bluuebunny/crossref_metadata_2025 huggingface dataset:
Cerebral Microvascular Imaging in Infants
Authors: Hwang Misun
Published: October 2023

Brain ultrasound in infants, although widely utilized, provides limited functional insights into the brain. Although color and power Doppler ultrasounds have allowed quantitative assessment of cerebral macrovascular flow dynamics, there is no standardized tool integrated into the current neurosonography protocol that allows cerebral microvascular flow assessment. The evaluation of anatomic and functional changes in cerebral microvessels is important, as microvascular alterations have been shown to precede macrovascular and tissue injury in a variety of neurologic diseases of infancy. In this regard, the cerebral microvascular imaging technique is a commercially available, advanced Doppler technique in which slow flow of cerebral microvessels can be detected via a static noise suppression algorithm. This article therefore shares the basic scan technique and clinical examples of the integrated use of microvascular imaging in neurosonography for infants, setting the stage for future clinical integration of the technique.
A Historical Perspective on Brachial Plexus Palsy Management: From Ancient Civilizations to the Modern Era
Authors: Gantiwala Shahina , Hamidian Jahromi Alireza , Konofaos Petros
Published: October 2023

Evidence of brachial plexus palsies and potential therapies have been identified by investigators across cultures and civilizations. It could be argued that there are early records of brachial plexus injuries in not only literary work but also paintings, sculptures, and ancient medical texts. The compiled ancient evidence in this review provides a historical framework of brachial plexus palsies and potential management techniques that have been utilized from ancient to modern time.
Multimodal profiling of peripheral blood identifies proliferating circulating effector CD4+T cells as predictors for response to integrin α4β7-blocking therapy in patients with inflammatory bowel disease
Authors: Horn Veronika , Cancino Camila , Steinheuer Lisa , Obermayer Benedikt , Fritz Konstantin , Nguyen Anke L. , Plattner Christina , Bösel Diana , Burns Marie , Schulz Axel Ronald , Mantzivi Eleni , Lissner Donata , Conrad Thomas , Mashreghi Mir-Farzin , Sonnenberg Elena , Beule Dieter , Flatz Lukas ,   TRR241 IBDome Consortium, Trjanoski Zlatko , Weidinger Carl , Mei Henrik E. , Siegmund Britta , Thurley Kevin , Hegazy Ahmed N.
Published: October 2023

Despite the success of biological therapies in inflammatory bowel disease (IBD), patient management remains challenging due to a lack of therapy response predictors. Here we prospectively sampled two cohorts of IBD patient cohorts receiving the anti-integrin α4β7 antibody vedolizumab. Samples were subjected to mass cytometry, single-cell RNA sequencing, single-cell V(D)J sequencing, serum proteomics, and multidimensional flow cytometry to comprehensively assess vedolizumab-induced immunological changes in the peripheral blood and their potential associations with treatment response. Vedolizumab induced changes in the abundance of both circulating innate and adaptive immune cell compartments and modified the T cell receptor diversity of circulating gut-homing CD4+memory T cells. Through integration of multimodal parameters and machine learning, we identify that pretreatment activated proliferating CD4+memory T cell abundance is associated with treatment failure, independent of clinical variables, thereby providing a reliable predictive classifier with significant implications for the personalized management of IBD patients.
A Normative Framework Dissociates Need and Motivation in Hypothalamic Neurons
Authors: Kim Kyu Sik , Lee Young Hee , Kim Yu-Been , Yun Jong Won , Song Ha Young , Park Joon Seok , Jung Sang-Ho , Sohn Jong-Woo , Kim Ki Woo , Kim HyungGoo R. , Choi Hyung Jin
Published: October 2023

Physiological needs evoke motivational drives to produce natural behaviours for survival. However, the temporally intertwined dynamics of need and motivation have made it challenging to differentiate these two components in previous experimental paradigms. Based on classic homeostatic theories, we established a normative framework to derive computational models of neural activity and behaviours for need-encoding and motivation-encoding neurons during events that induce predicted gain or loss. We further developed simple and intuitive experimental paradigms that enabled us to distinguish the distinct roles of subpopulations of neurons in the hypothalamus. Our results show that AgRP neurons and LHLepRneurons are consistent with need and motivation, respectively. Our study provides a parsimonious understanding of how distinct hypothalamic neurons separately encode need and motivation to produce adaptive behaviours for maintaining homeostasis.
Mendelian Randomization Reveals the Role of HMGCR in Pulmonary Arterial Hypertension Treatment, Independent of LDL Cholesterol Concentration
Authors: Wu Shixun , Pu Jie , Tang Zhiguo , Zhang Wei , Hou Fangxia , Wei Na , Cui Qianwei , Liu Fuqiang , Wang Junkui , Lu Ying , Wei Tao
Published: October 2023

Introduction

Specific lipid-reducing therapeutics, including statins, are known for mitigating cardiovascular diseases due to their comprehensive benefits including anti-inflammatory properties, antioxidative stress response, and enhancement of endothelial function. The objective of our study was to determine the causative impact of lipid-reducing agents (HMGCR inhibitors, PCSK9 inhibitors, and NPC1L1 inhibitor) on the outcomes of pulmonary hypertension via a two-sample Mendelian randomization (MR) analysis.

Methods

Two types of genetic tools were employed to estimate the exposure to lipid-lowering drugs, comprising expression quantitative trait loci of the drug’s target genes and genetic variations close to or within the target genes related to low-density lipoprotein (LDL cholesterol derived from a genome-wide association study). We utilized summary-data-based MR (SMR) and inverse-variance-weighted MR (IVWMR) methodologies for estimating effect sizes.

Results

SMR analysis indicated that elevated HMGCR expression correlates with increased pulmonary hypertension risk (β=-0.964, se=0.276). Yet, no evident causative link between HMGCR-regulated LDL cholesterol and COVID-19 hospitalization was observed in the IVW-MR analysis (β = -0.21, se= 0.17).

Conclusions

Our Mendelian randomization investigation unveiled a possible positive impact of lipid-lowering therapeutics on the prognosis of pulmonary hypertension. Importantly, no causal relation was established between LDL cholesterol and pulmonary hypertension.
Parallel detection of multi-contrast MRI and Deuterium Metabolic Imaging (DMI) for time-efficient characterization of neurological diseases
Authors: Liu Yanning , De Feyter Henk M. , Corbin Zachary A. , Fulbright Robert K. , McIntyre Scott , Nixon Terence W. , de Graaf Robin A.
Published: October 2023

Deuterium Metabolic Imaging (DMI) is a novel method that can complement traditional anatomical magnetic resonance imaging (MRI) of the brain. DMI relies on the MR detection of metabolites that become labeled with deuterium (2H) after administration of a deuterated substrate and can provide images with highly specific metabolic information. However, clinical adoption of DMI is complicated by its relatively long scan time. Here, we demonstrate a strategy to interleave DMI data acquisition with MRI that results in a comprehensive neuro-imaging protocol without adding scan time. The interleaved MRI-DMI routine includes four essential clinical MRI scan types, namely T1-weighted MP-RAGE, FLAIR, T2-weighted Imaging (T2W) and susceptibility weighted imaging (SWI), interwoven with DMI data acquisition. Phantom and in vivo human brain data show that MR image quality, DMI sensitivity, as well as information content are preserved in the MRI-DMI acquisition method. The interleaved MRI-DMI technology provides full flexibility to upgrade traditional MRI protocols with DMI, adding unique metabolic information to existing types of anatomical image contrast, without extra scan time.
The effect of primary health care on AIDS incidence and mortality: a cohort study of 3.4 million Brazilians
Authors: Pinto Priscila FPS , Macinko James , Silva Andréa F , Lua Iracema , Jesus Gabriela , Magno Laio , Santos Carlos AS Teles , Ichihara Maria Yury , Barreto Mauricio L , Moucheraud Corrina , Souza Luis E , Dourado Inês , Rasella Davide
Published: October 2023

Background

Primary Health Care (PHC) is essential for the health and wellbeing of people living with HIV/AIDS. This study evaluated the effects of one of the largest community-based PHC programs in the world, the Brazilian Family Health Strategy (FHS), on AIDS incidence and mortality.

Methods

A retrospective cohort study carried out in Brazil, from January 1 2007 to December 31 2015. We conducted a quasi-experimental effect evaluation using a cohort of 3,435,068 ≥13 years low-income individuals who were members of the 100 Million Brazilians Cohort, linked to AIDS diagnoses and deaths registries. We evaluated the effect of FHS on AIDS incidence and mortality and comparing outcomes between residents of municipalities with no FHS coverage with those in municipalities with full FHS coverage. We used multivariable Poisson regressions adjusted for all relevant municipal and individual-level demographic, socioeconomic, and contextual variables, and weighted with inverse probability of treatment weighting (IPTW). We also estimated FHS effect by sex and age, and performed a wide range of sensitivity and triangulation analyses.

Findings

FHS coverage was associated with lower AIDS incidence (rate ratio [RR]:0.76, 95%CI:0.68–0.84) and mortality (RR:0.68,95%CI:0.56–0.82). FHS effect was similar between men and women, but was larger in people aged ≥35 years old both for incidence (RR 0.62, 95%CI:0.53–0.72) and mortality (RR 0.56, 95%CI:0.43– 0.72).

Conclusions

AIDS should be an avoidable outcome for most people living with HIV today, and our study shows that FHS coverage could significantly reduce AIDS incidence and mortality among low-income populations in Brazil. Universal access to comprehensive healthcare through community-based PHC programs should be promoted to achieve the Sustainable Development Goals of ending AIDS by 2030.

Funding

Funded by the National Institute of Allergy and Infectious Diseases - NIAID/NIH, Grant Number: 1R01AI152938.
Predicting Individualized Outcomes for Deceased Kidney Donor Waitlisted Candidates and Recipients
Authors: Litvinovich Igor , Ng Yue-Harn , Chong Kelly , Argyropoulos Christos , Zhu Yiliang
Published: October 2023

Kidney transplantation remains the optimal treatment for end-stage kidney disease (ESKD). However, the persistent disparity between the demand and supply of deceased donor (DD) kidneys underscores the need for better tools to assess transplant outcomes and donor kidney quality. The current Kidney Allocation System (KAS) relies on the Kidney Donor Risk Index (KDRI) to quantify DD kidney quality, yet it combines allograft failure and patient death into a single outcome, limiting its accuracy.

In this paper we present refined statistical models to predict post-transplantation risk, differentiating between allograft failure and patient death as competing risks. Using comprehensive data from the Organ Procurement and Transplantation Network/Scientific Registry of Transplant Recipient (OPTN/SRTR) for 2000-2017, our models incorporate biological and clinical factors instead of donor race, account for within-center clustering and between-center variation, and capture non-linear relationships between risk factors.

Our results reveal distinct risk factors for allograft failure and patient death. These models provide more personalized risk estimates tailored to donor kidney quality and recipient characteristics, aiding shared decision-making on kidney acceptance. Comparisons with the original KDRI demonstrate the superiority of our separate models, with improved predictability and reduced bias. Our approach eliminates the need to conflate allograft failure and patient death, leading to more accurate risk assessment and better-informed decisions regarding kidney offers.

In conclusion, our study underscores the importance of distinguishing between allograft failure and patient death in kidney transplant risk assessment. By offering more precise risk estimates, our models enhance the transparency and efficiency of kidney acceptance decisions, ultimately benefiting both transplant providers and candidates. We also provide a web-based tool to facilitate this process, promoting better outcomes in kidney transplantation.

Key Points

Improved statistical models for kidney transplant risk assessment, separating the risks of allograft failure and patient death.

Models provide more personalized risk estimates, outperforming the existing Kidney Donor Risk Index (KDRI).

Models enhance transparency and accuracy in evaluating donor kidney quality, aiding both providers and candidates in decision-making.

Research improves the efficiency of kidney acceptance processes, leading to more successful transplants.
Keywords to success: a practical guide to maximise the visibility and impact of academic papers
Authors: Pottier Patrice , Lagisz Malgorzata , Burke Samantha , Drobniak Szymon M. , Downing Philip A. , Macartney Erin L. , Martinig April Robin , Mizuno Ayumi , Morrison Kyle , Pollo Pietro , Ricolfi Lorenzo , Tam Jesse , Williams Coralie , Yang Yefeng , Nakagawa Shinichi
Published: October 2023

In a growing digital landscape, enhancing the discoverability and resonance of scientific articles is essential. Here, we offer ten recommendations to amplify the discoverability of studies in scientific databases. Particularly, we argue that the strategic use and placement of key terms in the title, abstract, and keyword sections can boost indexing and appeal. By surveying 237 journals in ecology and evolutionary biology, we found that current author guidelines may unintentionally limit article discoverability. Our survey of 5842 studies revealed that authors frequently exhaust abstract word limits — particularly those capped under 250 words. This suggests that current guidelines may be overly restrictive and not optimised to increase the dissemination and discoverability of digital publications. Additionally, 91.9% of studies used redundant keywords in the title or abstract, undermining optimal indexing in databases. We encourage adopting structured abstracts to maximise the incorporation of key terms in titles, abstracts, and keywords. In addition, we encourage the relaxation of abstract and keyword limitations in journals with strict guidelines, and the inclusion of multilingual abstracts to broaden global accessibility. These evidence-based recommendations to editors are designed to improve article engagement and facilitate evidence synthesis, thereby aligning scientific publishing with the modern needs of academic research.
The amino acid sequence determines protein abundance through its conformational stability and reduced synthesis cost
Authors: Buric Filip , Viknander Sandra , Fu Xiaozhi , Lemke Oliver , Zrimec Jan , Szyrwiel Lukasz , Mueleder Michael , Ralser Markus , Zelezniak Aleksej
Published: October 2023

Understanding what drives protein abundance is essential to biology, medicine, and biotechnology. Driven by evolutionary selection, the amino acid sequence is tailored to meet the required abundance of proteomes, underscoring the intricate relationship between sequence and functional demand. Yet, the specific role of amino acid sequences in determining proteome abundance remains elusive. Here, we demonstrate that the amino acid sequence predicts abundance by shaping a protein’s conformational stability. We show that increasing the abundance provides metabolic cost benefits, underscoring the evolutionary advantage of maintaining a highly abundant and stable proteome. Specifically, using a deep learning model (BERT), we predict 56% of protein abundance variation inSaccharomyces cerevisiaesolely based on amino acid sequence. The model reveals latent factors linking sequence features to protein stability. To probe these relationships, we introduce MGEM (Mutation Guided by an Embedded Manifold), a methodology for guiding protein abundance through sequence modifications. We find that mutations increasing abundance significantly alter protein polarity and hydrophobicity, underscoring a connection between protein stability and abundance. Through molecular dynamics simulations andin vivoexperiments in yeast, we confirm that abundance-enhancing mutations result in longer-lasting and more stable protein expression. Importantly, these sequence changes also reduce metabolic costs of protein synthesis, elucidating the evolutionary advantage of cost-effective, high-abundance, stable proteomes. Our findings support the role of amino acid sequence as a pivotal determinant of protein abundance and stability, revealing an evolutionary optimization for metabolic efficiency.
A compact, ultrahigh-density headstage with high-fidelity hybrid integration for large-scale deep-brain opto-electrophysiology
Authors: Oh Sungjin , Kim Kanghwan , Lopez Ruiz Jose Roberto , Slager Nathan , Ko Eunah , Vöröslakos Mihály , Lanzio Vittorino , Song Hyunsoo , Park Sung-Yun , Yoon Euisik
Published: October 2023

Recent neuroscientific research seeks to comprehend the sophisticated deep-brain networks of neural circuits consisting of large scale neuronal ensembles across multiple brain regions. An ideal way to unveil the complex connectome might be stimulating individual neurons with high spatial resolution in a broad range of brain, while seamlessly monitoring the correspondent neuronal activities. Optogenetics is known as a key technology to enable such a goal thanks to its high spatial and temporal selectivity in neuromodulation. Existing silicon probe technologies have been able to partially achieve such a goal by recording broad region of brain activities through multiple electrodes per shank, but those cannot complete perfect coverage due to the limited channel counts for the optogenetic stimulation. Here, we present an high-channel-count optogenetic system with simultaneous 256 recoding and 128 optogenetic stimulation sites, exhibiting the highest channel density ever reported, enabled by a flexible polyimide cable-based hybrid-integration of a low-stimulation-artifact micro-LED (µLED) opto-electrode with a low-power and -noise, area-efficient CMOS interfacing integrated-circuit (IC). The presented optogenetic system provides 256-neuron-size electrodes (11 × 15 µm2) with a 40 µm inter-electrode pitch for high spatial oversampling in recording and 128-soma-size µLEDs (8 × 11 µm2) with a 20 µm inter-LED pitch for single-cell resolution in stimulation, resulting in a vertical span of 640 µm and a horizontal span of 2,100 µm with a total 8 shanks. For versatility in optogenetics-based experiments from small rodents to primates with user-preferable settings, the system base that provides programmability of recording and stimulation parameters and rest of signal processing, such as filtering, digitization, and data transmission including serial peripheral interface (SPI) has also been designed within small area of 23.8 × 28.8 mm2with only 3.5-gram weight, resulting in the highest channel density both in size (0.56 channels/mm2) and weight (109.71 channels/gram) among the state-of-the-art optogenetics-based neuromodulation systems. To verify the system operationin vivo, a compact optogenetics headstage has been also fabricated. Using the prepared optogenetic headstage, 169 isolated neurons have been observed with various stimulation intensities. The results offered in this article indicate that the presented hybrid integrated ultrahigh-density, high-channel-count headstage can be used to realize the massive-scale in-depth brain studies with optogenetics.
Effects of ocean acidification on red king crab larval survival and development
Authors: Long W. Christopher , Conrad Allie , Gardner Jennifer , Foy Robert J.
Published: October 2023

Ocean acidification, a decrease in oceanic pH resulting from the uptake of anthropogenic CO2, can be a significant stressor for marine organisms. In this study, we reared red king crab larvae from hatching to the first crab stage in four different pH treatments: current surface ambient, diel fluctuation to mimic larval migration between the surface and mixed layer under current ambient conditions, pH 7.8, and pH 7.5. Larvae were monitored throughout development and the average length of each stage was determined. At each of the zoeal stages, the glaucothoe stage, and the first crab stage, we measured survival, morphometry, dry mass, and carbon, nitrogen, calcium, and magnesium content. Red king crab larvae were highly resilient to ocean acidification. There were no differences among treatments in survival or in average stage length. Although there were clear ontogenetic trends in size, weight, and elemental composition, most of these did not vary with pH treatment. Zoeal morphology did not vary among treatments, although glaucothoe and C1 crabs were slightly smaller in pH 7.8 than in the ambient treatment. Ambient larvae also had a slightly higher mass than pH 7.8 larvae but not pH 7.5. Ambient larvae had higher magnesium contents than pH 7.8 and pH 7.5, but calcium levels were the same. Ambient larvae also had slightly lower carbon and nitrogen content than pH 7.8 and pH 7.5 larvae but only in the 4th zoeal stage. Overall this study suggests that red king crab larvae are well adapted to a wide range of pH conditions and are unlikely to be significantly affected by ocean acidification levels projected for the next two centuries.
NanoNERF: A nanoscale NERF blaster replica made of DNA
Authors: Takiguchi Lauren P. , Rober Mark B. , Olvera Jocelyn G. , Wacker Amanda L. , Fantasia Ryan J. , Liu Boyu , Shipley Wade , Tao Andrea , Kosuri Pallav
Published: October 2023

We used DNA origami to create NanoNERF, the world’s smallest NERF blaster replica (Figure 1). We based our design on the NERF modelMaverick Rev-6, and scaled the dimensions down three million times. NanoNERF is planar and measures ∼100 nm in length, with a length-to-width ratio closely resembling the original toy. Here, we describe the design, prototyping, and validation pipeline used to create the NanoNERF. We also discuss potential applications to motivate the creation of future nanoscale blasters with a firing functionality.
WASP facilitates tumor mechanosensitivity in T lymphocytes
Authors: Mandal Srishti , Melo Mariane , Gordiichuk Pavlo , Acharya Sayanti , Poh Yeh-Chuin , Li Na , Aung Aereas , Dane Eric L. , Irvine Darrell J. , Kumari Sudha
Published: October 2023

Cytotoxic T lymphocytes (CTLs) carry out immunosurveillance by scanning target cells of diverse physical properties for the presence of antigens. While the recognition of cognate antigen by the T cell receptor is the primary signal for CTL activation, it has become increasingly clear that the mechanical stiffness of target cells plays an important role in antigen-triggered T cell responses. However, the molecular machinery within CTLs that transduces the mechanical information of tumor cells remains unclear. We find that CTL’s mechanosensitive ability requires the activity of the actin-organizing protein Wiskott-Aldrich Syndrome Protein (WASP). WASP activation is modulated by the mechanical properties of antigen-presenting contexts across a wide range of target cell stiffnesses and activated WASP then mediates mechanosensitive activation of early TCR signaling markers in the CTL. Our results provide a molecular link between antigen mechanosensing and CTL immune response and suggest that CTL-intrinsic cytoskeletal organizing principles enable the processing of mechanical information from diverse target cells.
Dynamic metabolic and molecular changes during seasonal shrinking inSorex araneus
Authors: Thomas William R. , Baldoni Cecilia , Zeng Yuanyuan , Carlson David , Holm-Jacobsen Julie , Muturi Marion , von Elverfeldt Dominik , Nieland John , Dechmann Dina K. N. , Corthals Angelique , Dávalos Liliana M.
Published: October 2023

To meet the challenge of wintering in place many high-latitude small mammals reduce energy demands through hibernation. In contrast, short-lived Eurasian common shrews,Sorex araneus, remain active and shrink, including energy-intensive organs in winter, regrowing in spring in an evolved strategy called Dehnel’s phenomenon. How this size change is linked to metabolic and regulatory changes to sustain their high metabolism is unknown. We analyzed metabolic, proteomic, and gene expression profiles spanning the entirety of Dehnel’s seasonal cycle in wild shrews. We show regulatory changes to oxidative phosphorylation and increased fatty acid metabolism during autumn-to-winter shrinkage, as previously found in hibernating species. But in shrews we also found upregulated winter expression of genes involved in gluconeogenesis: the biosynthesis of glucose from non-carbohydrate substrates. Co-expression models revealed changes in size and metabolic gene expression interconnect via FOXO signaling, whose overexpression reduces size and extends lifespan in many model organisms. We propose that while shifts in gluconeogenesis meet the challenge posed by high metabolic rate and active winter lifestyle, FOXO signaling is central to Dehnel’s phenomenon, with spring downregulation limiting lifespan in these shrews.
Tick Innate Immune Responses to Hematophagy andEhrlichiaInfection at Single-Cell Resolution
Authors: Adegoke Abdulsalam , Ribeiro Jose M. C. , Smith Ryan C. , Karim Shahid
Published: October 2023

Ticks rely on robust cellular and humoral immune responses to control microbial infection. However, several aspects of the tick’s innate immune system remain uncharacterized, most notably that of the immune cells (called hemocytes), which are known to play a significant role in cellular and humoral responses toward microbes. Despite the importance of hemocytes in regulating microbial infection, our understanding of their basic biology and molecular mechanisms remains limited. Therefore, we believe that a more detailed understanding of the role of hemocytes in the interactions between ticks and tick-borne microbes is crucial to illuminate their function in vector competence and to help identify novel targets for developing new strategies to block tick-borne pathogen transmission. This study examined hemocytes from the lone star tick (Amblyomma americanum) at the transcriptomic level using the 10X genomics single-cell RNA sequencing platform to analyze hemocyte populations from unfed, partially blood-fed, andEhrlichia chaffeensis-infected ticks. Our data exhibit the identification of twelve and nineteen distinct hemocyte populations, respectively, from uninfected andEhrlichia-infected ticks. Our results show a significant increase of clusters representing granulocyte and oenocytoids populations withEhrlichiainfection. This work opens a new field of tick innate immunobiology to understand the role of hemocytes, particularly in response to prolonged blood-feeding (hematophagy) and tick-microbial interactions.

Significance

The immune response of ticks plays a crucial role in their ability to survive and transmit pathogens. Hemocytes, the primary immune cells in arthropods, are key mediators of tick’s immune defense and provide deep insights into immune responses to microbial infection. However, tick hemocytes’ cellular complexity and heterogeneity have posed challenges for comprehensive characterization. This study employed single-cell RNA sequencing (scRNA-seq) to profile tick hemocytes and elucidate their transcriptional diversity. We identified distinct subpopulations of hemocytes and characterized their unique gene expression profiles. We observed significant variation in immune-related gene expression between hemocyte subpopulations during hematophagy and in response toEhrlichiainfection, suggesting specialized functional roles. Our analysis revealed potential marker genes associated with specific hemocyte functions. Our study provides the first comprehensive single-cell atlas of tick hemocytes, shedding light on these cells’ molecular diversity and immune functions. The findings enhance our understanding of tick-host interactions and offer a step toward understanding arthropod immunobiology.
SARS-CoV-2 neurotropism-induced anxiety/depression-like behaviors require Microglia activation
Authors: Ge Qian , Zhou Shan , Porras Jose , Fu Panfeng , Wang Ting , Du Jianyang , Li Kun
Published: October 2023

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been associated with a wide range of “long COVID” neurological symptoms. However, the mechanisms governing SARS-CoV-2 neurotropism and its effects on long-term behavioral changes remain poorly understood. Using a highly virulent mouse-adapted SARS-CoV-2 strain, denoted as SARS2-N501YMA30, we demonstrated that intranasal inoculation of SARS2-N501YMA30results in viral dissemination to multiple brain regions, including the amygdala and hippocampus. Behavioral assays indicated a marked elevation in anxiety- and depression-like behaviors post infection. A comparative analysis of RNA expression profiles disclosed alterations in the post-infected brains. Additionally, we observed dendritic spine remodeling on neurons within the amygdala after infection. Infection with SARS2-N501YMA30was associated with microglial activation and a subsequent increase in microglia-dependent neuronal activity in the amygdala. Pharmacological inhibition of microglial activity subsequent to viral spike inoculation mitigates microglia-dependent neuronal hyperactivity. Transcriptomic analysis of infected brains revealed the upregulation of inflammatory and cytokine-related pathways, implicating microglia-driven neuroinflammation in the pathogenesis of neuronal hyperactivity and behavioral abnormality. Overall, these data provide critical insights into the neurological consequences of SARS-CoV-2 infection and underscore microglia as a potential therapeutic target for ameliorating virus-induced neurobehavioral abnormalities.
APOLLO: A genome-scale metabolic reconstruction resource of 247,092 diverse human microbes spanning multiple continents, age groups, and body sites
Authors: Heinken Almut , Hulshof Timothy Otto , Nap Bram , Martinelli Filippo , Basile Arianna , O’Brolchain Amy , O’Sullivan Neil Francis , Gallagher Celine , Magee Eimer , McDonagh Francesca , Lalor Ian , Bergin Maeve , Evans Phoebe , Daly Rachel , Farrell Ronan , Delaney Rose Marie , Hill Saoirse , McAuliffe Saoirse Roisin , Kilgannon Trevor , Fleming Ronan M.T. , Thinnes Cyrille C. , Thiele Ines
Published: October 2023

Computational modelling of microbiome metabolism has proved instrumental to catalyse our understanding of diet-host-microbiome-disease interactions through the interrogation of mechanistic, strain- and molecule-resolved metabolic models. We present APOLLO, a resource of 247,092 human microbial genome-scale metabolic reconstructions spanning 19 phyla and accounting for microbial genomes from 34 countries, all age groups, and five body sites. We explored the metabolic potential of the reconstructed strains and developed a machine learning classifier able to predict with high accuracy the taxonomic strain assignments. We also built 14,451 sample-specific microbial community models, which could be stratified by body site, age, and disease states. Finally, we predicted faecal metabolites enriched or depleted in gut microbiomes of people with Crohn’s disease, Parkinson disease, and undernourished children. APOLLO is compatible with the human whole-body models, and thus, provide unprecedented opportunities for systems-level modelling of personalised host-microbiome co-metabolism. APOLLO will be freely available underhttps://www.vmh.life/.
Biochemically-functionalized probes for cell type-specific targeting and recording in the brain
Authors: Zhang Anqi , Zwang Theodore J. , Lieber Charles M.
Published: October 2023

Selective targeting and modulation of distinct cell types and neuron subtypes is central to understanding complex neural circuitry, and could enable electronic treatments that target specific circuits while minimizing off-target effects. However, current brain-implantable electronics have not yet achieved cell-type specificity. We address this challenge by functionalizing flexible mesh electronic probes, which elicit minimal immune response, with antibodies or peptides to target specific cell markers. Histology studies reveal selective association of targeted neurons, astrocytes and microglia with functionalized probe surfaces without accumulating off-target cells. In vivo chronic electrophysiology further yields recordings consistent with selective targeting of these cell types. Last, probes functionalized to target dopamine 2 receptor expressing neurons show the potential for neuron subtype specific targeting and electrophysiology.
Liver microRNA transcriptome reveals miR-182 as link between type 2 diabetes and fatty liver disease in obesity
Authors: Krause Christin , Britsemmer Jan H. , Bernecker Miriam , Molenaar Anna , Taege Natalie , Lopez-Alcantara Nuria , Geißler Cathleen , Kaehler Meike , Iben Katharina , Judycka Anna , Wagner Jonas , Wolter Stefan , Mann Oliver , Pfluger Paul T. , Cascorbi Ingolf , Lehnert Hendrik , Stemmer Kerstin , Schriever Sonja C. , Kirchner Henriette
Published: October 2023

Background

The development of obesity-associated comorbidities such as type 2 diabetes (T2D) and hepatic steatosis has been linked to selected microRNAs in individual studies; however, an unbiased genome-wide approach to map T2D induced changes in the miRNAs landscape in human liver samples, and a subsequent robust identification and validation of target genes is still missing.

Methods

Liver biopsies from age- and gender-matched obese individuals with (n=20) or without (n=20) T2D were used for microRNA microarray analysis. The candidate microRNA and target genes were validated in 85 human liver samples, and subsequently mechanistically characterized in hepatic cells as well as by dietary interventions and hepatic overexpression in mice.

Results

Here we present the human hepatic microRNA transcriptome of type 2 diabetes in liver biopsies and use a novel seed prediction tool to robustly identify microRNA target genes, which were then validated in a unique cohort of 85 human livers. Subsequent mouse studies identified a distinct signature of T2D-associated miRNAs, partly conserved in both species. Of those, human-murine miR-182-5p was the most associated to whole-body glucose homeostasis and hepatic lipid metabolism. Its target geneLRP6was consistently lower expressed in livers of obese T2D humans and mice as well as under conditions of miR-182-5p overexpression. Weight loss in obese mice decreased hepatic miR-182-5p and restoredLrp6expression and other miR-182-5p target genes. Hepatic overexpression of miR-182-5p in mice rapidly decreased LRP6 protein levels and increased liver triglycerides and fasting insulin under obesogenic conditions after only seven days.

Conclusion

By mapping the hepatic miRNA-transcriptome of type 2 diabetic obese subjects, validating conserved miRNAs in diet-induced mice, and establishing a novel miRNA prediction tool, we provide a robust and unique resource that will pave the way for future studies in the field. As proof of concept, we revealed that the repression ofLRP6by miR-182-5p, which promotes lipogenesis and impairs glucose homeostasis, provides a novel mechanistic link between T2D and non-alcoholic fatty liver disease, and demonstrate in vivo that miR-182-5p can serve as a future drug target for the treatment of obesity-driven hepatic steatosis.

Graphical Abstract
A Drug-Free Pathogen Capture and Neutralizing Nasal Spray to Prevent Emerging Respiratory Infections
Authors: Joseph John , Baby Helna Mary , Quintero Joselyn Rojas , Kenney Devin , Mebratu Yohannes A , Bhatia Eshant , Shah Purna , Swain Kabir , Kaur Shahdeep , Li Xiang-Ling , Mwangi John , Snapper Olivia , Nair Remya , Agus Eli , Ranganathan Sruthi , Kage Julian , Gao Jingjing , Luo James N , Yu Anthony , Douam Florian , Tesfaigzi Yohannes , Karp Jeffrey M , Joshi Nitin
Published: October 2023

Respiratory infections pose a global health crisis. Vaccines are pathogen specific, and new vaccines are needed for mutants and emerging pathogens. Here, we report a “drug free” prophylactic platform - a “Pathogen Capture and Neutralizing Spray” (PCANS) that actsviaa multi-pronged approach to prevent a broad spectrum of respiratory infections. PCANS forms a protective coating in the nasal cavity that enhances the capture of large respiratory droplets. The coating acts as a physical barrier against a broad spectrum of viruses and bacteria, and rapidly neutralizes them, reducing the pathogen load by >99.99%. In mice, PCANS showed nasal retention for at least 8 h and was safe for daily administration. A single prophylactic dose of PCANS protected mice against supra-lethal dosages of a mouse-adapted H1N1 Influenza virus (PR8), reduced lung viral titer by >99.99%, improved survival, and suppressed pathological manifestations. Together, our data suggest PCANS as a promising daily-use prophylactic approach against current and emerging respiratory infections.
Automated Stimulation and Long-Term Remote Monitoring of Multi-Plex Microfluidic Organoid Chips
Authors: Sachs David M , Costa Kevin D
Published: October 2023

Developing a novel microfluidic organoid system required many experiments and iterations due to lack of knowledge about the relevant developmental biology. Collecting data on the developing organoids quickly escalated into a bottleneck as high throughput and long term culture resulted in a rapidly increasing number of specimens being observed. Commercially available automated microscope systems exist, but were either too expensive or not appropriate, and could not be modified. To satisfy the increasing need for automated data collection, a custom robotic system was developed to collect data from within a standard incubator. An X-Y belt driven gantry was designed with an architecture chosen to balance high accuracy, low cost, speed, and range of motion. Focus control was implemented with dual miniature leadscrews. A linear sliding mechanism was used to switch between two microscope objectives. 3D printed chip attachments were designed to implement illuminators for bright field imaging, and electrodes for stimulating the cardiac organoids. A fluorescent filter block was designed using a 3D printed piece to hold optical components, and a multi-band filter set that allowed for three color fluorescence without moving parts. A pulley driven tilting stage gravitationally biased the organoids during development. In order to ensure accurate image collection despite the inevitable position shifting of the chips, an image processing pipeline was developed for locating organoids using geometrical microfluidic chip features. The resulting robotic system automated imaging data collection on organoids and electrical and mechanical stimulation, in addition to being modifiable for future projects.
DIRECTED GRAPH THEORY FOR THE ANALYSIS OF BIOLOGICAL REGULATORY NETWORKS
Authors: Takane Martha , Bernal-González Saúl , Mauro-Moreno Jesús , García-López Gustavo , Méndez-Ambrosio Bruno , De-Miguel Francisco F.
Published: October 2023

Regulated biological networks are commonly represented as logical diagrams, in which the exact interactions between the elements remain out of sight. Here we propose a new type of excitation-inhibition graph based on Boolean logic, which we name “logical directed graph or simply, logical digraph of the biological system”. Such logical digraph allows the representation of every possible regulatory interaction among elements, based on Boolean interactions. The logical digraph contains information about the connectivity, dynamics, limit cycles, and attractors of the network. As proof of the application, the logical digraph was applied to analyze the functioning of the well-known neural network that produces oscillatory swimming in the mollusk Tritonia. Our method permits to transit from a regulatory network to its logical digraph and vice versa. In addition, we show that the spectral properties of the so-called state matrix provide mathematical evidence about why the elements in the attractors and limit cycles contain information about the dynamics of the biological system. Open software routines are provided for the calculations of the components of the network and the attractors and limit cycles. This approach offers new possibilities to visualize and analyze regulatory networks in biology.
Investigating markers of pulmonary aspiration in bronchoalveolar lavage from children with severe neurodisability
Authors: Maher Rosemary E , Trinick Ruth E , Dalzell Mark , Beynon Robert J , McNamara Paul S
Published: October 2023

Respiratory exacerbations are a frequent cause of hospitalisation in children with severe neurodisability (ND). Direct aspiration of food/saliva, reflux aspiration of gastric contents or a combination of both is thought to be a common cause of respiratory symptoms and disease, particularly when this occurs ‘silently’. A number of aspiration biomarkers, including bile acids and pepsin, have been proposed, however, no gold-standard diagnostic tests are currently available. In children with severe ND at high risk of both direct and reflux aspiration, we analysed lower airway samples for saliva- and/or gastric-specific proteins with biomarker potential.
BOLD: Blood-gas and Oximetry Linked Dataset – Open Source Research
Authors: Matos João , Struja Tristan , Gallifant Jack , Nakayama Luis , Charpignon Marie-Laure , Liu Xiaoli , Economou-Zavlanos Nicoleta , Cardoso Jaime S. , Johnson Kimberly S , Bhavsar Nrupen , Gichoya Judy , Celi Leo Anthony , Wong A. Ian
Published: October 2023

Pulse oximeters measure peripheral arterial oxygen saturation (SpO2) noninvasively, while the gold standard (SaO2) involves arterial blood gas measurement. There are known racial and ethnic disparities in their performance. BOLD is a new comprehensive dataset that aims to underscore the importance of addressing biases in pulse oximetry accuracy, which disproportionately affect darker-skinned patients.

The dataset was created by harmonizing three Electronic Health Record databases (MIMIC-III, MIMIC-IV, eICU-CRD) comprising Intensive Care Unit stays of US patients. Paired SpO2and SaO2measurements were time-aligned and combined with various other sociodemographic and parameters to provide a detailed representation of each patient. BOLD includes 49,099 paired measurements, within a 5-minute window and with oxygen saturation levels between 70-100%. Minority racial and ethnic groups account for ∼25% of the data – a proportion seldom achieved in previous studies. The codebase is publicly available.

Given the prevalent use of pulse oximeters in the hospital and at home, we hope that BOLD will be leveraged to develop debiasing algorithms that can result in more equitable healthcare solutions.
Repeat Testing of Mpox Specimens with Late CTs Improves Detection of Potential False Positive Cases
Authors: Shean Ryan C. , Hymas Weston C. , Klein Jeremy , Pyne Michael , Hillyard David R. , Bradley Benjamin T.
Published: October 2023

The global outbreak of mpox necessitated the rapid development of clinical assays for monkeypox virus detection. While the majority of mpox specimens have high viral loads with corresponding early CT values, reports have indicated some specimens with late CT values can represent false positive results. To mitigate this risk, the Centers for Disease Control and Prevention (CDC) published an advisory recommending repeat testing of all specimens with CT values ≥34. However, limited experimental data was available to support this specific cutoff. In this study, we examine whether a more conservative approach in which all specimens with CT values ≥29 are repeated would improve the detection of potential false positive results. Compared to the CDC algorithm, our approach identified an additional 20% (5/25) of potential false positive results. To assess the impact of this cutoff on laboratory workload, we estimated the expected increase in test volume and turnaround time (TAT) relative to the CDC method. Using a lower repeat threshold, test volume increased by 0.7% and the mean TAT for positive specimens increased by less than 15 minutes. Overall, a lower threshold than recommended by the CDC for repeating late CT mpox specimens may reduce the number of false positives reported while minimally impacting testing volume and TAT.
Shared genetic basis informs the roles of polyunsaturated fatty acids in brain disorders
Authors: Xu Huifang , Sun Yitang , Francis Michael , Cheng Claire F. , Modulla Nitya T.R. , Brenna J. Thomas , Chiang Charleston W. K. , Ye Kaixiong
Published: October 2023

The neural tissue is rich in polyunsaturated fatty acids (PUFAs), components that are indispensable for the proper functioning of neurons, such as neurotransmission. PUFA nutritional deficiency and imbalance have been linked to a variety of chronic brain disorders, including major depressive disorder (MDD), anxiety, and anorexia. However, the effects of PUFAs on brain disorders remain inconclusive, and the extent of their shared genetic determinants is largely unknown. Here, we used genome-wide association summary statistics to systematically examine the shared genetic basis between six phenotypes of circulating PUFAs (N = 114,999) and 20 brain disorders (N = 9,725-762,917), infer their potential causal relationships, identify colocalized regions, and pinpoint shared genetic variants. Genetic correlation and polygenic overlap analyses revealed a widespread shared genetic basis for 77 trait pairs between six PUFA phenotypes and 16 brain disorders. Two-sample Mendelian randomization analysis indicated potential causal relationships for 16 pairs of PUFAs and brain disorders, including alcohol consumption, bipolar disorder (BIP), and MDD. Colocalization analysis identified 40 shared loci (13 unique) among six PUFAs and ten brain disorders. Twenty-two unique variants were statistically inferred as candidate shared causal variants, including rs1260326 (GCKR), rs174564 (FADS2) and rs4818766 (ADARB1). These findings reveal a widespread shared genetic basis between PUFAs and brain disorders, pinpoint specific shared variants, and provide support for the potential effects of PUFAs on certain brain disorders, especially MDD, BIP, and alcohol consumption.