bluuebunny/crossref_metadata_2025 huggingface dataset:
Campylobacter californiensis sp. nov., isolated from cattle and feral swine
Authors: Miller William G. , Chapman Mary H. , Williams Tina G. , Wood Delilah F. , Bono James L. , Kelly David J.
Published: October 2024

Nine Campylobacter strains were isolated from cattle and feral swine faeces: three were recovered during a 2007 Campylobacter-associated outbreak linked to a dairy, and the other six were isolated during a 2009–2010 survey of farms and ranches in Central California. The species identification of these strains could not be determined by 16S rRNA gene sequencing but were most similar to Campylobacter concisus and Campylobacter mucosalis. Additional atpA typing indicated that the nine strains composed a discrete novel clade related to C. concisus and C. mucosalis. A polyphasic study was undertaken here to clarify their taxonomic position. Phylogenetic analyses were performed based on 16S rRNA gene sequences and the concatenated sequences of 330 core genes. The core gene analysis placed the nine strains into a clade well separated from the other Campylobacter taxa, indicating that these strains represent a novel Campylobacter species. Pairwise digital DNA–DNA hybridization and average nucleotide identity values between these strains and other campylobacters are lower than 16 and 73%, respectively, further supporting their placement into a novel taxon. Standard phenotypic testing was performed. All strains are microaerobic or anaerobic, motile, Gram-negative, slightly-curved rods that are oxidase positive but catalase negative. Strains can be distinguished from the other catalase-negative Campylobacter species using phenotypic markers such as motility, oxidase activity, cephalothin resistance, hippuricase activity, growth at 30 °C, and α-haemolysis. The data presented here show that these strains represent a novel species within Campylobacter, for which the name Campylobacter californiensis sp. nov. (type strain RM6914T=LMG 32304T=CCUG 75329T) is proposed.
KMT2d regulates tooth enamel development
Authors: Lee Jung-Mi , Jung Hunmin , Tang Qinghuang , Li Liwen , Lee Soo-Kyung , Lee Jae W , Kwon Hyuk-Jae (Edward)
Published: October 2024

Amelogenesis, the process of enamel formation, is tightly regulated and essential for producing the tooth enamel that protects teeth from decay and wear. Disruptions in amelogenesis can result in amelogenesis imperfecta, a group of genetic conditions characterized by defective enamel, including enamel hypoplasia, marked by thin or underdeveloped enamel. Mutations in the KMT2D (MLL4) gene, which encodes a histone H3-lysine 4-methyltransferase, are associated with Kabuki syndrome, a developmental disorder that can involve dental anomalies such as enamel hypoplasia. However, the specific role of KMT2D in amelogenesis remains poorly understood. To address this gap, we generated a conditional knockout mouse model with ectoderm-specific deletion of Kmt2d (Krt14-Cre;Kmt2dfl/fl, or Kmt2d-cKO) and characterized the resulting enamel defects using gross, radiographic, histological, cellular, and molecular analyses. Micro-computed tomography and scanning electron microscopy revealed that adult Kmt2d-cKO mice exhibited 100% penetrant amelogenesis imperfecta, characterized by hypoplastic and hypomineralized enamel, partially phenocopying human Kabuki syndrome. Additionally, Kmt2d-cKO neonates developed molar tooth germs with subtle cusp shape alterations and mild delays in ameloblast differentiation at birth. RNA-seq analysis of the first molar tooth germ at birth revealed that 33.7% of known amelogenesis-related genes were significantly downregulated in the Kmt2d-cKO teeth. Integration with KMT2D CUT&RUN-seq results identified 8 overlapping genes directly targeted by KMT2D. Re-analysis of a single-cell RNA-seq dataset in the developing mouse incisors revealed distinct roles for these genes in KMT2D-regulated differentiation across various cell subtypes within the dental epithelium. Among these genes, Satb1 and Sp6 are likely direct targets involved in the differentiation of pre-ameloblasts into ameloblasts. Taken together, we propose that KMT2D plays a crucial role in amelogenesis by directly activating key genes involved in ameloblast differentiation, offering insights into the molecular basis of enamel development and related dental pathologies.
Pannexin-2 deficiency disrupts visual pathways and leads to ocular defects in zebrafish
Authors: Shanbhag Riya , Zoidl Georg S.O. , Nakhuda Fatema , Sabour Shiva , Naumann Heike , Zoidl Christiane , Bahl Armin , Tabatabaei Nima , Zoidl Georg R.
Published: October 2024

Pannexin-2 (Panx2) is a unique ion channel localized to ER-mitochondria contact sites. These dynamic and specialized microdomains are abundant in neurons and glia and essential for cellular signaling and metabolism. While synaptic interactions are well-studied, the role of intracellular contacts, such as those of ER-mitochondrial junctions, in neuronal function and neurodegeneration remains largely unexplored. To investigate the roles of Panx2 in neuronal communication, we meticulously examined its expression pattern in the zebrafish brain and used TALEN technology to generate homozygous Panx2 knockout (Panx2Δ11) zebrafish. Our results demonstrate thatpanx2mRNA is present in several brain regions, notably in visual centers such as the optic tectum and the thalamus. In 6 days post fertilization TL (Panx2+/+) larvae, Panx2 expression was observed in the inner and outer plexiform layers of the retina and the arborization fields of the optic tract. Transcriptome profiling ofPanx2Δ11larvae by RNA-seq analysis revealed down-regulation of vision-related genes, specifically those involved in visual and sensory perception and lens development. Behavioral tests showed that loss of Panx2 leads to an altered ability to interpret visual information, such as changes in ambient illuminations, and respond with the characteristic motor action.Panx2Δ11larvae exhibited reduced locomotor activity during light and increased activity during dark phases. Additionally, the knockout larvae displayed significantly impaired optomotor response (OMR). Lastly, when we tested the retinal structure of adult zebrafish eyes using optical coherence tomography (OCT),Panx2Δ11fish revealed a longer mean axial length and a negative shift in retinal refractive error (RRE) values; both indicative of myopia. Our findings highlight a distinct, novel function of Panx2 in retinal development, visual perception, and ocular health, beyond its recognized roles in neurodevelopment and tumor-suppressing properties in cancer cells.
Why is implementing remote monitoring in virtual wards (Hospital at Home) for people living with frailty so hard? Qualitative interview study
Authors: Lindsay Rosie , Cunnington Paige , Dixon-Woods Mary
Published: October 2024

Background

There is relatively low uptake of remote monitoring on frailty virtual wards compared to virtual wards caring for people with other medical conditions. However, reasons for low uptake are poorly understood.

Objectives

To explore the views and experiences of frailty virtual wards stakeholders involved in implementing remote monitoring.

Methods

We conducted qualitative interviews with 42 stakeholders involved in delivery, design or evaluation of frailty virtual wards based in the United Kingdom (UK). Analysis was based on the constant comparative method.

Results

Many participants perceived that remote monitoring was only useful for a small sub-group of patients with frailty for a range of medical, practical and social reasons. Remote monitoring required new ways of working from patients, staff and carers. The nature of this work was not always sufficiently well understood, designed, or supported. Procurement practices were also seen to be mis-aligned with service needs, resulting in provision of equipment that was not fit for purpose. A further challenge in implementing remote monitoring in frailty virtual wards lay in tensions between national-level standardisation and enabling local flexibility.

Conclusions

Implementing remote monitoring in frailty virtual wards is challenged by lack of consensus on its suitability for this population, the extent and nature of change in clinical practices and work systems design required, and issues relating to equipment and standardisation. More co-design effort is needed to inform decision-making on remote monitoring for those with frailty.
Genetic Risk of Axonal Neuropathy Following Infection
Authors: Harkness J. Robert , McDermott John H. , Marsden Shea , Jamieson Peter , Metcalfe Kay A. , Khan Naz , Macken William L. , Pitceathly Robert D.S. , Record Christopher J. , Maroofian Reza , Kloepas Kloepa , Sabir Ataf , Islam Lily , Santra Saikat , Durmusalioglu Enise Avci , Atik Tahir , Isik Esra , Cogulu Ozgur , Urquhart Jill E. , Beaman Glenda M. , Demain Leigh A. , Jackson Adam , Blakes Alexander J.M. , Byers Helen M. , Bennett Hayley , Lin Wei-Hsiang , Adamson Antony , Patel Sanjai , Yue Wyatt W. , Taylor Robert W. , Reunert Janine , Marquardt Thorsten , Buchert-Lo Rebecca , Haack Tobias , Losch Heike , Ryba Lukas , Lassuthova Petra , Valkovičová Radka , Haberlová Jana , Lauerová Barbora , Trúsiková Eva , Polavarapu Kiran , Kilicarslan Ozge Aksel , Lochmüller Hanns , Zamani Mina , Chamanrou Niloofar , Shariati Gholamreza , Sadeghian Saeid , Azizimalamiri Reza , Maddirevula Sateesh , AlMuhaizea Muhammad , Alkuraya Fowzan S. , Horvath Rita , Gungor Serdal , Wakeling Emma , Manzur Adnan , Munot Pinki , Matthews Rachael , Banka Siddharth , Reilly Mary M. , Bennett Daimark , O’Keefe Raymond T. , Newman William G.
Published: October 2024

Background

Why some individuals experience severe neuropathy following infection is unknown. Nucleocytoplasmic trafficking (NCT) is an essential process in nucleated cells, and its disruption has been implicated in many neurodegenerative conditions including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia.

Methods

We performed genomic and clinical studies in 24 individuals from 12 families with acute onset axonal neuropathy. Genetic variants were characterized by thermal stability and enzymatic assays using recombinantly expressed protein. Protein localization was determined in patient fibroblasts using immunofluorescence following heat or oxidative stress. A humanizedDrosophilamodel was generated to determine the effect of stress onin vivofunction.

Results

We identified deleterious biallelic variants in humanRCC1, encoding a GTP exchange factor essential in maintaining Ran GTPase-dependent NCT function. Clinical presentations ranged from a rapidly progressive, fatal axonal neuropathy with encephalopathy to a mild motor neuropathy resulting in impaired walking. In most patients (n=22/24), neurological presentation was secondary to infection, resulting in prior diagnosis of Guillain-Barré syndrome (GBS) in 13. The efficiency of cellular Ran GDP-GTP exchange and the thermal stability of Rcc1 protein was reduced by disease-associated variants. Heat shock or oxidative stress revealed defects in Ran nuclear localization, impaired NCT, and TDP-43 mislocalization in patient fibroblasts. Disease associated variants were unable to rescue the thermosensitive phenotype of arcc1deficient hamster cell line.RCC1 Drosophilamodels revealed a fatal intolerance to oxidative stress.

Conclusion

We describe a novel autosomal recessive acute onset axonal neuropathy triggered by infection caused by biallelicRCC1variants, which mimics GBS and has important mechanistic overlap with ALS.
Single-cell imaging reveals a key role of Bck2 in budding yeast cell size adaptation to nutrient challenges
Authors: Chadha Yagya , Kukhtevich Igor V. , Padovani Francesco , Schneider Robert , Schmoller Kurt M.
Published: October 2024

Cell size is tightly controlled to optimize cell function and varies broadly depending on the organism, cell type, and environment. The budding yeastS. cerevisiaehas been successfully used as a model to gain insights into eukaryotic cell size control. Multiple regulators of cell size in steady-state conditions have been identified, such as the G1/S transition activators Cln3 and Bck2 and the inhibitor Whi5. Individual deletions of these regulators result in populations with altered mean cell volumes. However, size homeostasis remains largely intact. Here, we show that although the roles of Bck2 and Cln3 for cell size regulation appear largely redundant in steady-state, a switch from fermentable to non-fermentable growth media reveals a unique role for Bck2 in cell size adaptation to changing nutrients. We use live-cell microscopy and machine learning-assisted image analysis to track single cells and their progeny through the nutrient switch. We find that after the switch,bck2Δcells experience longer cell cycle arrests and more arrest-associated enlargement than wild-type,whi5Δorcln3Δcells, indicating that Bck2 becomes the critical G1/S activator in changing nutrients. Our work demonstrates that studying size regulation during nutrient shifts to mimic the dynamic environments of free-growing microorganisms can resolve apparent redundancies observed in steady-state size regulation.
Changes in brain connectivity and neurovascular dynamics during dexmedetomidine-induced loss of consciousness
Authors: Fotiadis Panagiotis , McKinstry-Wu Andrew R. , Weinstein Sarah M. , Cook Philip A. , Elliott Mark , Cieslak Matthew , Duda Jeffrey T. , Satterthwaite Theodore D. , Shinohara Russell T. , Proekt Alexander , Kelz Max B. , Detre John A. , Bassett Dani S.
Published: October 2024

Understanding the neurophysiological changes that occur during loss and recovery of consciousness is a fundamental aim in neuroscience and has marked clinical relevance. Here, we utilize multimodal magnetic resonance neuroimaging to investigate changes in regional network connectivity and neurovascular dynamics as the brain transitions from wakefulness to dexmedetomidine-induced unconsciousness, and finally into early-stage recovery of consciousness. We observed widespread decreases in functional connectivity strength across the whole brain, and targeted increases in structure-function coupling (SFC) across select networks— especially the cerebellum—as individuals transitioned from wakefulness to hypnosis. We also observed robust decreases in cerebral blood flow (CBF) across the whole brain—especially within the brainstem, thalamus, and cerebellum. Moreover, hypnosis was characterized by significant increases in the amplitude of low-frequency fluctuations (ALFF) of the resting-state blood oxygen level-dependent signal, localized within visual and somatomotor regions. Critically, when transitioning from hypnosis to the early stages of recovery, functional connectivity strength and SFC—but not CBF—started reverting towards their awake levels, even before behavioral arousal. By further testing for a relationship between connectivity and neurovascular alterations, we observed that during wakefulness, brain regions with higher ALFF displayed lower functional connectivity with the rest of the brain. During hypnosis, brain regions with higher ALFF displayed weaker coupling between structural and functional connectivity. Correspondingly, brain regions with stronger functional connectivity strength during wakefulness showed greater reductions in CBF with the onset of hypnosis. Earlier recovery of consciousness was associated with higher baseline (awake) levels of functional connectivity strength, CBF, and ALFF, as well as female sex. Across our findings, we also highlight the role of the cerebellum as a recurrent marker of connectivity and neurovascular changes between states of consciousness. Collectively, these results demonstrate that induction of, and emergence from dexmedetomidine-induced unconsciousness are characterized by widespread changes in connectivity and neurovascular dynamics.
Continuous lesion images drive more accurate predictions of outcomes after stroke than binary lesion images
Authors: Hope Thomas M.H. , Neville Douglas , Seghier Mohamed L. , Price Cathy J.
Published: October 2024

Current medicine cannot confidently predict who will recover from post-stroke impairments. Researchers have sought to bridge this gap by treating the post-stroke prognostic problem as a machine learning problem. Consistent with the observation that these impairments are caused by the brain damage that stroke survivors suffer, information concerning where and how much lesion damage they have suffered conveys useful prognostic information for these models. Much recent research has considered how best to encode this lesion information, to maximise its prognostic value. Here, we consider an encoding that, while not novel, has never before been formally examined in this context: ‘continuous lesion images’, which encode continuous evidence for the presence of a lesion, both within and beyond what might otherwise be considered the boundary of a binary lesion image. Current state of the art models employ information derived from binary lesion images. Here, we show that those models are significantly improved (i.e., with smaller Mean Squared Error between predicted and empirical outcome scores) when using continuous lesion images to predict a wide range of cognitive and language outcomes from a very large sample of stroke patients. We use further model comparisons to locate the predictive advantage to the provision of continuous lesion evidence beyond the boundary of binary lesion images. The continuous lesion images thus provide a straightforward way to incorporate details of both lesioned and non-lesioned tissue when predicting outcomes after stroke.
Microbicidal Mechanisms for Light-Activated Molecular Nanomachines inMycobacterium smegmatis: A Model for Pathogenic Bacteria
Authors: Galbadage Thushara , Liu Dongdong , Tour James M. , Cirillo Jeffrey D. , Gunasekera Richard S.
Published: October 2024

There is a global health crisis of antimicrobial resistance, with over a million deaths annually attributed to antimicrobial-resistant pathogens, and mycobacterial infections are a major cause of antimicrobial-resistant infections, leading to more deaths than any other single infectious agent. Notably, the rise of multidrug-resistant (MDR), extensively drug-resistant (XDR), and totally drug-resistant (TDR) strains ofMycobacterium tuberculosisled to higher mortality rates and challenge all existing antibiotic regimens. Light-activated molecular nanomachines (MNMs) represent a promising class of broad-spectrum antimicrobial agents that could help counter this rise in antimicrobial resistance. Addressing a key knowledge gap, this study explores the mechanisms of action for MNMs inMycobacterium smegmatis, a surrogate model for pathogenic mycobacteria. We show that fast rotor MNMs kill up to 97% ofM. smegmatisand co-localize with the bacteria as part of their mechanism of action. The ability to translate these observations to pathogenic mycobacteria was demonstrated by the ability of MNMs to kill 93.5% ofM. tuberculosisunder similar conditions. These findings suggest that MNMs may provide innovative sustainable antimicrobial agents for the treatment of drug-resistant mycobacterial infections.

Graphical Abstract

Bacteria exposed to MNMs have two distinct outcomes when activated by 365 nm light. Slow motors (MNM2and4)have no rotational action, remains outside the bacteria and have little to no effect on bacterial viability. Whereas fast motors (MNM1and3)co-localize and embed into the bacterial cell wall causing disruptions that lead to a significant reduction in bacterial viability.
Recurrent innovation of protein-protein interactions in theDrosophilapiRNA pathway
Authors: Riedelbauch Sebastian , Masser Sarah , Fasching Sandra , Lin Sung-Ya , Salgania Harpreet Kaur , Aarup Mie , Ebert Anja , Jeske Mandy , Levine Mia , Stelzl Ulrich , Andersen Peter
Published: October 2024

Despite being essential for fertility, genome defence pathway genes often evolve rapidly. However, little is known about the molecular basis of this adaptation. Here, we characterize the evolution of a protein interaction network within the PIWI-interacting small RNA (piRNA) genome defence pathway inDrosophilaat unprecedented scale and evolutionary resolution. We uncover pervasive rapid evolution of a protein interaction network anchored at the Heterochromatin Protein 1 (HP1) paralog Rhino. Using complementary phylogenetic analysis, high-throughput yeast-two-hybrid matrix screening, andin vivointeraction analyses in cross-species transgenic flies, we characterized three distinct evolutionary protein interaction trajectories across ∼40 million years ofDrosophilaevolution. The data set covering 11 piRNA pathway proteins of fiveDrosophilaspecies revealed several protein interactions that are fully conserved, indicating functional conservation despite overall rapid amino acid sequence change. Other interactions are preserved through co-evolution and were detected only between proteins within or from closely related species. We also identified sets of species-restricted protein interactions which, through rewiring of a Rhino-anchored transcription factor network, may preserve critical roles in enabling and adapting piRNA production from heterochromatic loci. In sum, our analyses dissected principles of interaction evolution in an adaptively evolving protein-protein interaction network uncovering evolutionary and functional insight into germline piRNA production acrossDrosophilaspecies. Our work provides key experimental evidence in support of a model proposing that intermolecular interaction innovation is a major molecular mechanism of evolutionary adaptation in protein-coding genes.
A Fibronectin (FN)-Silk 3D Cell Culture Model as a Screening Tool for Repurposed Antifibrotic Drug Candidates for Endometriosis
Authors: Teworte Sarah , Behrens Mark C. , Widhe Mona , Gurzeler Lukas-Adrian , Hedhammar My , Luciani Paola
Published: October 2024

This study advances sustainable pharmaceutical research for endometriosis by aligning with the UN Sustainable Development Goals on health, gender equality, and responsible consumption in developingin vitro3D cell culture models of endometriotic pathophysiology. Fibrosis is a key aspect of endometriosis, yet current models to study it remain limited, especially in 3D. This work aims to bridge the translational gap betweenin vitrofibrosis research and preclinical testing of non-hormonal drug candidates. When grown in a 3D matrix of sustainably produced silk protein functionalized with a fibronectin-derived cell adhesion motif (FN-silk), endometrial stromal and epithelial cells respond to transforming growth factor beta-1 (TGF-β1) in a physiological manner as probed at the mRNA level. For stromal cells, this response to TGF-β1 is not observed in spheroids, while epithelial cell spheroids behave similarly to epithelial cell FN-silk networks. Pirfenidone, an antifibrotic drug approved for the treatment of idiopathic pulmonary fibrosis, reverses TGF-β1-induced upregulation of mRNA transcripts involved in fibroblast-to-myofibroblast transdifferentiation of endometrial stromal cells in FN-silk networks, supporting the drug’s potential as a repurposed non-hormonal therapy for endometriosis. This study demonstrates how a sustainable approach – from project conceptualization to material selection – can be integrated into pharmaceutical research for women’s health.

Table of contents

This paper presentsin vitro3D cell culture models of fibrosis in endometriosis. Endometrial stromal and epithelial cells cultured in networks of silk protein functionalized with a fibronectin-derived cell adhesion motif showed physiological-like fibrotic behavior. Pirfenidone was able to reverse fibrosis of endometrial stromal cellsin vitro, demonstrating this model’s suitability as a screening tool for antifibrotic drugs for endometriosis.
Splicing dysregulation in glioblastoma alters the function of cell migration-related genes
Authors: Seong Minu , Bak-Gordon Pedro , Liu Zhaoqi , Canoll Peter D. , Manley James L.
Published: October 2024

Glioblastoma (GBM) has a poor prognosis with a high recurrence and low survival rate. Previous RNA-seq analyses have revealed that alternative splicing (AS) plays a role in GBM progression. Here, we present a novel AS analysis method (Semi-Q) and describe its use to identify GBM-specific AS events. We analyzed RNA-seq data from normal brain (NB), normal human astrocytes (NHAs) and GBM samples, and found that comparison between NHA and GBM was especially informative. Importantly, this analysis revealed that genes encoding cell migration-related proteins, including filamins (FLNs) and actinins (ACTNs), were among those most affected by differential AS. Functional assays revealed that dysregulated AS ofFLNA, BandCtranscripts produced protein isoforms that not only altered transcription of cell proliferation-related genes but also led to enhanced cell migration, resistance to cell death and/or mitochondrial respiratory function, while a dysregulated AS isoform ofACTN4enhanced cell migration. Together, our results indicate that cell migration and actin cytoskeleton-related genes are differentially regulated by AS in GBM, supporting a role for AS in facilitating tumor growth and invasiveness.
Validating the genusPocheina(Acrasidae, Heterolobosea, Excavata) leads to the recognition of three major lineages within Acrasidae
Authors: Tice Alexander K. , Regis Kevin , Shutt Timothy E. , Spiegel Frederick W. , Brown Matthew W. , Silberman Jeffery D.
Published: October 2024

PocheinaandAcrasisare two genera of heterolobosean sorocarpic amoebae within Acrasidae that have historically been considered close relatives. The two genera were differentiated based on their differing fruiting body morphologies. The validity of this taxonomic distinction was challenged when a SSU rRNA phylogenetic study placed an isolate morphologically identified as ‘Pocheina’roseawithin a clade ofAcrasis roseaisolates. The authors speculated that pocheinoid fruiting body morphology might be the result of aberrantA. roseafruiting body development, which if true, would nullify this taxonomic distinction between genera. To clarify Acrasidae systematics, we analyzed SSU rRNA and ITS region sequences from multiple isolates ofPocheina, Acrasis, andAllovahlkampfiagenerated by PCR and transcriptomics. We demonstrate that the initial SSU sequence attributed to ‘P. rosea’ originated from anA. roseaDNA contamination in its amplification reaction. Our analyses, based on morphology, SSU and 5.8S rRNA genes phylogenies, as well as comparative analyses of ITS1 and ITS2 sequences, resolve Acrasidae into three major lineages;Allovahlkampfiaand the strongly supported clades comprisingPocheinaandAcrasis. We confirm that the latter two genera can be identified by their fruiting body morphologies.
Something to sink your teeth into: the mechanics of tooth indentation in frugivorous fishes
Authors: Rosen Jack , Cohen Karly , Donatelli Cassandra M. , Summers Adam P. , Crofts Stephanie , Kolmann Matthew A.
Published: October 2024

Frugivorous vertebrates engage in a mutualism with fruiting plants: the former receive a nutrient subsidy and the latter benefit by having their seeds distributed far from parent plants. Vertebrate frugivores like primates and bats have particular morphologies, like wide jaws and blunt teeth, which are thought to aid in dismantling fruit and obtaining trapped sugars. However, variation among frugivores and fruits has made the identification of common frugivore phenotypes difficult. We measured the performance of frugivorous fish dentitions whether this performance was comparable to fruit-eating bats and primates. We also explored how fruit characteristics affect puncture performance, and how indentation of fruit differs mechanically from harder foods like nuts. Finally, we used photoelasticity and videography to visualize how serrasalmid dentitions propagate stresses in simple gel models. We expected that frugivore dentitions would exhibit low force and then high work when engaging fruit tissues. Aligning with our expectation, the most frugivorous serrasalmid we tested,Colossoma, had dental performance that matched the low force, high work model. Indentation behavior differed between food types, both between fruits and nuts, and among different fruits. We also documented considerable differences in the indentation performances of different serrasalmid dentitions, among frugivores, omnivores, and carnivores. We propose that some differences in the morphology of frugivore dentitions make them better for granivory (eating seeds) than the softer fruit tissues. Fishes exhibit convergent mechanical and morphological strategies with other vertebrates for obtaining nutrition from fruits and seeds.
Effects of temperature on the life-history traits ofMyzus persicaeand its efficiency in transmitting potato virus Y (PVY) in potato crops
Authors: Sokame Bonoukpoe M , Tonnang Henry E , Gamarra Heidy A , Carhuapoma Pablo , Kreuze Jan F , Arab Ali , Armbruster Peter A , Johnson Leah R , Villena Oswaldo C
Published: October 2024

Aphids are highly sensitive to temperature changes and play a crucial role in transmitting plant viruses, accounting for the transmission of more than 50% of viruses that cause disease in crops. Among them,Myzus persicaeis a major global pest, affecting over 400 plant species and transmitting more than 100 plant viruses, including potato virus Y (PVY), which poses a severe threat to potato crops. This study examines how temperature influences the life-history traits ofM. persicaeand its efficiency in transmitting PVY. Our research revealed that temperature significantly affects developmental duration, survival, and fecundity ofM. persicae. The aphids exhibit the longest lifespan at 10°C and the shortest at 30°C. Similarly, fecundity declined from 29.81 offspring per female at 10°C to 14.25 at 30°C. PVY transmission efficiency was highest at 20°C. We also mapped potential PVY transmission regions and identified tropical and subtropical areas as high-risk due to their favourable temperatures and aphid's abundance. Understanding these geographical variations is crucial for effective pest/disease management. Our findings emphasize the importance of integrating climatological, ecological, and epidemiological data to develop robust pest/disease management strategies to mitigate the impact ofM. persicaeand PVY on potato production and enhancing global food security.
No association betweenFMR1premutation and either ADHD or anxiety in 53,707 women undergoing genetic testing for family planning purposes
Authors: Klausner Liraz , Carmi Shai , Ben-Shachar Shay , Lev-El Halabi Noa , Basel-Salmon Lina , Goldstein Dana Brabbing
Published: October 2024

Background

AnFMR1full mutation, which causes Fragile X Syndrome, is defined as >200 repeats of the CGG motif in the gene’s 5’ untranslated region. A repeat count in the range 55-200 is considered anFMR1premutation (PM) and was previously associated with neuropsychiatric phenotypes. However, these associations did not always replicate and may be due to ascertainment bias. Here, we studied the association between PM and attention deficit hyperactivity disorder (ADHD) and anxiety using large population-based screening data.

Methods

We used data on women who underwent genetic screening in Rabin Medical Center in Israel for family planning purposes between 2001-2020. PM carriers were defined as subjects with 58-200 CGG repeats. We linked the genetic testing results to longitudinal electronic medical records (EMR) from Clalit Health Services. We defined ADHD and anxiety based on either a formal diagnosis or the purchase of relevant medications. As a positive control, we considered premature ovarian insufficiency (POI) and high follicle-stimulating hormone (FSH) levels before the age of 40. Our primary analysis used Cox regression with socioeconomic status, immigration, and age at testing as covariates.

Results

Our sample included 53,707 women: 464 PM carriers and 53,243 non-carriers. PM was associated with POI (hazard ratio (HR): 4.08, 95% confidence interval (CI): 2.16-7.72) and high FSH (HR: 3.43, 95% CI: 2.65-4.43). However, PM was not associated with either ADHD (HR 0.95; 95% CI: 0.51-1.77; 1331 events) or anxiety (HR 0.81; 95% CI: 0.47-1.39; 1814 events). The results were similar when the phenotype was defined based on medications and with logistic regression. Our study was sufficiently powered to detect HR about 2 or higher.

Discussion

We found no association between PM and either ADHD or anxiety. Our study is less prone to ascertainment bias towards affected families; however, the ascertained subjects are likely healthier than the population average. While our sample size is the largest to date, given the low frequency of PM carriers, small effects cannot be excluded.
Stroke in adults with primary intracranial tumours
Authors: Innes Stuart C. , Yin Lucia , Finnerty Gerald T.
Published: October 2024

BACKGROUND

Malignant primary intracranial tumours are associated with stroke. Knowing how stroke differs in patients with either benign or malignant primary intracranial tumours would give insights into how intracranial tumours affect stroke and would help to improve the limited stroke guidelines for these patients.

METHODS

We conducted a retrospective cohort study of patients with benign or malignant primary intracranial tumours admitted with stroke (2011 - 2022) to a single centre with regional stroke and neuro-oncology units. Data collected included: stroke aetiology, stroke timing relative to tumour diagnosis, pre-stroke disability, post-stroke disability, stroke recurrence and treatment.

RESULTS

We identified 258 patients who had an index stroke (120 haemorrhagic, 135 ischaemic, three coincident haemorrhagic/ischaemic) at or after the diagnosis of their primary intracranial tumour (71% benign, 29% malignant). Symptomatic intracranial haemorrhage was more commonly associated with malignant primary intracranial tumours. Patients with a malignant primary intracranial tumour were 2.7 times more likely to have a stroke than patients with a benign intracranial tumour. We estimated that the risk of ischaemic stroke and symptomatic intracranial haemorrhage within six months of diagnosis of a benign primary intracranial were respectively 2.5 and 5.0 times that of the general population. In-hospital mortality and level of disability at hospital discharge (median modified Rankin scale score, 4) were similar for patients with benign or malignant primary intracranial tumours. Stroke recurrence was 22% at one year. Statins were associated with reduced stroke recurrence.

Patients with malignant tumours and high post-stroke disability were less likely to receive chemotherapy after hospital discharge.

CONCLUSIONS

Our findings suggest that stroke is a wider issue for patients with primary intracranial tumours than commonly recognised. Our data indicated that statins may help to prevent stroke recurrence. Despite concerns about intracranial haemorrhage, antiplatelet agents should be considered after ischaemic stroke.
Identification and catalogue of viral transcriptional regulators in human diseases
Authors: Citu Citu , Chang Le , Manuel Astrid M. , Enduru Nitesh , Zhao Zhongming
Published: October 2024

Viral genomes encode viral transcriptional regulators (vTRs) that manipulate host gene expression to facilitate replication and evade immune detection. Nevertheless, their role in non-cancerous diseases remains largely underexplored. Here, we unveiled 268 new candidate vTRs from 14 viral families. We mapped vTRs’ genome-wide binding profiles and identified their potential human targets, which were enriched in immune-mediated pathways, neurodegenerative disorders, and cancers. Through vTR DNA-binding preference analysis, 283 virus-specific and human-like motifs were identified. Prioritized Epstein-Barr virus (EBV) vTR target genes were associated with multiple sclerosis (MS), rheumatoid arthritis, and systemic lupus erythematosus. The partitioned heritability study among 19 diseases indicated significant enrichment of these diseases in EBV vTR-binding sites, implicating EBV vTRs’ roles in immune-mediated disorders. Finally, drug repurposing analysis pinpointed candidate drugs for MS, asthma, and Alzheimer’s disease. This study enhances our understanding of vTRs in diverse human diseases and identifies potential therapeutic targets for future investigation.
Information Theory Optimization of Signals from Small Angle Scattering Measurements
Authors: Rambo Robert Paul , Tainer John A
Published: October 2024

Solution-state small angle scattering (SAS) using X-rays (SAXS) or neutrons (SANS), informs on the conformational states and assemblies of biological macromolecules (bioSAS) outside of cryo- and solid-state conditions. BioSAS measurements are resolution-limited and through an inverse Fourier transform, the measured SAS intensities directly relate to the physical space occupied by the particles via the 𝑃(𝑟)-distribution. Yet, this inverse transform of SAS data is canonicaly cast as an ill-posed, ill-conditioned problem requiring an indirect approach. Here, we show that with modern instrumentation and the application of information theory, the inverse transform of SAXS intensity data can be cast as a well-conditioned problem and that the ill-conditioning of the inverse problem is directly related to the Shannon number. By exploiting the oversampling enabled by modern detectors, a direct inverse Fourier transform of the SAXS data is possible provided the recovered information does not exceed the Shannon limit. The limit corresponds to the maximum number of significant singular values that can be recovered in a SAXS experiment suggesting the relationship between the Shannon limit and significant singular values is a fundamental property of band-limited inverse integral transform problems. An intrinsic challenge to the type of problem found in SAS, is identifying the best model while avoiding over-fitting. We propose a hybrid scoring function employing an information theory framework that assesses both the quality of the model-data fit as well as the quality of the recovered 𝑃(𝑟)-distribution. The hybrid score utilizes the Akaike Information Criteria and Durbin-Watson (𝐷𝑊 ) statistic that considers model complexity, i.e., degrees-of-freedom and randomness of the model-data residuals. Importantly, the described tests and findings extend the boundaries for bioSAXS by completing the information theory formalism initiated by Peter B. Moore to enable a quantitative measure of resolution in SAS, robustly determine maximum dimension, and more precisely define the best model to appropriately represent the observed scattering data.
Endogenous Huntingtin aggregates are a huge organized scaffold and mold for Golgi apparatus impaired by mutant Huntingtin protein
Authors: Ma Lixiang , Chen Xinyu , Liu Yang , Dai Lijun , Yang Weiqi , Buhe Hada , Ma Jixin , Song Chenyun , Li Li , Fan Dandan , Su Jianzhong , Saiyin Hexige
Published: October 2024

Huntington’s disease (HD), an incurable neurodegenerative disease, is caused by polyglutamine (polyQ) expansion in Huntingtin (HTT) protein. Despite HTTs naturally aggregating, huge variations of HTTs in visualizing methods make it unpredictable. Using 64 nm resolution scanning in the fibroblasts, induced neurons, organoids from an HD family, and human brain tissues, we revealed massive/long polyQ aggregates of HTTs formed by paralleled and interfused spindles that preferentially include flat Golgi stacks/ribbons/vesicles and disassembled in the mitotic and stressed cells with fragmented Golgi, brefeldin A (BFA) treatment and postfixation, and fragmented Golgi in the mitotic and stressed cells but not in BFA-treated cells binds to small HTTs. The disassembling of HTTs aggregates degraded HTTs. PolyQ aggregates with mutant HTT (mHTT)include a flat Golgi stack with a deformed surface, fragment easier in starvation, attach fewer Golgi/clathrin+vesicles and ARF1 than polyQ assemblies without mHTT in fibroblasts or striatal/cortical neurons, and cause intranuclear inclusion bodies in striatal neurons. ScRNA data of striatal GABAergic neurons reveal impaired Golgi- or vesicle-related activities. Collectively, polyQ aggregates of HTTs are a stable form and highly organized scaffold and mold for flat Golgi stacks/ribbons/vesicles, and the existence of mHTT in polyQ assemblies reduced ARF-related activities and impaired Golgi in striatal/cortical neurons.
ProteinAligner: A Multi-modal Pretraining Framework for Protein Foundation Models
Authors: Zhang Li , Guo Han , Schaffer Leah V , Ko Young Su , Singh Digvijay , Rahmani Hamid , Grotjahn Danielle , Villa Elizabeth , Gilson Michael , Wang Wei , Ideker Trey , Xing Eric , Xie Pengtao
Published: October 2024

Protein foundation models, particularly protein language models, have demonstrated strong success in learning meaningful representations of proteins using transformer architectures pretrained on large-scale protein datasets with self-supervised learning. These representations have been highly effective for downstream tasks such as predicting protein functions and properties. However, most current protein foundation models focus on pretraining with amino acid sequences, often neglecting additional modalities like protein structures and related literature, both of which provide valuable insights. To address this gap, we propose a multi-modal pretraining approach that integrates three key modalities - protein sequences, structures, and literature text. In our framework, the protein sequence modality serves as the anchor, with the other two modalities aligned to it, enhancing the model's capacity to capture more comprehensive protein information. ProteinAligner outperformed state-of-the-art protein foundation models in predicting protein functions and properties across diverse downstream tasks.
Decision analysis shows scientific and economic value of community-based monitoring in Madagascar
Authors: Soifer Lydia G. , Klinges David H. , Randriamiharisoa Lalatiana , Scheffers Brett R.
Published: October 2024

Community-based monitoring (CBM) could enable long-term biodiversity monitoring in remote areas and benefit local communities, but its benefits have rarely been quantified. We use a multi-criteria decision analysis framework to systematically examine the scientific and socioeconomic values and financial costs associated with biodiversity monitoring for vertebrates by scientists and local community members in six protected areas (PAs) in Madagascar, encompassing diverse ecosystems spanning tropical rainforests to spiny deserts. We compare the number of species observed during scientist and community surveys, identify the ‘ideal’ number of scientist and community surveys that would be required to maximize the scientific and socioeconomic values of monitoring efforts while minimizing financial cost, and compare monitoring plans across several conservation philosophies representing “ecocentric” and “people-centered” perspectives. Scientists generally observed more species than community members. However, including a greater proportion of surveys conducted by community members improves wildlife monitoring across PAs, taxonomic groups, and diverse conservation philosophies due to the lower financial cost of travel and compensation relative to monitoring exclusively conducted by scientists. While the valuation schemes we use are simplistic representations of the complex costs and values associated with CBM, this study indicates the benefits of community monitoring regardless of the conservation philosophy used to anchor valuation and decision-making. Increasing integration of CBM into existing conservation management could therefore offer a financially viable method to consistently monitor biodiversity and benefit local communities in the face of limited funding and global challenges.
Rapid and cost-effective production of high-quality insect genome sequences
Authors: Gilligan Josh , Inwood Sarah N , Harrop Thomas W.R. , Keddell Phoebe , McPhail Kate , Sproston Connor J , Williams Darren W , Petersen Gertje , Hovius Anton , Kaspar Julia , Guhlin Joseph G , Dearden Peter
Published: October 2024

Insects are the most diverse group of animals on earth, with nearly 1 million species described to date, yet this variation is not reflected within the ranks of genomes currently available. In the current age of genetics, the generation of high-quality reference genomes is invaluable, often necessary and expensive. We prove that insect genomes do not need to come at a large cost. We demonstrate a cost-efficient method for producing high-quality insect genomes, with comparisons to current reference assemblies.
Regional deficits in endogenous regeneration of mouse olfactory sensory neuron axons
Authors: Kunkhyen Tenzin , Curtis Kendall A. , Deakin Thomas P. , Huang Jane S. , Gregory Jordan D. , Cheetham Claire E.J.
Published: October 2024

Postnatal neurogenesis occurs in only a few regions of the mammalian nervous system. Hence, neurons that are lost due to neurodegenerative disease, stroke, traumatic brain injury or peripheral neuropathy cannot be replaced. Transplantation of stem cell-derived neurons provides a potential replacement strategy, but how these neurons can be encouraged to functionally integrate into circuits remains a significant challenge. In the mammalian olfactory epithelium (OE), olfactory sensory neurons (OSNs) continue to be generated throughout life from basal stem cells and can be repopulated even after complete ablation. However, the specialized population of navigator OSNs that ensures accurate odorant receptor-specific targeting of OSN axons to glomeruli in the olfactory bulb (OB) is only present perinatally. Despite this, some studies have reported complete regeneration of specific glomeruli, while others have found various degrees of recovery, following OSN cell death. Variability in the extent of both initial OSN ablation and subsequent repopulation of the OE, and the focus on anatomical recovery, leave the extent to which newly generated OSNs can reinnervate the OB unclear. Here, we employed the olfactotoxic drug methimazole to selectively ablate OSNs without damaging the basal stem cells that generate them, enabling us to assess the extent of functional recovery of OSN input to the OB in the context of complete OSN repopulation. We found profound deficits in the recovery of odor-evoked responses in OSN axons in the glomerular layer of the dorsal OB five weeks after OSN ablation, a time point at which OSNs are known to have repopulated the OE. Histological analysis of mature OSN axons in the OB at 10 and 20 weeks post-methimazole showed a persistent region-specific deficit in OSN axon reinnervation of the dorsal OB, with the dorsomedial region being particularly adversely affected. In contrast, reinnervation of the ventral, lateral and medial regions of the OB was almost complete by 10 weeks post-MMZ. Hence, we have identified a region-specific deficit in OSN reinnervation of the mouse OB, which sets the stage to identify the mechanisms that mediate successful vs. unsuccessful axonal regeneration in an endogenous population of stem cell-derived neurons.
Value Set Hub: Software for developing and curating high-quality value sets
Authors: Gold Sigfried , Flack Joseph E. , Lutters Wayne G. , Chute Christopher G.
Published: October 2024

Terminology value sets are central to research studies using real-world patient data. We describe the considerable challenges that arise when researchers develop value sets for their studies or reuse those made by others. We present Value Set Hub (VS-Hub), software to overcome these challenges, describing its design, implementation, features, use in the field, lessons learned, and future directions. Over a five-month period, VS-Hub has been used by over 200 users and has been used in the development and curation of 95 recommended value sets for commonly studied conditions, treatments, and lab tests. Particular innovations include the presentation of multiple value sets on the same screen for easy comparison, the display of compared value sets in the context of vocabulary hierarchies, the integration of these analytic features and value set authoring, and value set browsing features that encourage users to review existing value sets that may be relevant to their needs.