bluuebunny/crossref_metadata_2025 huggingface dataset:
Unified cross-modality integration and analysis of T-cell receptors and T-cell transcriptomes
Authors: Gao Yicheng , Dong Kejing , Gao Yuli , Jin Xuan , Liu Qi
Published: August 2023

Single-cell RNA sequencing and T-cell receptor sequencing (scRNA-seq and TCR-seq, respectively) technologies have emerged as powerful tools for investigating T-cell heterogeneity. However, the integrated analysis of gene expression profiles and TCR sequences remains a computational challenge. Herein, we present UniTCR, a unified framework designed for the cross-modality integration and analysis of TCRs and T-cell transcriptomes for a series of challenging tasks in computational immunology. By utilizing a dual-modality contrastive learning module and a single-modality preservation module to effectively embed each modality into a common latent space, UniTCR demonstrates versatility across various tasks, including single-modality analysis, modality gap analysis, epitope-TCR binding prediction and TCR profile cross-modality generation. Extensive evaluations conducted on multiple scRNA-seq/TCR-seq paired datasets showed the superior performance of UniTCR. Collectively, UniTCR is presented as a unified and extendable framework to tackle diverse T-cell-related downstream applications for exploring T-cell heterogeneity and enhancing the understanding of the diversity and complexity of the immune system.
LIANA+: an all-in-one cell-cell communication framework
Authors: Dimitrov Daniel , Schäfer Philipp Sven Lars , Farr Elias , Rodriguez Mier Pablo , Lobentanzer Sebastian , Dugourd Aurelien , Tanevski Jovan , Ramirez Flores Ricardo Omar , Saez-Rodriguez Julio
Published: August 2023

The growing availability of single-cell and spatially-resolved transcriptomics has led to the rapidly growing popularity of methods to infer cell-cell communication. Many approaches have emerged, each capturing only a partial view of the complex landscape of cell-cell communication.

Here, we present LIANA+, a scalable framework to decode coordinated inter- and intracellular signalling events from single- and multi-condition datasets in both single-cell and spatially-resolved data. Beyond integrating and extending established methodologies and a rich knowledge base, LIANA+ enables novel analyses using diverse molecular mediators, including those measured in multi-omics data. Accessible as an open-source Python package athttps://github.com/saezlab/liana-py, LIANA+ provides a comprehensive set of synergistic components to study cell-cell communication.

Abstract Figure
Cross-tissue comparison of telomere length and quality metrics of DNA among individuals aged 8 to 70 years
Authors: Wolf Sarah E. , Hastings Waylon J. , Ye Qiaofeng , Etzel Laura , Apsley Abner T. , Chiaro Christopher , Heim Christine C. , Heller Thomas , Noll Jennie G. , Schreier Hannah M.C. , Shenk Chad E. , Shalev Idan
Published: August 2023

Telomere length (TL) is an important biomarker of cellular aging, yet its links with health outcomes may be complicated by use of different tissues. We evaluated within- and between-individual variability in TL and quality metrics of DNA across five tissues using a cross-sectional dataset ranging from 8 to 70 years (N=197). DNA was extracted from all tissue cells using the Gentra Puregene DNA Extraction Kit. Absolute TL (aTL) in kilobase pairs was measured in buccal epithelial cells, saliva, dried blood spots (DBS), buffy coat, and peripheral blood mononuclear cells (PBMCs) using qPCR. aTL significantly shortened with age for all tissues except saliva and buffy coat, although buffy coat was available for a restricted age range (8 to 15 years). aTL did not significantly differ across blood-based tissues (DBS, buffy coat, PBMC), which had significantly longer aTL than buccal cells and saliva. Additionally, aTL was significantly correlated for the majority of tissue pairs, with partial Spearman’s correlations controlling for age and sex ranging from ⍴ = 0.18 to 0.51. We also measured quality metrics of DNA including integrity, purity, and quantity of extracted DNA from all tissues and explored whether controlling for DNA metrics improved predictions of aTL. We found significant tissue variation: DNA from blood-based tissues had high DNA integrity, more acceptable A260/280 and A260/230 values, and greater extracted DNA concentrations compared to buccal cells and saliva. Longer aTL was associated with lower DNA integrity, higher extracted DNA concentrations, and higher A260/230, particularly for saliva. Model comparisons suggested that incorporation of quality DNA metrics improves models of TL, although relevant metrics vary by tissue. These findings highlight the merits of using blood-based tissues and suggest that incorporation of quality DNA metrics as control variables in population-based studies can improve TL predictions, especially for more variable tissues like buccal and saliva.
Interspecific continuity of normative systems (the end of the paradigm of human exceptionalism)
Authors: Gandarillas Chicote L. , De La Cuesta Aguado P.M.
Published: August 2023

After fifteen years observing a troop of western lowland gorillas (Gorilla gorilla) outside their natural habitat under human care we believe we can demonstrate that gorillas govern their behavior and social interactions by norms functionally equivalent to legal norms that pursue group stability and social peace maintenance and can be “translated” into concepts created for legal science. Consequently, we conclude that also in the legal sciences and, especially, in the juridicial-criminal science, the paradigm of human exceptionality must be overcome to open the doors to reflect on the possibility of establishing the paradigm of continuity between human and non-human normative systems.
Paneth cells disruption and intestinal dysbiosis contribute to the development of Hirschsprung-associated enterocolitis in a benzalkonium chloride-induced Hirschsprung’s disease rat model
Authors: Budianto Iskandar Rahardjo , Kusmardi Kusmardi , Maulana Andi Muhammad , Arumugam Somasundaram , Afrin Rejina , Soetikno Vivian
Published: August 2023

Background

Hirschsprung-associated enterocolitis (HAEC) is a life-threatening complication of Hirschsprung’s disease (HSCR). This study investigated the role of Paneth cells (PCs) and gut microbiota in HAEC development.

Methods

Male Sprague-Dawley rats with HSCR were established by exposure of 0.1% (n = 30) benzalkonium chloride (BAC) to rectosigmoid serosa and sacrificed at 1-, 3-, 5-, 8-, and 12-weeks postintervention. The sham group was included and sacrificed on Week 12. Hematoxylin-Eosin staining was conducted to count the number of ganglionic cells and analyze the degree of enterocolitis. Intestinal barrier function was assessed for the ratio of anti-peripherin, occludin and acetylcholinesterase (AChE)/butyrylcholinesterase (BChE). PCs antimicrobial peptide (AMP) was evaluated by cryptdins, secretory Phospholipase A2, and lysozyme levels by qRT-PCR, respectively. 16S rRNA high throughput sequencing on faecal samples was used to analyze the changes in intestinal microbiota diversity in each group.

Results

Compared with sham groups, 0.1% BAC group rats had fewer ganglion cells after 1-week postintervention. Occludin and peripherin were decreased, and AChE/BChE ratio was increased, respectively. Sigmoid colon tissues from BAC-treated rats showed increased α-defensins positive PCs on Week 5 postintervention. Conversely, PCs-produced AMP tended to decrease from Week 5 to Week 12. Rats in the sham group demonstrated increasedLactobacillusand decreasedBacteroides, while rats in the 0.1% BAC exhibited reciprocal changes. Enterocolitis occurred from Week 1 postintervention onwards.

Conclusion

Disruption of PCs in the Week 5 postintervention and dysbiosis exacerbate the occurrence of HAEC. This research sheds new light on the cellular mechanisms of HAEC development.
Connection between drug-mediated neurotransmission and salivary microbiome
Authors: Hisamatsu Daisuke , Ogata Yusuke , Takeshige-Amano Haruka , Suda Wataru , Hatano Taku , Asaoka Daisuke , Mabuchi Yo , Naraoka Yuna , Sato Nobuhiro , Asada Takashi , Hattori Nobutaka , Hattori Masahira , Akazawa Chihiro
Published: August 2023

Salivary microbiome alterations associated with cognitive function have been reported in patients with neurodegenerative diseases1–3. Gut microorganisms can modulate therapeutic efficacy via drug metabolism4–7. Additionally, several drugs against diabetes and inflammatory bowel disease can lead to microbial dysbiosis8–10. However, the effect of central nervous system (CNS) drug use on the microbiome remains unknown. Here, we show that the usage of anti-dementia drugs, including donepezil and memantine, more largely affects the salivary microbiome composition than the gut microbiome composition. We observed salivary microbiome diversity reduction in patients with neurodegenerative diseases who receivedN-methyl-D-aspartate receptor inhibitor drugs. Furthermore, the use of acetylcholine-modulating drugs contributed to the salivary microbiome composition, suggesting that the salivary microbiome responds to changes in CNS drug-induced cerebral acetylcholine and glutamate levels. Multivariate analysis adjusted with or without the use of anti-dementia drugs demonstrated that the difference in the salivary microbiome correlated with cognitive function. We show the unique salivary microbiome structure of CNS drug users, suggesting the possibility of monitoring pharmacokinetics using the salivary microbiome. Our results also provide evidence of the presence of the microbiome–oral–brain axis and will accelerate the elucidation of the interplay between the salivary microbiome and neurodegeneration.
The Lifespan Trajectories of Brain Activities Related to Cognitive Control
Authors: Li Zhenghan , Petersen Isaac T. , Wang Lingxiao , Radua Joaquim , Yang Guo-chun , Liu Xun
Published: August 2023

Cognitive control plays a pivotal role in guiding human goal-directed behavior. While existing studies have documented an inverted U-shaped trajectory of cognitive control both behaviorally and anatomically, little is known about the corresponding changes in functional brain activation with age. To bridge this gap, we conducted a comprehensive meta-analysis of 129 neuroimaging studies using conflict tasks, encompassing 3,388 participants aged from 5 to 85 years old. We have three major findings: 1) The inverted U-shaped trajectory is the predominant pattern; 2) Cognitive control-related brain regions exhibit heterogeneous lifespan trajectories: the frontoparietal control network follows inverted U-shaped trajectories, peaking between 24 and 40 years, while the dorsal attention network demonstrates no clear trajectories; 3) Both the youth and the elderly show weaker brain activities and greater left laterality than young to middle-aged adults. These results reveal the lifespan trajectories of cognitive control, highlighting heterogeneous fluctuations in brain networks with age.

Classification:Biological Sciences/Psychological and Cognitive Sciences
Injectable butyrate-prodrug micelles induce long-acting immune modulation and suppress autoimmune arthritis in mice
Authors: Cao Shijie , Budina Erica , Wang Ruyi , Sabados Matthew , Solanki Ani , Nguyen Mindy , Hultgren Kevin , Dhar Arjun , Hubbell Jeffrey A.
Published: August 2023

Dysbiosis is linked to autoimmune diseases such as rheumatoid arthritis (RA), where microbial metabolites, such as short chain fatty acids (SCFAs), mediate the so-called gut-joint axis. The therapeutic potential of SCFAs is limited due to the frequent and high oral dosage requirements. RA is characterized by aberrant activation of peripheral T cells and myeloid cells. We aim to deliver butyrate, an SCFA, directly to the lymphatics using a polymeric micelle as a butyrate prodrug, creating a depot for inducing long-lasting immunomodulatory effects. Notably, negatively charged micelles (Neg-ButM) demonstrate superior efficacy in targeting the lymphatics post-subcutaneous administration, and were retained in the draining lymph nodes, spleen, and liver for over a month. In a mouse RA model, we found that Neg-ButM substantially mitigated arthritis symptoms and promoted tolerogenic phenotypes in T cells and myeloid cells, both locally and systemically. These findings suggest potential applications of this approach in treating inflammatory autoimmune diseases.
Robust Adaptive Deep Brain Stimulation Control of Non-Stationary Cortex-Basal Ganglia-Thalamus Network Models in Parkinson’s Disease
Authors: Fang Hao , Berman Stephen A. , Wang Yueming , Yang Yuxiao
Published: August 2023

Closed-loop deep brain stimulation (DBS) is a promising therapy for Parkinson’s disease (PD) that works by adjusting DBS patterns in real time from the guidance of feedback neural activity. Current closed-loop DBS mainly uses threshold-crossing on-off controllers or linear time-invariant (LTI) controllers to regulate the basal ganglia (BG) beta band oscillation power. However, the critical cortex-BG-thalamus network dynamics underlying PD are nonlinear, non-stationary, and noisy, hindering the accurate and robust control of PD neural dynamics using current closed-loop DBS methods. Here, we develop a new robust adaptive closed-loop DBS method for regulating cortex-BG-thalamus network dynamics in PD. We first build an adaptive state-space model to quantify the dynamic, nonlinear, and non-stationary neural activity. We then construct an adaptive estimator to track the nonlinearity and non-stationarity in real time. We next design a robust controller to automatically determine the DBS frequency based on the estimated PD neural state while reducing the system’s sensitivity to high-frequency noise. We adopt and tune a biophysical cortex-BG-thalamus network model as a testbed to simulate various nonlinear and non-stationary neural dynamics for evaluating DBS methods. We find that under different nonlinear and non-stationary neural dynamics, our robust adaptive DBS method achieved accurate regulation of the BG beta band oscillation power with small control error, bias, and deviation. Moreover, the accurate regulation generalizes across different therapeutic targets and consistently outperforms state-of-the-art on-off and LTI DBS methods. These results have implications for future designs of clinically-viable closed-loop DBS systems to treat PD and other neurological and neuropsychiatric disorders.
Canonical Wnt transcriptional complexes are essential for induction of nephrogenesis but not maintenance or proliferation of nephron progenitors
Authors: Bugacov Helena , Der Balint , Kim Sunghyun , Lindström Nils O. , McMahon Andrew P.
Published: August 2023

Wnt regulated transcriptional programs are associated with both the maintenance of mammalian nephron progenitor cells (NPC) and their induction, initiating the process of nephrogenesis. How opposing transcriptional roles are regulated remain unclear. Using anin vitromodel replicatingin vivoevents, we examined the requirement for canonical Wnt transcriptional complexes in NPC regulation. In canonical transcription, Lef/Tcf DNA binding proteins associate the transcriptional co-activator β-catenin. Wnt signaling is readily substituted by CHIR99021, a small molecule antagonist of glycogen synthase kinase-3β (GSK3β). GSK3β inhibition blocks Gskβ-dependent turnover of β-catenin, enabling formation of Lef/Tcf/β-catenin transcriptional complexes, and enhancer-mediated transcriptional activation. Removal of β-catenin activity from NPCs under cell expansion conditions (low CHIR) demonstrated a non-transcriptional role for β-catenin in the CHIR-dependent proliferation of NPCs. In contrast, CHIR-mediated induction of nephrogenesis, on switching from low to high CHIR, was dependent on Lef/Tcf and β-catenin transcriptional activity. These studies point to a non-transcriptional mechanism for β-catenin in regulation of NPCs, and potentially other stem progenitor cell types. Further, analysis of the β-catenin-directed transcriptional response provides new insight into induction of nephrogenesis.

Summary Statement

The study provides a mechanistic understanding of Wnt/ β-catenin activity in self-renewal and differentiation of mammalian nephron progenitors.
A patient-derived blood-brain barrier model for screening copper bis(thiosemicarbazone) complexes as potential therapeutics in Alzheimer’s disease
Authors: Wasielewska Joanna M. , Szostak Kathryn , McInnes Lachlan E. , Quek Hazel , Chaves Juliana C. S. , Liddell Jeffrey R. , Koistinaho Jari , Oikari Lotta E. , Donnelly Paul S. , White Anthony R.
Published: August 2023

Alzheimer’s disease (AD) is the most prevalent cause of dementia characterised by progressive cognitive decline. Addressing neuroinflammation represents a promising therapeutic avenue to treat AD, however, the development of effective anti-neuroinflammatory compounds is often hindered by their limited blood-brain barrier (BBB) permeability. Consequently, there is an urgent need for accurate, preclinical AD patient-specific BBB models to facilitate the early identification of immunomodulatory drugs capable of efficiently crossing human AD BBB.

This study presents a unique approach to BBB drug permeability screening as it utilises the familial AD patient-derived induced brain endothelial-like cells (iBEC)-based model, which exhibits increased disease relevance and serves as an improved BBB drug permeability assessment tool when compared to traditionally employedin vitromodels. To demonstrate its utility as a small molecule drug candidate screening platform, we investigated the effects of CuII(atsm) and a library of novel metal bis(thiosemicarbazone) complexes – a class of compounds exhibiting anti-neuroinflammatory therapeutic potential in neurodegenerative disorders. By evaluating the toxicity, cellular accumulation and permeability of those compounds in the AD patient-derived iBEC, we have identified CuII(dtsm) as an emerging drug candidate with enhanced transport across the AD BBB. Furthermore, we have developed a multiplex approach where AD patient-derived iBEC were combined with immune modulators TNFα and IFNγ to establish anin vitromodel representing the characteristic neuroinflammatory phenotype at the patient’s BBB. Here we observed that treatment with CuII(dtsm) not only reduced the expression of proinflammatory cytokine genes but also reversed the detrimental effects of TNFα and IFNψ on the integrity and function of the AD iBEC monolayer. This suggests a novel pathway through which copper bis(thiosemicarbazone) complexes may exert neurotherapeutic effects in AD by mitigating BBB neuroinflammation and related BBB integrity impairment.

Together, the presented model provides an effective and easily scalablein vitroBBB platform for screening AD drug candidates. Its improved translational potential makes it a valuable tool for advancing the development of metal-based compounds aimed at modulating neuroinflammation in AD.

Graphical abstract
Non-linear mendelian randomization: detection of biases using negative controls with a focus on BMI, Vitamin D and LDL cholesterol
Authors: Hamilton Fergus W , Hughes David A , Spiller Wes , Tilling Kate , Smith George Davey
Published: August 2023

Mendelian randomisation (MR) is an established technique in epidemiological investigation, using the principle of random allocation of genetic variants at conception to estimate the causal linear effect of an exposure on an outcome. Extensions to this technique include non-linear approaches that allow for differential effects of the exposure on the outcome depending on the level of the exposure. A widely used non-linear method is the residual approach, which estimates the causal effect within different strata of the non-genetically predicted exposure (i.e. the “residual” exposure). These “local” causal estimates are then used to make inferences about non-linear effects. Recent work has identified that this method can lead to estimates that are seriously biased, and a new method - the doubly-ranked method – has been introduced as a possibly more robust approach. In this paper, we perform negative control outcome analyses in the MR context. These are analyses with outcomes onto which the exposure should have no predicted causal effect. Using both methods we find clearly biased estimates in certain situations. We additionally examined a situation for which there are robust randomised controlled trial estimates of effects - that of low density lipoprotein cholesterol (LDL-C) reduction onto myocardial infarction, where randomised trials have provided strong evidence of the shape of the relationship. The doubly-ranked method did not identify the same shape as the trial data, and for LDL-C and other lipids they generated some highly implausible findings. Therefore, we suggest that until there is extensive simulation and empirical methodological work demonstrating that these methods generally produce meaningful findings use of them is suspended. If authors feel it is imperative that they report results from them there should be strong justification for this, and a number of sanity checks (such as analysis of negative and positive control outcomes) should be provided.
Visceral adipose macrophage content does not associate with body mass index or systemic inflammation in COVID-19: an autopsy study
Authors: Su Steven H. , Nobel Yael R. , Besharati Sepideh , del Portillo Armando , Anderson Michaela R. , Freedberg Daniel E.
Published: August 2023

Introduction

Adiposity, especially visceral adiposity with elevated body mass index (BMI), is associated with a hyperinflammatory syndrome and poor outcomes in patients with COVID-19. In other diseases such as obesity, type 2 diabetes, and rheumatoid arthritis, systemic inflammation is driven directly by visceral adipose macrophages which release pro-inflammatory cytokines. Currently it is unknown whether visceral adipose tissue macrophage content may similarly explain the observation that COVID-19 patients with elevated BMI are at risk for a hyperinflammatory syndrome and death.

Methods

This was a retrospective study of hospitalized adults who died of COVID-19 between March 2020 and June 2020 and underwent autopsy. Visceral adipose tissue macrophage content was quantified by histological staining of visceral adipose tissue samples with CD68, using pericolic fat gathered at autopsy from each subject. Clinical data including inflammatory markers such as erythrocyte sedimentation rate (ESR), C-reactive Protein (CRP), Troponin, D-dimer, Interleukin-6 (IL-6), and ferritin as well as BMI were collected from electronic medical records.

Results

A total of 39 subjects were included in this study. There was no association between BMI and visceral adipose tissue macrophage content (Spearman R=0.025, p=0.88). Additionally, there was no association between adipose tissue macrophage content and any of the systemic markers of inflammation measured including ESR, CRP, Troponin, D-dimer, IL-6, and Ferritin (p>0.05 for all markers).

Conclusion

Unlike chronic diseases such as obesity, type 2 diabetes, and rheumatoid arthritis, elevated BMI is not associated with increased visceral adipose tissue macrophage content in patients who died of COVID-19. Additionally, among patients who died of COVID-19, visceral adipose tissue macrophage content is not associated with markers of systemic inflammation. These results suggest that the elevations in systemic markers of inflammation—and the hyperinflammatory syndrome often observed during acute COVID-19—does not directly originate from visceral adipose macrophages as it seems to in chronic disease states.
Preventing tuberculosis with community-based care in an HIV-endemic setting: a modeling analysis
Authors: Ross Jennifer M. , Greene Chelsea , Bayer Cara J. , Dowdy David W. , van Heerden Alastair , Heitner Jesse , Rao Darcy W. , Roberts D. Allen , Shapiro Adrienne E. , Zabinsky Zelda B. , Barnabas Ruanne V.
Published: August 2023

Introduction

Antiretroviral therapy (ART) and TB preventive treatment (TPT) both prevent tuberculosis (TB) disease and deaths among people living with HIV. Differentiated care models, including community-based care, can increase uptake of ART and TPT to prevent TB in settings with a high burden of HIV-associated TB, particularly among men.

Methods

We developed a gender-stratified dynamic model of TB and HIV transmission and disease progression among 100,000 adults ages 15-59 in KwaZulu-Natal, South Africa. We drew model parameters from a community-based ART initiation and resupply trial in sub-Saharan Africa (Delivery Optimization for Antiretroviral Therapy, DO ART) and other scientific literature. We simulated the impacts of community-based ART and TPT care programs during 2018-2027, assuming that community-based ART and TPT care were scaled up to similar levels as in the DO ART trial (i.e., ART coverage increasing from 49% to 82% among men and from 69% to 83% among women) and sustained for ten years. We projected the number of TB cases, deaths, and disability-adjusted life years (DALYs) averted relative to standard, clinic-based care. We calculated program costs and incremental cost-effectiveness ratios from the provider perspective.

Results

If community-based ART care could be implemented with similar effectiveness to the DO ART trial, increased ART coverage could reduce TB incidence by 27.0% (range 21.3% - 34.1%) and TB mortality by 36.0% (range 26.9% - 43.8%) after ten years. Increasing both ART and TPT uptake through community-based ART with TPT care could reduce TB incidence by 29.7% (range 23.9% - 36.0%) and TB mortality by 36.0% (range 26.9% - 43.8%). Community-based ART with TPT care reduced gender disparities in TB mortality rates by reducing TB mortality among men by a projected 39.8% (range 32.2% - 46.3%) and by 30.9% (range 25.3% - 36.5%) among women. Over ten years, the mean cost per DALY averted by community-based ART with TPT care was $846 USD (range $709 - $1,012).

Conclusions

By substantially increasing coverage of ART and TPT, community-based care for people living with HIV could reduce TB incidence and mortality in settings with high burdens of HIV-associated TB and reduce TB gender disparities.
Multiplexing cortical brain organoids for the longitudinal dissection of developmental traits at single cell resolution
Authors: Caporale Nicolò , Castaldi Davide , Rigoli Marco Tullio , Cheroni Cristina , Trattaro Sebastiano , Valenti Alessia , Bonfanti Matteo , Stucchi Sarah , Tobon Alejandro Lopez , Ricca Dario , Lessi Manuel , Pezzali Martina , Vitriolo Alessandro , Schmid Katharina T. , Heinig Matthias , Theis Fabian J. , Villa Carlo Emanuele , Testa Giuseppe
Published: August 2023

The combination of brain organoid and single cell omic technologies holds transformative potential to dissect human neurobiology at high resolution and with mechanistic precision. Delivering this promise in the context of human neurodiversity, physiological and pathological alike, requires however a major leap in scalability, given the need for experimental designs that include multiple individuals and, prospectively, population cohorts. To lay the foundation for this, we implemented and benchmarked complementary strategies to multiplex brain organoids. Following an extended longitudinal design with a uniquely informative set of timepoints, we pooled cells from different induced pluripotent stem cell lines either during organoids generation (upstream multiplexing in mosaic models) or before single cell-RNAseq library preparation (downstream multiplexing). We developed a new method, SCanSNP, and an aggregated call to deconvolve organoids cell identities, overcoming current criticalities in doublets prediction and low quality cells identification and improving accuracy over state of the art algorithms. Integrating single cell transcriptomes and analysing cell types across neurodevelopmental stages and multiplexing modalities, we validated the feasibility of both multiplexing methods in charting neurodevelopmental trajectories at high resolution, linking their specificity to genetic variation between individual lines. Together, this multiplexing suite of experimental and computational methods provides an enabling resource for disease modelling at scale and paves the way towards anin vitroepidemiology paradigm.
The essential roles of Dicer-mediated mTORC1 signaling in parathyroid gland integrity and function: Insights from genetic mouse models and clinical data
Authors: Hassan Alia , Khalaily Nareman , Kilav-Levin Rachel , Castello Barbara Del , Manley Nancy Ruth , Ben-Dov Iddo Z. , Naveh-Many Tally
Published: August 2023

Secondary hyperparathyroidism (SHP) frequently accompanies chronic kidney disease (CKD), contributing to morbidity and mortality in patients. Our previous findings demonstrated that PT-Dicer-/-mice, with parathyroid specific deletion ofDicerand consequently microRNA, maintained normal serum PTH levels but failed to increase serum PTH in response to the major inducers of PTH secretion, hypocalcemia and CKD. Additionally, we elucidated a critical role of mTORC1 in CKD-induced SHP. We now explored the roles of Dicer and mTORC1 in parathyroid development and function. Despite sustaining normal serum PTH levels, PT-Dicer-/-mice displayed apoptotic loss of intact parathyroid glands postnatally, which were replaced by scattered cell clusters, and reduced mTORC1 activity. PT-mTORC1-/-mice exhibited the absence of intact parathyroid glands, while retaining normal serum PTH levels, mirroring the characteristics of PT-Dicer-/-mice. Conversely, PT-Tsc1-/-mice with hyperactivated mTORC1 exhibited enlarged glands and elevated serum PTH and calcium levels. Significantly, PT-Dicer-/-;Tsc1-/-double knockout mice demonstrated a reversal of the aparathyroidism of PT-Dicer-/-mice, preserving intact parathyroid glands and reinstating CKD-induced SHP. Lastly, data collected from a network of 106 healthcare organizations demonstrated that drug-induced mTOR inhibition is associated with reduced elevation of serum PTH levels in kidney transplant recipients. The latter findings offer physiological validation for our observations in genetically modified mouse models, highlighting the central role of mTORC1 signaling in CKD-SHP. Altogether, our results indicate that mTOR operates downstream of Dicer and miRNA. Consequently, Dicer, miRNA and mTORC1 collectively play a crucial role in maintaining the postnatal integrity and function of the parathyroid glands.
‘Mindin Vitro’ platforms: Versatile, scalable, robust and open solutions to interfacing with living neurons
Authors: Zhang Xiaotian , Dou Zhi , Kim Seung-Hyun , Upadhyay Gaurav , Havert Daniel , Kang Sehong , Kazemi Kimia , Huang Kai-Yu , Aydin Onur , Huang Raymond , Rahman Saeedur , Ellis-Mohr Austin , Noblet Hayden A. , Lim Ki H. , Chung Hee Jung , Gritton Howard J. , Saif M. Taher A. , Kong Hyun Joon , Beggs John M. , Gazzola Mattia
Published: August 2023

Motivated by the unexplored potential ofin vitroneural systems for computing, and by the corresponding need of versatile, scalable interfaces for multimodal interaction, we present an accurate, modular, fully customizable and portable recording/stimulation solution that can be easily fabricated, robustly operated, and broadly disseminated. A reconfigurable platform that works across multiple industry standards enables a complete signal chain, from neural substrates sampled through high-density Micro-Electrode Arrays (MEAs) to data acquisition, downstream analysis and cloud storage. Built-in modularity supports the seamless integration of electrical/optical stimulation and fluidic interfaces. Custom MEA fabrication leverages maskless photolithography, favoring the rapid prototyping of a variety of configurations and spatial topologies. Through a native analysis and management software suite, the utility and robustness of our system is demonstrated across neural cultures and applications, including embryonic stem cell-derived and primary neurons, organotypic brain slices, 3D engineered tissue mimics, concurrent calcium imaging and long-term recording. Overall, our technology, termed ‘Mindin Vitro’ to underscore the computing inspiration, provides an end-to-end solution that can be widely deployed due to its affordable (>10X cost-reduction) and open-source nature, catering to the expanding needs of both conventional and unconventional electrophysiology.
Non-antibiotic pharmaceuticals exhibit toxicity againstEscherichia coliat environmentally relevant concentrations with no evolution of cross-resistance to antibiotics
Authors: Hall Rebecca J , Snaith Ann E , Element Sarah J , Moran Robert A , Smith Hannah , Cummins Elizabeth A , Bottery Michael J , Chowdhury Kaniz F , Sareen Dipti , Ahmad Iqbal , Blair Jessica M A , Carter Laura J , McNally Alan
Published: August 2023

Antimicrobial resistance can arise in the natural environment via prolonged exposure to the effluent surrounding manufacturing facilities. These facilities also produce non-antibiotic pharmaceuticals, and the effect of these on the surrounding microbial communities is less clear; whether they have inherent toxicity, or whether long-term exposure might select for cross-resistance to antibiotics. To this end, we screened four non-antibiotic pharmaceuticals (acetaminophen, ibuprofen, propranolol, met formin) and titanium dioxide for toxicity againstEscherichia coliK-12 MG1655 and conducted a 30 day selection experiment to assess the effect of long-term exposure. All compounds reduced the maximum optical density reached byE. coliat a range of concentrations including one of environmental relevance, with transcriptome analysis identifying upregulated genes related to stress response and multidrug efflux in response ibuprofen treatment. The non-antibiotic pharmaceuticals did not select for significant genetic changes following a 30 day exposure, and no evidence of selection for cross-resistance to antibiotics was observed for population evolved in the presence of ibuprofen in spite of the differential gene expression after exposure to this compound. This work suggests that these non-antibiotic pharmaceuticals, at environmental concentrations, do not select for cross-resistance to antibiotics inE. coli.
Ecological drift during colonization drives within- and between-host heterogeneity in animal symbiont populations
Authors: Chen Jason Z. , Kwong Zeeyong , Gerardo Nicole M. , Vega Nic M.
Published: August 2023

Host-associated microbiomes vary greatly in composition both within and between host individuals, providing the raw material for natural selection to act on host-microbe associations. Nonetheless, the drivers of compositional heterogeneity in host-associated microbiomes have only rarely been examined. To understand how this heterogeneity arises, we utilize the squash bug,Anasa tristis, and its bacterial symbionts in the genusCaballeronia. We artificially modulate symbiont bottleneck size and strain diversity during colonization to demonstrate the significance of ecological drift, which causes stochastic fluctuations in community composition. Consistent with predictions from the neutral theory of biodiversity, ecological drift alone can account for heterogeneity in symbiont community composition between hosts, even when two strains are nearly genetically identical. When acting on competing, unrelated strains, ecological drift can maintain symbiont genetic diversity among different hosts by stochastically determining the dominant strain within each host. Finally, ecological drift mediates heterogeneity in isogenic symbiont populations even within a single host, along a consistent gradient running the anterior-posterior axis of the symbiotic organ. Our results demonstrate that symbiont population structure across scales does not necessarily require host-mediated selection, but emerges as a result of ecological drift acting on both isogenic and unrelated competitors. Our findings illuminate the processes that might affect symbiont transmission, coinfection, and population structure in nature, which can drive the evolution of host-microbe symbiosis and microbe-microbe interactions within host-associated microbiomes.
Gaming expertise induces meso-scale brain plasticity and efficiency mechanisms as revealed by whole-brain modeling
Authors: Coronel-Oliveros Carlos , Medel Vicente , Orellana Sebastián , Rodiño Julio , Lehue Fernando , Cruzat Josephine , Tagliazucchi Enzo , Brzezicka Aneta , Orio Patricio , Kowalczyk-Grębska Natalia , Ibáñez Agustín
Published: August 2023

Video games are a valuable tool for studying the effects of training and neural plasticity on the brain. However, the underlaying mechanisms related to plasticity-induced brain structural changes and their impact in brain dynamics are unknown. Here, we used a semi-empirical whole-brain model to study structural neural plasticity mechanisms linked to video game expertise. We hypothesized that video game expertise is associated with neural plasticity-mediated changes in structural connectivity that manifest at the meso-scale level, resulting in a more segregated functional network topology. To test this hypothesis, we combined structural connectivity data of StarCraft II video game players (VGPs, n = 31) and non-players (NVGPs, n = 31), with generic fMRI data from the Human Connectome Project and computational models, with the aim of generating simulated fMRI recordings. Graph theory analysis on simulated data was performed during both resting-state conditions and external stimulation. VGPs’ simulated functional connectivity was characterized by a meso-scale integration, with increased local connectivity in frontal, parietal and occipital brain regions. The same analyses at the level of structural connectivity showed no differences between VGPs and NVGPs. Regions that increased their connectivity strength in VGPs are known to be involved in cognitive processes crucial for task performance such as attention, reasoning, and inference. In-silico stimulation suggested that differences in FC between VGPs and NVGPs emerge in noisy contexts, specifically when the noisy level of stimulation is increased. This indicates that the connectomes of VGPs may facilitate the filtering of noise from stimuli. These structural alterations drive the meso-scale functional changes observed in individuals with gaming expertise. Overall, our work sheds light into the mechanisms underlying structural neural plasticity triggered by video game experiences.
AI identifies potent inducers of breast cancer stem cell differentiation based on adversarial learning from gene expression data
Authors: Li Zhongxiao , Napolitano Antonella , Fedele Monica , Gao Xin , Napolitano Francesco
Published: August 2023

Cancer stem cells (CSCs) are a subpopulation of cancer cells within tumors that exhibit stem-like properties, and represent a potentially effective therapeutic target towards long-term remission by means of differentiation induction. By leveraging an Artificial Intelligence (AI) approach solely based on transcriptomics data, this study scored a large library of small molecules based on their predicted ability to induce differentiation in stem-like cells. In particular, a deep neural network model was trained using publicly available single-cell RNA-Seq data obtained from untreated human induced pluripotent stem cells at various differentiation stages and subsequently utilized to screen drug-induced gene expression profiles from the LINCS database. The challenge of adapting such different data domains was tackled by devising an adversarial learning approach that was able to effectively identify and remove domain-specific bias during the training phase. Experimental validation in MDA-MB-231 and MCF7 cells demonstrated the efficacy of 5 out of 6 tested molecules among those scored highest by the model. In particular, the efficacy of triptolide, OTS-167, quinacrine, granisetron, and A-443654 offer a potential avenue for targeted therapies against breast CSCs.
Yeast TLDc domain-containing proteins control assembly and subcellular localization of the V-ATPase
Authors: Klössel Samira , Zhu Ying , Amado Lucia , Bisinski Daniel D. , Ruta Julia , Liu Fan , González Montoro Ayelén
Published: August 2023

Yeast vacuoles, equivalent to lysosomes in other eukaryotes, are important acidic degradative organelles as well as storage compartments and signaling hubs. To perform these functions, they rely on important protein complexes, including the V-ATPase, responsible for organelle acidification. In this study, we used cross-linking mass spectrometry to characterize the protein complexes of isolated vacuoles. We were able to detect many known protein-protein interactions, including known protein complexes, as well as undescribed ones. Among these, we identified the uncharacterized TLDc domain-containing protein Rtc5 as a novel interactor of the V-ATPase. We show that Rtc5 localizes to the vacuole membrane depending on N-myristoylation and on its interactions with the V-ATPase. We further analyzed the influence of this protein, and the second yeast TLDc domain-containing protein, Oxr1, on V-ATPase function. We find that both Rtc5 and Oxr1 promote the disassembly of the vacuolar V-ATPasein vivo, counteracting the role of the assembly chaperone, the RAVE complex. Finally, Oxr1 is necessary for the retention in the late Golgi complex of an organelle-specific subunit of the V-ATPase. Collectively, our results shed light on thein vivoroles of yeast TLDc domain-containing proteins in relation to the V-ATPase, highlighting the multifaceted regulation of this crucial protein complex.
Multimodal Imaging Investigation of Rich Club Alterations in Alzheimer’s Disease and Mild Cognitive Impairment: Amyloid Deposition, Structural Atrophy, and Functional Activation Differences
Authors: Markett Sebastian , Boeken Ole J. , Wudarczyk Olga A. ,   the Alzheimer’s Disease Neuroimaging Initiative
Published: August 2023

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Alzheimer’s disease (AD) is characterized by significant cerebral dysfunction, including increased amyloid deposition, gray matter atrophy, and changes in brain function. The involvement of highly connected network hubs, known as the “rich club,” in the pathology of the disease remains inconclusive despite previous research efforts. In this study, we aimed to systematically assess the link between the rich club and AD using a multimodal neuroimaging approach.

We employed network analyses of diffusion MRI, longitudinal assessments of gray matter atrophy, amyloid deposition measurements using PET imaging, and meta-analytic data on functional activation differences. Our study focused on evaluating the role of both the core and extended rich club regions in individuals with Mild Cognitive Impairment (MCI) and those diagnosed with Alzheimer’s Disease.

Our findings revealed that rich club regions exhibited accelerated gray matter atrophy and increased amyloid deposition in both MCI and Alzheimer’s Disease. Importantly, these regions remained unaffected by altered functional activation patterns observed outside the core rich club regions. These results shed light on the connection between two major AD biomarkers and the rich club, providing valuable insights into AD as a potential disconnection syndrome.
Flexiplex: A versatile demultiplexer and search tool for omics data
Authors: Cheng Oliver , Ling Min Hao , Wang Changqing , Wu Shuyi , Ritchie Matthew E. , Göke Jonathan , Amin Noorul , Davidson Nadia M.
Published: August 2023

The process of analyzing high throughput sequencing data often requires the identification and extraction of specific target sequences. This could include tasks such as identifying cellular barcodes and UMIs in single cell data, and specific genetic variants for genotyping. However, existing tools which perform these functions are often task-specific, such as only demultiplexing barcodes for a dedicated type of experiment, or are not tolerant to noise in the sequencing data. To overcome these limitations, we developed Flexiplex, a versatile and fast sequence searching and demultiplexing tool for omics data, which is based on the Levenshtein distance and thus allows imperfect matches. We demonstrate Flexiplex’s application on three use cases, identifying cell line specific sequences in Illumina short-read single cell data, and discovering and demultiplexing cellular barcodes from noisy long-read single cell RNA-seq data. We show that Flexiplex achieves an excellent balance of accuracy and computational efficiency compared to leading task-specific tools. Flexiplex is available athttps://davidsongroup.github.io/flexiplex/.
Space and epigenetic inheritance determine inter-individual differences in siderophore gene expression in bacterial colonies
Authors: Mridha Subham , Wechsler Tobias , Kümmerli Rolf
Published: August 2023

Heterogeneity in gene expression among cells in clonal groups is common in bacteria. Albeit ubiquitous, it often remains unclear what the sources of variation are and whether variation has functional significance. Here, we tracked the expression of genes involved in the synthesis of iron-chelating siderophores (pyoverdine and pyochelin) in individual cells of the bacteriumPseudomonas aeruginosaduring colony growth on surfaces using time-lapse fluorescence microscopy, to explore potential sources and functions of cellular heterogeneity. Regarding sources, we found that the physical position of cells within the colony and epigenetic gene expression inheritance from mother to daughter cells significantly contributed to cellular heterogeneity. In contrast, cell pole age and cellular lifespan had no effect. Regarding functions, our results indicate that cells optimize their siderophore investment strategies (pyoverdine vs. pyochelin) along a gradient from the centre to the edge of the colony. Moreover, we found evidence that cell lineages with above-average siderophore investment increase the fitness of cell lineages with below-average investment through cooperative sharing of secreted siderophores. Altogether, our study highlights that single-cell experiments combined with automated image and cell-tracking analyses can identify sources of heterogeneity and yield adaptive explanations for gene expression variation among clonal bacterial cells.