bluuebunny/crossref_metadata_2025 huggingface dataset:
PREVALENCE AND FACTORS ASSOCIATED WITH ASYMPTOMATIC HYPOGLYCEMIA AMONG PRETERM NEWBORNS IN DAR ES SALAAM REGIONAL REFERRAL HOSPITALS, TANZANIA: A CROSS SECTIONAL ANALYTICAL STUDY PROTOCOL
Authors: Salum Shani Shamsi , Kalabamu Florence Salvatory , Fataki Maulidi Rashid , Omary Salha Ally , Mohamed Ummulkheir Hamid , Kizwi Hillary Abdillah , Leshabari Kelvin Melkizedeck
Published: October 2022

Background

Hypoglycemia is the most common metabolic abnormality in newborns. It is still unclear whether the condition is truly pathological, especially if it occurs transiently during the 1st 24 hours of birth in an asymptomatic phase. Besides, there is hardly any data on the burden of asymptomatic neonatal hypoglycemia and its associated factors among preterm newborns in Africa.

Aim

To assess the prevalence and associated factors of asymptomatic neonatal hypoglycemia among preterm newborns in a typical African settings.

Design and Methods

We plan to conduct a quick, cross-sectional analytical hospital-based survey at all public regional referral hospitals in Dar es Salaam, Tanzania. We will consider all preterm newborns delivered in the specified settings between June 2022 and December 2022. Our study population will be all preterm newborns delivered at Dar es Salaam public regional referral hospitals. Our target population will be all preterm newborns with asymptomatic hypoglycemia. All newborns with clinically detected congenital anomalies and those who will be delivered at home but brought to the facilities for care will thus be excluded from the study. Our primary outcome measure will be neonatal RBG < 2.6 mmol/L without any symptoms associated with hypoglycemia. Maternal, fetal and early neonatal (> 6 hours but within 24 hours post-delivery) factors will be logistically regressed against the outcome variable after appropriate model validation. Unless otherwise stated, an α-level of 5% will be used as a limit of type I error in findings. Written informed consent will be obtained from mothers of each newborn prior to inclusion into the study.

Main Outcome measure

Prevalence of asymptomatic hypoglycemia among preterm newborns in Dar es Salaam hospitals.

Relevance of the findings to science, policy & practice

Current clinical practice does not provide evidence for routine glycaemic screening among preterm newborns asymptomatic for hypoglycemia. The study will have a potential to assess stata of preterm newborn with asymptomatic hypoglycemia
Potential risk polarization for acute myocardial infarction during the COVID-19 pandemic: Single-center experiences in Osaka, Japan
Authors: Furui Masato , Kawajiri Kenji , Yoshida Takeshi , Kakii Bunpachi , Oshiro Norikazu , Asanuma Mai , Nishioka Hiroaki , Wada Hideichi
Published: October 2022

This study compared the time course and outcomes of acute myocardial infarction, including mechanical complications and hospital mortality, before and after the coronavirus disease 2019 (COVID-19) pandemic at a regional core hospital in South Osaka, Japan. Moreover, it identified predictors for hospital mortality and mechanical complications. In total, 503 patients who underwent emergency percutaneous coronary intervention between January 2011 and December 2021 at our institution were examined retrospectively. The time course of acute myocardial infarction, mechanical complications, and mortality rate before and after the COVID-19 emergency declaration were compared. Overall, 426 patients with ST-segment elevation myocardial infarction and 77 patients with non-ST-segment elevation myocardial infarction were identified. For patients with ST-segment elevation myocardial infarction, the onset-to-door time was longer (181 vs. 156 min, P = 0.001) and mechanical complications were worse (7.8% vs. 2.6%, P = 0.025) after the emergency declaration of COVID-19 than before the pandemic. Age, low ejection fraction, out-of-hospital cardiac arrest, and mechanical complications were identified as independent risk factors for hospital mortality among patients with ST-segment elevation myocardial infarction, using multivariable analysis. Post-declaration, age, walk-ins, referrals, and intra-aortic balloon pump use were independent predictors of mechanical complications among patients with ST-segment elevation myocardial infarction. Onset-to-door time and mechanical complication rate increased after the COVID-19 declaration among patients with ST-segment elevation myocardial infarction. Arrival by walk-in and a referral that caused treatment delay were identified as independent risk factors for mechanical complication, in addition to age, use of intra-aortic balloon pump, and post-declaration of COVID-19. Therefore, the risks posed by the COVID-19 pandemic might have a polarization tendency resulting from the relief or worsening of cardiac symptoms.
Association of gamma-glutamyl transferase variability with risk of osteoporotic fractures: A nationwide cohort study
Authors: Kim Dongyeop , Kim Jee Hyun , Lee Heajung , Hong Iksun , Chang Yoonkyung , Song Tae-Jin
Published: October 2022

Objectives

Gamma-glutamyl transferase (GGT) is related to inflammation, osteoporosis, and vascular diseases. Recently, changes in metabolic parameters have been proposed as disease biomarkers. We aimed to assess longitudinally the association of GGT variability with osteoporotic fractures.

Methods

From the National Health Insurance Service-Health Screening Cohort database, participants who underwent three or more health examinations between 2003 and 2008 were included (n=1,072,432). Variability indexes were as follows: (1) coefficient of variation (CV), (2) standard deviation (SD), and (3) variability independent of the mean (VIM). The primary outcome was occurrence of osteoporotic fracture, defined as identification of one of the following international classification of diseases-10 codes: vertebral fracture (S22.0, S22.1, S32.0, S32.7, T08, M48.4, M48.5, M49.5), hip fracture (S72.0, S72.1), distal radius fracture (S52.5, S52.6), or humerus fracture (S42.2, S42.3).

Results

During a median of 12.3 years (interquartile range 12.1 – 12.6), osteoporotic fractures occurred in 49,677 (4.6%) participants. In multivariable analysis, GGT variability based on CV positively correlated with the occurrence of osteoporotic fracture (adjusted hazard ratio [HR] of the highest quartile compared with the lowest quartile 1.15, 95% confidence interval [CI] 1.12-1.18,P< 0.001). These results were consistent even when GGT variability was defined by SD (adjusted HR 1.22, 95% CI 1.19-1.25,P< 0.001) and VIM (adjusted HR 1.12, 95% CI 1.09-1.15,P< 0.001).

Conclusions

Increased GGT variability is associated with an increased risk of osteoporotic fractures in the Korean population. Maintaining constant and stable GGT level may help reduce the risk of osteoporotic fractures.
Diencephalic or hippocampal amnesia – different etiologies, common mechanisms
Authors: Segobin Shailendra , Ambler Melanie , Laniepce Alice , Platel Hervé , Chételat Gael , Groussard Mathilde , Pitel Anne-Lise
Published: October 2022

Objectives

To compare regional volume deficits within the Papez circuit in Alzheimer’s disease (AD) and Korsakoff’s syndrome (KS), taking into account the neurodegenerative nature of AD.

Methods

18 KS patients, 40 AD patients (20 with Moderate AD (MAD) matched on cognitive deterioration with KS patients and 20 with Severe AD (SAD)), and 70 healthy controls underwent structural MRI examination. Volumes of the hippocampi, thalami, cingulate gyri, mammillary bodies (MB) and mammillothalamic tracts (MTT) were extracted.

Results

For the anterior and posterior cingulate gyri, and anterior thalamic nuclei, all patient groups were significantly affected compared to controls but did not differ between each other. Lower volumes were observed in all patient groups compared to controls in the entire thalamus, mediodorsal thalamic nuclei and MB, but these regions were more severely damaged in KS compared to AD. MTT volumes were significantly damaged in KS only. Hippocampi were affected in all patient groups but more severely in the SAD than in the KS and MAD.

Interpretation

The specificity of KS compared to AD relies on the severity of the MB and mediodorsal nuclei shrinkage, as well as the atrophy of the MTT. Several nodes of the Papez circuit were damaged to the same extent in AD and KS: the anterior thalamic nuclei, the cingulate cortex and the hippocampus (in MAD only). Our results encourage considering common mechanisms in the pathophysiology of amnesia regardless of etiology and question the relevance of the classical distinction between hippocampal and diencephalic amnesia.
Low back pain service utilization and costs: association with number of visits of chiropractic manipulation, active care, manual therapy or acupuncture. A retrospective cohort study
Authors: Elton David , Zhang Meng
Published: October 2022

Background

For individuals with low back pain (LBP), in the absence of serious pathology clinical practice guidelines (CPG) recommend a stepped approach to management with first-line emphasis on natural history, self-care, and non-pharmaceutical therapies. For individuals with non-surgical LBP initially contacting a chiropractor (DC), physical therapist (PT), or licensed acupuncturist (LAc), the purpose of this retrospective cohort study was to examine the dose response association between the number of visits of chiropractic manipulative therapy (CMT), active care (AC), manual therapy (MT), or acupuncture, exposure to second- and third-line services, and total episode cost.

Methods

A national sample of individuals with a single episode of non-surgical LBP occurring in 2017-2019 was analyzed using episode of care as the unit of analysis. The primary independent variables were initial contact with either a DC, PT, or LAc, and the number of visits of CMT, AC, MT, or acupuncture. Dependent measures included rate and timing of use of 13 types of health care services and total episode cost.

Results

132,199 continuously insured individuals aged 18 years and older initially contacted 21,336 different DCs, 2,734 PTs and 1,339 LAcs for a single episode of non-surgical LBP. These individuals were associated with $62,185,930 in expenditures. The most common number of visits was 1 to 3 - CMT (48.2% of episodes), AC (29.7%), MT (32.1%), and acupuncture (27.0%). For each service, 1 to 3 visits was associated with the lowest rate of exposure to second- and third-line services although rate differences between visit dose categories were generally not significant or clinically. Episode total cost and duration increased significantly with increasing number of visits. CMT was associated with lowest median total episode cost at each level of visit utilization.

Conclusions

For non-surgical LBP episodes initially contacting a DC, PT or LAc, 1 to 3 visits of CMT, AC, MT, or acupuncture was the most common level of utilization, associated with the lowest exposure to second- and third-line services and lowest total episode cost. Among, CMT, AC, MT, and acupuncture, CMT was associated with the lowest total episode cost at each level of utilization. A higher number of visits of CMT, AC, MT or acupuncture was associated with significantly higher total cost, without meaningful impact on exposure to second- or third-line services. Unmeasured clinical benefits may be associated with higher visit counts and warrants further study.
Prediction of atrial fibrillation and stroke using machine learning models in UK Biobank
Authors: Papadopoulou A. , Harding D. , Slabaugh G. , Marouli E. , Deloukas P.
Published: October 2022

We employed machine learning (ML) approaches to evaluate 2,199 clinical features and disease phenotypes available in the UK Biobank as predictors for Atrial Fibrillation (AF) risk. After quality control, 99 features were selected for analysis in 21,279 prospective AF cases and equal number of controls. Different ML methods were employed, including LightGBM, XGBoost, Random Forest (RF), Deep Neural Network (DNN),) and Logistic Regression with L1 penalty (LR). In order to eliminate the black box character of the tree-based ML models, we employed Shapley-values (SHAP), which are used to estimate the contribution of each feature to AF prediction. The area-under-the-roc-curve (AUROC) values and the 95% confidence intervals (CI) per model were: 0.729 (0.719, 0.738) for LightGBM, 0.728 (0.718, 0.737) for XGBoost, 0.716 (0.706,0.725) for DNN, 0.715 (0.706, 0.725) for RF and 0.622 (0.612, 0.633) for LR. Considering the running time, memory and stability of each algorithm, LightGBM was the best performing among those examined. DeLongs test showed that there is statistically significant difference in the AUROCs between penalised LR and the other ML models. Among the top important features identified for LightGBM, using SHAP analysis, are the genetic risk score (GRS) of AF and age at recruitment. As expected, the AF GRS had a positive impact on the model output, i.e. a higher AF GRS increased AF risk. Similarly, age at recruitment also had a positive impact increasing AF risk. Secondary analysis was performed for the individuals who developed ischemic stroke after AF diagnosis, employing 129 features in 3,150 prospective cases of people who developed ischemic stroke after AF, and equal number of controls in UK Biobank. The AUC values and the 95% CI per model were: 0.631 (0.604, 0.657) for XGBoost, 0.620 (0.593, 0.647) for LightGBM, 0.599 (0.573, 0.625) for RF, 0.599 (0.572, 0.624) for SVM, 0.589 (0.562, 0.615) for DNN and 0.563 (0.536, 0.591) for penalised LR. DeLongs test showed that there is no evidence for significant difference in the AUROCs between XGBoost and all other examined ML models but the penalised LR model (pvalue=2.00 E-02). Using SHAP analysis for XGBoost, among the top important features are age at recruitment and glycated haemoglobin. DeLongs test showed that there is evidence for statistically significant difference between XGBoost and the current clinical tool for ischemic stroke prediction in AF patients, CHA2DS2-VASc (pvalue=2.20E-06), which has AUROC and 95% CI of 0.611 (0.585, 0.638).
Engineered vasculature induces functional maturation of pluripotent stem cell-derived islet organoids
Authors: Nguyen-Ngoc Kim-Vy , Jun Yesl , Sai Somesh , Bender R. Hugh F. , Kravets Vira , Zhu Han , Hatch Christopher J. , Schlichting Michael , Gaetani Roberto , Mallick Medhavi , Hachey Stephanie J. , Christman Karen L. , George Steven C. , Hughes Christopher C.W. , Sander Maike
Published: October 2022

Blood vessels play a critical role in pancreatic islet health and function, yet current culture methods to generate islet organoids from human pluripotent stem cells (SC-islets) lack a vascular component. Here, we engineered 3D vascularized SC-islet organoids by assembling SC-islet cells, human primary endothelial cells (ECs) and fibroblasts both in a non-perfused model and a microfluidic device with perfused vessels. Vasculature improved stimulus-dependent Ca2+influx into SC-β-cells, a hallmark of β-cell function that is blunted in non-vascularized SC-islets. We show that an islet-like basement membrane is formed by vasculature and contributes to the functional improvement of SC-β-cells. Furthermore, cell-cell communication networks based on scRNA-seq data predicted BMP2/4-BMPR2 signaling from ECs to SC-β-cells. Correspondingly, BMP4 augmented the SC-β-cell Ca2+response and insulin secretion. These vascularized SC-islet models will enable further studies of crosstalk between β-cells and ECs and can serve asin vivo-mimicking platforms for disease modeling and therapeutic testing.
Versatile methanotrophs form an active methane biofilter in the oxycline of a seasonally stratified coastal basin
Authors: Venetz Jessica , Żygadłowska Olga M. , Lenstra Wytze K. , van Helmond Niels A.G.M. , Nuijten Guylaine H.L. , Wallenius Anna J. , Martins Paula Dalcin , Slomp Caroline P. , Jetten Mike S.M. , Veraart Annelies J.
Published: October 2022

The potential and drivers of microbial methane removal in the water column of seasonally stratified coastal ecosystems and the importance of the methanotrophic community composition for ecosystem functioning are not well explored. Here, we combined depth profiles of oxygen and methane with 16S rRNA gene amplicon sequencing, metagenomics, and methane oxidation rates at discrete depths in a stratified coastal marine system (Lake Grevelingen, The Netherlands). Three amplicon sequence variants (ASVs) belonging to different genera of aerobicMethylomonadaceaeand the corresponding three methanotrophic metagenome-assembled genomes (MOB-MAGs) were retrieved by 16S rRNA sequencing and metagenomic analysis respectively. The abundances of the different methanotrophic ASVs and MOB-MAGs peaked at different depths along the methane oxygen counter-gradient and the MOB-MAGs show a quite diverse genomic potential regarding oxygen metabolism, partial denitrification, and sulfur metabolism. Moreover, potential aerobic methane oxidation rates indicated high methanotrophic activity throughout the methane oxygen counter-gradient, even at depths with lowin situmethane or oxygen concentration. This suggests that niche-partitioning with high genomic versatility of the presentMethylomonadaceaemight contribute to the functional resilience of the methanotrophic community and ultimately the efficiency of methane removal in the stratified water column of marine Lake Grevelingen.
Visual Occlusions Result in Phase Synchrony Within Multiple Brain Regions Involved in Sensory Processing and Balance Control
Authors: Symeonidou Evangelia-Regkina , Ferris Daniel P.
Published: October 2022

There is a need to develop appropriate balance training interventions to minimize the risk of falls. Recently, we found that intermittent visual occlusions can substantially improve the effectiveness and retention of balance beam walking practice (Symeonidou and Ferris 2022). We sought to determine how the intermittent visual occlusions affect electrocortical activity during beam walking. We hypothesized that areas involved in sensorimotor processing and balance control would demonstrate spectral power changes and inter-trial coherence modulations after loss and restoration of vision. Ten healthy young adults practiced walking on a treadmill-mounted balance beam while wearing high-density EEG and experiencing reoccurring visual occlusions. Results revealed spectral power fluctuations and inter-trial coherence changes in the visual, occipital, temporal, and sensorimotor cortex as well as the posterior parietal cortex and the anterior cingulate. We observed a prolonged alpha increase in the occipital, temporal, sensorimotor, and posterior parietal cortex after the occlusion onset. In contrast, the anterior cingulate showed a strong alpha and theta increase after the occlusion offset. We observed transient phase synchrony in the alpha, theta, and beta bands within the sensory, posterior parietal, and anterior cingulate cortices immediately after occlusion onset and offset. Our results provide support for cross-modal phase resetting and enhanced processing in areas involved in sensory processing and balance control as an explanation for increased long-term balance improvement when training with intermittent visual occlusions. Our training intervention could be implemented in senior and rehabilitation centers, improving the quality of life of elderly and neurologically impaired individuals.
Comparative analysis of primary auditory cortical responses in bats and mice to repetitive stimuli trains
Authors: Deane Katrina E. , García-Rosales Francisco , Klymentiev Ruslan , Hechavarria Julio C. , Happel Max F. K.
Published: October 2022

The brains of black 6 mice (Mus musculus) and Seba’s short-tailed bats (Carollia perspicillata) weigh roughly the same and share mammalian neocortical laminar architecture. Bats have highly developed sonar calls and social communication and are an excellent neuroethological animal model for auditory research. Mice are olfactory and somatosensory specialists, used frequently in auditory neuroscience for their advantage of standardization and wide genetic toolkit. This study presents an analytical approach to overcome the challenge of inter-species comparison with existing data. In both data sets, we recorded with linear multichannel electrodes down the depth of the primary auditory cortex (A1) while presenting repetitive stimuli trains at ~5 and ~40 Hz to awake bats and mice. We found that while there are similarities between cortical response profiles in both, there was a better signal to noise ratio in bats under these conditions, which allowed for a clearer following response to stimuli trains. Model fit analysis supported this, illustrating that bats had stronger response amplitude suppression to consecutive stimuli. Additionally, continuous wavelet transform revealed that bats had significantly stronger power and phase coherence during stimulus response and mice had stronger power in the background. Better signal to noise ratio and lower intertrial phase variability in bats could represent specialization for faster and more accurate temporal processing at lower metabolic costs. Our findings demonstrate a potentially different general auditory processing principle; investigating such differences may increase our understanding of how the ecological need of a species shapes the development and function of its nervous system.
Linking Enlarged Choroid Plexus with Plasma Analyte and Structural Phenotypes in Clinical High Risk for Psychosis: A Multisite Neuroimaging Study
Authors: Bannai Deepthi , Reuter Martin , Hegde Rachal , Hoang Dung , Adhan Iniya , Gandu Swetha , Pong Sovannarath , Raymond Nick , Zeng Victor , Chung Yoonho , He George , Sun Daqiang , van Erp Theo G.M. , Addington Jean , Bearden Carrie E. , Cadenhead Kristin , Cornblatt Barbara , Mathalon Daniel H. , McGlashan Thomas , Jeffries Clark , Stone William , Tsuang Ming , Walker Elaine , Woods Scott W. , Cannon Tyrone D. , Perkins Diana , Keshavan Matcheri , Lizano Paulo
Published: October 2022

Background

Choroid plexus (ChP) enlargement exists in first-episode and chronic psychosis, but whether enlargement occurs before psychosis onset is unknown. This study investigated whether ChP volume is enlarged in individuals with clinical high-risk (CHR) for psychosis and whether these changes are related to clinical, neuroanatomical, and plasma analytes.

Methods

Clinical and neuroimaging data from the North American Prodrome Longitudinal Study 2 (NAPLS2) was used for analysis. 509 participants (169 controls, 340 CHR) were recruited. Conversion status was determined after 2-years of follow-up, with 36 psychosis converters. The lateral ventricle ChP was manually segmented from baseline scans. A subsample of 31 controls and 53 CHR had plasma analyte and neuroimaging data.

Results

Compared to controls, CHR (d=0.23, p=0.017) and non-converters(d=0.22, p=0.03)demonstrated higher ChP volumes, but not in converters. In CHR, greater ChP volume correlated with lower cortical(r=-0.22, p<0.001), subcortical gray matter(r=-0.21, p<0.001), and total white matter volume(r=-0.28,p<0.001), as well as larger lateral ventricle volume(r=0.63,p<0.001). Greater ChP volume correlated with makers functionally associated with the lateral ventricle ChP in CHR [CCL1(r=-0.30, p=0.035), ICAM1(r=0.33, p=0.02)], converters [IL1β(r=0.66, p=0.004)], and non-converters [BMP6(r=-0.96, p<0.001), CALB1(r=-0.98, p<0.001), ICAM1(r=0.80, p=0.003), SELE(r=0.59, p=0.026), SHBG(r=0.99, p<0.001), TNFRSF10C(r=0.78, p=0.001)].

Conclusions

CHR and non-converters demonstrated significantly larger ChP volumes compared to controls. Enlarged ChP was associated with neuroanatomical alterations and analyte markers functionally associated with the ChP. These findings suggest that the ChP may be a key explanatory biomarker in CHR for psychosis.
Synaptic mechanisms for associative learning in the cerebellar nuclei
Authors: Broersen Robin , Albergaria Catarina , Carulli Daniela , Carey Megan R. , Canto Cathrin B. , De Zeeuw Chris I.
Published: October 2022

Associative learning during delay eyeblink conditioning (EBC) depends on an intact cerebellum. However, the relative contribution of changes in the cerebellar nuclei to learning remains a subject of ongoing debate. In particular, little is known about the changes in synaptic inputs to cerebellar nuclei neurons that take place during EBC and how they shape the membrane potential of these neurons. Here, we probed the ability of these inputs to support associative learning in mice, and investigated structural and cell-physiological changes within the cerebellar nuclei during learning. We find that optogenetic stimulation of mossy fiber afferents to the anterior interposed nucleus (AIP) can substitute for a conditioned stimulus and is sufficient to elicit conditioned responses (CRs) that are adaptively well-timed. Further, EBC induces structural changes in mossy fiber and inhibitory inputs, but not of climbing fiber inputs, and it leads to changes in subthreshold processing of AIP neurons that correlate with conditioned eyelid movements. The changes in synaptic and spiking activity that precede the CRs allow for a decoder to distinguish trials with a CR. Our data reveal how structural and physiological modifications of synaptic inputs to cerebellar nuclei neurons can facilitate learning.
Age-specific activation of microglial genes in a mouse model of AD
Authors: Zhou Haoyang , Yu Yizhou
Published: October 2022

Alzheimer’s disease (AD) is a neurodegenerative disease that increases its prevalence with age. AD is characterized by a progressive loss of cognitive function, leading to dementia. The conventional pathological hallmarks of AD include deposition of amyloid plaque, aggregation of neurofibrillary tangles, and sustained inflammation. Recent studies have confirmed that immune responses play an important role in AD progression. Single-cell RNA-sequencing (RNA-seq) studies of the AD mouse model identified the disease-associated microglia (DAM) population during AD progression, where the pro-inflammatory activity was mediated by Trem2. However, the time points and nature of DAM activation remain largely unknown. Here, we compared the time-result bulk sequencing andsingle nuclei RNA sequencing data in a mouse model of AD. We identified an age-dependent activation of Trem2 targeted immune-related genes. We showed that Trem2 affected DAM activation at an early stage (4-8 months) rather than the late stage (12-16 months). Our results highlight an age-dependent change in the Trem2-linked immune response in AD.
Mining impactful discoveries from the biomedical literature
Authors: Moreau Erwan , Hardiman Orla , Heverin Mark , O’Sullivan Declan
Published: October 2022

Motivation

Literature-Based Discovery (LBD) aims to help researchers to identify relations between concepts which are worthy of further investigation by text-mining the biomedical literature. While the LBD literature is rich and the field is considered mature, standard practice in the evaluation of LBD methods is methodologically poor and has not progressed on par with the domain. The lack of properly designed and decent-sized benchmark dataset hinders the progress of the field and its development into applications usable by biomedical experts.

Results

This work presents a method for mining past discoveries from the biomedical literature. It leverages the impact made by a discovery, using descriptive statistics to detect surges in the prevalence of a relation across time. This method allows the collection of a large amount of time-stamped discoveries which can be used for LBD evaluation or other applications. The validity of the method is tested against a baseline representing the state of the art “time sliced” method.

Availability

The source data used in this article are publicly available. The implementation and the resulting data are published under open-source license:https://github.com/erwanm/medline-discoveries(code)https://zenodo.org/record/5888572(datasets). An online exploration tool is also provided athttps://brainmend.adaptcentre.ie/.

Contact

erwan.moreau@adaptcentre.ie
PNPO-PLP Axis Senses Prolonged Hypoxia by Regulating Lysosomal Activity
Authors: Sekine Hiroki , Takeda Haruna , Kishino Akihiro , Anzawa Hayato , Isagawa Takayuki , Ohta Nao , Kato Nobufumi , Kimura Shu , Liu Zun , Kato Koichiro , Katsuoka Fumiki , Yamamoto Masayuki , Miura Fumihito , Ito Takashi , Takahashi Masatomo , Izumi Yoshihiro , Fujita Hiroyuki , Yamagata Hitoshi , Takeda Norihiko , Bamba Takeshi , Suzuki Norio , Kinoshita Kengo , Motohashi Hozumi
Published: October 2022

Oxygen is critical for all metazoan organisms on the earth and impacts various biological processes in physiological and pathological conditions. While oxygen sensing systems inducing acute hypoxic response, including HIF pathway, have been identified, those operating in prolonged hypoxia remain to be elucidated. Here, we show that pyridoxine 5’-phosphate oxidase (PNPO) that catalyzes bioactivation of vitamin B6 serves as an oxygen sensor and regulates lysosomal activity in macrophages. Decline of PNPO activity under prolonged hypoxia reduced an active form of vitamin B6, pyridoxal 5’-phosphate (PLP), and inhibited lysosomal activity, leading to the augmentation of inflammatory response of macrophages. The PNPO-PLP axis creates a distinct layer of oxygen sensing, which gradually turns down and up the PLP-dependent metabolism according to prolonged changes in oxygen availability.
Formation and three-dimensional architecture ofLeishmaniaadhesion in the sand fly vector
Authors: Yanase Ryuji , Moreira-Leite Flávia , Rea Edward , Wilburn Lauren , Sádlová Jovana , Vojtkova Barbora , Pružinová Katerina , Taniguchi Atsushi , Nonaka Shigenori , Volf Petr , Sunter Jack D.
Published: October 2022

Attachment to a substrate to maintain position in a specific ecological niche is a common strategy across biology, especially for eukaryotic parasites. During development in the sand fly vector, the eukaryotic parasiteLeishmaniaadheres to the stomodeal valve, as the specialised haptomonad form. Dissection of haptomonad adhesion is a critical step for understanding parasite transmission. Nevertheless, haptomonad studies are limited, as this is a technically challenging life cycle form to investigate. Here, we have combined three-dimensional electron microscopy approaches, including serial block face scanning electron microscopy (SBFSEM) and serial tomography to dissect the organisation and architecture of haptomonads in the sand fly. We showed that the attachment plaque contains distinct structural elements. Using time-lapse light microscopy, we identified five stages of haptomonad differentiation, and showed that calcium is necessary for haptomonad adhesion to the surface. This study provides the structural and regulatory foundations of the haptomonad form, which are critical for a holistic understanding ofLeishmaniatransmission.
Prophage taming by the adherent-invasiveEscherichia coliLF82 upon macrophage infection
Authors: Misson Pauline , Bruder Emma , Cornuault Jeffrey K. , Paepe Marianne De , Demarre Gaëlle , Petit Marie-Agnès , Espeli Olivier , Lecointe François
Published: October 2022

Adherent-invasiveEscherichia coli(AIEC) strains are frequently recovered from stools of patients with dysbiotic microbiota. They have remarkable properties of adherence to the intestinal epithelium, and survive better than otherE. coliin macrophages. The best studied of these AIEC is probably strain LF82, which was isolated from a Crohn’s disease patient. This strain contains five complete prophages, which have not been studied until now. We undertook their analysis, bothin vitroand inside macrophages, and show that all of them form virions. The Gally prophage is by far the most active, generating spontaneously over 108viral particles per mL of culture supernatantsin vitro, more than 100-fold higher than the other phages. Gally is over-induced after a genotoxic stress generated by ciprofloxacin and trimethoprim. However, upon macrophage infection, Gally virion production is decreased by more than 20-fold, and the transcription profile of the prophage indicates that part of the structural module is specifically repressed while the replication module is overexpressed compared to unstressed culture conditions. We conclude that strain LF82 has evolved an efficient way to “tame” its most active prophage upon macrophage infection, which may participate to its good survival in macrophages. The results are discussed in light of the active lysogeny process.

AUTHOR SUMMARY

Prophages are bacterial viruses stably integrated into their host, to which they can provide new functions, thus increasing their fitness in the environment. Thereby, they can participate to the virulence of bacterial pathogens. However, prophages are double-edged swords that can be awakened in response to genotoxic stresses, resulting in the death of their bacterial host. This raises the question of the effect of this type of stress in the natural environments where their bacterial hosts exert their virulence. In this study, we characterized the five active prophages present inEscherichia coliLF82, a strain belonging to the intestinal microbiota and suspected to be involved in Crohn’s disease via its ability to invade macrophages, a highly genotoxic environment. We show that LF82 inhibits the awakening of its prophages in macrophages, allowing it to survive there. Moreover, deletion of its most active prophage does not affect the viability of LF82 in this environment. These results show that LF82 has tamed its prophages in macrophages and also suggest that if they convey fitness advantages, they probably do so in environments differing from macrophages, and which remain to be discovered.
Bacterial chemoreceptor signaling complexes control kinase activity by stabilizing the catalytic domain of CheA
Authors: Tran Thomas , Karunanayake Mudiyanselage Aruni P. K. K. , Eyles Stephen J. , Thompson Lynmarie K.
Published: October 2022

Motile bacteria have a chemotaxis system that enables them to sense their environment and direct their swimming towards favorable conditions. Chemotaxis involves a signaling process in which ligand binding to the extracellular domain of the chemoreceptor alters the activity of the histidine kinase, CheA, bound ∼300 Å away to the distal cytoplasmic tip of the receptor, to initiate a phosphorylation cascade that controls flagellar rotation. The cytoplasmic domain of the receptor is thought to propagate this signal via changes in dynamics and/or stability, but it is unclear how these changes modulate the kinase activity of CheA. To address this question, we have used hydrogen deuterium exchange mass spectrometry to probe the structure and dynamics of CheA within functional signaling complexes of theE. coliaspartate receptor cytoplasmic fragment, CheA, and CheW. Our results reveal that stabilization of the P4 catalytic domain of CheA correlates with kinase activation. Furthermore, differences in activation of the kinase that occur during sensory adaptation depend on receptor destabilization of the P3 dimerization domain of CheA. Finally, hydrogen exchange properties of the P1 domain that bears the phosphorylated histidine identify the dimer interface of P1/P1’ in the CheA dimer and support an ordered sequential binding mechanism of catalysis, in which dimeric P1/P1’ has productive interactions with P4 only upon nucleotide binding. Thus stabilization/destabilization of domains is a key element of the mechanism of modulating CheA kinase activity in chemotaxis, and may play a role in the control of other kinases.
Spatiotemporal coordination of stem cell behavior following alveolar injury
Authors: Chioccioli Maurizio , Magruder Sumner , McDonough John E. , Nouws Jessica , Yang Tao , Gonzalez David , Borriello Lucia , Traub Brian , Ye Xianjun , Hendry Caroline E. , Entenberg David , Krishnaswamy Smita , Kaminski Naftali , Sauler Maor
Published: October 2022

Tissue repair requires a highly coordinated cellular response to injury. In the lung, alveolar type 2 (AT2) cells act as stem cells and can replace both themselves and alveolar type 1 cells (AT1); however, the complex orchestration of AT2 stem cell activity following lung injury is poorly understood owing to the inability of tracking individual stem cells and their dynamic behavior over time. Here, we apply live time lapse imaging to ex vivo mouse precision cut lung slice (PCLS) culture and in vivo mouse lung to track individual GFP-labeled AT2 cells following induction of alveolar injury by bleomycin. We observe highly dynamic movement of AT2 cells, including migration within and between alveoli. To map the dynamic evolution of AT2 cell behavior, we introduce Live Cell Encoder (LCE-PHATE), a novel method for converting static snapshots from time lapse imaging into single points representative of entire, dynamic cellular trajectories. Applying LCE-PHATE, we observe the emergence of at least three distinct morphokinetic AT2 cell states associated with AT2 stem cell injury response. Finally, small molecule-based inhibition of Rho-associated protein kinase (ROCK) pathway significantly reduced motility of AT2 stem cells following injury and reduced expression of Krt8, a marker of intermediate progenitor cells. Together, our results uncover motility of alveolar stem cells as a new injury response mechanism in the lung and reveal properties of stem cell motility at high cellular resolution.
Mapping the “missing” pathways of the anterior cingulate cortex in the human brain
Authors: Tang Wei , Guaje Javier , Fadnavis Shreyas , Garyfallidis Eleftherios
Published: October 2022

The anterior cingulate cortex (ACC) is functionally closely related with the insula and the ventral lateral prefrontal cortex (vlPFC). Extensive work on their functional relationships has led to the salience network theory and advanced understanding of value-based learning and decision making. However, the anatomical connections between the ACC and the two regions remain unknown in the human brain. Despite the anatomical ground truth established by nonhuman primate (NHP) tract-tracing, diffusion magnetic resonance imaging (dMRI) has not seen success identifying homologous pathways in humans. In this study we show that the negative finding does not reflect a cross-species discrepancy but rather a technical issue. We used NHP dMRI as a bridge to compare the ground-truth pathways in NHPs and dMRI-derived pathways in humans. The insight from NHP data helped pinpoint a bias in fiber orientation distribution functions (fODFs) caused by the disproportion of anterior-posterior vs. medial-lateral fibers in the human brain. Guided by this information, we successfully recovered the ACC-insula and ACC-vlPFC pathways that followed the same trajectories as in the NHP dMRI and tract-tracing data. Our findings provide an anatomical basis for the functional interactions among the ACC, the insula and the vlPFC.
Development of a soil inoculation method coupled with blocker-mediated 16S rRNA gene amplicon sequencing reveals the effect of antibacterial T6SS on agrobacteria tumorigenesis and gallobiome composition
Authors: Wang Si-Chong , Chen Ai-Ping , Chou Shu-Jen , Kuo Chih-Horng , Lai Erh-Min
Published: October 2022

The type VI secretion system (T6SS) is deployed by many proteobacteria to secrete effector proteins into bacterial competitors for competition or eukaryotic cells for pathogenesis. Agrobacteria, a group of soil-borne phytopathogens causing crown gall disease on various plant species, deploys the T6SS to attack closely- and distantly-related bacterial speciesin vitroandin planta. Current evidence suggests that the T6SS is not essential for pathogenesis under direct inoculation but it remains unknown whether the T6SS influences natural disease incidence or the microbial community within crown galls (i.e., gallobiome). To address these two key questions, we established a soil inoculation method on wounded tomato seedlings that mimics natural infections and developed a bacterial 16S rRNA gene amplicon enrichment sequencing platform. By comparing theAgrobacteriumwild-type strain C58 with two T6SS mutants, we demonstrate that the T6SS influences both disease occurrence and gallobiome composition. Based on multiple inoculation trials across seasons, all three strains could induce tumors but the mutants had significantly lower disease incidences. The season of inoculation played a more important role than the T6SS in shaping the gallobiome. The influence of T6SS was evident in summer, in which twoSphingomonasspecies and the family Burkhoderiaceae were enriched in the gallobiome induced by the mutants. Furtherin vitrocompetition and colonization assay demonstrated the T6SS-mediated antagonism to aSphingomonassp. R1 strain isolated from tomato rhizosphere in this study. In conclusion, this work demonstrates that theAgrobacteriumT6SS promotes tumorigenesis in infection process and provides competitive advantages in gall-associated microbiota.

IMPORTANCE

The T6SS is widespread among Proteobacteria and used for interbacterial competition by agrobacteria, which are soil inhabitants and opportunistic bacterial pathogens causing crown gall disease in a wide range of plants. Current evidence indicates that the T6SS is not required for gall formation when agrobacteria are inoculated directly on plant wounding sites. However, in natural settings, agrobacteria may need to compete with other bacteria in bulk soil to gain access to plant wounds and influence microbial community inside crown galls. The role of the T6SS in these critical aspects of disease ecology have remained largely unknown. In this study, we successfully developed aSoilInoculation method coupled withBlocker-mediated enrichment ofBacterial 16S rRNA gene AmpliconSequencing, named as SI-BBacSeq, to address these two important questions. We provided evidence that the T6SS promotes disease occurrence and influences crown gall microbiota composition by interbacterial competition.
Expanding the epitranscriptomic RNA sequencing and modification mapping mass spectrometry toolbox with field asymmetric waveform ion mobility and electrochemical elution liquid chromatography
Authors: Lauman Richard , Kim Hee Jong , Pino Lindsay K. , Scacchetti Alessandro , Bonasio Roberto , Garcia Benjamin A.
Published: October 2022

Post-transcriptional modifications of RNA strongly influence RNA structure and function. Recent advances in RNA sequencing and mass spectrometry (MS) methods have identified over 140 of these modifications on a wide variety of RNA species. Most next-generation sequencing approaches can only map one RNA modification at a time, and while MS can assign multiple modifications simultaneously in an unbiased manner, MS cannot accurately catalog and assign RNA modifications in complex biological samples due to limitations in fragment length and coverage depth. Thus, a facile method to identify novel RNA modifications while simultaneously locating them in the context of their RNA sequences is still lacking. We combined two orthogonal modes of RNA ion separation before mass-spectrometry identification: high-field asymmetric ion mobility separation (FAIMS) and electrochemically modulated liquid chromatography (EMLC). FAIMS RNA-MS increases both coverage and throughput, while the EMLC LC-MS orthogonally separates RNA of different length and charge. The combination of the two methods offers a broadly applicable platform to improve length and depth of MS-based RNA sequencing while providing contextual access to the analysis of RNA modifications.
Tuned Fitness Landscapes for Benchmarking Model-Guided Protein Design
Authors: Thomas Neil , Agarwala Atish , Belanger David , Song Yun S. , Colwell Lucy J.
Published: October 2022

Advancements in DNA synthesis and sequencing technologies have enabled a novel paradigm of protein design where machine learning (ML) models trained on experimental data are used to guide exploration of a protein fitness landscape. ML-guided directed evolution (MLDE) builds on the success of traditional directed evolution and unlocks strategies which make more efficient use of experimental data. Building an MLDE pipeline involves many design choices across the design-build-test-learn loop ranging from data collection strategies to modeling, each of which has a large impact on the success of designed sequences. The cost of collecting experimental data makes benchmarking every component of these pipelines on real data prohibitively difficult, necessitating the development ofsyntheticlandscapes where MLDE strategies can be tested. In this work, we develop a framework called SLIP (“Synthetic Landscape Inference for Proteins”) for constructing biologically-motivated synthetic landscapes with tunable difficulty based on Potts models. This framework can be extended to any protein family for which there is a sequence alignment. We show that without tuning, Potts models are easy to optimize. In contrast, our tuning framework provides landscapes sufficiently challenging to benchmark MLDE pipelines. SLIP is open-source and is available athttps://github.com/google-research/slip.
Hormone-induced enhancer assembly requires an optimal level of hormone receptor multivalent interactions
Authors: Chen Lizhen , Zhang Zhao , Han Qinyu , Rodrigues Leticia , Zboril Emily , Adhikari Rashmi , Li Xin , Ko Su-Hyuk , Xue Pengya , Smith Emilie , Xu Kexin , Wang Qianben , Huang Tim Hui-Ming , Chong Shasha , Liu Zhijie
Published: October 2022

Transcription factors (TFs) activate enhancers to drive cell-specific gene programs in response to signals, but our understanding of enhancer assembly during signaling events is incomplete. Here, we show that Androgen Receptor (AR), a steroid hormone-regulated transcription factor, forms condensates through multivalent interactions in response to androgen signaling to orchestrate enhancer assembly. We demonstrate that the intrinsically disordered N-terminal domain (NTD) of AR drives 1,6-Hexanediol-sensitive condensate formation and that NTD deletion or aromatic residue mutation reduces AR self-association and abolishes AR transcriptional activity. AR NTD can be substituted by intrinsically disordered regions (IDRs) from selective proteins for AR condensation capacity and transactivation function. Surprisingly, strengthened AR condensation capacity caused by extending the polyQ tract within AR NTD also leads to impaired transcriptional activity without affecting AR binding on enhancers. Furthermore, either NTD deletion or polyQ extension reduces heterotypic multivalent interactions between AR and other enhancer components. These results suggest the importance of an optimal level of AR condensation in mediating AR-AR homotypic and AR-cofactor heterotypic interactions to regulate enhancer assembly in response to signals. Our study supports the notion that alteration of the fine-tuned multivalent IDR-IDR interactions might underlie AR-related human pathologies, thereby providing novel molecular insights for potential therapeutic strategies to treat prostate cancer and other AR-involved diseases by targeting AR multivalent interactions.