bluuebunny/crossref_metadata_2025 huggingface dataset:
Adlercreutzia wanghongyangiae sp. nov., and Adlercreutzia shanghongiae sp. nov., two new members of the genus Adlercreutzia isolated from plateau pika (Ochotona curzoniae)
Authors: Liu Xiaorui , Ye Lin , Yang Jing , Yang Caixin , Huang Yuyuan , Pu Ji , Liu Liyun , Zhou Huimin , Ning Shuo , Cao Linglin , Xu Jianguo
Published: October 2024

Four anaerobic, Gram-stain-positive, non-motile, non-sporulating rod-shaped bacterial strains (R7T, R21, R22 and R25T) were isolated from the intestinal contents of plateau pika (Ochotona curzoniae) collected from the Qinghai–Tibet Plateau, PR China. The four isolates grew at between 25 and 42 °C (optimally at 35–37 °C), and with 0.3–3.3% NaCl (w/v) [optimum, 1.3% (w/v)]. Adding l-arginine to the medium could promote their growth. Strains R7T and R21 were most closely related to Adlercreutzia caecimuris B7T (97.48% 16S rRNA gene sequence similarity). Strains R25T and R22 were most closely related to Adlercreutzia equolifaciens DSM 19450T (98.25% 16S rRNA gene sequence similarity). The genome sequences of R7T and R25T were 2.89 and 2.90 Mb in size with 63.6 and 62.8 mol% DNA G+C contents, respectively. Phylogenetic analysis based on 16S rRNA gene sequences and core genes revealed that R7T and R21 were most closely related to A. caecimuris B7T and Adlercreutzia mucosicola DSM 19490T, whereas R25T and R22 were most closely related to A. equolifaciens DSM 19450T and Adlercreutzia rubneri ResAG-91T. R7T, R25T and the closely related species had average nucleotide identity (ANI) values of 81.9–83.2% as well as digital DNA–DNA hybridisation (dDDH) values between 27.3 and 27.9%, which clearly indicated that they represent two novel species within the genus Adlercreutzia. For R7T and R25T, meso-diaminopimelic acid was the diagnostic diamino acid in the cell-wall peptidoglycan, and the whole cell sugars included galactose, glucose and ribose. On the basis of these results, we propose that strains R7T and R25T represent two novel species of the genus Adlercreutzia, namely Adlercreutzia wanghongyangiae sp. nov. and Adlercreutzia shanghongiae sp. nov., respectively. The type strains are R7T (=GDMCC 1.4459T=KCTC 25860T) and R25T (=GDMCC 1.4458T=KCTC 25861T).
Rhodococcus navarretei sp. nov. and Pseudarthrobacter quantipunctorum sp. nov., two novel species with the ability to biosynthesize fluorescent nanoparticles, isolated from soil samples at Union Glacier, Antarctica
Authors: Carrasco Valentina , Vargas-Reyes Matías , Lagos-Moraga Sebastián , Dietz-Vargas Claudio , Allendes-Ormazábal Daniela , Meza-Inzunza Juan , Rojas-Morales Fernanda , Durán-Villegas Sebastián , Valenzuela-Ibaceta Felipe , Cabrera Ma. Ángeles , Pérez-Donoso José M.
Published: October 2024

Two Gram-stain-positive bacterial strains, EXRC-4A-4T and RC-2-3T, were isolated from soil samples collected at Union Glacier, Antarctica. Based on 16S rRNA gene sequence similarity, strain EXRC-4A-4T was identified as belonging to the genus Rhodococcus, and strain RC-2-3T to the genus Pseudarthrobacter. Further genomic analyses, including average nucleotide identity and digital DNA–DNA hybridization, suggested that these strains represent new species. Strain EXRC-4A-4T exhibited growth at temperatures ranging from 4 to 28 °C (optimum between 20 and 28 °C), at pH 5.0–9.0 (optimum, pH 6.0), and in the presence of 0–5.0% NaCl (optimum between 0 and 1% NaCl). Strain RC-2-3T grew at 4–28 °C (optimum growth at 28 °C), pH 6.0–10 (optimum, pH 7.0) and in the presence of 0–5.0% NaCl (optimum, 1% NaCl). The fatty acid profile of EXRC-4A-4T was dominated by C17:1 ω-7, while that of RC-2-3T was dominated by anteiso-C15 : 0. The draft genome sequences revealed a DNA G+C content of 64.6 mol% for EXRC-4A-4T and 65.8 mol% for RC-2-3T. Based on this polyphasic study, EXRC-4A-4T and RC-2-3T represent two novel species within the genera Rhodococcus and Pseudarthrobacter, respectively. We propose the names Rhodococcus navarretei sp. nov. and Pseudarthrobacter quantipunctorum sp. nov. The type strains are Rhodococcus navarretei EXRC-4A-4T and Pseudarthrobacter quantipunctorum RC-2-3T. These strains have been deposited deposited in the CChRGM and BCCM/LMG culture collections with entry numbers RGM 3539/LMG 33621 and RGM 3538/LMG 33620, respectively.
Multiple stressors in river networks: local and downstream effects on freshwater macroinvertebrates
Authors: Burgazzi Gemma , Juvigny-Khenafou Noël P.D. , Schreiner Verena C. , Manfrin Alessandro , Jupke Jonathan , Piggott Jeremy , Harvey Eric , Terui Akira , Leese Florian , Schäfer Ralf B.
Published: October 2024

River networks are complex ecosystems characterized by a continuous exchange of material and energy through longitudinal gradients. These ecosystems are threatened by various human-induced stressors, which frequently co-occur and may interact in complex ways, potentially triggering cascading effects in the river network. Aiming at assessing single and combined effects of flow intermittency and light pollution on macroinvertebrate communities, we performed a multiple stressors experiment in 18 flow-through mesocosms. Each mesocosm was designed to mimic a simplified river network, with two upstream tributaries merging downstream, to assess both local and cascading effects. The experiment was performed in Summer 2021 for seven weeks (26 days of colonization, 23 days of treatment), applying the stressors either separately or combined in the upstream sections, in a randomized block design. Flow intermittency was simulated as the ponded phase of the drying process, whereas light pollution was applied with LED strips (set at 10 lux) that automatically turned on at sunset and off at sunrise. Drifting macroinvertebrates were sampled weekly during the treatment phase, and benthic macroinvertebrates at the end of the treatment phase. Both stressors individually applied had negative effects on the benthos, whereas drift decreased with flow intermittency and increased with light pollution. When combined upstream, stressors showed dominant effects of flow intermittency on the benthos and interactive effects on the drift. The effects of the single stressors and their interactions propagated along the river network, with stronger downstream effects when stressors co-occurred upstream. These findings showed that the spatial distribution of multiple stressors along the river network can affect their resultant downstream effects, highlighting the importance of framing multiple stressors research in a spatial context. Considering the pressing needs of the growing human population, our results represent a step forward in anticipating cumulative stressors effects, informing efficient conservation strategies for protecting freshwater ecosystems.
Attenuated ectopic action potential firing in parvalbumin expressing interneurons in a mouse model of Dravet Syndrome
Authors: Hill Sophie F. , Wengert Eric R. , Goldberg Ethan M. , Theyel Brian
Published: October 2024

Dravet syndrome is caused by heterozygous loss-of-function variants inSCN1A, which encodes the voltage-gated sodium channel Nav1.1. Our recent work suggests that a primary pathogenic mechanism of Dravet syndrome is impaired action potential propagation along axons of cortical parvalbumin-positive fast-spiking GABAergic interneurons (PVINs). Ectopic action potentials (EAPs) are action potentials that initiate distal to the axon initial segment. We recently demonstrated that a large proportion of PVINs fire EAPs during periods of increased excitation. Although their function remains unknown, EAPs may play a role in amplifying (when occurring in excitatory cells) and/or preventing seizures (when occurring in interneurons). Regardless of function, their generation in distal axons suggests that EAP frequency could be a useful proxy for distal axonal excitability. We hypothesized that EAPs are attenuated in PVINs from Dravet syndrome (Scn1a+/-) mice due to dysfunction of the distal axon. We induced EAPs in PVINs in acute brain slices prepared from male and female wildtype (WT) andScn1a+/-mice at P18-21 and P35-56, when we have previously identified axonal conduction deficits inScn1a+/-PVINs. We elicited EAPs in 17/22 (77%) of WT PVINs, including 6 (22%) that exhibited barrages of EAPs. In contrast,Scn1a+/-PVINs never fired barrages (0%), and only 8/23 (34%) exhibited even single EAPs. This finding adds to the body of evidence supporting impaired action potential propagation in Dravet syndrome PVINs, and is the first evidence of impaired EAP firing in a disease model, suggesting that dysregulation of EAPs could be involved in the pathophysiology of human disease.
Understanding the Challenges of Medicine Optimisation Among Older People from Ethnic Minority Communities (Aged 60 Years and Above) With Polypharmacy in Primary Care: A Realist Review Protocol
Authors: Hamed Nesrein , Bates Clare , Khan Muhammed Umair , Maidment Ian
Published: October 2024

Background

The number of older adults from ethnic minority communities (EMCs) in England and Wales particularly those aged 60 and above is increasing. This demographic change, which is usually coupled with the prevalence of polypharmacy among these populations presents unique challenges in the context of medicine optimisation. Failure in this context can lead to exacerbated health disparities, non-adherence, and inappropriate prescribing (whether over or under).

This review builds on the MEMORABLE study which was also a realist study that explored medication management in older people. This study aims to understand the complexities of medicine optimisation and what works and does not work, when and under what circumstances for older adults from EMCs. Key possible areas include cultural backgrounds, traditional beliefs, and systemic barriers that may influence health-seeking behaviours and medicine optimisation.

Methods

The review follows the five-step approach. Firstly, we will establish initial program theories to highlight the expected context, mechanisms, and outcomes. Following this, a formal search for evidence will be conducted. The third step involves the selection and appraisal of studies, studies will be screened by title, abstract/keywords and full text against inclusion and exclusion criteria. In the fourth stage, data from these studies will be extracted, recorded, and coded. The final step will synthesise this information, to test, refine, and expand our initial programme theories to understand how medicine optimisation works or does not work in these populations.

Discussion

This review will be conducted in line with the RAMESES reporting standards. This will include publishing the review in a scientific journal and submitting abstracts for presentation at both national and international primary care and pharmacy practice conferences. Once we improve the understanding of how medicine optimisation works for these populations with polypharmacy in primary care effective interventions can be developed.

Systematic review registration

PROSPERO registration number CRD42023432204
Changing pattern in presentation of infective conjunctivitis during COVID-19 pandemic in a tertiary eye hospital in Nepal
Authors: Thinley  , Gurung Reeta , Gurung Hom Bahadur , Poudel Manish , Banjara Pradeep
Published: October 2024

Purpose

To evaluate changes in the pattern of presentation of infective conjunctivitis during COVID-19 pandemic at a Tertiary Eye Hospital in Nepal.

Methods

This was a single-center retrospective cross-sectional study that analyzed cases of infective conjunctivitis at Tilganga Institute of Ophthalmology, Nepal from January 2018 to December 2022 using data from electronic medical records. The data from 2020 and 2021 were considered as the COVID era. Cases of corneal foreign body during the same period were used as a control.

Results

The number of cases of infective conjunctivitis decreased by 64.86% (95% CI, -64.82% to -64.94%; p<0.001) during the COVID-19 pandemic. Sharp decrease was noted after the implementation of lockdowns and preventive measures. However, in post-pandemic era, the number of cases increased by 24.6 % (95% CI, +24.57% to +24.66%; P<0.001). In contrast, the cases of corneal foreign body increased by 41.63 % (95% CI, +41.59% to +41.66%; p <0.001).

Conclusion

The number of cases of infective conjunctivitis at our hospital decreased significantly during the COVID-19 pandemic. This reduction in number and change in pattern of presentation might be attributed to the widespread implementation of preventive public health measures during the pandemic period.
Predicting Inhibitors of OATP1B1 via Heterogeneous OATP-Ligand Interaction Graph Neural Network (HOLIgraph)
Authors: Mardikoraem Mehrsa , Eaves Joelle N. , Belecciu Theodore , Pascual Nathaniel , Aljets Alexander , Hagenbuch Bruno , Shapiro Erik M. , Orlando Benjamin J. , Woldring Daniel R.
Published: October 2024

Organic anion transporting polypeptides (OATPs) are membrane transporters crucial for drug uptake and distribution in the human body. OATPs can mediate drug-drug interactions (DDIs) in which the interaction of one drug with an OATP impairs the uptake of another drug, resulting in potentially fatal pharmacological effects. Predicting OATP-mediated DDIs is challenging, due to limited information on OATP inhibition mechanisms and inconsistent experimental OATP inhibition data across different studies. This study introduces Heterogeneous OATP-Ligand Interaction Graph Neural Network (HOLIgraph), a novel computational model that integrates molecular modeling with a graph neural network to enhance the prediction of drug-induced OATP inhibition. By combining ligand (i.e., drug) molecular features with protein-ligand interaction data from rigorous docking simulations, HOLIgraph outperforms traditional DDI prediction models which rely solely on ligand molecular features. HOLIgraph achieved a median balanced accuracy of over 90 percent when predicting inhibitors for OATP1B1, significantly outperforming purely ligand-based models. Beyond improving inhibition prediction, the data used to train HOLIgraph can enable the characterization of protein residues involved in inhibitory drug-OATP interactions. We identified certain OATP1B1 residues that preferentially interact with inhibitors, including I46 and K49. We anticipate such interaction information will be valuable to future structural and mechanistic investigations of OATP1B1.

Scientific Contribution

HOLIgraph introduces a new paradigm for DDI prediction by incorporating protein-ligand interactions derived from docking simulations into a graph neural net framework. This approach, enabled by recent structural breakthroughs for OATP1B1, represents a significant departure from traditional models that rely only on ligand features. By achieving high predictive accuracy and uncovering mechanistic insights, HOLIgraph sets a new trajectory for computational tools in drug design and DDI prediction.
Representation of male features in the female mouse Accessory Olfactory Bulb, and their stability during the estrus cycle
Authors: Cohen Oksana , Ben-Shaul Yoram
Published: October 2024

Most behaviors result from integration of external and internal inputs. For example, social behavior requires information about conspecifics and internal physiological states. Like many other mammals, female mice undergo a reproductive cycle during which their physiology and behavioral responses to males change dramatically: during estrus, they are more receptive to male mating attempts. A critical element in reproductive behavior is the investigative stage, which in mice, and many other species, strongly relies on chemosensation. While the initial approach mostly involves the main olfactory system (MOS), once physical contact is established, the vomeronasal system (VNS) is engaged to provide information about potential partners’ characteristics. Given the estrus-stage dependent behavioral response, we asked whether representations of male features in the first brain relay of the VNS, namely, the accessory olfactory bulb (AOB), change during the cycle. To this end, we used a stimulus set comprising urine samples from males from different strains and virility levels, and from estrus and non-estrus females. The stimulus set was designed to reveal if response patterns of AOB neurons conform to ethologically relevant dimensions such as sex, strain, and particularly, male virility state. Using extracellular recordings in anesthetized female mice, we find that most ethological categories contained in our data set are not over-represented by AOB neurons, suggesting that early stages of VNS processing encode conspecific information efficiently. Then, comparing neuronal activity in estrus and non-estrus females, we found that overall, response characteristics at the single neuron and population levels remain stable during the reproductive cycle. The few changes that do occur, are not consistent with a systematic modulation of responses to male features. Our findings imply that the AOB presents a stable account of conspecific features to more advanced processing stages.
Mapping grey and white matter activity in the human brain with isotropic ADC-fMRI
Authors: Spencer Arthur P C , Nguyen-Duc Jasmine , de Riedmatten Inès , Szczepankiewicz Filip , Jelescu Ileana O
Published: October 2024

Functional MRI (fMRI) using the blood-oxygen level dependent (BOLD) signal provides valuable insight into grey matter activity. However, uncertainty surrounds the white matter BOLD signal. Apparent diffusion coefficient (ADC) offers an alternative fMRI contrast sensitive to transient cellular deformations during neural activity, facilitating detection of both grey and white matter activity. Further, through minimising vascular contamination, ADC-fMRI has the potential to overcome the limited temporal specificity of the BOLD signal. However, the use of linear diffusion encoding introduces sensitivity to fibre directionality, while averaging over multiple directions comes at great cost to temporal resolution. In this study, we used spherical b-tensor encoding to impart diffusion sensitisation in all directions per shot, providing an ADC-fMRI contrast capable of detecting activity independently of fibre directionality. We provide evidence from two task-based experiments on a clinical scanner that isotropic ADC-fMRI is more temporally specific than BOLD-fMRI, and offers more balanced mapping of grey and white matter activity. We further demonstrate that isotropic ADC-fMRI detects white matter activity independently of fibre direction, while linear ADC-fMRI preferentially detects activity in voxels containing fibres perpendicular to the diffusion encoding direction. Thus, isotropic ADC-fMRI opens avenues for investigation into whole-brain grey and white matter functional connectivity.
Macrophages expressing chimeric cytokine receptors have an inflammatory phenotype and anti-tumoral activity upon IL-10 or TGFβ stimulation
Authors: Traxel Sabrina , Schmidt Florian , Beerli Corina , Vuong Dinh-Van , Speck Roberto F. , Bredl Simon
Published: October 2024

Background: Triple-negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that lacks hormone receptors and HER2 amplification, making it unresponsive to standard hormone or HER2-targeted therapies. Although immune checkpoint inhibitors (ICIs) have shown promise in tumors with high lymphocyte infiltration, their efficacy remains limited in tumors with minimal lymphocyte infiltration. To overcome this challenge, we developed a novel approach to reprogram tumor-associated macrophages (TAMs) from an immunosuppressive to an inflammatory phenotype within the tumor microenvironment (TME), aiming to enhance therapeutic outcomes in TNBC. Methods: We designed a chimeric cytokine receptor (ChCR) that triggers STAT1 signaling upon stimulation with IL-10 or TGFβ, cytokines prevalent in the TME that typically drive immunosuppression. Human primary macrophages were transduced with a lentiviral vector expressing the ChCR. Changes in their phenotype, secretome, and transcriptome were analyzed following stimulation. The anti-tumoral activity of these reprogrammed macrophages was assessed using co-culture assays with 3D TNBC spheroids. Results: ChCR-expressing macrophages showed robust STAT1 activation in response to IL-10 or TGFβ stimulation, resulting in an inflammatory phenotype similar to IFNγ activation, as confirmed by phenotypic markers, and transcriptomic profiling. These ChCR-stimulated macrophages demonstrated significant anti-tumoral effects in 3D TNBC spheroids. Moreover, ChCR stimulation led to the upregulation of CXCL9 and CXCL10, chemokines essential for lymphocyte recruitment, and genes associated with good response to ICIs. Conclusion: We successfully engineered ChCRs that reprogram TAMs within an IL-10- and TGFβ-rich environment, inducing an inflammatory phenotype and anti-tumoral activity. The expression of CXCL9 and CXCL10 further supports lymphocyte recruitment, potentially facilitating greater lymphocyte infiltration and disrupting the immunosuppressive TME. This approach offers a promising strategy to improve immunotherapy outcomes in TNBC patients, particularly those with low immune cell infiltration, thereby addressing a critical unmet clinical need.
Synthetic chaperone based on Hsp90-Tau interaction inhibits pathological Tau aggregation and rescues physiological Tau-Microtubule interaction
Authors: Di Lorenzo Davide , Bisi Nicolo , Kaffy Julia , Ramirez Lisa Marie , Zweckstetter Markus , Lequin Olivier , Garfagnini Irene , Luo Jinghui , Hannappel Yvonne , Ennen Inga , Dodero Veronica , Sewald Norbert , Gelmi Maria Luisa , Tonali Nicolo , Brandt Roland , Ongeri Sandrine
Published: October 2024

The accumulation of intracellular aggregates of Tau protein is one main hallmark of Alzheimer’s disease (AD) and is the consequence of Tau conformational changes, increased phosphorylation, and self-association to form fibrillar aggregates. This pathological process prevents the physiological interaction of Tau with microtubules to the detriment of the structural integrity of neurons. In healthy cells, aberrant protein misfolding and aggregation are counteracted by chaperone proteins whose protective capacity decreases with age. The role of the chaperone Hsp90 and the mechanism by which it can prevent Tau aggregation toxicity are controversial. The innovative strategy of mimicking Hsp90 through the design of the β-hairpin like peptidomimeticβ-Hsp90, inspired by two Hsp90/Tau interaction sequences, is presented here.β-Hsp90inhibits Tau aggregation bothin vitroandin cells, restoring Tau’s physiological interaction with microtubules.β-Hsp90, which interacts with the P1 region of Tau, is more effective than individual peptide sequences from the chaperone HSP90 and another β-hairpin mimic based on Tau sequences. Moreover,β-Hsp90dramatically reduces AD-associated Aβ1-42aggregation, offering the development of a dual inhibitor. This work paves the way for the design of new drugs targeting devastating untreated amyloid diseases, by mimicking physiological chaperones with small synthetic peptide drugs.
A stepwise, modular design of building uniform brain assembloids representing the dynamic cellular interplay between neurons and glial cells
Authors: Kim Eunjee , Kim Yunhee , Hong Soojung , Kim Inha , Lee Juhee , Yoo Jong-Yeon , Kim Jihyun , Yoo Kwangmin , Kim Joung-Hun , Choi Jungmin , Shin Kunyoo
Published: October 2024

Current brain organoid technology fails to provide adequate patterning cues to induce a mature structure that represent the complexity of the human brain. Here, we developed a module-based cellular reconstitution technology to sequentially build uniform forebrain assembloids with mature cortical structures and functional connectivity. The uniformity and maturity of the newly-conceived forebrain assembloids were achieved by creating single-rosette-based organoids at the early stage, whose sizes were big and consistent with the treatment of Wnt and Hedgehog agonists, followed by spatial reconstitution with the Reelin-expressing neuronal layer and non-neuronal glial cells. The resulting single-rosette-based forebrain assembloids were highly uniform and reproducible without significant batch effects, solving major heterogeneity issues caused by difficulties in controlling the number and size of rosettes in conventional multi-rosette organoids. Furthermore, these forebrain assembloids structurally and functionally recapitulated the physiology of the human brain, including the six-layered cortical structure, functional connectivity, and dynamic cellular interplay between neurons and glial cells. Our study thus provided an innovative preclinical model to study a range of neurological disorders, understanding the pathogenesis of which requires an organoid system capable of representing the dynamic cellular interactions and the maturity of the human brain.
A low-cost, open-source 3D printer for multimaterial and high-throughput direct ink writing of soft and living materials
Authors: Weiss Jonathan D. , Mermin-Bunnell Alana , Solberg Fredrik S. , Tam Tony , Rosalia Luca , Sharir Amit , Rütsche Dominic , Sinha Soham , Choi Perry S. , Shibata Masafumi , Palagani Yellappa , Nilkant Riya , Paulvannan Kiruthika , Ma Michael , Skylar-Scott Mark A.
Published: October 2024

Direct ink writing is a 3D printing method that is compatible with a wide range of structural, elastomeric, electronic, and living materials, and it continues to expand its uses into physics, engineering, and biology laboratories. However, the large footprint, closed hardware and software ecosystems, and expense of commercial systems often hamper widespread adoption. Here, we present a compact, simple-to-build, low-cost, multimaterial, and high-throughput direct ink writing 3D printer platform with detailed assembly files and instructions provided freely online. In contrast to existing low-cost 3D printers and bioprinters, which typically modify off-the-shelf plastic 3D printers, this system is built from scratch, offering a lower cost and full customizability. Despite its low cost, we demonstrate advanced active mixing and multimaterial multinozzle 3D (MM3D) printing methods, which previously have relied on expensive and custom motion control platforms. We finally introduce embedded multinozzle and 3D gradient nozzle designs that offer high throughput and graded 3D parts. This powerful, easy-to-build, and customizable printing platform can help stimulate a vibrant biomaker community of engineers, biologists, and educators.
mTOR signaling promotes cytokine production in T cells through 3’UTR-mediated translation control
Authors: Jurgens Anouk P. , Zwijnen Josephine , van Alphen Floris P.J. , Bradarić Antonia , Rooijers Koos , Hoogendijk Arie J. , Popović Branka , Wolkers Monika C.
Published: October 2024

T cells are key contributors to clear our body from infected and malignant cells. When T cells respond to target cells, they undergo profound translational alterations. The evolutionary and highly conserved kinase mammalian target of rapamycin (mTOR) is a central mediator of T cell differentiation, homeostasis, and T cell activation, including the production of the key pro-inflammatory cytokines TNF, IL2, and IFNγ. mTOR was shown to execute its translation activity through TOP motifs located in the 5’ Untranslated region (5’UTR) of its target genes. Here, we uncovered a distinct mechanism of mTOR signaling on cytokine production in T cells, which is under control of the 3’UTR. Even though non-classical TOP motifs are present in cytokine 3’UTRs, they do not contribute to mTOR-mediated translation regulation. Rather, AU-rich elements (AREs) are required for mTOR-mediated cytokine production. Furthermore, we discovered that the RNA binding protein DDX21 binds to 3’UTR AREs and confers the mTOR-mediated translation control. In conclusion, we here present a previously unappreciated ARE-dependent, 3’UTR-mediated mode of action that mTOR employs to regulate cytokine production.
Spatiotemporal patterns of theta-band activity during rapid-eye movement sleep: a magnetoencephalography analysis
Authors: Provias Vasiliki , Schoenauer Monika , Gais Steffen , Albouy Philippe , Born Jan , Bergmann Til Ole , Coffey Emily BJ
Published: October 2024

Theta oscillations (4-8 Hz) in frontal cortical regions are present to different degrees across states of consciousness. In sleep, theta is prominent in periods of rapid eye-movement (REM) sleep. Theta has been linked to processes of memory consolidation; however, its mechanistic contribution specifically during REM sleep is not well understood. Interestingly, in the wake state, frontal theta activity increases during effortful cognitive tasks involving executive functions such as working memory, hinting at similarities in circuitry, and potentially, function. The aim of the present work is to create a spatially resolved, whole-brain characterisation of REM oscillatory activity in healthy human subjects, distinguishing theta from neighbouring frequency bands, differentiating substages of REM sleep (phasic and tonic REM), and comparing REM theta to that which is evoked during a working memory task. To that end, we analysed magneto- and electroencephalography (M/EEG) data recorded during overnight sleep in 10 healthy subjects, and similar data from 17 healthy subjects who performed a working memory task, using a novel whole-brain, source-localised MEG approach. Our results show that (i) theta activity has a frontal midline topography that is distinct from those of other prominent frequency bands in REM (delta, alpha, beta), (ii) theta activity in frontal midline regions is best observed within a focused 5-7 Hz range, separating it from occipital alpha activity, (iii) REM theta is dominant over the frontal midline but is also observed in several sub-cortical areas, (iv) theta is more widespread in tonic than phasic REM sleep, and (v) the focused frontal midline theta pattern observed in REM phasic sleep is the most similar of all observed sleep substages to theta evoked by a working memory task. These results enhance our understanding of theta physiology in REM sleep and suggest future targets for research into REM's role in learning and memory.
ClassiCOL: LC-MS/MS analysis for ancient species Classification via Collagen peptide ambiguation
Authors: Engels Ian , Burnett Alexandra , Robert Prudence , Pironneau Camille , Abrams Grégory , Bouwmeester Robbin , Van der Plaetsen Peter , Di Modica Kévin , Otte Marcel , Straus Lawrence Guy , Fischer Valentin , Bray Fabrice , Mesuere Bart , De Groote Isabelle , Deforce Dieter , Daled Simon , Dhaenens Maarten
Published: October 2024

LC-MS/MS extends on the MALDI-TOF ZooMS approach by providing fragmentation spectra for each peptide. However, ancient bone samples generate sparse datasets containing only a few collagen proteins, rendering target-decoy strategies unusable and increasing uncertainty in peptide annotation. ClassiCOL embraces and even extends this ambiguity using a novel ‘isoBLAST’ approach. The exhaustive set of potential peptide candidates created in this way is then used to retain or reject different potential paths at each taxonomic branching point down to the taxonomic level attainable with the sample information, always allowing for potential mixtures in the process. As an end point, all considered ambiguity is graphically represented with a clear prioritization of the species in the sample. Using public as well as in-house data, we demonstrate the performance of this universal postprocessing approach on different instruments and explore the possibility of identifying genetic as well as sample mixtures. Diet reconstruction from 40,000 year old cave hyena coprolites illustrates the exciting potential of this approach.

Teaser

ClassiCOL is a postprocessing tool that allows for more accurate species classification from LC-MS/MS measurements of collagen.
STARTS: A self-adapted spatio-temporal framework for automatic E/MEG source imaging
Authors: Feng Zhao , Guan Cuntai , Sun Yu
Published: October 2024

To obtain accurate brain source activities, the highly ill-posed source imaging of electro- and magneto-encephalography (E/MEG) requires proficiency in incorporation of biophysiological constraints and signal-processing techniques. Here, we propose a spatio-temporal-constrainted E/MEG source imaging framework-STARTS that can reconstruct the source in a fully automatic way. Specifically, a block-diagonal covariance was adopted to reconstruct the source extents while maintain spatial homogeneity. Temporal basis functions (TBFs) of both sources and noises were estimated and updated in a data-driven fashion to alleviate the influence of noises and further improve source localization accuracy. The performance of the proposed STARTS was quantitatively assessed through a series of simulation experiments, wherein superior results were obtained in comparison with the benchmark ESI algorithms (including LORETA, EBI-Convex, & SI-STBF). Additional validations on epileptic and resting-state EEG data further indicate that the STARTS can produce neurophysiologically plausible results. Moreover, a computationally efficient version of STARTS–smooth STARTS was also introduced with an elementary spatial constraint, which exhibited comparable performance and reduced execution cost. In sum, the proposed STARTS, with its advanced spatio-temporal constraints and self-adapted update operation, provides an effective and efficient approach for E/MEG source imaging.
scChat: A Large Language Model-Powered Co-Pilot for Contextualized Single-Cell RNA Sequencing Analysis
Authors: Lu Yen-Chun , Varghese Ashley , Nahar Rahul , Chen Hao , Shao Kunming , Bao Xiaoping , Li Can
Published: October 2024

Data-driven methods, including unsupervised and supervised learning, have become essential tools for analyzing single-cell RNA sequencing (scRNA-seq) data. However, these approaches cannot incorporate research context into the analysis, limiting their ability to provide in-depth, contextual insights to researchers. We introduce scChat, a pioneering AI assistant designed for contextualized scRNA-seq analysis. Unlike existing tools that focus on standard tasks like cell annotation, scChat offers advanced capabilities, including research context-based analysis of experimental outcomes, detailed validation of research hypotheses, identification of potential explanations when hypotheses fail, and suggestions for next-step experimental design. Powered by a large language model (LLM), scChat integrates function calls for quantitative tasks, employs retrieval-augmented generation to reduce hallucination, and uses an LLM-powered search engine to seamlessly incorporate current literature into the analytical conversation.
Meru co-ordinates spindle orientation with cell polarity and cell cycle progression
Authors: McLellan Melissa M. , Aerne Birgit L. , Dhoul Jennifer J. Banerjee , Tapon Nicolas
Published: October 2024

Correct mitotic spindle alignment is essential for tissue architecture and plays an important role in cell fate specification through asymmetric cell division. Spindle tethering factors such asDrosophilaMud (NuMA in mammals) are recruited to the cell cortex and capture astral microtubules, pulling the spindle in the correct orientation. However, how spindle tethering complexes read the cell polarity axis and how spindle attachment is coupled to mitotic progression remains poorly understood. We explore these questions inDrosophilasensory organ precursors (SOPs), which divide asymmetrically to give rise to the epidermal mechanosensory bristles. We show that the scaffold protein Meru, which is recruited to the posterior cortex by the Frizzled/Dishevelled planar cell polarity complex, in turn recruits Mud, linking the spindle tethering and polarity machineries. Furthermore, Cyclin A/Cdk1 associates with Meru at the posterior cortex, promoting the formation of the Mud/Meru/Dsh complex via Meru and Dsh phosphorylation. Thus, Meru couples spindle orientation with cell polarity and provides a cell cycle-dependent cue for spindle tethering.
Myocarditis and neutrophil-mediated vascular leakage but not cytokine storm associated with fatal murine leptospirosis
Authors: Papadopoulos Stylianos , Hardy David , Vernel-Pauillac Frédérique , Tichit Magali , Boneca Ivo G. , Werts Catherine
Published: October 2024

Leptospirosis is a neglected re-emerging zoonosis caused byLeptospiraspirochetes. Its pathophysiology remains mysterious, especially in the case of severe infection withL. interrogans.

In the field of infectious diseases, the cause of death is rarely investigated in preclinical models. Here, for the first time, we identified unanticipated organ failures associated with death in a murine model of acute leptospirosis.

Despite clinical similarities between bacterial sepsis and leptospirosis, striking differences were observed. Neither lung, liver, or kidney injury nor cytokine storm, or massive necroptosis could explain death. In contrast, severe leptospirosis was associated with high serum levels of the anti-inflammatory cytokine IL-10 and the chemokine RANTES, neutrophilia, pancreatitis and vascular damage. Unexpectedly, we demonstrated neutrophil-induced vascular permeability, making neutrophils a potential new therapeutic target. Strikingly, the main cause of death was myocarditis, an overlooked complication of human leptospirosis.

These features are also found in patients, making this model a paradigm for better understanding human leptospirosis and designing novel therapeutic strategies.
A three-country analysis of the gut microbiome indicates taxon associations with diet vary by location and strain
Authors: Khatib Lora , Song Se Jin , Dilmore Amanda H , Sanders Jon G , Brennan Caitriona , Hernandez Alejandra Rios , Myers Tyler , Oles Renee , Farmer Sawyer , Cowart Charles , Birmingham Amanda , Diaz Edgar A. , Nizet Oliver , Gilbert Kat , Litwin Nicole , Das Promi , Nowinski Brent , Bryant Mackenzie , Tribelhorn Caitlin , Sanders-Bodai Karenina , Chaumont Soline , Knol Jan , Roeselers Guus , Laiola Manolo , Shetty Sudarshan A. , Veiga Patrick , Tap Julien , Derrien Muriel , Koutnikova Hana , Cotillard Aurélie , Lay Christophe , Tovar Armando R. , Torres Nimbe , Arteaga Liliana , González Antonio , McDonald Daniel , Bartko Andrew , Knight Rob
Published: October 2024

Emerging research suggests that diet plays a vital role in shaping the composition and function of the gut microbiota. While significant efforts have been made to identify general patterns linking diet to the gut microbiome, much of this research lacks representation from low- and middle-income countries such as Mexico. Additionally, both diet and the gut microbiome have highly complex and individualized configurations, and there is growing evidence that tailoring diets to individual gut microbiota profiles may optimize the path toward improving or maintaining health and preventing disease. Using fecal metagenomic data from 1,291 individuals across three countries, we examine two bacterial genera prevalent in the human gut,PrevotellaandFaecalibacterium, which have gained significant attention due to their potential roles in human health. We find that they show significant associations with many aspects of diet, but that these associations vary in scale and direction, depending on the level of metagenomic resolution and the contextual population. These results highlight the growing importance of assembling metagenomic datasets that are standardized, comprehensive, and representative of diverse populations to increase our ability to tease apart the complex relationship between diet and the microbiome.
A combinatorial approach to ALS therapies in the PrP.TDP43-315 model of ALS; complications and tribulations
Authors: Fromholt Susan , Lopez Amanda , Xu Guilian , Lu Qing , Wymer James , Borchelt David R.
Published: October 2024

Effective treatment for sporadic amyotrophic lateral sclerosis has been steadily advancing towards combinatorial therapies. For many years, riluzole was the only approved drug and it offered modest benefits. In 2017, edaravone was approved for ALS and became the first drug to be used in combination with riluzole. In the present study, we have attempted to build on the concepts of combinatorial therapy by testing novel drug combinations in a transgenic mouse model. Mice that express A315T mutant TDP43, using the mouse prion promoter, have been reported to develop many of the symptoms of ALS, including paralysis. Aberrant TDP43 function is a common feature in sporadic ALS, and thus TDP43 transgenic models may recapitulate disease processes that occur in humans with sporadic ALS. Although the PrP.TDP43-A315T model has been reported to develop abnormalities in gut motility that contribute to early mortality, recent studies indicated that gut motility issues could be mitigated by feeding mice with gel-based diets rather than the standard dry chow. In the present study, we have attempted to use the PrP.TDP43-A315T model to test whether we could identify a drug combination that synergized to extend life span in this model substantially. The drug combinations were built around the existing drug modalities, adding additional drugs that had indications of utility from the literature. To mitigate gut motility issues, we fed the mice gel-based diets with or without added drug combinations. Although the gel-based diets extended life expectancy in PrP.TDP43-A315T mice, most of the animals still developed gut motility abnormalities that may have contributed to early mortality. None of the drug combinations we tested extended life expectancy in this model substantially.
Assembly of branched chain amino acid (BCAA) to toxic fibrils may be related to pathogenesis of Maple syrup urine disease (MSUD)
Authors: Kanth Chandra P , Patel Monisha , Dave Raj , Singh Ankur , Joshi Aayushi , Pandey Manoj Kumar , Bhatia Dhiraj , Gour Nidhi
Published: October 2024

Inborn errors of metabolism (IEMs) are a group of diseases caused by mutations in single genes, leading to the buildup of metabolites that are typically toxic or disrupt normal cellular function. The etiological relation of metabolic disorders has been uncovered through the study of metabolite amyloids. Various metabolites that accumulate in IEMs have been reported to self-assemble into organized structures. These structures exhibit similar physicochemical properties as proteinaceous amyloid fibrils. In this context, our study illustrated the aggregation properties of Branched chain amino acid (BCAA) i.e. Isoleucine, Leucine and Valine that accumulate in Maple syrup urine disease (MSUD) to investigate their propensities to assemble into amyloid-like fibrils. The structural morphologies of BCAA were studied via. microscopic techniques like Scanning electron microscopy (SEM), optical microscopy and phase contrast microscopy. Further, characterization techniques were employed to understand the physicochemical properties of the self-assemblies and its underlying mechanism. The amyloid-like nature of these aggregates was confirmed using Thioflavin T (ThT) and Congo Red (CR) assays, indicating a possible cytotoxic effect. The MTT assay reveals BCAAs were cytotoxic and significantly decrease cell viability. Our study plays a key role in understanding the physicochemical properties of MSUD in association to amyloid disease, possibly paving the way for the development of therapeutic solutions in the future.

Graphical Abstract

The self-assembly of BCAA-Ile, Leu, Val was investigated and the findings indicate that their aggregation may follow an amyloidogenic pathway.
Live-cell transcriptomics with engineered virus-like particles
Authors: Najia Mohamad Ali , Borrajo Jacob , Le Anna , Tsai FuNien , Huang Jeremy Y. , Griffith Linda G. , Daley George Q. , Blainey Paul C.
Published: October 2024

The transcriptional state of a cell provides a multi-parameter representation of gene expression programs that reflect its identity and phenotype. However, current transcriptomic profiling technologies result in destruction of the biological sample, preventing direct analysis of transcriptional dynamics in the same living cells over time. Here, we developed a synthetic RNA export system called cellular ‘self-reporting’ to address this fundamental technological limitation. We repurposed the murine leukemia virus retroviral protein Gag to enable diverse types of immortalized and primary mammalian cells to package cellular RNA molecules in virus-like particles (VLPs) for export into the extracellular environment. We applied self-reporting to interrogate the transcriptome-wide dynamics that occur during neuronal differentiation from induced pluripotent stem cells and detected gene expression profiles from individual live cells. Leveraging this genetically encodable approach, we expanded the capabilities of self-reporting through molecular engineering of VLP components. Pseudotyping VLPs with epitope-tagged envelope proteins enabled multiplexed selective live-cell readout of transcriptional states from heterogeneous co-cultures. Furthermore, structure-guided protein engineering of Gag fusions with human RNA binding domains improved the mRNA representation in self-reporting readouts and enabled the directed export of libraries of synthetic barcode transcripts. Taken together, this work establishes self-reporting as a facile and broadly enabling technology for live-cell, transcriptome-scale profiling of dynamic processes across diverse cell types and biological applications.
G4mer: An RNA language model for transcriptome-wide identification of G-quadruplexes and disease variants from population-scale genetic data
Authors: Zhuang Farica , Gutman Danielle , Islas Nathaniel , Guzman Bryan B , Jimenez Alli , Jewell San , Hand Nicholas J , Nathanson Katherine , Dominguez Daniel , Barash Yoseph
Published: October 2024

RNA G-quadruplexes (rG4s) are key regulatory elements in gene expression, yet the effects of genetic variants on rG4 formation remain underexplored. Here, we introduce G4mer, an RNA language model that predicts rG4 formation and evaluates the effects of genetic variants across the transcriptome. G4mer significantly improves accuracy over existing methods, highlighting sequence length and flanking motifs as important rG4 features. Applying G4mer to 5’ untranslated region (UTR) variations, we identify variants in breast cancer-associated genes that alter rG4 formation and validate their impact on structure and gene expression. These results demonstrate the potential of integrating computational models with experimental approaches to study rG4 function, especially in diseases where non-coding variants are often overlooked. To support broader applications, G4mer is available as both a web tool and a downloadable model.