bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional analysis of conservedC. elegansbHLH family members uncovers lifespan control by a peptidergic hub neuron
Authors: Aguilar G. Robert , Vidal Berta , Ji Hongzhu , Evenblij Joke , Ji Hongfei , Valperga Giulio , Liao Chien-Po , Fang-Yen Christopher , Hobert Oliver
Published: July 2024

Throughout the animal kingdom, several members of the basic helix-loop-helix (bHLH) family act as proneural genes during early steps of nervous system development. Roles of bHLH genes in specifying terminal differentiation of postmitotic neurons have been less extensively studied. We analyze here the function of fiveC. elegansbHLH genes, falling into three phylogenetically conserved subfamilies, which are continuously expressed in a very small number of postmitotic neurons in the central nervous system. We show (a) that two orthologs of the vertebrate bHLHb4/b5 genes, calledhlh-17andhlh-32,function redundantly to specify the identity of a single head interneuron (AUA), as well as an individual motor neuron (VB2), (b) that thePTF1aorthologhlh-13acts as a terminal selector to control terminal differentiation and function of the sole octopaminergic neuron class inC. elegans, RIC, and (c) that the NHLH1/2 orthologhlh-15controls terminal differentiation and function of the peptidergic AVK head interneuron class, a known neuropeptidergic signaling hub in the animal. Strikingly, through null mutant analysis and cell-specific rescue experiments, we find that loss ofhlh-15/NHLHin the peptidergic AVK neurons and the resulting abrogation of neuropeptide secretion causes a substantially expanded lifespan of the animal, revealing an unanticipated impact of a central, peptidergic hub neuron in regulating lifespan, which we propose to be akin to hypothalamic control of lifespan in vertebrates. Taken together, our functional analysis reveals themes of bHLH gene function during terminal differentiation that are complementary to the earlier lineage specification roles of other bHLH family members. However, such late functions are much more sparsely employed by members of the bHLH transcription factor family, compared to the function of the much more broadly employed homeodomain transcription factor family.
A wavelet-based approach generates quantitative, scale-free and hierarchical descriptions of 3D genome structures and new biological insights
Authors: Pellow Ryan , Comeron Josep M
Published: July 2024

Eukaryotes fold their genomes within nuclei in three-dimensional space, with coordinated multiscale structures including loops, topologically associating domains (TADs), and higher-order chromosome territories. This 3D organization plays essential roles in gene regulation and development, responses to physiological stress, and disease. However, current methodologies to infer these 3D structures from genomic data have limitations. These include varying outcomes depending on the resolution of the analysis and sequencing depth, qualitative results that hinder statistical comparisons, lack of insight into the frequency of the structures in samples with many genomes, and no direct inference of hierarchical structures. These shortcomings can make it difficult for the rigorous comparison of 3D properties across genomes, between experimental conditions, or species. To address these challenges, we developed a wavelet transform-based method (WaveTAD) that describes the 3D nuclear organization in a resolution-free, probabilistic, and hierarchical manner. WaveTAD generates probabilities that capture the variable frequency within samples and shows increased accuracy and sensitivity compared to current approaches. We applied WaveTAD to multiple datasets fromDrosophila, mouse, and humans to illustrate new biological insights that our more sensitive and quantitative approach provides, such as the widespread presence of embryonic 3D organization before zygotic genome activation, the effect of multiple CTCF units on the stability of loops and TADs, and the association between gene expression and TAD structures in COVID-19 patients or sex-specific transcription inDrosophila.
A Single Trophoblast Layer Acts as the Gatekeeper at the Endothelial-Hematopoietic Crossroad in the Placenta
Authors: Home Pratik , Ghosh Ananya , Kumar Ram Parikshan , Ray Soma , Gunewardena Sumedha , Kumar Rajnish , Dasgupta Purbasa , Roy Namrata , Saha Abhik , Ouseph Madhu M. , Leone Gustavo W. , Paul Soumen
Published: July 2024

During embryonic development the placental vasculature acts as a major hematopoietic niche, where endothelial to hematopoietic transition ensures emergence of hematopoietic stem cells (HSCs). However, the molecular mechanisms that regulate the placental hematoendothelial niche are poorly understood. Using a parietal trophoblast giant cell (TGC)-specific knockout mouse model and single-cell RNA-sequencing, we show that the paracrine factors secreted by the TGCs are critical in the development of this niche. Disruptions in the TGC-specific paracrine signaling leads to the loss of HSC population and the concomitant expansion of a KDR+/DLL4+/PROM1+ hematoendothelial cell-population in the placenta. Combining single- cell transcriptomics and receptor-ligand pair analyses, we also define the parietal TGC- dependent paracrine signaling network and identify Integrin signaling as a fundamental regulator of this process. Our study elucidates novel mechanisms by which non-autonomous signaling from the primary parietal TGCs maintain the delicate placental hematopoietic- angiogenic balance and ensures embryonic and extraembryonic development.
Langerhans cells regulate immunity in adulthood by regulating postnatal dermal lymphatic development
Authors: Sim Ji Hyun , Bell Richard , Feng Zhonghui , Chyou Susan , Shipman William D , Kataru Raghu P. , Ivashkiv Lionel , Mehrara Babak , Lu Theresa T.
Published: July 2024

The communication between skin and draining lymph nodes is crucial for well-regulated immune responses to skin insults. The skin sends antigen and other signals via lymphatic vessels to regulate lymph node activity, and regulating dermal lymphatic function is another means to control immunity. Here, we show that Langerhans cells (LCs), epidermis-derived antigen-presenting cells, mediate dermal lymphatic expansion and phenotype acquisition postnatally, a function is independent of LC entry into lymphatic vessels. This postnatal LC-lymphatic axis serves in part to control inflammatory systemic T cell responses in adulthood. Our data provide a tissue-based mechanism by which LCs regulate T cells remotely across time and space and raise the possibility that immune diseases in adulthood could reflect compromise of the LC-lymphatic axis in childhood.
Local keratinocyte-nociceptor interactions enhance obesity-mediated small fiber neuropathy via NGF-TrkA-PI3K signaling axis
Authors: Koui Yuta , Song Shuxuan , Dong Xinzhong , Mukouyama Yoh-suke
Published: July 2024

The pathology of diabetic small fiber neuropathy, characterized by neuropathic pain and axon degeneration, develops locally within the skin during the stages of obesity and pre-diabetes. However, the initiation and progression of morphological and functional abnormalities in skin sensory nerves remains elusive. To address this, we utilized ear skin from mice with diet-induced obesity (DIO), the mouse models for obesity and pre-type 2 diabetes. We evaluated pain-associated wiping behavior and conductedex vivolive Ca2+imaging of the DIO ear skin to detect sensory hypersensitivity. Our findings reveal sensory hypersensitivity in skin nociceptive axons followed by axon degeneration. Further mechanistic analysis identified keratinocytes as a major source of nerve growth factor (NGF) in DIO skin, which locally sensitizes nociceptors through NGF-mediated signaling. Indeed, the local inactivation of NGF and its receptor TrkA-mediated downstream signaling, including the phosphoinositide 3-kinases (PI3K) pathway, suppresses sensory hypersensitivity in DIO skin. Thus, targeting these local interactions between keratinocytes and nociceptors offers a therapeutic strategy for managing neuropathic pain, avoiding the adverse effects associated with systemic interventions.
Elp1 function in placode-derived neurons is critical for proper trigeminal ganglion development
Authors: Hines Margaret A. , Taneyhill Lisa A.
Published: July 2024

Background

The trigeminal nerve is the largest cranial nerve and functions in somatosensation. Cell bodies of this nerve are positioned in the trigeminal ganglion, which arises from the coalescence of neural crest and placode cells. While this dual cellular origin has been known for decades, the molecular mechanisms controlling trigeminal ganglion development remain obscure. We performed RNAsequencing on the forming chick trigeminal ganglion and identifiedElongator acetyltransferase complex subunit 1(Elp1) for further study. Mutations inELP1cause familial dysautonomia (FD), a fatal disorder characterized by the presence of smaller trigeminal nerves and sensory deficits. While Elp1 has established roles in neurogenesis, its functions in placode cells during trigeminal gangliogenesis have not been investigated.

Results

To this end, we used morpholinos to deplete Elp1 from chick trigeminal placode cells. Elp1 knockdown decreased trigeminal ganglion size and led to aberrant innervation of the eye by placode-derived neurons. Trigeminal nerve branches exhibited fewer axons, and abnormal interactions between placode-derived neurons and neural crest cells were observed.

Conclusions

These findings reveal a new role for Elp1 in chick placode-derived neurons during trigeminal ganglion development. These results have potential high significance to provide new insights into trigeminal ganglion development and the etiology of FD.

Bullet points

Elp1 is expressed in undifferentiated neural crest cells and placode-derived neurons contributing to the trigeminal ganglion.

Elp1 knockdown in trigeminal placode cells reduces trigeminal ganglion size.

Elp1 depletion from trigeminal placode cells leads to aberrant target tissue innervation and disrupts proper neural crest-placodal neuron interactions in the trigeminal ganglion.

Grant sponsor and number

NIH R01DE024217 and NIH R03HD108480.
Portal bile acids and microbiota along the murine intestinal tract exhibit sex differences in physiology
Authors: Reichardt Francois , Lucas Lauren , Okyere Lydia , Choi Jim , Amador-Nogez Daniel , Gaulke Christopher , Anakk Sayeepriyadarshini
Published: July 2024

Microbes in the intestine transform bile acids during transit, altering their functional and signaling capacities before absorption into the portal vein. Sex differences in the gut microbiota have been noted, but their consequence on bile acid composition is unclear. Here, we investigated the composition and imputed functional potential of microbes in the small and large intestine together with portal and systemic bile acids. Female and male mice exhibit distinct microbial diversity throughout the length of the intestine leading to dimorphism in genes related to bile acid transformation. Subsequently, we found that the total portal bile acid concentrations were doubled in female mice compared to males. Conversely, oxo-bile acids that are rare in systemic circulation represented almost 30 percent of the portal pool in the male mice. Oxo- and deconjugated- bile acids were absent in germ-free mice consistent with microbe-mediated bile acid transformation. More importantly, gnotobiotic mice do not show sex differences in portal bile acids. Taken together, we demonstrate that sex differences in gut microbiota cause dimorphism in bile acid levels within the enterohepatic loop.
Protein-Induced Membrane Strain Drives Supercomplex Formation
Authors: Pöverlein Maximilian C. , Jussupow Alexander , Kim Hyunho , Kaila Ville R. I.
Published: July 2024

Mitochondrial membranes harbor the electron transport chain (ETC) that powers oxidative phosphorylation (OXPHOS) and drives the synthesis of ATP. Yet, under physiological conditions, the OXPHOS proteins operate as higher-order supercomplex (SC) assemblies, although their functional role remains poorly understood and much debated. By combining large-scale atomistic and coarse-grained molecular simulations with analysis of cryo-electron microscopic data and statistical as well as kinetic models, we show here that the formation of the mammalian I/III2supercomplex reduces the molecular strain of inner mitochondrial membranes by altering the local membrane thickness, and leading to an accumulation of both cardiolipin and quinone around specific regions of the SC. We find that the SC assembly also affects the global motion of the individual ETC proteins with possible functional consequences. On a general level, our findings suggest that molecular crowding and entropic effects provide a thermodynamic driving force for the SC formation, with a possible flux enhancement in crowded biological membranes under constrained respiratory conditions.

Significance Statement

The membrane-bound proteins of respiratory chains power oxidative phosphorylation (OXPHOS) and drive the synthesis of ATP. However, recent biochemical and structural data show that the OXPHOS proteins operate as higher-order supercomplex assemblies for reasons that remain elusive and much debated. Here we show that the mammalian respiratory supercomplexes reduce the molecular strain of inner mitochondrial membranes and enhance the allosteric crosstalk by altering the protein dynamics with important biochemical and physiological implications.
Massive experimental quantification of amyloid nucleation allows interpretable deep learning of protein aggregation
Authors: Thompson Mike , Martín Mariano , Olmo Trinidad Sanmartín , Rajesh Chandana , Koo Peter K. , Bolognesi Benedetta , Lehner Ben
Published: July 2024

Protein aggregation is a pathological hallmark of more than fifty human diseases and a major problem for biotechnology. Methods have been proposed to predict aggregation from sequence, but these have been trained and evaluated on small and biased experimental datasets. Here we directly address this data shortage by experimentally quantifying the amyloid nucleation of >100,000 protein sequences. This unprecedented dataset reveals the limited performance of existing computational methods and allows us to train CANYA, a convolution-attention hybrid neural network that accurately predicts amyloid nucleation from sequence. We adapt genomic neural network interpretability analyses to reveal CANYA’s decision-making process and learned grammar. Our results illustrate the power of massive experimental analysis of random sequence-spaces and provide an interpretable and robust neural network model to predict amyloid nucleation.
RFMix-reader: Accelerated reading and processing for local ancestry studies
Authors: Benjamin Kynon J.M.
Published: July 2024

Motivation

Local ancestry inference is a powerful technique in genetics, revealing population history and the genetic basis of diseases. It is particularly valuable for improving eQTL discovery and fine-mapping in admixed populations. Despite the widespread use of theRFMixsoftware for local ancestry inference, large-scale genomic studies face challenges of high memory consumption and processing times when handlingRFMixoutput files.

Results

Here, I presentRFMix-reader, a new Python-based parsing software, designed to streamline the analysis of large-scale local ancestry datasets. This software prioritizes computational eiciency and memory optimization, leveraging GPUs when available for additional speed boosts. By overcoming these data processing hurdles,RFMix-readerempowers researchers to unlock the full potential of local ancestry data for understanding human health and health disparities.

Availability

RFMix-readeris freely available on PyPI athttps://pypi.org/project/rfmix-reader/, implemented in Python 3, and supported on Linux, Windows, and Mac OS.

Contact

KynonJade.Benjamin@libd.org

Supplementary information

Supplementary data are available athttps://rfmix-reader.readthedocs.io/en/latest/.
Dynamical forces drive organ morphology changes during embryonic development
Authors: Manna Raj Kumar , Retzlaff Emma M. , Hinman Anna Maria , Lan Yiling , Abdel-Razek Osama , Bates Mike , Hehnly Heidi , Amack Jeffrey D. , Manning M. Lisa
Published: July 2024

Organs and tissues must change shape in precise ways during embryonic development to execute their functions. Multiple mechanisms including biochemical signaling pathways and biophysical forces help drive these morphology changes, but it has been difficult to tease apart their contributions, especially from tissue-scale dynamic forces that are typically ignored. We use a combination of mathematical models andin vivoexperiments to study a simple organ in the zebrafish embryo called Kupffer’s vesicle. Modeling indicates that dynamic forces generated by tissue movements in the embryo produce shape changes in Kupffer’s vesicle that are observed during development. Laser ablations in the zebrafish embryo that alter these forces result in altered organ shapes matching model predictions. These results demonstrate that dynamic forces sculpt organ shape during embryo development.
HERV-derived epitopes represent new targets for T-cell based immunotherapies in ovarian cancer
Authors: Bonaventura Paola , Tabone Olivier , Estornes Yann , Page Audrey , Mutez Virginie , Delles Marie , Moran Sarah , Dubois Clarisse , Lacourrege Marjorie , Tawfik Dina , Etchegaray Ema , Valente Adrian , Boulos Rasha E. , Jimenez Dominguez Gabriel , Chuvin Nicolas , Gadot Nicolas , Wang Qing , Valladeau-Guilemond Jenny , Depil Stéphane
Published: July 2024

Background

Ovarian cancer represents the most lethal gynecological cancer with poor results of checkpoint inhibitors. Human endogenous retroviruses (HERVs) are aberrantly expressed by tumor cells and may represent a source of shared T cell epitopes for cancer immunotherapy regardless of the tumor mutational burden.

Methods

A transcriptomic analysis based on RNA-sequencing (RNA-seq) was developed to quantify the expression of HERV-K sequences containing the selected epitopes. The presence of HERV-K/HML-2 Gag antigen was then assessed by immunohistochemistry (IHC) on tumor microarrays from ovarian cancer samples and normal ovarian tissues. A specific immunopeptidomics approach was developed to detect epitopes on HLA molecules. Epitope-specific CD8+T cells were quantified by multimer staining andin vitrotarget cell killing was evaluated using xCELLigence technology.In vivoantitumor efficacy of HERV-specific T cells was assessed in an avian embryo model.

Results

Epitope-containing HERV transcripts were significantly higher in ovarian cancers compared to normal tissues. The presence of HERV-K/HML-2 Gag antigen was confirmed by IHC in 20/40 (50%) ovarian cancers while no Gag expression was found in normal ovarian tissue samples. Immunopeptidomics analysis showed the presence of epitopes on HLA molecules on the surface of ovarian tumor cell lines but not on normal primary cells from critical tissues. HERV-specific T cells were detected among tumor infiltrating lymphocytes (TILs) from ovarian cancers, confirming the immunogenicity of these epitopes in patients.In vitro, HERV-specific T cells specifically killed ovarian cancer cells in an HLA class I-restricted manner while sparing normal HLA-A2-positive primary cells derived from critical tissues. Epitope-specific CD8+T cells exhibited a strong anti-tumoral activityin vivo, inducing a highly significant decrease in tumor volume in comparison with control groups.

Conclusion

These results provide the preclinical rationale for developing T-cell based approaches against HERV-K-derived epitopes in ovarian cancer.

Graphical abstract

Some HERVs are specifically overexpressed in ovarian cancer compared to normal tissues.

HERV-K/HML-2 Gag antigen is detected by immunohistochemistry in ovarian cancers but not in normal ovarian tissues. Furthermore, HERV-K-derived epitopes are presented on HLA molecules on the surface of ovarian cancer cells but not on normal cells.

These epitopes are immunogenic in patients and induce high-avidity CD8+T cells that specifically kill ovarian cancer cellsin vitroandin vivowhile sparing normal cells.
Stretching the structural envelope of isomeric imatinib analogs that reduce β-amyloid production by modulating both β- and γ-secretase cleavages of APP
Authors: Netzer William J. , Sinha Anjana , Ghias Mondana , Chang Emily , Gindinova Katherina , Mui Emily , Seo Ji-Seon , Sinha Subhash C.
Published: July 2024

We previously showed that the anticancer drug imatinib mesylate (IMT, trade name: Gleevec) and a chemically distinct compound, DV2-103 (a kinase-inactive derivative of the potent Abl and Src kinase inhibitor, PD173955) lower Aβ levels at low micromolar concentrations primarily through a lysosome-dependent mechanism that renders APP less susceptible to proteolysis by BACE1 without directly inhibiting BACE1 enzymatic activity, or broadly inhibiting the processing of other BACE1 substrates. Additionally, IMT indirectly inhibits γ-secretase and stimulates autophagy, and thus may decrease Aβ levels through multiple pathways. In two recent studies we demonstrated similar effects on APP metabolism caused by derivatives of IMT and DV2-103. In the present study we investigated how so many structurally diverse compounds affect APP metabolism in the same way, with similar potencies and production of APP metabolites. To this end, we synthesized and tested radically altered IMT regioisomers that possess medium structural similarity to IMT. Independent of structural similarity, these isomers manifest widely differing potencies in altering APP metabolism. These will enable us to choose the most potent isomers for further derivatization.
Desert ant (Melophorus bagoti) dumpers learn from experience to improve waste disposal and show spatial fidelity
Authors: deeti sudhakar , Cheng Ken
Published: July 2024

The Central Australian red honey-pot ant Melophorus bagoti maintains non-cryptic ground-nesting colonies in the semi-desert habitat, performing all the activities outside the nest during the hottest periods of summer days. These ants rely on path integration and view-based cues for navigation. They manage waste by taking out unwanted food, dead nestmates, and some other wastes, typically depositing such items at distances > 5 m from the nest entrance, a process called dumping. We found that over multiple runs, dumpers headed in the same general direction, showing sector fidelity. Experienced ants dumped waste more efficiently than naive ants. Naive individuals, lacking prior exposure to the outdoor environment around the nest, exhibited much scanning and meandering during waste disposal. In contrast, experienced ants dumped waste with straighter paths and a notable absence of scanning behaviour. Furthermore, experienced dumpers deposited waste at a greater distance from the nest compared to their naive counterparts. We also investigated the navigational knowledge of naive and experienced dumpers by displacing them 2 metres away from the nest. Naive dumpers were not oriented towards the nest in their initial trajectory at any of the 2m test locations, whereas experienced dumpers were oriented towards the nest at all test locations. Naive dumpers were nest-oriented as a group, however, at the test location nearest to where they dumped their waste. These differences suggest that in red honey ants, learning supports waste disposal, with dumping being refined through experience. Dumpers gain greater spatial knowledge through repeated runs outside the nest, contributing to successful homing behaviour.
MALAT1expression indicates cell quality in single-cell RNA sequencing data
Authors: Clarke Zoe A. , Bader Gary D.
Published: July 2024

Single-cell RNA sequencing (scRNA-seq) has revolutionized our understanding of cell types and tissues. However, empty droplets and poor quality cells are often captured in single cell genomics experiments and need to be removed to avoid cell type interpretation errors. Many automated and manual methods exist to identify poor quality cells or empty droplets, such as minimum RNA count thresholds and comparing the gene expression profile of an individual cell to the overall background RNA expression of the experiment. A versatile approach is to use unbalanced overall RNA splice ratios of cells to identify poor quality cells or empty droplets. However, this approach is computationally intensive, requiring a detailed search through all sequence reads in the experiment to quantify spliced and unspliced reads. We found that the expression level ofMALAT1,a non-coding RNA retained in the nucleus and ubiquitously expressed across cell types, is strongly correlated with this splice ratio measure and thus can be used to similarly identify low quality cells in scRNA-seq data. Since it is easy to visualize the expression of a single gene in single-cell maps,MALAT1expression is a simple cell quality measure that can be quickly used during the cell annotation process to improve the interpretation of cells in tissues of human, mouse and other species with a conservedMALAT1function.
Parallelized Droplet Vitrification Enables Single-Run Vitrification of the Whole Rat Liver Hepatocyte Yield
Authors: Taggart M. S. , Tchir A. , Van Dieren L. , Chen H. , Hassan M. , Taveras C. , Lellouch AG. , Toner M. , Sandlin R. D. , Uygun K.
Published: July 2024

Drug discovery pipelines rely on the availability of isolated primary hepatocytes for investigating potential hepatotoxicity prior to clinical application. These hepatocytes are typically isolated from livers rejected for transplantation and subsequently cryopreserved for later usage. The gold-standard cryopreservation technique, slow-freezing, is a labor-intensive process, with significant post-storage viability loss. In this work, we introduce parallelized droplet vitrification, a technique for high-volumetric, rapid vitrification of suspended cells. We show the utility of this technique through the single-run vitrification of the whole-rate liver hepatocyte yield, resulting in a 1600% increase in single-batch vitrification and a 500% increase in droplet generation rate compared to previous droplet vitrification approaches. Additionally, we showed that these implementations maintained improved post-preservation outcomes in primary rat hepatocytes.
Spatial and temporal transmission dynamics of respiratory syncytial virus in New Zealand before and after the COVID-19 pandemic
Authors: Jelley Lauren , Douglas Jordan , O’Neill Meaghan , Berquist Klarysse , Claasen Ana , Wang Jing , Utekar Srushti , Johnston Helen , Judy Bocacao , Allais Margot , de Ligt Joep , Tan Chor Ee , Seeds Ruth , Wood Tim , Aminisani Nayyereh , Jennings Tineke , Welch David , Turner Nikki , McIntyre Peter , Dowell Tony , Trenholme Adrian , Byrnes Cass ,   The SHIVERS investigation team, Webby Richard , French Nigel , Winter David , Huang Q. Sue , Geoghegan Jemma L
Published: July 2024

Human respiratory syncytial virus (RSV) is a major cause of acute respiratory infection. In 2020, RSV was effectively eliminated from the community in New Zealand due to non-pharmaceutical interventions (NPI) used to control the spread of COVID-19. However, in April 2021, following a brief quarantine-free travel agreement with Australia, there was a large-scale nationwide outbreak of RSV that led to reported cases more than five times higher, and hospitalisations more than three times higher, than the typical seasonal pattern. In this study, we generated 1,471 viral genomes of both RSV-A and RSV-B sampled between 2015 and 2022 from across New Zealand. Using a phylodynamics approach, we used these data to better understand RSV transmission patterns in New Zealand prior to 2020, and how RSV became re-established in the community following the relaxation of COVID-19 restrictions. We found that in 2021, there was a large epidemic of RSV in New Zealand that affected a broader age group range compared to the usual pattern of RSV infections. This epidemic was due to an increase in RSV importations, leading to several large genomic clusters of both RSV-A ON1 and RSV-B BA9 genotypes in New Zealand. However, while a number of importations were detected, there was also a major reduction in RSV genetic diversity compared to pre-pandemic seasonal outbreaks. These genomic clusters were temporally associated with the increase of migration in 2021 due to quarantine-free travel from Australia at the time. The closest genetic relatives to the New Zealand RSV genomes, when sampled, were viral genomes sampled in Australia during a large, off-season summer outbreak several months prior, rather than cryptic lineages that were sustained but not detected in New Zealand. These data reveal the impact of NPI used during the COVID-19 pandemic on other respiratory infections and highlight the important insights that can be gained from viral genomes.
Genomic epidemiology demonstrates spatially clustered, local transmission ofPlasmodium falciparumin forest-going populations in southern Lao PDR
Authors: Chen Ying-An , Vickers Eric Neubauer , Aranda-Diaz Andres , Murphy Maxwell , Gerlovina Inna , Rerolle Francois , Dantzer Emily , Hongvanthong Bouasy , Chang Hsiao-Han , Lover Andrew A. , Hathaway Nicholas J. , Bennett Adam , Greenhouse Bryan
Published: July 2024

While there has been significant progress in controlling falciparum malaria in the Lao People’s Democratic Republic (PDR), sporadic cases persist in southern provinces where the extent and patterns of transmission remain largely unknown. To assess parasite transmission in this area, 53Plasmodium falciparum(Pf) positive cases detected through active test and treat campaigns from December 2017 to November 2018 were sequenced, targeting 204 highly polymorphic amplicons. Two R packages,MOIREandDcifer, were applied to assess the multiplicity of infections (MOI), effective MOI (eMOI), within-host parasite relatedness, and between-host parasite relatedness (). Genomic data were integrated with survey data to characterize the temporal and spatial structures of identified clusters. The positive cases were mainly captured during the focal test and treat campaign conducted in 2018, and in the Pathoomphone area, which had the highest test positivity and forest activity. About 30% of the cases were polyclonal infections, with over half of theses (63%) showing within-host relatedness greater than 0.6, suggesting that cotransmission rather than superinfection was primarily responsible for maintaining polyclonality. A large majority of cases (81%) were infected by parasites genetically linked to one or more other cases. We identified five genetically distinct clusters in forest fringe villages within the Pathoomphone district, characterized by a high degree of genetic relatedness between parasites (mean= 0.8). Four smaller clusters of 2-3 cases linked Moonlapamok and Pathoomphone districts, with an averageof 0.6, suggesting cross-district transmission. Most of the clustered cases occurred within 20 km and 2 months of each other, consistent with focal transmission. Transmission clusters identified in this study confirm the role of ongoing focal parasite transmission occurring within the forest or forest-fringe in the highly mobile population.

Author summary

In low-transmission settings, integrating genomic data could help capture fine-scale dynamics in circulating parasites that may not be easily detected by traditional surveillance. Our work demonstrates that even with very few malaria cases, incorporating active surveillance and genomic analysis can help track residual transmission pockets and routes, including among highly mobile populations whose infection sources are historically difficult to trace. Transmission clusters identified in this study provided clear evidence of ongoing focal transmission ofPlasmodium falciparumin southern Laos. The addition of high-resolution genomic data to active surveillance can aid in targeting and assessing interventions in similar areas approaching elimination.
Pervasive patterns in the songs of passerine birds resemble human music universals and are linked with production and cognitive mechanisms
Authors: James Logan S , Oudyk Kendra , Wall Erin M , Chen Yining , Pearse William D , Sakata Jon T
Published: July 2024

Music is a complex learned behavior that is ubiquitous among humans, and many musical patterns are shared across geography and cultures (“music universals”). Knowing whether these universals are specific to humans or shared with other animals is important to understand how production-related factors (motor biases and constraints) or cognitive factors (learning) contribute to the emergence of these acoustic patterns. Bird song is often described as an animal analogue of human music, and some studies of individual avian species highlight acoustic similarities between bird song and music. However, expansive and comparative approaches are necessary to identify universal patterns within bird song, reveal mechanisms associated with these patterns, and draw parallels to music universals. Here, we adopt such an approach and analyze the prevalence of acoustic patterns (sequences) across ∼300 species of passerines, spanning both oscines (songbirds; vocal learners) and their sister clade, suboscines (passerines that produce songs that are not learned), as well as within a global corpus of human vocal music. This approach allowed us to directly test hypotheses that phonation mechanisms or vocal learning shape the emergence of universal patterns. We first document acoustic patterns that were widely shared across passerines and similar to music universals (e.g., small pitch intervals), highlighting the role of shared vocal production mechanisms in these patterns. Consistent with a contribution of vocal learning, we observed patterns (e.g., alternation in durations) there were more similar between oscines and humans than between suboscines and humans. Interestingly, we also discovered patterns (e.g., pitch alternation) that were inconsistent with a contribution of vocal learning and were more similar between suboscines and humans than between oscines and humans. This research provides the broadest evidence of shared universals in vocal performance across birds and humans and highlights convergent mechanisms shaping communication patterns.
Excitability modulations of somatosensory perception do not depend on feedforward neuronal population spikes
Authors: Stephani T. , Villringer A. , Nikulin V. V.
Published: July 2024

Neural states shape perception at earliest cortical processing levels. Previous work in humans showed a relationship between initial cortical excitation, as indicated by the N20 component of the somatosensory evoked potential (SEP), pre-stimulus alpha oscillations, and the perceived intensity in a somatosensory discrimination paradigm. Here we address the follow-up question whether these excitability dynamics reflect changes in feedforward or feedback signals. We leveraged high-frequency oscillations (HFO) as a metric for neuronal population spiking activity of the first excitatory feedforward volley in the somatosensory cortex, non-invasively extracted from electroencephalography (EEG) data of 32 male human participants. Using Bayesian statistics, we found evidence against the involvement of HFO in moment-to-moment variability of perceived stimulus intensity, in contrast to previously observed pre-stimulus alpha and N20 effects. Given that the N20 component presumably reflects backpropagating membrane potentials towards the apical dendrites, we argue that top-down feedback processes (e.g., related to alpha oscillations) may thus rely on modulations at distal dendritic sites of involved pyramidal cells rather than on output firing changes at their basal compartments.
CyNET- a network analysis framework for high dimensionality, system level analyses of the functional Immunome
Authors: Kumar Pavanish , Yeo Joo Guan , Poh Su Li , Hazirah Sharifah Nur , Sutamam Nursyuhadah Binte , Ang WX Gladys , Chellamuthu Vasuki Ranjani , Wasser Martin , Thai Yeo Kee , Leong Jing Yao , Ramakrishna Lakshmi , Arkachaisri Thaschawee , Albani Salvatore
Published: July 2024

The immune system is a complex “Network of Networks”, in which various immune cell subsets interact and influence each other’s functions, ultimately determining immune competence and the control or onset of disease. The coordinated interactions between these cell subsets determine whether the outcome is a normal physiological state or a pathological condition. Established statistical procedures largely ignore the interactions between subsets and rely on statistically significant changes in the frequency of cell subsets. We developed CyNET (CytometryNetwork)— an analysis platform based on a network science approach to understand the immune system holistically. CyNET enables us to quantify the systems level and subsets level properties. We show that changes in the centrality of the nodes (immune subsets) reflect better biological functions than changes in frequency. We used CyNET to analyze the immune development along the chronological age gradient. Peripheral blood cells from healthy newborns (cord blood), adults (20 to 55 years), and elderly (70 years and above) human subjects were further used for validation using single-cell transcriptomics. We found that network edge density, degree centralization, and assortativity score reflect the maturation and development of the immune system along the age axis, thus enabling the characterisation of the functional architecture of the Immunome and the identification of key functional hubs within the immune networks.
Unaware Processing of Words Activates Experience-Derived Information in Conceptual-Semantic Brain Networks
Authors: Ghio Marta , Cassone Barbara , Tettamanti Marco
Published: July 2024

The recognition of manipulable objects results from the encoding of sensory input in combination with predictive decoding of experience-derived visuomotor information stored in conceptual-semantic representations. This grounded interpretive processing was previously found to subsist even under unaware perception of manipulable object pictures. In this fMRI study, we first aimed to extend this finding by testing whether experientially grounded visuomotor representations are unawarely recruited when manipulable objects are not visually depicted, but only referred to by words presented subliminally through continuous flash suppression. Second, we assessed the generalizability of decoding experience-derived conceptual information to other semantic categories, by extending our investigation to subliminally presented emotion words and testing for unaware recruitment of grounded emotion representations in the limbic system. Univariate analysis of data sampled from 21 human participants (14 females) showed that manipulable object words selectively activated a left-lateralized visuomotor network, both when words were presented below perceptual threshold and when participants subjectively reported lack of stimulus awareness. Emotion words selectively engaged the bilateral limbic network, although univariate analysis did not provide evidence for its recruitment under subliminal perceptual conditions. In turn, multivariate pattern analysis showed that neural codes associated with both manipulable object and emotion words could be decoded even in the absence of perceptual awareness. These findings suggest that the brain automatically engages in conceptual-semantic decoding of experience-derived information not only when circumstances require to interact with manipulable objects and emotions, but also when these referents are dislocated in time and space and only referred to by words.
Deciphering binding site conformational variability of substrate promiscuous and specialist enzymes
Authors: Thakur Deeksha , Verma Paras , Pandit Shashi Bhushan
Published: July 2024

Substrate promiscuity is the ability of enzymes to catalyze reactions with alternate substrate(s) beyond their physiologically relevant ones. Such promiscuous activities expand enzymes functional landscape, enabling evolution or designing novel biochemical reactions. The molecular basis of substrate promiscuity remains elusive, though previous studies have suggested roles of active site structural features, such as flexibility, hydrophobicity, sub-sites, and electrostatics. Moreover, a recent hypothesis proposes the role of active site conformational variability in promiscuity. Accordingly, promiscuous enzymes could accommodate alternate substrate(s) through their pre-existing conformations, whereas specialists have a dominant conformation for their native substrates. To explore the role of active site conformational flexibility in substrate promiscuity, we compared the conformational states of two substrate promiscuous and specialist enzymes by analyzing their binding site structural dynamics from long-time explicit solvent molecular dynamics. Using tICA, we generated conformational states from simulations of the holo-conformation of enzymes. In addition to visual analysis of the variability of binding site conformation states, we performed quantitative estimation of the same using the native functionality score, which measures the contact similarity of conformations to the native structure. We observed that both specialist and generalist enzymes exhibited varied numbers of substrate binding site competent states, indicating that conformational flexibility to accept alternate substrates could exist in both groups of enzymes. Further, it caters to the view of substrate promiscuity as a continuum feature of enzymes.
Modeling causal signal propagation in multi-omic factor space with COSMOS
Authors: Dugourd Aurelien , Lafrenz Pascal , Mañanes Diego , Paton Victor , Fallegger Robin , Kroger Anne-Claire , Turei Denes , Shtylla Blerta , Saez-Rodriguez Julio
Published: July 2024

Understanding complex diseases requires approaches that jointly analyze omic data across multiple biological layers, including signaling, gene regulation, and metabolism. Existing data-driven multi-omic analysis methods, such as multi-omic factor analysis (MOFA), can identify associations between molecular features and phenotypes, but they are not designed to integrate existing mechanistic molecular knowledge, which can provide further actionable insights. We introduce an approach that connects data-driven analysis of multi-omic data with systematic integration of mechanistic prior knowledge using COSMOS+ (Causal Oriented Search of Multi-Omics Space). We show how factor analysis’ output can be used to estimate activities of transcription factors and kinases as well as ligand-receptor interactions, which in turn are integrated with network-level prior-knowledge to generate mechanistic hypotheses about paths connecting deregulated molecular features. Our approach offers an interpretable framework to generate actionable insights from multi-omic data particularly suited for high dimensional datasets such as patient cohorts.

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Oxytocin facilitates social behavior of female rats via selective modulation of interneurons in the medial prefrontal cortex
Authors: Schimmer Stephanie , Lefevre Arthur , Lebedeva Julia , Rozov Andrey , Kania Alan , Raftogianni Androniki , Afordakos Konstantinos , Tiwari Rishika , Netser Shai , Patwell Ryan , Hefter Dimitri , Boender Arjen , Podpecan Yuval , Schubert Tim , Sanetra Anna , Trenk Aleksandra , Gugula Anna , Hurlemann Rene , Althammer Ferdinand , Blasiak Anna , Melzer Sarah , Monyer Hannah , Wagner Shlomo , Eliava Marina , Grinevich Valery
Published: July 2024

The hypothalamic neuropeptide oxytocin is best known for its prosocial behavioral effects. However, the precise anatomical and cellular targets for oxytocin in the cortex during social behavior remain elusive. Here we show that oxytocin neurons project directly to the medial prefrontal cortex where evoked axonal oxytocin release facilitates social behaviors in adult female rats. In conjunction, we report that local oxytocin receptor (OTR+) expressing cells are predominantly interneurons whose activation promotes social interaction. In particular, in a state of food deprivation, this inhibitory neuronal subpopulation shifts the preference from appetitive food stimuli towards a social stimulus. We further demonstrate that activation of these OTR+interneurons inhibits principal cells specifically projecting to the basolateral amygdala, thus providing a putative mechanism of selective oxytocin action in this sociability promoting cortical network.
SlNAP2promoted fruit ripening by directly binding theACS2promoter and interacting withEIL3
Authors: Wu Xuetong , Fang Hua , Huang Dengjing , Hou Xuemei , Qiao Yali , Li Changxia , Li Ailing , Huang Yi , Zhang Zhongxing , Liu Zhiya , Liu Yayu , Liao Weibiao
Published: July 2024

The ripening process of tomato fruit is affected by a variety of environmental factors and genetic regulators. NAC transcription factors (TFs) function in a multitude of biological processes, while the current knowledge on the participation of NAC TFs in the regulatory network of fruit ripening is relatively limited. In this study, we isolated a NAC TFs, NAP2, which acts as a positive transcription activator in tomato fruit ripening. We also observed a notable delay in the ripening process ofSlNAP2silenced and knockout mutant fruit. In particular, ethylene production was obviously inhibited inSlNAP2mutant fruit. Y1H and DLR assays showed that SlNAP2 directly binds to the promoter ofSlACS2and activates its transcriptional activity. Furthermore, SlNAP2 and SlEIL3 physically interaction was demonstrated by yeast two-hybrid (Y2H), luciferase complementation (LUC), bimolecular fluorescence complementation (BiFC) and coimmunoprecipitation analysis (CoIP) assays. Meanwhile, the pigment content, firmness and the transcript levels of genes associated with carotenoid and chlorophyll metabolism and cell wall metabolism were also potentially affected by theSlNAP2deletion; however, it has remained unclear whether these genes are also directly regulated bySlNAP2. Therefore, our findings indicate that SlNAP2 directly binds toSlACS2promoter to activate its expression and promote ethylene generation, which in turn interacts with EIL3 to enhance the function of ethylene in tomato fruit ripening. Collectively, our data contribute to understanding the interaction of NAC TFs and ethylene in tomato fruit ripening, thereby enhancing our knowledge of the ripening regulatory network that governs tomato fruit maturation.