bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between Stage 1 Hypertension Defined by the 2017 ACC/AHA Hypertension Guideline and Cardiovascular Risk: A Large Cohort Study from the UK
Authors: Li Fu-Rong , Wu Xian-Bo
Published: April 2020

Importance

The 2017 American College of Cardiology (ACC)/American Heart Association (AHA) hypertension (HTN) guideline lowered the threshold for HTN from 140/90 mmHg to 130/80 mmHg for systolic/diastolic blood pressure (SBP/DBP), resulting in a newly defined stage 1 HTN with an SBP/DBP reading of 130–139/80–89 mmHg. Few studies have assessed the impact of the redefined HTN on cardiovascular outcomes among UK population.

Objective

To examine the effects of the revised ACC/AHA stage 1 HTN blood pressure parameters on the prevalence of HTN and related cardiovascular disease (CVD) risk in a large UK population.

Design

Adult men and women from a national cohort study in the UK.

Setting

The UK Biobank Study.

Participants

A total of 470,625 adults (mean age 56 years) with available data on blood pressure (BP) and without history of CVDs at baseline.

Main outcome measures

Prevalence of HTN and incident composite CVD outcomes.

Methods

Prospective CVD events were analysed for survival in relation to BP measures using Cox proportional hazards regression models, adjusting for potential confounders. The associations are described by hazard ratios (HRs) and 95% confidence intervals (CIs).

Results

By adopting the 2017 ACC/AHA HTN guideline, an additional 24.7% of the participants were classified as having ACC/AHA stage 1 HTN, which resulted in a prevalence of HTN of 75.1% at baseline. During a mean follow-up period of 8.1 years, ACC/AHA stage 1 HTN (130–139/80–89 mmHg) was associated with a significantly increased risk of CVD (HR 1.20; 95% CI 1.10–1.30) compared to the risk associated with a normal BP (<120/80 mmHg). The excess risk of CVD associated with ACC/AHA stage 1 HTN was mainly driven by myocardial infarction (HR 1.19; 95% CI 1.05-1.36) and haemorrhagic stroke (HR 1.40; 95% CI 1.08-1.81), rather than ischaemic stroke (HR 1.02; 95% CI 0.87-1.19) and CVD death (HR 1.07; 95% CI 0.90-1.26).

Conclusions

The adoption of the 2017 ACC/AHA guideline would lead to a dramatic increase in the prevalence of HTN in the UK Biobank cohort study. Evidence from the present national cohort study may support lowering the threshold for HTN from 140/90 mmHg to 130/80 mmHg in the UK.
Hypertension Subtype Defined by the 2017 ACC/AHA Blood Pressure Guidelines and Risk of Cardiovascular Disease: A Large Prospective Cohort Study
Authors: Li Fu-Rong , Wu Xian-Bo
Published: April 2020

Background

The 2017 American College of Cardiology/American Heart Association (ACC/ AHA) blood pressure (BP) guideline lowered the hypertension threshold from a systolic blood pressure/diastolic blood pressure level of ≥140/90 mm Hg to ≥130/80 mm Hg. The significance of hypertension subtype under the new definition has not been fully explored.

Objective

To examine the associations of isolated systolic hypertension (ISH) and isolated diastolic hypertension (IDH) by the 2017 ACC/AHA guidelines with risk of cardiovascular disease (CVD) among the UK population.

Design

Prospective population-based cohort study

Setting

UK Biobank

Participants and Methods

We included 470,625 participants who were free of CVD at baseline and had available data on BP measures. Of these, 13,157 CVD events were recorded (median follow-up 8.1 years), including 6,865 nonfatal myocardial infarctions (MI), 3,415 nonfatal ischemic strokes (ISs), 1,118 nonfatal hemorrhagic strokes (HSs), and 2,971 CVD deaths. Participants were categorized into 5 groups: normal BP, normal high BP, ISH, IDH and systolic and diastolic hypertension (SDH). The associations of each type of hypertension for the risk of CVD were estimated using a Cox proportional hazards regression model with adjustment for potential confounding factors.

Results

According to the hypertension threshold of ≥130/80 mm Hg by ACC/AHA guideline, both ISH (HR 1.35, 95% CI 1.24-1.46) and IDH (HR 1.22, 95% CI 1.11-1.36) were significantly associated with higher risk of overall CVD risk, compared with those with normal BP. ISH was predictive of most CVD risk, except for IS; while the excess CVD risk associated with IDH appeared to be driven mainly by MI. We found heterogeneity by sex and age regarding the effects of IDH on overall CVD risk, with the associations stronger in women and younger adults (age < 60 years) and null in men and older adults (age ≥60 years).

Conclusions

ISH and IDH by the ACC/AHA BP guideline were both associated with increased risk of CVD, highlighting the justification to lower the criteria of hypertension definition in the UK. Further research is needed to identify participants with IDH who are at especially greater risk for developing CVD.
Systematic review of COVID-19 autopsies: accelerated hyaluronan concentration as the primary driver of morbidity and mortality in high-risk COVID-19 patients: with therapeutic introduction of an oral hyaluronan inhibitor in the prevention of “Induced Hyaluronan Storm” Syndrome
Authors: Mong Michael A. , Awkal Jacob A. , Marik Paul E.
Published: April 2020

To date, the fundamental drivers of the morbidity and mortality in COVID-19 remain uncertain. Clinicians worldwide appear to be at a loss to know how to prevent and treat the severe respiratory distress in these patients effectively. Consequently, the fundamental mechanisms leading to death in high-risk patients need to be discovered and addressed with urgency. The post-mortem autopsy remains an essential part of both discovering the cause of death in a particular individual, but also in advancing the science and treatment of disease, especially in the case of novel pathogens such as SARS-CoV-2[2]. The goal of an autopsy is to discover the cause of death (COD) using a macro/microscopic investigation. Because lung weight is often affected by the cause of death and the last breath occurs very near if not at death, the evaluation of the lungs is one of the starting points of any COD investigation[3]. A comprehensive search was performed to systematically review all reported autopsy findings in COVID-19 patients with respect to lung weights and histologic findings. We then compared these findings with the results of a targeted literature review of hyaluronan in relationship to acute respiratory distress syndrome (ARDS). In total, data from 38 autopsies were identified. From this group, 36 autopsies of COVID-19 patients were selected for detailed review and statistical analysis. The average lung weight of those who were determined to have died as a result of SARS-CoV-2 was 1683g approximately 3.2 times the normal lung weight. Hyaline membranes were consistently identified on histologic sections. A review of the literature reveals that markedly elevated lung weights and hyaline membranes and have been associated with the pathophysiology of ARDS since 1967. However, the key role key of hyaluronan in driving the morbidity and mortality of the condition has heretofore not been fully recognized. We propose that the induced hyaluronan storm syndrome or IHS, is a model that addresses the heretofore perplexing respiratory failure that is the proximal cause of death. An aggressive research effort should be undertaken to discover why the majority of individuals who are exposed to the virus are minimally symptomatic, while a minority of high-risk individuals rapidly progress to respiratory failure and death.

“You may take notes for 20 years, from morning to night at the bedside of the sick, upon the diseases of the viscera, and all will be to you only a confusion of symptoms…a train of incoherent phenomena. Open a few bodies and this obscurity will disappear.” - Marie-François-Xavier Bichat (1771–1802), “The Father of Histology”[1].
Flow cytometric analysis and purification of airway epithelial cell subsets
Authors: Bonser Luke R. , Koh Kyung Duk , Johansson Kristina , Choksi Semil P. , Cheng Dan , Liu Leqian , Sun Dingyuan I. , Zlock Lorna T. , Eckalbar Walter L. , Finkbeiner Walter E. , Erle David J.
Published: April 2020

The human airway epithelium is essential in homeostasis, and epithelial dysfunction contributes to chronic airway disease. Development of flow cytometric methods to characterize subsets of airway epithelial cells will enable further dissection of airway epithelial biology. Leveraging single cell RNA-sequencing (scRNA-seq) data in combination with known cell type-specific markers, we developed panels of antibodies to characterize and isolate the major airway epithelial subsets (basal, ciliated, and secretory cells) from human bronchial epithelial cell cultures. We also identified molecularly distinct subpopulations of secretory cells and demonstrated cell subset-specific expression of low abundance transcripts and micro-RNAs that are challenging to analyze with current scRNA-seq methods. These new tools will be valuable for analyzing and separating airway epithelial subsets and interrogating airway epithelial biology.
Audiometric profiles and patterns of benefit. A data-driven analysis of subjective hearing difficulties and handicaps
Authors: Sanchez-Lopez Raul , Dau Torsten , Whitmer William M.
Published: April 2020

Objective

Hearing rehabilitation attempts to compensate for auditory dysfunction, reduce hearing difficulties and minimize participation restrictions that can lead to social isolation. However, there is no systematic approach to assess the quality of the intervention at an individual level that might help to evaluate the need of further hearing rehabilitation in the hearing care clinic.

Design

A data-driven analysis on subjective data reflecting hearing disabilities and handicap was chosen to explore “benefit patterns” as a result of rehabilitation in different audiometric groups. The method was based on: 1) Dimensionality reduction; 2) Stratification; 3) Archetypal analysis; 4) Clustering; and 5) Item importance estimation.

Study sample

572 hearing-aid users completed questionnaires of hearing difficulties (speech, spatial and qualities hearing scale; SSQ) and hearing handicap (HHQ).

Results

The data-driven approach revealed four benefit profiles that were different for each audiometric group. The groups with low degree of high-frequency hearing loss (HLHF) showed a priority for rehabilitating hearing handicaps, whereas the groups with HLHF > 50 dB HL showed a priority for improvements in speech understanding.

Conclusions

The patterns of benefit and the stratification approach might guide the clinical intervention strategy and improve the efficacy and quality of service in the hearing care clinic.
Rapid identification of SARS-CoV-2-infected patients at the emergency department using routine testing
Authors: Kurstjens Steef , van der Horst Armando , Herpers Robert , Geerits Mick W.L. , Kluiters-de Hingh Yvette C.M. , Göttgens Eva-Leonne , Blaauw Martinus J.T. , Thelen Marc H.M. , Elisen Marc G.L.M. , Kusters Ron
Published: April 2020

Background

The novel coronavirus disease 19 (COVID-19), caused by SARS-CoV-2, spreads rapidly across the world. The exponential increase in the number of cases has resulted in overcrowding of emergency departments (ED). Detection of SARS-CoV-2 is based on an RT-PCR of nasopharyngeal swab material. However, RT-PCR testing is time-consuming and many hospitals deal with a shortage of testing materials. Therefore, we aimed to develop an algorithm to rapidly evaluate an individual’s risk of SARS-CoV-2 infection at the ED.

Methods

In this multicenter retrospective study, routine laboratory parameters (C-reactive protein, lactate dehydrogenase, ferritin, absolute neutrophil and lymphocyte counts), demographic data and the chest X-ray/CT result from 967 patients entering the ED with respiratory symptoms were collected. Using these parameters, an easy-to-use point-based algorithm, called the corona-score, was developed to discriminate between patients that tested positive for SARS-CoV-2 by RT-PCR and those testing negative. Computational sampling was used to optimize the corona-score. Validation of the model was performed using data from 592 patients.

Results

The corona-score model yielded an area under the receiver operating characteristic curve of 0.91 in the validation population. Patients testing negative for SARS-CoV-2 showed a median corona-score of 3 versus 11 (scale 0-14) in patients testing positive for SARS-CoV-2 (p<0.001). Using cut-off values of 4 and 11 the model has a sensitivity and specificity of 96% and 95%, respectively.

Conclusion

The corona-score effectively predicts SARS-CoV-2 RT-PCR outcome based on routine parameters. This algorithm provides the means for medical professionals to rapidly evaluate SARS-CoV-2 infection status of patients presenting at the ED with respiratory symptoms.
A simulation of a COVID-19 epidemic based on a deterministic SEIR model
Authors: Carcione José M. , Santos Juan E. , Bagaini Claudio , Ba Jing
Published: April 2020

An epidemic disease caused by a new coronavirus has spread in Northern Italy with a strong contagion rate. We implement an SEIR model to compute the infected population and number of casualties of this epidemic. The example may ideally regard the situation in the Italian Region of Lombardy, where the epidemic started on February 24, but by no means attempts to perform a rigorous case study in view of the lack of suitable data and uncertainty of the different parameters, namely, the variation of the degree of home isolation and social distancing as a function of time, the number of initially exposed individuals and infected people, the incubation and infectious periods and the fatality rate.

First, we perform an analysis of the results of the model, by varying the parameters and initial conditions (in order the epidemic to start, there should be at least one exposed or one infectious human). Then, we consider the Lombardy case and calibrate the model with the number of dead individuals to date (April 28, 2020) and constraint the parameters on the basis of values reported in the literature. The peak occurs at day 37 (March 31) approximately, when there is a rapid decrease, with a reproduction ratio R0 = 3 initially, 1.36 at day 22 and 0.78 after day 35, indicating different degrees of lockdown. The predicted death toll is almost 15325 casualties, with 2.64 million infected individuals at the end of the epidemic. The incubation period providing a better fit of the dead individuals is 4.25 days and the infectious period is 4 days, with a fatality rate of 0.00144/day [values based on the reported (official) number of casualties]. The infection fatality rate (IFR) is 0.57 %, and 2.36 % if twice the reported number of casualties is assumed. However, these rates depend on the initially exposed individuals. If approximately nine times more individuals are exposed, there are three times more infected people at the end of the epidemic and IFR = 0.47 %. If we relax these constraints and use a wider range of lower and upper bounds for the incubation and infectious periods, we observe that a higher incubation period (13 versus 4.25 days) gives the same IFR (0.6 % versus 0.57 %), but nine times more exposed individuals in the first case. Other choices of the set of parameters also provide a good fit of the data, but some of the results may not be realistic. Therefore, an accurate determination of the fatality rate and characteristics of the epidemic is subject to the knowledge of precise bounds of the parameters.

Besides the specific example, the analysis proposed in this work shows how isolation measures, social distancing and knowledge of the diffusion conditions help us to understand the dynamics of the epidemic. Hence, the importance to quantify the process to verify the effectiveness of the lockdown.
COVID-19 in Iran, a comprehensive investigation from exposure to treatment outcomes
Authors: Ashraf Mohammad Ali , Shokouhi Nasim , Shirali Elham , Davari-tanha Fateme , Memar Omeed , Kamalipour Alireza , Azarnoush Ayein , Mabadi Avin , Ossareh Adele , Sanginabadi Milad , Azad Talat Mokhtari , Aghaghazvini Leila , Ghaderkhani Sara , Poordast Tahereh , Pourdast Alieh , Nazemi Pershang
Published: April 2020

Purpose

There is a growing need for information regarding the recent coronavirus disease of 2019 (Covid-19). We present a comprehensive report of Covid-19 patients in Iran.

Methods

One hundred hospitalized patients with Covid-19 were studied. Data on potential source of exposure, demographic, clinical, and paraclinical features, therapy outcome, and post-discharge follow-up were analyzed.

Results

The median age of the patients was 58 years, and the majority of the patients (72.7%) were above 50 years of age. Fever was present in 45.2% of the patients on admission. The most common clinical symptoms were shortness of breath (74%) and cough (68%). Most patients had elevated C-reactive protein (92.3%), elevated erythrocyte sedimentation rate (82.9%), lymphocytopenia (74.2 %) on admission. Lower lobes of the lung were most commonly involved, and ground-glass opacity (81.8%) was the most frequent finding in CT scans. The administration of hydroxychloroquine improved the clinical outcome of the patients. Lopinavir/ritonavir was efficacious at younger ages. Of the 70 discharged patients, 40% had symptom relapse, (8.6%) were readmitted to the hospital, and 3 patients (4.3%) died.

Conclusion

This report demonstrates a heterogeneous nature of clinical manifestations in patients affected with Covid-19. The most common presenting symptoms are non-specific, so attention should be made on broader testing, especially in age groups with the greatest risk and younger individuals who can serve as carriers of the disease. Hydroxychloroquine and lopinavir/ritonavir (in younger age group) can be potential treatment options. Finally, patients discharged from the hospital should be followed up because of potential symptom relapse.
Eye movement evaluation in Multiple Sclerosis and Parkinson’s Disease using a Standardized Oculomotor and Neuro-ophthalmic Disorder Assessment (SONDA)
Authors: Grillini Alessandro , Renken Remco J. , Vrijling Anne C. L. , Heutink Joost , Cornelissen Frans W.
Published: April 2020

Evaluating the state of the oculomotor system of a patient is one of the fundamental tests done in neuro-ophthalmology. However, up to date, very few quantitative standardized tests of eye movements quality exist, limiting this assessment to confrontational tests reliant on subjective interpretation. Furthermore, quantitative tests relying on eye movement properties such as pursuit gain and saccade dynamics are often insufficient to capture the complexity of the underlying disorders and are often (too) long and tiring. In this study, we present SONDA (Standardised Oculomotor and Neurological Disorder Assessment): this test is based on analyzing eye tracking recorded during a short and intuitive continuous tracking task. We tested patients affected by Multiple Sclerosis (MS) and Parkinson’s Disease (PD) and find that: (1) the saccadic dynamics of the main sequence alone are not sufficient to separate patients from healthy controls; (2) the combination of spatio-temporal and statistical properties of saccades and saccadic dynamics enables an identification of oculomotor abnormalities in both MS and PD patients. We conclude that SONDA constitutes a powerful screening tool that allows an in-depth evaluation of (deviant) oculomotor behavior in a few minutes of non-invasive testing.
Automated Contouring and Planning for Hippocampal-Avoidant Whole-Brain Radiotherapy
Authors: Feng Christine H. , Cornell Mariel , Moore Kevin L. , Karunamuni Roshan , Seibert Tyler M.
Published: April 2020

Purpose

Design and evaluate a workflow using commercially available artificial intelligence tools for automated hippocampal segmentation and treatment planning to efficiently generate clinically acceptable hippocampal-avoidant whole brain (HA-WBRT) radiotherapy plans.

Methods and Materials

We retrospectively identified 100 consecutive adult patients treated for brain metastases outside the hippocampal region. Each patient’s T1 post-contrast brain MRI was processed using FDA-approved software that provides segmentations of brain structures in 5-7 minutes. Automated hippocampal segmentations were reviewed for accuracy and edited manually if necessary, then converted to files compatible with a commercial treatment planning system, where hippocampal avoidance regions and planning target volumes (PTV) were generated. Other organs-at-risk (OARs) were previously contoured per clinical routine. A RapidPlan knowledge-based planning routine was applied for a prescription of 30 Gy in 10 fractions using volumetric modulated arc therapy (VMAT) delivery. Plans were evaluated based on NRG CC001 dose-volume objectives.

Results

Of the 100 cases, 99 (99%) had acceptable automated hippocampi segmentations without manual intervention. Knowledge-based planning was applied to all cases; the median processing time was 9 minutes 59 seconds (range 6:53 – 13:31). All plans met per-protocol dose-volume objectives for PTV per the NRG CC001 protocol. For comparison, only 66.0% of plans on NRG CC001 met PTV goals per protocol, with 26.3% within acceptable variation. In this study, 43 plans (43%) met OAR constraints, and the remaining 57 (57%) were within acceptable variation, compared to 42.9% and 48.6% on NRG CC001, respectively. No plans in this study had unacceptable dose to OARs, compared to 0.8% of manually generated plans from NRG CC001.

Conclusion

An automated pipeline harnessing the efficiency of commercially available artificial intelligence tools can generate clinically acceptable VMAT HA-WBRT plans with minimal manual intervention. This process could improve clinical efficiency for a treatment established to improve patient outcomes over standard WBRT.
An Interactive Tool to Forecast US Hospital Needs in the Coronavirus 2019 Pandemic
Authors: Locey Kenneth J. , Webb Thomas A. , Khan Jawad , Antony Anuja K. , Hota Bala
Published: April 2020

Hospital enterprises have been continually faced with anticipating the spread of COVID- 19 and the effects it is having on visits, admissions, bed needs, and crucial supplies. While many studies have focused on understanding the basic epidemiology of the disease, few open source tools have been made available to aid hospitals in their planning. We developed a web-based application (available at: http://covid19forecast.rush.edu/) for US states and territories that allows users to choose from a suite of models already employed in characterizing the spread of COVID-19. Users can obtain forecasts for hospital visits and admissions as well as anticipated needs for ICU and non-ICU beds, ventilators, and personal protective equipment supplies. Users can also customize a large set of inputs, view the variability in forecasts over time, and download forecast data. We describe our web application and its models in detail and provide recommendations and caveats for its use. Our application is primarily designed for hospital leaders, healthcare workers, and government official who may lack specialized knowledge in epidemiology and modeling. However, specialists can also use our open source code as a platform for modification and deeper study. As the dynamics of COVID-19 change, our application will also change to meet emerging needs of the healthcare community.
Presynaptic APP levels and synaptic homeostasis are regulated by Akt phosphorylation of Huntingtin
Authors: Bruyère Julie , Abada Yah-Se , Vitet Hélène , Fontaine Gaëlle , Deloulme Jean-Christophe , Cès Aurélia , Denarier Eric , Pernet-Gallay Karin , Andrieux Annie , Humbert Sandrine , Potier Marie Claude , Delatour Benoît , Saudou Frédéric
Published: April 2020

Studies have suggested that amyloid precursor protein (APP) regulates synaptic homeostasis, but the evidence has not been consistent. In particular, signaling pathways controlling APP transport to the synapse in axons and dendrites remain to be identified. Having previously shown that Huntingtin (HTT), the scaffolding protein involved in Huntington’s disease, regulates neuritic transport of APP, we used a microfluidic corticocortical neuronal network-on-a-chip to examine APP transport and localization to the pre- and post-synaptic compartments. We found that HTT, upon phosphorylation by the Ser/Thr kinase Akt, regulates APP transport in axons but not dendrites. Expression of an unphosphorylatable HTT decreased axonal anterograde transport of APP, reduced presynaptic APP levels, and increased synaptic density. Ablatingin vivoHTT phosphorylation in APPPS1 mice, which overexpress APP, reduced presynaptic APP levels, restored synapse number and improved learning and memory. The Akt-HTT pathway and axonal transport of APP thus regulate APP presynaptic levels and synapse homeostasis.
Molecular Basis for the Adaptive Evolution of Environment Sensing by H-NS Proteins
Authors: Zhao Xiaochuan , Kharchenko Vladlena , Hameed Umar F. Shahul , Liao Chenyi , Huser Franceline , Remington Jacob M. , Radhakrishnan Anand K. , Jaremko Mariusz , Jaremko Łukasz , Arold Stefan T. , Li Jianing
Published: April 2020

The DNA-binding protein H-NS is a pleiotropic gene regulator in gram-negative bacteria. Through its capacity to sense temperature and other environmental factors, H-NS allows pathogens like Salmonella to adapt their gene expression, and hence toxicity and biological responses, to their presence inside or outside warm-blooded hosts. To investigate how this sensing mechanism may have evolved to fit different bacterial lifestyles, we compared H-NS orthologs from bacteria that infect humans, plants, and insects, and from bacteria that live on a deep-sea hypothermal vent. The combination of biophysical characterization, high-resolution proton-less NMR spectroscopy and molecular simulations revealed, at an atomistic level, how the same general mechanism was adapted to specific habitats and lifestyles. In particular, we demonstrate how environment-sensing characteristics arise from specifically positioned intra- or intermolecular electrostatic interactions. Our integrative approach clarified the mechanism for H-NS–mediated environmental sensing and suggests that it resulted from the exaptation of an ancestral protein feature.
Label-free single-instance protein detection in vitrified cells
Authors: Rickgauer J. Peter , Choi Heejun , Lippincott-Schwartz Jennifer , Denk Winfried
Published: April 2020

A general method to map molecular interactions and conformational states in structurally intact cells would find wide application in biochemistry and cell biology. We used a library of images— calculated on the basis of known structural data—as search templates to detect targets as small as the “head” domain (350 kDa) of the ribosome’s small subunit in single-tilt electron cryo-micrographs by cellular high resolution template matching (cHRTM). Atomically precise position and orientation estimates reveal the conformation of individual ribosomes and enable the detection of specifically bound ligands down to 24 kDa. We show that highly head-swivelled states are likely to play a role in mRNA translocation in living cells. cHRTM outperforms cryo-electron tomography three-fold in sensitivity and completely avoids the vicissitudes of exogenous labelling.
Genetic dissection of glutamatergic neuron subpopulations and developmental trajectories in the cerebral cortex
Authors: Matho Katherine S. , Huilgol Dhananjay , Galbavy William , He Miao , Kim Gukhan , An Xu , Lu Jiangteng , Wu Priscilla , Di Bella Daniela J. , Shetty Ashwin S. , Palaniswamy Ramesh , Hatfield Joshua , Raudales Ricardo , Narasimhan Arun , Gamache Eric , Levine Jesse , Tucciarone Jason , Szelenyi Eric , Harris Julie A. , Mitra Partha P. , Osten Pavel , Arlotta Paola , Huang Z. Josh
Published: April 2020

Diverse types of glutamatergic pyramidal neurons (PyNs) mediate the myriad processing streams and output channels of the cerebral cortex, yet all derive from neural progenitors of the embryonic dorsal telencephalon. Here, we establish genetic strategies and tools for dissecting and fate mapping PyN subpopulations based on their developmental and molecular programs. We leverage key transcription factors and effector genes to systematically target the temporal patterning programs in progenitors and differentiation programs in postmitotic neurons. We generated over a dozen temporally inducible mouse Cre and Flp knock-in driver lines to enable combinatorial targeting of major progenitor types and projection classes. Intersectional converter lines confer viral access to specific subsets defined by developmental origin, marker expression, anatomical location and projection targets. These strategies establish an experimental framework for understanding the hierarchical organization and developmental trajectory of PyN subpopulations that assemble cortical processing networks and output channels.
Female-specific upregulation of insulin pathway activity mediates the sex difference inDrosophilabody size plasticity
Authors: Millington Jason W. , Chao Chien , Sun Ziwei , Basner-Collins Paige J. , Brownrigg George P. , Wat Lianna W. , Hudry Bruno , Miguel-Aliaga Irene , Rideout Elizabeth J.
Published: April 2020

Nutrient-dependent body size plasticity differs between the sexes in most species, including mammals. Previous work inDrosophilashowed that body size plasticity was higher in females, yet the mechanisms underlying the sex difference in body size plasticity remain unclear. Here, we discover that a protein-rich diet augments body size in females and not males because of a female-specific increase in activity of the conserved insulin/insulin-like growth factor signaling pathway (IIS). This increased IIS activity was triggered by a diet-induced increase instunted, and requiredDrosophila insulin-like peptide 2, illuminating new sex-specific roles for these genes. Importantly, we show that sex determination genetransformerregulates the diet-induced increase instuntedand IIS activity, and mediates the sex difference in body size plasticity. This identifies one sex-specific mechanism underlying the nutrient-dependent regulation of IIS activity and body size plasticity, providing vital insight into conserved mechanisms that mediate sex differences in phenotypic plasticity.
Actin in Dendritic Spines Self-Organizes into a Critical State
Authors: Bonilla-Quintana Mayte , Wörgötter Florentin , D’Este Elisa , Tetzlaff Christian , Fauth Michael
Published: April 2020

It is known that dendritic spines change their size and shape spontaneously and sometimes to a large degree, but the function of this remains unclear. Here, we quantify these changes using time-series analysis of confocal data and demonstrate that spine size can follow different autoregressive integrated moving average (ARIMA) models and that shape- and size-changes are not correlated. We capture this behavior with a biophysical model, based on the spines’ actin dynamics, and find the presence of 1/fnoise. When investigating its origins, the model predicts that actin in the dendritic spines self-organizes into a critical state, which creates a fine balance between static actin filaments and free monomers. We speculate that such a balance might be functionally beneficially to allow a spine to quickly reconfigure itself after LTP induction.
RADSex: a computational workflow to study sex determination using Restriction Site-Associated DNA Sequencing data
Authors: Feron Romain , Pan Qiaowei , Wen Ming , Imarazene Boudjema , Jouanno Elodie , Anderson Jennifer , Herpin Amaury , Journot Laurent , Parrinello Hugues , Klopp Christophe , Kottler Verena A. , Roco Alvaro S. , Du Kang , Kneitz Susanne , Adolfi Mateus , Wilson Catherine A. , McCluskey Braedan , Amores Angel , Desvignes Thomas , Goetz Frederick W. , Takanashi Ato , Kawaguchi Mari , Detrich H. William , Oliveira Marcos , Nobrega Rafael , Sakamoto Takashi , Nakamoto Masatoshi , Wargelius Anna , Karlsen Ørjan , Wang Zhongwei , Stöck Matthias , Waterhouse Robert M. , Braasch Ingo , Postlethwait John H. , Schartl Manfred , Guiguen Yann
Published: April 2020

The study of sex determination and sex chromosome organisation in non-model species has long been technically challenging, but new sequencing methodologies are now enabling precise and high-throughput identification of sex-specific genomic sequences. In particular, Restriction Site-Associated DNA Sequencing (RAD-Seq) is being extensively applied to explore sex determination systems in many plant and animal species. However, software designed to specifically search for sex-biased markers using RAD-Seq data is lacking. Here, we present RADSex, a computational analysis workflow designed to study the genetic basis of sex determination using RAD-Seq data. RADSex is simple to use, requires few computational resources, makes no prior assumptions about type of sex-determination system or structure of the sex locus, and offers convenient visualization through a dedicated R package. To demonstrate the functionality of RADSex, we re-analyzed a published dataset of Japanese medaka, Oryzias latipes, where we uncovered a previously unknown Y chromosome polymorphism. We then used RADSex to analyze new RAD-Seq datasets from 15 fish species spanning multiple systematic orders. We identified the sex determination system and sex-specific markers in six of these species, five of which had no known sex-markers prior to this study. We show that RADSex greatly facilitates the study of sex determination systems in non-model species and outperforms the commonly used RAD-Seq analysis software STACKS. RADSex in speed, resource usage, ease of application, and visualization options. Furthermore, our analysis of new datasets from 15 species provides new insights on sex determination in fish.
The kinase Isr1 negatively regulates hexosamine biosynthesis inS. cerevisiae
Authors: Alme Emma B , Stevenson Erica , Krogan Nevan J , Swaney Danielle L , Toczyski David P
Published: April 2020

TheS. cerevisiae ISR1gene encodes a putative kinase with no ascribed function. Here, we show that Isr1 acts as a negative regulator of the highly-conserved hexosamine biosynthesis pathway (HBP), which converts glucose into uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), the carbohydrate precursor to protein glycosylation, GPI-anchor formation, and chitin biosynthesis. Overexpression ofISR1is lethal and, at lower levels, causes sensitivity to tunicamycin and resistance to calcofluor white, implying impaired protein glycosylation and reduced chitin deposition. Gfa1 is the first enzyme in the HBP and is conserved from bacteria and yeast to humans. The lethality caused byISR1overexpression is rescued by co-overexpression ofGFA1or exogenous glucosamine, which bypassesGFA1’sessential function. Gfa1 is phosphorylated in anISR1-dependent fashion and mutation ofISR1-dependent sites ameliorates the lethality associated withISR1overexpression. Isr1 contains a phosphodegron that is phosphorylated by Pho85 and subsequently ubiquitinated by the SCF-Cdc4 complex, largely confining Isr1 protein levels to the time of bud emergence. Mutation of this phosphodegron stabilizes Isr1 and recapitulates the overexpression phenotypes. As Pho85 is a cell cycle and nutrient responsive kinase, this tight regulation of Isr1 may serve to dynamically regulate flux through the HBP and modulate how the cell’s energy resources are converted into structural carbohydrates in response to changing cellular needs.

Author Summary

Protein phosphorylation is an essential regulatory mechanism that controls most cellular processes, integrating a variety of environmental signals to drive cellular growth. Yeast encode over 100 kinases, yet many remain poorly characterized. TheS. cerevisiaegeneISR1encodes a putative kinase with no ascribed function. Here, we show thatISR1decreases the synthesis of a critical structural carbohydrate, uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), by mediating inhibition of one of the enzymes responsible for its synthesis, Gfa1. UDP-GlcNAc is the precursor to protein glycosylation, GPI anchor formation, and chitin synthesis, the first two of which are essential and conserved in humans. Throughout the cell cycle, and in response to changing environmental conditions, the cell must balance its use of glucose for energy production and generation of these structural carbohydrates. Here we show that Isr1 is regulated by both cell cycle and nutrient changes, and is rapidly degraded in a phosphorylation dependent manner. Isr1-mediated inhibition of UDP-GlcNAc synthesis may serve as a mechanism of dynamically regulating how the cell utilizes glucose in response to its environment.
The tomato DELLA protein PROCERA promotes ABA responses in guard cells by upregulating ABA transporter
Authors: Shohat Hagai , Illouz-Eliaz Natanella , Kanno Yuri , Seo Mitsunori , Weiss David
Published: April 2020

Plants reduce transpiration to avoid drought stress by stomatal closure. While abscisic acid (ABA) has a central role in the regulation of stomatal closure under water-deficit conditions, we demonstrated in tomato that the gibberellin (GA) response inhibitor, the DELLA protein PROCERA (PRO), promotes ABA-induced stomatal closure and gene transcription in guard cells. To study how PRO affects stomatal closure, we performed RNAseq analysis of isolated guard cells and identified the ABA transportersABA-IMPORTING TRANSPORTER1.1(AIT1.1) andAIT1.2, also called in ArabidopsisNPF4.6, as upregulated by PRO. Tomato has fourAIT1genes, but onlyAIT1.1andAIT1.2were upregulated by PRO, and onlyAIT1.1exhibited high expression in guard cells. Functional analysis ofAIT1.1in yeast confirmed its activity as an ABA transporter, possibly importer. CRISPR-Cas9-defrivedait1.1mutant exhibited increased transpiration, larger stomatal aperture and reduced response to ABA. Moreover,ait1.1suppressed the promoting effects of PRO on ABA-induced stomatal closure and gene expression in guard cells. The negative interaction between GA and ABA has been studied for many years in numerous plant species. These studies suggest that the crosstalk is mediated by changes in hormone biosynthesis and signaling. Our results suggest that it is also mediated by changes in hormone transport.

One-sentence Summary

The tomato DELLA protein PROCERA promoted abscisic acid-induced stomatal closure and gene expression by upregulating the expression of the ABA transporterABA-IMPORTING TRANSPORTER1 in guard cells.
Quantification of lysogeny caused by phage coinfections in microbial communities from biophysical principles
Authors: Luque Antoni , Silveira Cynthia
Published: April 2020

Temperate phages can integrate in their bacterial host genome to form a lysogen, often modifying the phenotype of the host. Lysogens are dominant in the microbial-dense environment of the mammalian-gut. This observation contrasts with the long-standing hypothesis of lysogeny being favored in microbial communities with low densities. Here we hypothesized that phage coinfections—the most studied molecular mechanism of lysogeny in lambda phage—increases at high microbial abundances. To test this hypothesis, we developed a biophysical model of coinfection and stochastically sampled ranges of phage and bacterial concentrations, adsorption rates, lysogenic commitment times, and community diversity from marine and gut microbiomes. Based on lambda experiments, a Poisson process assessed the probability of lysogeny via coinfection in these ecosystems. In 90% of the sampled marine ecosystems, lysogeny stayed below 10% of the bacterial community. In contrast, 25% of the sampled gut communities stayed above 25% of lysogeny, representing an estimated nine trillion lysogens formed via phage coinfection in the human gut every day. The prevalence of lysogeny in the gut was a consequence of the higher densities and faster adsorption rates. In marine communities, which were characterized by lower densities and phage adsorption rates, lysogeny via coinfection was still possible for communities with long lysogenic commitments times. Our study suggests that physical mechanisms can favor coinfection and cause lysogeny at poor growth conditions (long commitment times) and in rich environments (high densities and adsorption rates).

Importance

Phage integration in bacterial genomes manipulate microbial dynamics from the oceans to the human gut. This phage-bacteria interaction, called lysogeny, is well-studied in laboratory models, but its environmental drivers remain unclear. Here we quantified the frequency of lysogeny via phage coinfection—the most studied mechanism of lysogeny—by developing a biophysical model that incorporated a meta-analysis of the properties of marine and gut microbiomes. Lysogeny was found to be more frequent in high-productive environments like the gut, due to higher phage and bacterial densities and faster phage adsorption rates. At low cell densities, lysogeny via coinfection was possible for hosts with long duplication times. Our research bridges the molecular understanding of lysogeny with the ecology of complex microbial communities.
Safety and Efficacy of Avaren-Fc Lectibody Targeting HCV High-Mannose Glycans in a Human Liver Chimeric Mouse Model
Authors: Dent Matthew , Hamorsky Krystal , Vausselin Thibaut , Dubuisson Jean , Miyata Yoshinari , Morikawa Yoshio , Matoba Nobuyuki
Published: April 2020

Infection with hepatitis C virus (HCV) remains to be a major cause of morbidity and mortality worldwide despite the recent advent of highly effective direct-acting antivirals. The envelope glycoproteins of HCV are heavily glycosylated with a high proportion of high-mannose glycans (HMGs), which serve as a shield against neutralizing antibodies and assist in the interaction with cell-entry receptors. However, currently there is no approved therapeutic targeting this potentially druggable biomarker. Here, we investigated the therapeutic potential of the lectibody Avaren-Fc (AvFc), a HMG-binding lectin-Fc fusion protein.In vitroassays showed AvFc’s capacity to neutralize cell culture-derived HCV in a genotype independent manner with IC50values in the low nanomolar range. A histidine buffer-based AvFc formulation was developed for in vivo studies using the PXB human liver chimeric mouse model. Systemic administration of AvFc was well tolerated; after 11 consecutive doses every other day at 25 mg/kg, there were no significant changes in body or liver weights, nor any impact noted in blood human albumin levels or serum alanine aminotransferase activity. Gross necropsy and liver pathology further confirmed the lack of discernible toxicity. This treatment regimen successfully prevented genotype 1a HCV infection in all animals, while an AvFc mutant lacking HMG binding activity failed to block the infection. These results suggest that targeting envelope HMGs is a promising therapeutic approach against HCV infection. In particular, AvFc may provide a safe and efficacious means to prevent recurrent infection upon liver transplantation in HCV-related end-stage liver disease patients.
Circulating microRNA-762 upregulates colorectal cancer might through Wnt-1/β-catenin signaling
Authors: Lai Peng-Sheng , Chang Wei-Min , Chen Ying-Yin , Lin Yi-Feng , Liao Hui-Fen , Chen Chung-Yu
Published: April 2020

Background

A number of microRNAs (miRNAs) have been demonstrated to be correlated with the diagnosis, progression and prognosis of colorectal cancer (CRC). However, the key miRNAs and the associated signaling pathways that regulate the growth and metastasis of CRC remain unclear.

Methods

The circulating miRNAs from BALB/c mice with CRC CT26 cell implantation were assayed by microarray. Then, mmu-miR-762 mimic and inhibitor were transfected to CT26 cells for analysis of cell viability, invasion, and epithelial-mesenchymal transition (EMT), cell cycle, and regulatory molecule expression. Human subjects were included for comparison the circulating has-miR-762 levels in CRC patients and control donors, as well as the patients with and without distant metastasis.

Results

The miRNA levels in mice with CRC cell implantation indicated that plasma mmu-miR-762 was upregulated. Transfection of mmu-miR-762 mimic to CT26 cells increased cell viability, invasion, and EMT, whereas transfection of mmu-miR-762 inhibitor decreased the above abilities. Cells treated with high-concentration mmu-miR-762 inhibitor induced cell cycle arrest at G0/G1 phase. Western blot analysis showed that mmu-miR-762 mimic transfection upregulated the expression of Wnt-1 and β-catenin. Further analysis was performed to demonstrate the correlation of has-miR-762 with CRC patients. The results showed that serum has-miR-762 levels in CRC patients were higher than in control donors. Among the CRC patients, patients with distant metastasis showed higher serum has-miR-762 levels than patients without distant metastasis.

Conclusions

The present study demonstrated that circulating miR-762 might be a biomarker with upregulation of CRC cell growth and invasion through the Wnt/β-catenin signaling.
Multiple environmental parameters impact core lipid cyclization in Sulfolobus acidocaldarius
Authors: Cobban Alec , Zhang Yujiao , Zhou Alice , Weber Yuki , Pearson Ann , Leavitt William D.
Published: April 2020

Environmental reconstructions based on microbial lipids require understanding the coupling between environmental conditions and membrane physiology. The paleotemperature proxy TEX86is built on the observation that archaea alter the number of five- and six-membered rings in the hydrophobic core of their glycerol dibiphytanyl glycerol tetraether (GDGT) membrane lipids when growing at different temperatures. However, recent work with these archaea also highlights a role for other factors, such as pH or energy availability in determining the degree of core lipid cyclization. To better understand the role of these variables we cultivated a model Crenarchaeon,Sulfolobus acidocaldarius, over a range in temperature, pH, oxygen flux, or agitation speed, and quantified the changes in growth rate, biomass yield, and core lipid compositions. The average degree of cyclization in core lipids correlated with growth rate under most conditions. When considered alongside other experimental findings from both the thermoacidophilic and mesoneutrophilic archaea, the results suggest the cyclization of archaeal lipids records a universal response to energy availability at the cellular level. Although we isolated the effects of individual parameters, there remains a need for multi-factor experiments (e.g., pH + temperature + redox) to establish a robust framework to interpret biomarker records of environmental change.
NK cells orchestrate splenic cDC1 migration to potentiate antiviral protective CD8+ T cell responses
Authors: Ghilas Sonia , Ambrosini Marc , Cancel Jean-Charles , Massé Marion , Lelouard Hugues , Dalod Marc , Crozat Karine
Published: April 2020

A successful immune response relies on a tightly regulated delivery of the right signals to the right cells at the right time. Here we show that innate and innate-like lymphocytes use two mechanisms to orchestrate in time and space the functions of conventional type 1 dendritic cells (cDC1) in spleen. Early after murine cytomegalovirus infection, XCL1 production by lymphocytes with innate functions attracts red pulp cDC1 near IFN-γ-producing NK cells, generating superclusters around infected cells in the marginal zone. There, cDC1 and NK cells physically interact reinforcing their reciprocal activation. Targeted IL-12 delivery and IL-15/IL-15Rα transpresentation by cDC1 trigger NK cell activation and expansion. In return, activated NK cells deliver GM-CSF to cDC1, triggering their CCR7-dependent relocalization into the T cell zone. This NK cell-dependent licensing of cDC1 accelerates the priming of virus-specific CD8+T cells. Our findings reveal a novel mechanism through which cDC1 bridge innate and adaptive immunity.