bluuebunny/crossref_metadata_2025 huggingface dataset:
Mpox Virus is Inhibited By Nucleoside Analogues Including the Acyclic Phosphonates Tenofovir and Adefovir
Authors: Lee Jasper , Boggs Emerson Ailidh , Zhang Huanchun , Tedbury Philip R. , Sarafianos Stefan G.
Published: July 2023

Mpox virus (MPXV) is an orthopoxvirus that causes the human disease mpox, which is characterized by fever, myalgia, and formation of rashes and lesions, and which garnered worldwide attention due to a global outbreak in 2022. In response to the outbreak, the antivirals tecovirimat, cidofovir, and brincidofovir have been used as emergency treatment for mpox. However, because of drug resistance and toxicity risks with those compounds, there is still a need for additional antivirals to treat orthopoxvirus diseases. Since cidofovir is a nucleoside analogue, we investigated a selection of other such compounds for antiviral activity against orthopoxviruses. We developed in vitro screening assays using fluorescent strains of vaccinia virus (VACV) and modified vaccinia Ankara (MVA) to measure the antiviral potency of test compounds. We found that tenofovir alafenamide and adefovir dipixovil, both acyclic phosphonates, had strong potential combinations of anti-orthopoxvirus activity and low toxicity after testing them against MVA and VACV, with EC50values in the single digit micromolar and nanomolar range, while other potential hits included trifluridine and two arabinosides. We then recapitulated the results with MPXV using a luciferase-based assay. These data reinforce the interest of repurposing nucleoside analogues as antivirals to treat poxvirus infections and provide a basis for high throughput screening and mechanistic and antiviral resistance studies.
Initial and corrective submovement encoding differences within primary motor cortex during precision reaching
Authors: Schwartze Kevin C , Lee Wei-Hsien , Rouse Adam G
Published: July 2023

Precision reaching tasks often require corrective submovements for successful completion. Most studies of reaching have focused on single initial movements, and the cortical encoding model was implied to be the same for all submovements. However, corrective submovements may show different encoding patterns from the initial submovement with distinct patterns of activation across the population. Two rhesus macaques performed a precision center-out-task with small targets. Neural activity from single units in primary motor cortex and associated behavioral data were recorded to evaluate movement characteristics. Neural population data and individual neuronal firing rates identified with a peak finding algorithm to identify peaks in hand speed were examined for encoding differences between initial and corrective submovements. Individual neurons were fitted with a regression model that included the reach vector, position, and speed to predict firing rate. For both initial and corrective submovements, the largest effect remained movement direction. We observed a large subset changed their preferred direction greater than 45° between initial and corrective submovements. Neuronal depth of modulation also showed considerable variation when adjusted for movement speed. By utilizing principal component analysis, neural trajectories of initial and corrective submovements progressed through different neural subspaces. These findings all suggest that different neural encoding patterns exist for initial and corrective submovements within the cortex. We hypothesize that this variation in how neurons change to encode small, corrective submovements might allow for a larger portion of the neural space being used to encode a greater range of movements with varying amplitudes and levels of precision.

New and Noteworthy

Neuronal recordings matched with kinematic behavior were collected in a precision center-out task that often required corrective movements. We reveal large differences in preferred direction and depth of modulation between initial and corrective submovements across the neural population. We then present a model of the neural population describing how these shifts in tuning create different subspaces for signaling initial and corrective movements likely to improve motor precision.
Contrasting carbon cycle along tropical forest aridity gradients in W Africa and Amazonia
Authors: Zhang-Zheng Huanyuan , Bredu Stephen Adu , Duah-Gyamfi Akwasi , Moore Sam , Addo-Danso Shalom D. , Ibrahim Forzia , Amissah Lucy , Valentini Riccardo , Djagbletey Gloria , Anim-Adjei Kelvin , Owusu-Afriyie Kennedy , Gvozdevaite Agne , Ruiz-Jaen Maria C. , Girardin Cécile A.J. , Rifai Sami , Dahlsjö Cecilia , Riutta Terhi , Deng Xiongjie , Tang Minxue , Sun Yuheng , Prentice Iain Colin , Menor Imma Oliveras , Malhi Yadvinder
Published: July 2023

2

Tropical forests cover large areas of equatorial Africa and play a significant role in the global carbon cycle. However, there has been a lack of in-situ measurements to understand the forests’ gross and net primary productivity (GPP and NPP) and their allocation. Here we present the first detailed field assessment of the carbon budget of multiple forest sites in Africa, by monitoring 14 one-hectare plots along an aridity gradient in Ghana. When compared with an equivalent aridity gradient in Amazonia using the same measurement protocol, the studied West African forests generally had higher GPP and NPP and lower carbon use efficiency (CUE). The West African aridity gradient consistently shows the highest NPP, CUE, GPP, and autotrophic respiration at a medium-aridity site, Bobiri. Notably, NPP and GPP of the site are the highest yet reported anywhere in the tropics using similar methods. Widely used data products (MODIS and FLUXCOM) substantially underestimate productivity when compared toin situmeasurements, in Amazonia and especially in Africa. Our analysis suggests that the high productivity of the African forests is linked to their large GPP allocation to canopy and semi-deciduous characteristics, which may be a result of a seasonal climate coupled with high soil fertility.
Distinct genetic origins of eumelanin intensity and barring patterns in cichlid fishes
Authors: Brandon A. Allyson , Michael Cassia , Baez Aldo Carmona , Moore Emily C. , Ciccotto Patrick J. , Roberts Natalie B. , Roberts Reade B. , Powder Kara E.
Published: July 2023

Pigment patterns are incredibly diverse across vertebrates and are shaped by multiple selective pressures from predator avoidance to mate choice. A common pattern across fishes, but for which we know little about the underlying mechanisms, is repeated melanic vertical bars. In order to understand genetic factors that modify the level or pattern of vertical barring, we generated a genetic cross of 322 F2hybrids between two cichlid species with distinct barring patterns,Aulonocara koningsiandMetriaclima mbenjii. We identify 48 significant quantitative trait loci that underlie a series of seven phenotypes related to the relative pigmentation intensity, and four traits related to patterning of the vertical bars. We find that genomic regions that generate variation in the level of eumelanin produced are largely independent of those that control the spacing of vertical bars. Candidate genes within these intervals include novel genes and those newly-associated with vertical bars, which could affect melanophore survival, fate decisions, pigment biosynthesis, and pigment distribution. Together, this work provides insights into the regulation of pigment diversity, with direct implications for an animal’s fitness and the speciation process.
The domed architecture ofGiardia’s ventral disc is necessary for attachment and host pathogenesis
Authors: Hagen KD , Nosala C , Hilton NA , Müller A , Holthaus D , Laue M , Klotz C , Aebisher A , Dawson SC
Published: July 2023

After ingestion of dormant cysts, the widespread protozoan parasiteGiardia lambliacolonizes the host gastrointestinal tract via direct and reversible attachment using a novel microtubule organelle, the ventral disc. Extracellular attachment to the host allows the parasite to resist peristaltic flow, facilitates colonization and is proposed to cause damage to the microvilli of host enterocytes as well as disrupt host barrier integrity. The 9 µm in diameter ventral disc is defined by a highly complex architecture of unique protein complexes scaffolded onto a spiral microtubule (MT) array of one hundred parallel, uniformly spaced MT polymers that bend approximately one and a quarter turns to form a domed structure. To investigate the role of disc-mediated attachment in causing epithelial cell damage, we used a new approach to rapidly create a stable quadruple knockout ofGiardiaof an essential ventral disc protein, MBP, using a new method of CRISPR-mediated gene disruption with multiple positive selectable markers. MBP quadruple KO mutant discs lack the characteristic domed architecture and possess a flattened “crescent” or horseshoe-shaped conformation that lacks the overlapping region, with severe defects in the microribbon-crossbridge (MR-CB) complex structure. MBP KO mutants are also unable to resist fluid flow required for attachment to inert surfaces. Importantly, MBP KO mutants have 100% penetrance off positive selection, which is essential for quantification ofin vivoimpacts of disc and attachment mutants with host cells. Using a new gastrointestinal organoid model of pathogenesis, we found that MBP KO infections had a significantly reduced ability to cause the barrier breakdown characteristic of wild-type infections. Overall, this work provides direct evidence of the role of MBP in creating the domed disc, as well as the first direct evidence that parasite attachment is necessary for host pathology, specifically epithelial barrier breakdown.
APOBEC3 activity promotes the survival and evolution of drug-tolerant persister cells during acquired resistance to EGFR inhibitors in lung cancer
Authors: Garcia Nina Marie G. , Becerra Jessica N. , McKinney Brock J. , DiMarco Ashley V. , Wu Feinan , Fitzgibbon Matthew , Alvarez James V.
Published: July 2023

APOBEC mutagenesis is one of the most common endogenous sources of mutations in human cancer and is a major source of genetic intratumor heterogeneity. High levels of APOBEC mutagenesis are associated with poor prognosis and aggressive disease across diverse cancers, but the mechanistic and functional impacts of APOBEC mutagenesis on tumor evolution and therapy resistance remain relatively unexplored. To address this, we investigated the contribution of APOBEC mutagenesis to acquired therapy resistance in a model of EGFR-mutant non-small cell lung cancer. We find that inhibition of EGFR in lung cancer cells leads to a rapid and pronounced induction of APOBEC3 expression and activity. Functionally, APOBEC expression promotes the survival of drug-tolerant persister cells (DTPs) following EGFR inhibition. Constitutive expression of APOBEC3B alters the evolutionary trajectory of acquired resistance to the EGFR inhibitor gefitinib, making it more likely that resistance arises throughde novoacquisition of the T790M gatekeeper mutation and squamous transdifferentiation during the DTP state. APOBEC3B expression is associated with increased expression of the squamous cell transcription factor ΔNp63 and squamous cell transdifferentiation in gefitinib-resistant cells. Knockout of p63 in gefitinib-resistant cells reduces the expression of the ΔNp63 target genes IL1α/β and sensitizes these cells to the third-generation EGFR inhibitor osimertinib. These results suggest that APOBEC activity promotes acquired resistance by facilitating evolution and transdifferentiation in DTPs, and suggest that approaches to target ΔNp63 in gefitinib-resistant lung cancers may have therapeutic benefit.
High prevalence of hypertension and high-normal blood pressure: findings from a large population-based survey of young adults in Zimbabwe
Authors: Sabapathy Kalpana , Mwita Fredrick Cyprian , Dauya Ethel , Bandason Tsitsi , Simms Victoria , Dziva Chikwari Chido , Doyle Aoife M , Ross David , Shah Anoop , Hayes Richard , Schutte Aletta E , Kranzer Katharina , Ferrand Rashida Abbas
Published: July 2023

Background

Most cardiovascular mortality is due to hypertension and onset may be in youth. We investigated the prevalence of and risk factors for elevated blood pressure (BP) (hypertension (≥140/90mmHg) and high-normal BP (130-139/85-89mmHg)) among youth in Zimbabwe.

Methods

A population-based survey of randomly sampled 18-24 year olds from 24 communities in three provinces was conducted, with standardised questionnaires to collect socio-demographic, behavioural and clinical data. Height, weight and BP were recorded. The association of potential risk factors with elevated BP was examined using multivariable logistic regression.

Findings

Of 17,682 participants recruited (98% of those eligible), 17,637 had complete data. The median age was 20 (IQR: 19-22) years and 60.7% were female. After excluding pregnant women (N=754), the prevalence of hypertension and high-normal BP was 7.4% (95% CI:7.0-7.8) and 12.2% (95% CI:12.7-13.7), respectively. Prevalence of hypertension was higher in men (8.7% (95% CI:8.2-9.6) vs 6.6% (95% CI:6.0-6.9) in men and women, respectively) but with age increased to equivalent levels among women (at 18y 7.3% (95% CI:6.2-8.6) and 4.3% (95% CI:3.5-5.2); at 23-24 years 10.9% (95% CI:9.3-12.5) and 9.50% (95% CI:8.4-10.7) in men and women, respectively). After adjusting for confounders, male sex ((aOR) 1.53 (95% CI:1.36-1.74)), increasing age (19-20 years aOR:1.20 (1.00-1.44); 21-22 years aOR:1.45 (95% CI 1.20-1.75); 23-24 years aOR 1.90 (95% CI:1.57-2.30), vs 18 years) and obesity (aOR 1.94 (95% CI:1.53-2.47)) were associated with hypertension. Being underweight (aOR 0.79 (0.63-0.98)) and living with HIV (aOR 0.71 (95% CI:0.55-0.92)) were associated with lower odds of hypertension.

Interpretation

Prevalence of elevated BP is high among youth in SSA and rises rapidly with age. Further research is needed to understand drivers of BP elevation and the extent of target organ damage in youth in SSA, to guide implementation of prevention and management strategies.

Funding

Wellcome Trust.
Herpesvirus infections eliminate safeguards against breast cancer and its metastasis: comparable to hereditary breast cancers
Authors: Friedenson Bernard
Published: July 2023

Breast cancer has no simple explanation. I tested the hypothesis that Epstein-Barr (EBV) infections promote the disease because they disable breast cancer safeguards. I used bioinformatics of public information from approximately 2100 breast cancers. Results demonstrate that chromosome breakpoints in breast and ovarian cancer cluster around the same breakpoints in diverse EBV-associated cancers. Cancers unrelated to EBV do not have these clusters. Breast cancers overexpress a methylation signature caused by active EBV infection. EBV remnants interspace between MHC genes and piRNA clusters as CRISPR- like evidence of past infection. I then found breast cancer breakpoints cluster around EBV docking sites. This clustering occurs because EBV breaks chromosomes and then damages breast cancers safeguards: BRCA1/2 pathways, SMC5/6, and mitotic controls. Finally, EBV causes the same losses that drive breast cancer metastasis. Activated EBV bypasses all these safeguards without large numbers of particles or continuing presence. Immunizing against EBV proteins may prevent breast, ovarian, and other cancers.

Human papilloma virus promotes cervical cancer because it disables tumor suppressors. EBV in breast cancer resembles this model. EBV variants disable a variety of molecular and cellular safeguards that protect against breast cancer.
GroEL-proteotyping of bacterial communities by tandem mass spectrometry
Authors: Klaes Simon , Madan Shobhit , Deobald Darja , Cooper Myriel , Adrian Lorenz
Published: July 2023

Profiling bacterial populations in mixed communities is a common task in microbiology. 16SrRNA-based sequencing is a widely accepted and functional approach but relies on amplification primers and cannot quantify isotope incorporation. Tandem mass spectrometry proteotyping is an effective alternative for taxonomically profiling microorganisms. We suggest that targeted proteotyping approaches can complement traditional population analyses. Therefore, we describe an approach to assess bacterial community compositions at the family level using the taxonomic marker protein GroEL, which is ubiquitously found in bacteria, except few obligate intracellular species. We refer to our method as GroEL-proteotyping. GroEL-proteotyping is based on high-resolution tandem mass spectrometry of GroEL peptides and identification of GroEL-derived taxa via a Galaxy workflow and a subsequent Python-based analysis script. Its advantage is that it can be performed with a curated and extendable sample-independent database and that GroEL can be pre-separated by SDS-PAGE to reduce sample complexity, improving GroEL identification while simultaneously decreasing the instrument time. GroEL-proteotyping was validated by employing it on a comprehensive raw data set obtained through a metaproteome approach from synthetic microbial communities as well as real human gut samples. Our data show that GroEL-proteotyping enables fast and straightforward profiling of highly abundant taxa in bacterial communities at reasonable taxonomic resolution.
Modulation of alpha oscillations by attention is predicted by hemispheric asymmetry of subcortical regions
Authors: Ghafari Tara , Mazzetti Cecilia , Garner Kelly , Gutteling Tjerk , Jensen Ole
Published: July 2023

Evidence suggests that subcortical structures play a role in high-level cognitive functions such as the allocation of spatial attention. While there is abundant evidence in humans for posterior alpha band oscillations being modulated by spatial attention, little is known about how subcortical regions contribute to these oscillatory modulations, particularly under varying conditions of cognitive challenge. In this study, we combined MEG and structural MRI data to investigate the role of subcortical structures in controlling the allocation of attentional resources by employing a cued spatial attention paradigm with varying levels of perceptual load. We asked whether hemispheric lateralization of volumetric measures of the thalamus and basal ganglia predicted the hemispheric modulation of alpha-band power. Lateral asymmetry of the globus pallidus, caudate nucleus, and thalamus predicted attention-related modulations of posterior alpha oscillations. When the perceptual load was applied to the target and the distractor was salient caudate nucleus asymmetry predicted alpha-band modulations. Globus Pallidus was predictive of alpha-band modulations when either the target had a high load, or the distractor was salient, but not both. Finally, the asymmetry of the thalamus predicted alpha band modulation when neither component of the task was perceptually demanding. In addition to delivering new insight into the subcortical circuity controlling alpha oscillations with spatial attention, our finding might also have clinical applications. We provide a framework that could be followed for detecting how structural changes in subcortical regions that are associated with neurological disorders can be reflected in the modulation of oscillatory brain activity.
HumanHPSE2gene transfer ameliorates bladder pathophysiology in a mutant mouse model of urofacial syndrome
Authors: Lopes Filipa M. , Grenier Celine , Jarvis Benjamin W. , Mahdy Sara Al , Lène-McKay Adrian , Gurney Alison M. , Newman William G. , Waddington Simon N. , Woolf Adrian S. , Roberts Neil A.
Published: July 2023

Rare early onset lower urinary tract disorders include defects of functional maturation of the bladder. Current treatments do not target the primary pathobiology of these diseases. Some have a monogenic basis, such as urofacial, or Ochoa, syndrome (UFS). Here, the bladder does not empty fully because of incomplete relaxation of its outflow tract, and subsequent urosepsis can cause kidney failure. UFS is associated with biallelic variants ofHPSE2, encoding heparanase-2. This protein is detected in pelvic ganglia, autonomic relay stations that innervate the bladder and control voiding. Bladder outflow tracts ofHpse2mutant mice display impaired neurogenic relaxation. We hypothesized thatHPSE2gene transfer soon after birth would ameliorate this defect and explored an adeno-associated viral (AAV) vector-based approach.AAV9/HPSE2,carrying humanHPSE2driven byCAG, was administered intravenously into neonatal mice. In the third postnatal week, transgene transduction and expression were sought, andex vivomyography was undertaken to measure bladder function. In mice administeredAAV9/HPSE2, the viral genome was detected in pelvic ganglia. HumanHPSE2was expressed and heparanase-2 became detectable in pelvic ganglia of treated mutant mice. On autopsy, wild-type mice had empty bladders whereas bladders were uniformly distended in mutant mice, a defect ameliorated byAAV9/HPSE2treatment. Therapeutically,AAV9/HPSE2significantly ameliorated impaired neurogenic relaxation ofHpse2mutant bladder outflow tracts. Impaired neurogenic contractility of mutant detrusor smooth muscle was also significantly improved. These results constitute first steps towards curing UFS, a clinically devastating genetic disease featuring a bladder autonomic neuropathy.

In the first gene therapy for genetic bladder disease, we cured autonomic neurons using AAV-mediated gene delivery in a mouse model of urofacial syndrome.
Phage therapy minimally affects the water microbiota in an Atlantic salmon (Salmo salar) rearing system while still preventing infection
Authors: Fiedler Alexander W. , Gundersen Madeleine S. , Vo Toan P. , Almaas Eivind , Vadstein Olav , Bakke Ingrid
Published: July 2023

Excessive usage of antibiotics threatens the bacterial diversity in the microbiota of animals. An alternative to antibiotics that has been suggested to not disturb the microbiota is (bacterio)phage therapy. In this study, we challenged germ-free and microbially colonized yolk sac fry of Atlantic salmon withFlavobacterium columnareand observed that the mere presence of a microbiota protected the fish against lethal infection. We then investigated the effect of phage-or oxytetracycline treatment on fish survival and rearing water bacterial community characteristics using 16S rRNA gene amplicon sequencing. Phage treatment led to an increased survival ofF. columnare-challenged fish and reduced the relative amounts of the pathogen in the water microbiota. In the absence ofF. columnare, phage treatment did not affect the composition or the α-diversity of the rearing water microbiota. In the presence of the phage’s host, phage treatment induced minor changes to the bacterial community composition, without affecting the α-diversity. Surprisingly, oxytetracycline treatment had no observable effect on the water microbiota and did not reduce the relative abundance ofF. columnarein the water. In conclusion, we showed that phage treatment prevents mortality while not negatively affecting the rearing water microbiota, thus suggesting that phage treatment may be a suitable alternative to antibiotics. We also demonstrated a protective effect of the microbiota in Atlantic salmon yolk sac fry.
A Novel Humanized Immune Stroma PDX Cancer Model for Therapeutic Studies
Authors: Yang Dongli , Beddows Ian , Tang Huijuan , Cascio Sandra , McGonigal Stacy C. , Bai Shoumei , Johnson Benjamin K. , Powers John J. , Acharya Rajesh , Bao Riyue , Bruno Tullia C. , Soong Thing R. , Conejo-Garcia Jose R. , Shen Hui , Bility Moses T. , Buckanovich Ronald J.
Published: July 2023

Standard preclinical human tumor models lack a human tumor stroma. However, as stroma contributes to therapeutic resistance, the lack of human stroma may make current models less stringent for testing new therapies. To address this, using patient-derived tumor cells, patient derived cancer-associated mesenchymal stem/progenitor cells, and human endothelial cells, we created a Human Stroma-Patient Derived Xenograft (HS-PDX) tumor model. HS-PDX, compared to the standard PDX model, demonstrate greater resistance to targeted therapy and chemotherapy, and better reflect patient response to therapy. Furthermore, HS-PDX can be grown in mice with humanized bone marrow to create humanized immune stroma patient-derived xenograft (HIS-PDX) models. The HIS-PDX model contains human connective tissues, vascular and immune cell infiltrates. RNA sequencing analysis demonstrated a 94-96% correlation with primary human tumor. Using this model, we demonstrate the impact of human tumor stroma on response to CAR-T cell therapy and immune checkpoint inhibitor therapy. We show an immunosuppressive role for human tumor stroma and that this model can be used to identify immunotherapeutic combinations to overcome stromally mediated immunosuppression. Combined, our data confirm a critical role for human stoma in therapeutic response and indicate that HIS-PDX can be an important tool for preclinical drug testing.

Statement of Significance

We developed a tumor model with human stromal, vascular, and immune cells. This model mirrors patient response to chemotherapy, targeted therapy, and immunotherapy, and can be used to study therapy resistance.
Mechanical Force Imprints Neutrophils to Orchestrate Pulmonary Homeostasis
Authors: Wang Jin , Kang Haixia , Zhao Wenying , Bai Wenjuan , Qi Xin , Yan Kepeng , Miao Naijun , Dong Dong , Wang Yuanyuan , Thanabalasuriar Ajitha , Zhang Dachuan , Ye Youqiong , Xu Tian-le , Li Bin , Wang Jing
Published: July 2023

Neutrophils are the most abundant immune cells that constantly patrol and marginate into the vascular beds of multiple tissues to support immune homeostasis. The extent to which neutrophils undergo adaptation in response to diverse tissue microenvironments, and the resultant biological implications of such adaptation, remains unclear. Here, we performed intravital imaging, transcriptional, and functional analyses of neutrophils in different tissues. Our findings showed that the lung harbors a transcriptionally distinct neutrophil population with unique migratory behaviors. These resident-like neutrophils guarantee a rapid response upon infection and play an important role in maintaining the homeostasis of pulmonary vasculature. Notably, pulmonary neutrophils are imprinted by mechanical cues via the mechanosensitive ion channel Piezo1. Mice with conditional Piezo1 ablation lost lung-specific neutrophil signatures, and showed impaired lung capillary angiogenesis. Furthermore, these mice displayed increased susceptibility to airway infection. Collectively, these data identify mechanical sensing via Piezo1 as an important driver for tissue-specialized neutrophils that support pulmonary homeostasis.
Genome-wide transformation reveals extensive exchange across closely relatedBacillusspecies
Authors: Förster Mona , Rathmann Isabel , Yüksel Melih , Power Jeffrey J. , Maier Berenike
Published: July 2023

Bacterial transformation is an important mode of horizontal gene transfer that helps spread genetic material across species boundaries. Yet, the factors that pose barriers to genome-wide cross-species gene transfer are poorly characterized. Here, we develop a replacement accumulation assay to study the effects of genomic distance on transfer dynamics. UsingBacillus subtilisas recipient and various species of the genusBacillusas donors, we find that the rate of orthologous replacement decreases exponentially with the divergence of their core genomes. We reveal that at least 96 % of theB. subtiliscore genes are accessible to replacement by alleles fromBacillus spizizenii. For the more distantly relatedBacillus atrophaeus, gene replacement events cluster at genomic locations with high sequence identity and preferentially replace ribosomal genes. Orthologous replacement also creates mosaic patterns between donor and recipient genomes, rearranges the genome architecture, and governs gain and loss of accessory genes. We conclude that cross-species gene transfer is dominated by orthologous replacement of core genes which occurs nearly unrestricted between closely related species. At a lower rate, the interplay between the core and accessory genomes gives rise to more complex genome dynamics.
A densely sampled and richly annotated acoustic dataset from a wild bird population
Authors: Recalde Nilo Merino , Estandía Andrea , Pichot Loanne , Vansse Antoine , Cole Ella F. , Sheldon Ben C.
Published: July 2023

We present a high-resolution, densely-sampled dataset of wild bird songs collected over multiple years from a single population of Great Tits (Parus major) in the UK. The dataset includes over 1,100,000 individual acoustic units from 109,963 richly annotated songs, sung by more than 400 individual birds, and provides unprecedented detail on the vocal behaviour of wild birds. Here, we describe the data collection and processing procedures and provide a summary of the data. We also discuss potential research questions that can be addressed using this dataset, including behavioural repeatability and stability, links between vocal performance and reproductive success, the timing of song production, syntactic organisation of song production, and song learning in the wild. We have made the dataset and associated software tools publicly available with the aim that other researchers can benefit from this resource and use it to further our understanding of bird vocal behaviour in the wild.
Polymodal sensory perception of mechanical and chemical cues drives robust settlement and metamorphosis of a marine pre-vertebrate zooplanktonic larva
Authors: Hoyer Jorgen , Kolar Kushal , Athira Athira , Burgh Meike van den , Dondorp Daniel , Liang Zonglai , Chatzigeorgiou Marios
Published: July 2023

The Earth’s oceans brim with an incredible diversity of microscopic planktonic animals, many of which correspond to the transient larval stage in the life cycles of benthic marine organisms. The mechanisms by which marine larvae use their nervous system to sense and process diverse environmental cues (physical and chemical) in the water column and the benthos to settle and metamorphose is a major problem across the fields of neuroscience, development, evolution and ecology, yet they remain largely unclear.

Here, we employ Ca2+imaging and behavioral assays using the larval form of the protochordateCiona intestinalisto characterise the mechanical and chemical stimuli these larvae respond to during settlement and metamorphosis. We also identify the polymodal sensory cells that detect these stimuli. Whole brain Ca2+imaging further revealed that the presentation or removal of ethological chemosensory stimuli engages the activities of different neuronal sub-populations resulting in brain state changes, which may underlie behavioral action selections and metamorphosis. Finally, chemogenetic interrogation coupled to behavioral analysis reveals that peptidergic sensory neurons including polymodal cells capable of chemotactile perception and chemosensory/neurosecretory cells of proto-placodal ectoderm origin play a pivotal role in regulating stimulus induced settlement and metamorphosis. This work suggests that marine zooplanktonic larvae utilise their streamlined nervous systems to perform multimodal integration of ethologically physical and chemical cues to explore the oceanic water column and benthos.
Efficient numerosity estimation under limited time
Authors: Heng Joseph A. , Woodford Michael , Polania Rafael
Published: July 2023

The ability to rapidly estimate non-symbolic numerical quantities is a well-conserved sense across species with clear evolutionary advantages. Despite its importance, the rapid representation and estimation of numerosity is surprisingly imprecise and biased. However, a formal explanation for this seemingly irrational behavior remains unclear. We develop a unified normative theory of numerosity estimation that parsimoniously incorporates in a single framework information processing constraints alongside Brownian diffusion noise to capture the effects of time exposure of sensory estimations, logarithmic encoding of numerosity representations, and optimal inference via Bayesian decoding. We show that for a given allowable biological capacity constraint our model naturally endogenizes time perception during noisy efficient encoding to predict the complete posterior distribution of numerosity estimates. This model accurately predicts many features of human numerosity estimation as a function of temporal exposure, indicating that humans can rapidly and efficiently sample numerosity information over time. Additionally, we demonstrate how our model fundamentally differs from a thermodynamically-inspired formalization of bounded rationality, where information processing is modeled as acting to shift away from default states. The mechanism we propose is the likely origin of a variety of numerical cognition patterns observed in humans and other animals.

Author summary

Humans have the ability to estimate the number of elements in a set without counting. We share this ability with other species, suggesting that it is evolutionarily relevant. However, despite its relevance, this sense is variable and biased. What is the origin of these imprecisions? We take the view that they are the result of an optimal use of limited neural resources. Because of these limitations, stimuli are encoded with noise. The observer then optimally decodes these noisy representations, taking into account its knowledge of the distribution of stimuli. We build on this view and incorporate stimulus presentation time (or contrast) directly into the encoding process using Brownian motion. This model can parsimoniously predict key characteristics of our perception and outperforms quantitatively and qualitatively a popular modeling approach that considers resource limitations at the stage of the response rather than the encoding.
“In silicocharacterization of Protein L-Iso-Aspartate-O-Methyltransferases (PIMT) ofShigella flexneri”
Authors: Gupta Akanksha , Mardi Pragati , Saumya  , Mishra Prasanta Kumar K.
Published: July 2023

There are only a few protein repair enzymes known. One of them, Protein Iso-Aspartate Methyltransferases (PIMT), also known as Protein Carboxyl Methyltransferases (PCMT), is responsible for converting Iso-Aspartate (abnormal amino acid residues) to Aspartate (normal amino acid residues). PCMT is an enzyme found in a wide range of living organisms. In the present study, the amino acid sequence of PIMT ofShigella flexneriwas retrieved and the 3D structure is predicted. Further, it is characterized byin silicoapproaches and its interaction with one of the target proteinsi. e. rpoS is studied.
Structure-guided engineering of biased-agonism in the human niacin receptor via single amino acid substitution
Authors: Yadav Manish K. , Sarma Parishmita , Ganguly Manisankar , Mishra Sudha , Maharana Jagannath , Zaidi Nashrah , Dalal Annu , Singh Vinay , Saha Sayantan , Mahajan Gargi , Sharma Saloni , Chami Mohamed , Banerjee Ramanuj , Shukla Arun K.
Published: July 2023

The Hydroxycarboxylic acid receptor 2 (HCA2), also known as the niacin receptor or GPR109A, is a prototypical G protein-coupled receptor that plays a central role in the inhibition of lipolytic and atherogenic activities in our body. Interestingly, GPR109A activation also results in vasodilation that is linked to the side-effect of flushing associated with dyslipidemia drugs such as niacin. This receptor continues to be a key target for developing novel pharmacophores and lead compounds as potential therapeutics in dyslipidemia with minimized flushing response, however, the lack of structural insights into agonist-binding and receptor activation has limited the efforts. Here, we present five different cryo-EM structures of the GPR109A-G-protein complexes with the receptor bound to dyslipidemia drugs, niacin or acipimox, non-flushing agonists, MK6892 or GSK256073, and recently approved psoriasis drug, monomethyl fumarate (MMF). These structures allow us to visualize the binding mechanism of agonists with a conserved molecular interaction network, and elucidate the previously lacking molecular basis of receptor activation and transducer-coupling. Importantly, cellular pharmacology experiments, guided by the structural framework determined here, elucidate pathway-selective biased signaling elicited by the non-flushing agonists. Finally, taking lead from the structural insights, we successfully engineered receptor mutants via single amino acid substitutions that either fail to elicit agonist-induced transducer-coupling or exhibits G-protein signaling bias. Taken together, our study provides previously lacking structural framework to understand the agonist-binding and activation of GPR109A, and opens up the possibilities of structure-guided novel drug discovery targeting this therapeutically important receptor.
Comparisons of two receptor pathways in a single cell-type reveal features of signalling specificity
Authors: Ma Yan , Flückiger Isabelle , Nicolet Jade , Pang Jia , Dickinson Joe , De Bellis Damien , Emonet Aurélia , Fujita Satoshi , Geldner Niko
Published: July 2023

To respond appropriately to diverse stimuli, cells harbour numerous receptor pathways yet share downstream signalling components. Mitogen-Activated Protein Kinase (MPK) cascades, present in all eukaryotes, act as central hubs shared amongst diverse signalling pathways. How signalling specificity is maintained within a single plant cell-type is not well understood. We engineered a genetic background for direct comparisons of a developmental and an immunity pathway in the Arabidopsis root endodermis. We show the two pathways maintain distinct outputs despite similar MPK phosphorylation patterns. Systematic activation of all individual MPK Kinases (MKKs) in the endodermis revealed that different MKK groups can drive distinct outputs. We propose that specificity is achieved through a balance of combinatorial activation and cross-pathway inhibition within the MPK cascade. Our findings demonstrate the ability of MPK cascades to generate diverse outputs in one plant cell-type, providing new insights into the mechanisms contributing to signalling specificity.
Oscillatory waveform shape and temporal spike correlations differ across bat frontal and auditory cortex
Authors: García-Rosales Francisco , Schaworonkow Natalie , Hechavarria Julio C.
Published: July 2023

Neural oscillations are associated with diverse computations in the mammalian brain. The waveform shape of oscillatory activity measured in cortex relates to local physiology, and can be informative about aberrant or dynamically changing states. However, how waveform shape differs across distant yet functionally and anatomically related cortical regions is largely unknown. In this study, we capitalize on simultaneous recordings of local field potentials (LFPs) in the auditory and frontal cortices of awake, maleCarollia perspicillatabats to examine, on a cycle-by-cycle basis, waveform shape differences across cortical regions. We find that waveform shape differs markedly in the fronto-auditory circuit even for temporally correlated rhythmic activity in comparable frequency ranges (i.e. in the delta and gamma bands) during spontaneous activity. In addition, we report consistent differences between areas in the variability of waveform shape across individual cycles. A conceptual model predicts higher spike-spike and spike-LFP correlations in regions with more asymmetric shape, a phenomenon that was observed in the data: spike-spike and spike-LFP correlations were higher in frontal cortex. The model suggests a relationship between waveform shape differences and differences in spike correlations across cortical areas. Altogether, these results indicate that oscillatory activity in frontal and auditory cortex possess distinct dynamics related to the anatomical and functional diversity of the fronto-auditory circuit.

Significance statement

The brain activity of many animals displays intricate oscillations, which are usually characterized in terms of their frequency and amplitude. Here, we study oscillations from the bat frontal and auditory cortices on a cycle-by-cycle basis, additionally focusing on their characteristic waveform shape. The study reveals clear differences across regions in waveform shape and oscillatory regularity, even when the frequency of the oscillations is similar. A conceptual model predicts that more asymmetric waveforms result from stronger correlations between neural spikes and electrical field activity. Such predictions were supported by the data. The findings shed light onto the unique properties of different cortical areas, providing key insights into the distinctive physiology and functional diversity within the fronto-auditory circuit.
The substrate quality of CK2 target sites has a determinant role on their function and evolution
Authors: Bradley David , Garand Chantal , Belda Hugo , Gagnon-Arsenault Isabelle , Treeck Moritz , Elowe Sabine , Landry Christian R
Published: July 2023

Most biological processes are regulated by peptide-recognition modules (PRMs) that bind to short linear motifs (SLiMs). Such interactions are rapidly reversible and often occur at low affinity. The protein kinase domain represents one such binding module, and known substrates may have full or only partial matches to the kinase recognition motif, a property known as ‘substrate quality’. However, it is not yet clear whether differences in substrate quality represent neutral variation along the phosphosite sequence or if these differences have functional consequences that are subject to selection. We explore this question in detail for the acidophilic kinase CK2. CK2 is well-characterised, clinically important, and a fundamental enzyme for many aspects of cell biology. We show that optimal CK2 sites are phosphorylated at maximal stoichiometries and found in many conditions whereas minimal substrates are phosphorylated at lower stoichiometries, are more dynamic during the cell cycle, and have regulatory functions. Optimal CK2 sites also tend to be older and more conserved than minimal sites, and evolutionary simulations indicate that the substrate quality of CK2 phosphosites is often tuned by selection. For intermediate target sites, increases or decreases to substrate quality may be deleterious, which we demonstrate experimentally for a CK2 substrate at the kinetochore. The results together suggest that minimal and optimal phosphosites are strongly differentiated in terms of their functional and evolutionary properties.
β-hydroxybutyrate is a metabolic regulator of proteostasis in the aged and Alzheimer disease brain
Authors: Madhavan SS , Roa Diaz S , Peralta S , Nomura M , King CD , Lin A , Bhaumik D , Shah S , Blade T , Gray W , Chamoli M , Eap B , Panda O , Diaz D , Garcia TY , Stubbs BJ , Lithgow GJ , Schilling B , Verdin E , Chaudhuri AR , Newman JC
Published: July 2023

Loss of proteostasis is a hallmark of aging and Alzheimer disease (AD). Here, we identify β-hydroxybutyrate (βHB), a ketone body, as a regulator of protein solubility in the aging brain. βHB is a small molecule metabolite which primarily provides an oxidative substrate for ATP during hypoglycemic conditions, and also regulates other cellular processes through covalent and noncovalent protein interactions. We demonstrate βHB-induced protein insolubility acrossin vitro,ex vivo, andin vivomouse systems. This activity is shared by select structurally similar metabolites, is not dependent on covalent protein modification, pH, or solute load, and is observable in mouse brainin vivoafter delivery of a ketone ester. Furthermore, this phenotype is selective for pathological proteins such as amyloid-β, and exogenous βHB ameliorates pathology in nematode models of amyloid-β aggregation toxicity. We have generated a comprehensive atlas of the βHB-induced protein insolublomeex vivoandin vivousing mass spectrometry proteomics, and have identified common protein domains within βHB target sequences. Finally, we show enrichment of neurodegeneration-related proteins among βHB targets and the clearance of these targets from mouse brain, likely via βHB-induced autophagy. Overall, these data indicate a new metabolically regulated mechanism of proteostasis relevant to aging and AD.
Baited reconstruction with 2D template matching for high-resolution structure determinationin vitroandin vivowithout template bias
Authors: Lucas Bronwyn A. , Himes Benjamin A. , Grigorieff Nikolaus
Published: July 2023

Cryogenic electron microscopy (cryo-EM) has revolutionized structural biology, rapidly increasing the number of available molecular structures. Because of this, as well as advances in structure prediction, the focus of structural biology has begun to shift to studying macromolecular structures in their native cellular environment. A dominant feature of cryo-EM images is shot noise, making the identification of small particles of interest difficult. This is further compounded by structural noise if these particles are imaged against a background of other molecules, such as inside a cell. 2D template matching (2DTM) can be used to localize complexes with high precision, even in the presence of cellular background. Once localized, these particles may be averaged together in 3D reconstructions; however, regions included in the template may suffer from template bias, leading to inflated resolution estimates and making the interpretation of high-resolution features unreliable. We evaluate conditions that minimize template bias and show that molecular featuresnotpresent in the template can be reconstructed at high resolution from targets found by 2DTM, extending prior work at low-resolution.

Moreover, we present a quantitative metric for template bias to aid the interpretation of 3D reconstructions calculated with particles localized using high-resolution templates and fine angular sampling.
Spatial confinement ofTrypanosoma bruceiin microfluidic traps provides a new tool to study free swimming parasites
Authors: De Niz Mariana , Frachon Emmanuel , Gobaa Samy , Bastin Philippe
Published: July 2023

Trypanosoma bruceiis the causative agent of African trypanosomiasis and is transmitted by the tsetse fly (Glossina spp.). All stages of this extracellular parasite possess a single flagellum that is attached to the cell body and confers a high degree of motility. While several stages are amenable to culturein vitro,longitudinal high-resolution imaging of free-swimming parasites has been challenging, mostly due to the rapid flagellar beating that permanently twists the cell body. Here, using microfabrication, we generated various microfluidic devices with traps of different geometrical properties. Investigation of trap topology allowed us to define the one most suitable for singleT. bruceiconfinement within the field of view of an inverted microscope while allowing the parasite to remain motile. Chips populated with V-shaped traps allowed us to investigate various phenomena in cultured procyclic stage wild-type parasites, and to compare them with parasites whose motility was altered upon knockdown of a paraflagellar rod component. Among the properties that we investigated were trap invasion, exploratory behaviour, and the visualization of organelles labelled with fluorescent dyes. We envisage that this “Tryp-Chip” will be a useful tool for the scientific community, as it could allow high-throughput, high-temporal and high-spatial resolution imaging of free-swimmingT. bruceiparasites.