstrained grasps. When unconstrained, participants rarely selected precision grips, favoring multi-digit grasps. Nevertheless, in both conditions, participants shifted grasps towards the objects’ center of mass and, when grasp factors conflicted, the variability in their selections increased, indicating greater uncertainty about the optimal strategy. Further, despite favoring multidigit grasps, participants consistently placed the thumb and index finger on the same positions on the objects, suggesting that in multidigit grasps, the additional fingers primarily provided support. Our findings thus reveal that object material affects unconstrained grasping similarly to precision grip and imply that previous precision grip research may extend to unconstrained, multidigit conditions.

NEW & NOTEWORTHY

Most grasping research focuses on two-digit ‘precision grips’, yet humans have more than two fingers. Here, we test whether previous precision grip findings apply to unconstrained grasping. We find that participants often use more than two digits when free to choose but consistently place thumb and index finger similarly on objects regardless of the number of fingers used. Our results thus highlight how the large body of precision grip literature can extend to multidigit grasping.
DUSP6 is upregulated in metastasis and influences migration and metabolism in pancreatic cancer cells
Authors: Tannus Ruckert Mariana , McKinnon Walsh R. , Bye Bailey A , Eades Austin E , Yan Wei , Bednar Filip , Shi Jiaqi , Lyssiotis Costas A , VanSaun Michael , Silva Silveira Vanessa
Published: January 2025

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive tumor, predominantly triggered by the acquisition of mutant KRAS, and is present in approximately 95% of PDAC cases. The recent introduction of KRAS inhibitors has been a source of tremendous enthusiasm; however, therapeutic resistance has emerged, and combination approaches are needed. In particular, it is important to understand how downstream signaling of KRAS supports PDAC growth. For example, DUSP6, a dual-specificity phosphatase that modulates ERK1/2 phosphorylation and RAS pathway activity, has emerged as an important regulator of KRAS-MAPK signaling. Analysis across diverse bulk RNA-seq datasets revealed that DUSP6 is markedly overexpressed in primary tumor samples compared to non-tumoral pancreatic tissue. Interestingly, both human bulk and single-cell RNA-seq data indicated that DUSP6 was upregulated in epithelial cells within the tumor. Further examination showed that DUSP6 was also overexpressed in metastatic samples relative to primary tumor samples, and this upregulation correlated with the quasi-mesenchymal/squamous molecular subtype. Pertaining to its clinical significance, patients with high DUSP6 expression exhibited a poorer prognosis for overall survival than those with low expression. Subsequent gene set enrichment analysis of publicly available datasets revealed the enrichment of pathways associated with cell migration and metabolism in metastatic samples. To elucidate the role of DUSP6 in these pathways, we developed PDAC cell lines stably knocked down DUSP6 and observed a concurrent increase in ERK/MAPK activation. Additionally, suppression of DUSP6 demonstrated PDAC cell-specific alterations in migratory capacity . Next, we assessed the metabolism of PDAC cell lines following DUSP6 knockdown and observed a notable increase in basal glycolysis. Interestingly, despite the observed alterations in migratory capacity and glycolytic metabolism upon DUSP6 modulation, the combined approach of DUSP6 downregulation and glycolysis inhibition failed to affect the observed migratory phenotype, suggesting that glycolytic demands did not drive the migratory phenotype . In summary, these findings suggest that DUSP6 elicits two independent functions in PDAC: migratory capacity and glycolysis metabolism, providing new insights into the function of DUSP6 in PDAC.
The yeast CST and Polα/primase complexes act in concert to ensure proper telomere maintenance and protection
Authors: Calugaru Kimberly , Yu Eun Young , González-Rodríguez Nayim , Coloma Javier , Lue Neal F.
Published: January 2025

Polα/primase, the polymerase that initiates DNA synthesis at replication origins, also completes the task of genome duplication by synthesizing the telomere C-strand under the control of the CST complex. Using cryo-EM structures of the human CST-Polα/primase-DNA complex as guides in conjunction with AlphaFold modeling, we identified structural elements in yeast CST and Polα/primase that promote complex formation. Mutating these structures inCandida glabrataStn1, Ten1, Pri1 and Pri2 abrogated the stimulatory activity of CST on Polα/primasein vitro,supporting the functional relevance of the physical contacts in cryo-EM structures as well as the conservation of mechanisms between yeast and humans. Introducing these mutations intoC. glabratayielded two distinct groups of mutants. One group exhibited progressive, telomerase-dependent telomere elongation without evidence of DNA damage. The other manifested slow growth, telomere length heterogeneity, ssDNA accumulation and elevated C-circles, which are indicative of telomere deprotection. These telomere deprotection phenotypes are altered or suppressed by mutations in multiple DDR and DNA repair factors. We conclude that in yeast, the telomerase inhibition and telomere protection function previously ascribed to the CST complex are mediated jointly by both CST and Polα/primase, highlighting the critical importance of a replicative DNA polymerase in telomere regulation.
Integrating predator energetic balance, risk-taking behavior and microhabitat in functional response: Untangling indirect interactions in a multispecies vertebrate community
Authors: Beardsell Andréanne , Dulude-De-Broin Frédéric , Gauthier Gilles , Gravel Dominique , Legagneux Pierre , DeLong John P. , Berteaux Dominique , Bêty Joël
Published: January 2025

1

Predator-prey interactions are universal, governing the flow of energy between trophic levels and shaping ecological communities. Despite >70 years of research, our knowledge of the mechanisms modulating the strength of these interactions is limited.

To untangle proximate mechanisms governing species interactions and improve our ability to quantify interaction strength, we developed a mechanistic model that integrates predator risk-taking behavior, predator energetic balance and anti-predator refuges in a natural vertebrate community.

Our model, based on species traits and behavior, was inspired by the Arctic tundra, where the main predator (the arctic fox) feeds primarily on cyclic small rodents (lemmings) and eggs of various tundra-nesting bird species such as sandpipers eggs(non-risky prey) and gulls eggs (risky prey). We confront the model predictions with 20 years of data on species density and reproductive success.

According to the energetic model, lemmings are the most important contributor to the energetic balance of foxes, with a threshold density of 89 lemmings per km2required to switch to a positive energetic balance. When the fox energetic balance goes from positive (high lemming density) to negative (low lemming density), the acquisition rate of gull eggs increases 1.7 times on shores and 9.5 times on islands, a partial refuge and riskier habitat for the predator. Variation in gull hatching success generated by the mechanistic model aligned with empirical observations for both habitat.

Our results show that changes in predator energetic balance, translating into a change in attack and capture probabilities, can be a major mechanism underlying predator-mediated effect of lemmings on gulls hatching success.

This study is a critical step towards the integration of energetic and landscape characteristics into predator-multiprey models and presents one of the rare mechanistic models parameterized in a natural vertebrate community. Such a model can strongly improve our ability to quantify interaction strengths in multi-species communities.
HAPP: High-Accuracy Pipeline for Processing deep metabarcoding data
Authors: Sundh John , Granqvist Emma , Iwaszkiewicz-Eggebrecht Ela , Manoharan Lokeshwaran , van Dijk Laura J. A. , Goodsell Robert , Godeiro Nerivania N. , Bellini Bruno C. , Łukasik Piotr , Miraldo Andreia , Roslin Tomas , Tack Ayco J. M. , Andersson Anders F. , Ronquist Fredrik
Published: January 2025

We introduce HAPP, a high-accuracy pipeline for processing deep metabarcoding data, leveraging data richness to enhance the signal-to-noise-ratio. Starting with denoised amplicon sequence variants, the pipeline consists of four steps: (1) additional chimera removal, using UCHIME and a strict sample-based approach; (2) taxonomic annotation, combiningk-mer matching (SINTAX) to a reference library with phylogenetic placement (EPA-NG) on a reference tree; (3) OTU clustering using SWARM, an open-source algorithm with precision and recall comparable to RESL used in circumscribing BOLD BINs; and (4) noise filtering (NUMTs and sequencing errors), using a new algorithm introduced here, NEEAT, which combines “echo” signals across samples with detection of unusual evolutionary signatures among clusters with similar DNA sequences. HAPP computations are parallelized across taxa, making analyses tractable on very large datasets. The performance of HAPP was validated through extensive benchmarks, involving CO1 data from BOLD and Malaise trap data, demonstrating significant improvements over the state of the art.
Two neuropeptide signalings regulate post-mating refusal behavior and reproductive system in male crickets
Authors: Zhu Zhen , Nagata Shinji
Published: January 2025

After mating, insects always perform mating refusal behavior, termed post-mating refractoriness, due to physiological restrictions. Male crickets,Gryllus bimaculatus, characteristically exhibit 1-hour post-mating refractory stage, controlled by terminal abdominal ganglion. The molecular mechanisms underlying the male-specific precisely timed refractory stage remain elucidated. Here we show that among 28 neuropeptide precursors expressed in the terminal abdominal ganglion,DH31,myosuppressin,allatotropin, andsNPFexhibited male-specific expression based on RT-qPCR andin situhybridization. However, RNA interference experiments showed that only knockdown ofallatotropinandsNPFchanged the duration of the refractoriness. Furthermore,allatotropinandsNPFknockdown influenced functions of male reproductive system by inhibiting seminal fluid secretion from male accessory gland and decreasing sperm storage in seminal vesicles, respectively. Knockdown of their receptors caused similar phenotypes. In conclusion, this study demonstrated the regulation of post-mating refusal behavior and reproductive system by Allatotropin and sNPF signalings in male crickets.
Kinesin-1 is highly flexible and adopts an open conformation in the absence of cargo
Authors: Smith Evelyn R. , Turner Emma D. , Abdelhamid Mahmoud A. S. , Craggs Timothy D. , Twelvetrees Alison E.
Published: January 2025

Kinesin-1 is an essential anterograde microtubule motor protein. The core kinesin motor is a homodimer of two heavy chains; N-terminal motor domains hydrolyse ATP and walk along microtubules, whilst a long elongated coiled-coil stalk and an intrinsically disordered C-terminal tail region bind cargos. Kinesin autoinhibition is key to preventing futile ATP consumption and occurs, at least in part, through direct interactions between N-terminal motor domains and C-terminal inhibitory motifs. Despite significant advances in our understanding of kinesin walking, little is known about the kinesin-1 conformational landscape of the stalk and tail domains. Here we apply solution based biophysical analysis tools to study conformational changes in kinesin-1, with full rotational freedom, and in response to changes in ionic strength, mutations, and the presence of microtubules. This has allowed us to uncover the inherent flexibility in kinesin-1 which gives insights into autoinhibition and the regulation of intracellular transport.
Contrasted effect of climate and anthropogenic change on future invasion risk of a solitary beeAmegilla pulchra
Authors: Dubos Nicolas , Geslin Benoit , Jourdan Hervé , Renault David , Zakardjian Marie
Published: January 2025

Amegilla pulchrais a solitary bee from Australia that has recently been spread throughout many islands of the Pacific. The non-regulated human-driven spread of the species may affect the local pollinator communities and their interactions with host plants. We used an ecological niche modelling approach, accounting for non-equilibrium and anthropogenic spread with the most recently recommended approach, and predicted the potential spread of the species under current and future conditions. We expected climate change and increase in human density to offer new suitable environments for the spread of the species. Invasion risks will increase in the future overall, but more in the non-native regions compared to the native region. In the native region, the projected effect of future environmental change was highly contrasted, with increasing invasion risk in human-dense areas but decreasing elsewhere. We found high risks of invasion in eastern Asia and provided a world ranking of entry points for surveillance priority which accounts for maritime traffic. This study highlights potential contrasted effects between climate and anthropogenic change, with differing projections between the native and the non-native regions. Public awareness and prevention will be the key to prevent further spread and mitigate potential adverse effects of the species on island systems. In regions that are already invaded, we propose that habitat restoration is a promising strategy for both the mitigation of the spread and the conservation of local communities.
Molecular architecture of human dermal sleeping nociceptors
Authors: Körner Jannis , Howard Derek , Solinski Hans Jürgen , Moreno Marisol Mancilla , Haag Natja , Fiebig Andrea , Bhuiyan Shamsuddin A. , Toklucu Idil , Bott Raya , Sankaranarayanan Ishwarya , Tavares-Ferreira Diana , Shiers Stephanie , Inturi Nikhil N. , Maxion Anna , Ernst Lisa , Bonaguro Lorenzo , Schulte-Schrepping Jonas , Beyer Marc D. , Stiehl Thomas , Renthal William , Kurth Ingo , Price Theodore , Schmelz Martin , Namer Barbara , Tripathy Shreejoy , Lampert Angelika
Published: January 2025

Human dermal sleeping nociceptors display ongoing activity in neuropathic pain, affecting 10% of the population. Despite advances in rodents, a molecular marker for these mechano-insensitive C-fibers (CMis) in human skin remains elusive, preventing targeted therapy. In this translational Patch-seq study, we combine single-cell transcriptomics following electrophysiological characterization with single-nucleus and spatial transcriptomics from pigs and humans. We functionally identified CMis in pig sensory neurons with patch-clamp using adapted protocols from human microneurography. We identified oncostatin-M-receptor (OSMR) and somatostatin (SST) as marker genes for CMis. Following dermal injection in healthy human volunteers, oncostatin-M, the ligand of OSMR, exclusively modulates CMis. We identified the entire molecular architecture of human dermal sleeping nociceptors, providing new therapeutic targets and the basis for a mechanistic understanding of neuropathic pain.

One Sentence Summary

We identify the molecular architecture and specifically OSMR and SST as molecular markers for human dermal sleeping nociceptors, key players in the generation of neuropathic pain.

Short version

In this Patch-seq study, we identify OSMR and SST as molecular markers for human dermal sleeping nociceptors, key players in the generation of neuropathic pain.
Near 100% genome editing efficiency with a one-step all RNA prime editing system in a human reporter iPSC line
Authors: Wettschurack Kyle , Skarnes William C. , Pellegrino Enrica , Robinson Morgan , Yang Yang
Published: January 2025

CRISPR/Cas9 nucleases offer powerful tools for genome editing but can cause unintended mutations at the target site due to the creation of double-stranded DNA breaks. Prime editing (PE) is arguably a safer technology as it relies on the creation of single-strand DNA nicks and avoids possible indels. Despite its precision, current PE systems are limited by relatively low editing efficiency in non-immortalized cells. Here, we optimized prime editing in human induced pluripotent stem cells (hiPSCs) using a fluorescence-based assay to achieve near-complete editing of a BFP transgene. Using an all-RNA approach, precise prime editing of a single nucleotide variant was observed in >95% of cells with minimal unintended edits at the target site.
Intrinsic functional connectivity delineates transmodal language functions
Authors: Salvo J.J. , Anderson N.L. , Braga R.M.
Published: January 2025

Communication involves the translation of sensory information (e.g., heard words) into abstract concepts according to abstract rules (e.g., the meaning of those words). Accordingly, using language involves an interplay betweenunimodalbrain areas that process sensory information andtransmodalareas that respond to linguistic input regardless of the input modality (e.g., reading sentences vs. listening to speech). Previous work has shown that intrinsic functional connectivity (iFC), when performed within individuals, can delineate a distributed language network that overlaps in detail with regions activated by a reading task. The network was widely distributed across multiple brain regions, recapitulating an organization that is characteristic of association cortex, and which suggests that the distributed language network serves transmodal, not unimodal, functions. Here, we tested whether the distributed language network encapsulates transmodal functions by assessing its degree of overlap with two language tasks, one auditory (i.e., listening to speech) and one visual (i.e., reading sentences). The results show that the distributed language network aligns well with regions activated by both tasks, supporting a transmodal function. Further, the boundaries of the distributed language network along the lateral temporal cortex serve as a good proxy for the division between transmodal language and auditory functions: presentation of sounds (i.e., filtered, incomprehensible speech) evoked activity that was largely outside of the distributed language network but closely followed the network boundaries. These findings support that individualized iFC estimates can delineate the division between sensory-linked and abstract linguistic functions. We conclude that within-individual iFC may be viable for language mapping in individuals with aphasia who cannot perform language tasks in the scanner.
Molecular epidemiology ofAscaris lumbricoidesfollowing multiple rounds of community-wide treatment: who infects whom?
Authors: Landeryou Toby , Maddren Rosie , Hearn Jack , Belachew Mahlet , Rayment Gomez Santiago , Liyew Ewnetu Firdawek , Forbes Kathryn , Mengistu Birhan , Lawton Scott , Eze Jude , Tasew Geremew , Angulo Ufaysa , Anderson Roy
Published: January 2025

Control and elimination of the parasiteAscaris lumbricoidesrelies on mass administration using a limited number of anti-helminthics. Whilst these programs have reduced the infection intensity and prevalence within many endemic regions transmission is poorly understood, with reinfection commonly occurring following cessation of treatment. Here, we utilise genomic data to understand parasite transmission within and between households in a community and the genomic impact of repeated MDA. We sequenced 54 whole-genomes from individuals in a longitudinal cohort epidemiological study of transmission and drug treatment extending over 6 years. We found that fine-scale population structure exists in spatially distinct clusters of infected individuals with reinfection occurring within or between geographically close households. This observation helps inform the policy of future control in low prevalence settings suggesting more targeted treatment of infection hotspots We found evidence of positive selection acting on members of gene families previously implicated in reduced drug efficacy but detect no high frequency of impactful variants. As efforts to eliminateA. lumbricoidesintensify, our study provides a foundation for genomic surveillance to help identify both who infects whom and the impact of repeated drug treatment.
Short activation domains control chromatin association of transcription factors
Authors: Fan Vinson B , Darzacq Xavier , Staller Max V
Published: January 2025

Transcription factors regulate gene expression with DNA-binding domains (DBDs) and activation domains. It is generally assumed that DBDs are solely responsible for interacting with DNA and chromatin. Here, we used single-molecule tracking of transcription factors in living cells to find that short activation domains can control the fraction of molecules bound to chromatin. Activation domains with high bound fractions also have longer residence times on chromatin. Mutations in activation domains that increase activity of a transcriptional reporter increase the fraction of molecules bound to chromatin. Reciprocally, mutations that decrease reporter activity decrease fraction bound. These effects were consistent across three activation domains and three DBD classes. Taken together, these results suggest that activation domains play a major role in tethering transcription factors to chromatin, challenging the traditional view that the DBD is solely responsible for binding chromatin.
Stress-driven emergence of heritable non-genetic drug resistance
Authors: Xie Jinglin L. , Yin Sifei , Yang Theodore S. , Chandrasekher Kiran , Hanson Luke , Kim Sang Hu , Esqueda Lucas , Hogan Catherine A. , Banaei Niaz , Round June L. , Ost Kyla S. , Berman Judith , Jarosz Daniel F.
Published: January 2025

Drug resistance is the chief cause of treatment failure for therapies targeting chronic and infectious diseases. Whether the emergence of resistance is accelerated by environmental exposure to low levels of therapeutics remains controversial. Here, we report a non-genetic mechanism of stress adaptation that promotes heritable resistance to the widely used antifungal drug fluconazole. In the human fungal pathogenCandida albicans,transient exposure to subtherapeutic fluconazole doses induces a protective response that we term para-resistance. Like conventional resistance mechanisms, para-resistance is heritable. However, it does not arise from genetic mutations and can revert spontaneously. Systematic analyses of para-resistant isolates suggest that its key regulators include the stress-activated MAP kinase Hog1, the histone deacetylase subunit Snt1, the chromatin regulator Rap1, and the Sko1 transcriptional factor. Notably, molecules that disrupt biomolecular condensation and prion propagation – crucial for the inheritance of protein assemblies – block the induction of para-resistance, whereas inhibiting histone deacetylases facilitates its induction. We find that para-resistance is common in clinical isolates and, remarkably, passage through the mammalian gut triggers its acquisition, compromising fluconazole’s therapeutic efficacy. Our work defines a pervasive, prion-like epigenetic mechanism of stress adaptation and highlights potential strategies to mitigate the rapid emergence of drug resistance.
Discovery ofNANOGenhancers and their essential roles in self-renewal and differentiation in human embryonic stem cells
Authors: Yan Jielin , Luo Renhe , Rosen Bess P. , Liu Dingyu , Wong Wilfred , Leslie Christina S. , Huangfu Danwei
Published: January 2025

Human embryonic stem cells (hESCs) are notable for their ability to self-renew and to differentiate into all tissue types in the body.NANOGis a core regulator of hESC identity, and dynamic control of its expression is crucial to maintain the balance between self-renewal and differentiation. Transcriptional regulation depends on enhancers, butNANOGenhancers in hESCs are not well characterized. Here we report twoNANOGenhancers discovered from a CRISPR interference screen in hESCs. Deletion of a single copy of either enhancer significantly reducedNANOGexpression, compromising self-renewal and increasing differentiation propensity. Interestingly, these twoNANOGenhancers are involved in a tandem duplication event found in certain primates including humans but not in mice. However, the duplicated counterparts do not regulateNANOGexpression. This work expands our knowledge of functional enhancers in hESCs, and highlights the sensitivity of the hESC state to the dosage of core regulators and their enhancers.
Human shape perception spontaneously discovers the biological origin of novel, but natural, stimuli
Authors: Dehn Kira I. , Maiello Guido , Hartmann Frieder T. , Morgenstern Yaniv , Hawkins Sara Joy , Offner Thomas , Walter Joshua , Hassenklöver Thomas , Manzini Ivan , Fleming Roland W.
Published: January 2025

Humans excel at categorizing objects by shape. This facility involves identifying shape features that objects have in common with other members of their class and relies—at least in part—on semantic/cognitive constructs. For example, plants sprout branches, fish grow fins, shoes are molded to our feet. Can humans parse shapes according to the processes that give shapes their key characteristics, even when such processes are hidden? To answer this, we investigated how humans perceive the shape of cells from the olfactory system ofXenopus laevistadpoles. These objects are novel to most humans yet occur in nature and cluster into classes following their underlying biological function. We reconstructed 3D cell models through 3D-microscopy and photogrammetry, then conducted psychophysical experiments. Human participants performed two tasks: they arranged 3D-printed cell models by similarity and rated them along eight visual dimensions. Participants were highly consistent in their arrangements and ratings and spontaneously grouped stimuli to reflect the cell classes, unwittingly revealing the underlying processes shaping these forms. Our findings thus demonstrate that human perceptual organization mechanisms spontaneously parse the biological systematicities of never-before-seen, natural shapes. Integrating such human perceptual strategies into automated systems may enhance morphology-based analysis in biology and medicine.
Breaking Barriers in Crosslinking Mass Spectrometry: Enhanced Throughput and Sensitivity with the Orbitrap Astral Mass Analyzer
Authors: Müller Fränze , Stejskal Karel , Mechtler Karl
Published: January 2025

The advancement of crosslinking mass spectrometry (CLMS) has significantly enhanced the ability to study protein-protein interactions and complex biological systems. This study evaluates the performance of the Orbitrap Astral and Eclipse mass spectrometers in CLMS workflows, focusing on the identification of low-abundance crosslinked peptides. The comparison employed consistent liquid chromatography setups and experimental conditions, using Cas9 crosslinked with PhoX and DSSO as quality control samples. Results demonstrated that the Astral analyzer outperformed the Eclipse, achieving over 40% more unique residue pairs (URP) due to its superior sensitivity and dynamic range, attributed to its multi-reflection time-of-flight analyzer and nearly lossless ion transmission. Additionally, the study revealed that single higher-energy collisional dissociation (HCD) fragmentation methods significantly outperformed stepped HCD methods on the Astral, while the Eclipse maintained similar performance across both approaches. Gradient optimization experiments further highlighted the impact of separation times on crosslink identifications, with longer gradients yielding higher identification rates. Collectively, this work underscores the importance of instrumentation choice, fragmentation strategies, and method optimization in maximizing CLMS performance for protein interaction studies.
Preferences for tongue swab-versus sputum-based testing in the context of TB care: a Best-Worst Scaling exercise in Vietnam and Zambia
Authors: del Mar Castro Maria , Le Hien , Muzazu Seke , Pham Nam , Trinh Trang , Nyirenda Herbert , Shabalu Patricia , West Nora , Phan Ha , Cattamanchi Adithya , Denkinger Claudia M. , Muyoyeta Monde , Kerkhoff Andrew D.
Published: January 2025

Background

The development of non-sputum-based tests is an urgent priority to increase access to tuberculosis (TB) diagnostic testing. Understanding preferences of people undergoing testing is critical for designing tests and strategies aligned with their needs.

Methods

We conducted a survey and Best-Worst Scaling (BWS) exercise to determine relative preferences for tongue swab-vs. sputum-based testing among people (≥13 years) with presumptive TB at primary health centers in Vietnam and Zambia. The BWS assessed sixteen TB test features, including accuracy, sample type, turnaround time, cost, and service aspects. We analyzed preferences using Hierarchical Bayes modeling and identified distinct preference groups using Latent Class Multinomial Logit analyses (LCA).

Results

Among 409 participants enrolled, 356 (87%) met quality criteria for analysis. When asked directly, most participants preferred providing tongue swabs over sputum (58% vs 29%, p<0.001; 13% no preference). In the BWS exercise, tongue swab was also preferred over sputum (mean rescaled preference weight [MPW] 6.4 [95%CI: 5.9-6.8] vs. 5.0 [95%CI: 4.6-5.4]). However, support and counseling (MPW=14.0), sensitivity (MPW=12.3), specificity (MPW=10.2), and provider attitude (MPW=7.4) were the most important features overall. Less important features included facility opening hours (MPW=3.4) and the influence of trusted sources on testing decisions (MPW=2.2). LCA identified five distinct preference groups, but support and counseling were universally valued. Participants in Groups 2 (27.3%; n=97) and 3 (17.1%; n=61) valued tongue swabs over many other features. Group 5 participants (11%; n=39) strongly valued sputum-based testing.

Conclusions

Participants in Vietnam and Zambia preferred tongue swab-based TB testing over sputum. However, sample type was less important than test accuracy and other TB care features affecting the testing experience.