bluuebunny/crossref_metadata_2025 huggingface dataset:
LATE MERISTEM IDENTITY1 regulates leaf margin development via the auxin transporter geneSMOOTH LEAF MARGIN1
Authors: Wang Xiao , Zhang Juanjuan , Xie Yangyang , Liu Xiu , Wen Lizhu , Wang Hongfeng , Zhang Jing , Li Jie , Han Lu , Yu Xiaolin , Mysore Kirankumar S. , Wen Jiangqi , Zhou Chuanen
Published: June 2021

Plant leaves have evolved into diverse shapes and LATE MERISTEM IDENTITY1 (LMI1) and its putative paralogous genes encode homeodomain leucine zipper transcription factors that are proposed evolutionary hotspots for the regulation of leaf development in plants. However, the LMI1-mediated regulatory mechanism underlying leaf shape formation is largely unknown. MtLMI1a and MtLMI1b are putative orthologs of LMI1 in the model legume barrelclover (Medicago truncatula). Here, we investigated the role of MtLMI1a and MtLMI1b in leaf margin morphogenesis by characterizing loss-of-function mutants. MtLMI1a and MtLMI1b are expressed along leaf margin in a near-complementary pattern, and they redundantly promote development of leaf margin serrations, as revealed by the relatively smooth leaf margin in their double mutants. Moreover, MtLMI1s directly activate expression of SMOOTH LEAF MARGIN1 (SLM1), which encodes an auxin efflux carrier, thereby regulating auxin distribution along the leaf margin. Further analysis indicates that MtLMI1s genetically interact with NO APICAL MERISTEM (MtNAM) and the ARGONAUTE7 (MtAGO7)-mediated trans-acting short interfering RNA3 (TAS3 ta-siRNA) pathway to develop the final leaf margin shape. The participation of MtLMI1s in auxin-dependent leaf margin formation is interesting in the context of functional conservation. Furthermore, the diverse expression patterns of LMI1s and their putative paralogs within key domains are important drivers for functional specialization, despite their functional equivalency among species.
“We Don’t Know” Means “They’re Not Sure”
Authors: Graham Matthew H
Published: June 2021

The most familiar approach to handling respondent uncertainty about survey questions, the “don’t know” (DK) response, has an inconvenient feature: it records no direct information about respondents’ confidence in their answers. This article shows that DK responses contain more information than meets the eye. Using 161 survey questions from 11 surveys conducted between 1993 and 2019, the analysis demonstrates that the percentage of respondents saying DK can explain about half the variation in average confidence among respondents who provided an answer (i.e., those who did not say DK). This “we don’t know” means “they’re not sure” heuristic is especially reliable for relative comparisons between similar questions. For example, in a battery of favorability questions featuring two recent presidents and 10 contenders for the 2020 Democratic presidential nomination, the percentage DK explains more than 90 percent of the variation in average confidence among those who offered an opinion. To provide a deeper intuition, the article draws upon a threshold model of DK responding, which is consistent with a range of existing research on the properties of DK responses.
Muon spin motion at the crossover regime between Gaussian and Lorentzian distribution of magnetic fields
Authors: Umar Muhamad Darwis , Ishida Katsuhiko , Murayama Rie , Puspita Sari Dita , Widyaiswari Utami , Fronzi Marco , Rozak Harion , Zaharim Wan Nurfadhilah , Watanabe Isao , Iwasaki Masahiko
Published: June 2021

The muon spin relaxation method is a powerful microscopic tool for probing the electronic states of materials by observing local magnetic field distributions on the muon. It often happens that a distribution of local magnetic fields shows an intermediate state between Gaussian and Lorentzian shapes. In order to generally describe these intermediate field distributions, we considered the convolution of two isotropic distributions in three dimensions and derived exact muon-spin relaxation functions which can be applied to all crossover regimes between Gaussian and Lorentzian.
Nambu dynamics and its noncanonical Hamiltonian representation in many degrees of freedom systems
Authors: Horikoshi Atsushi
Published: June 2021

Nambu dynamics is a generalized Hamiltonian dynamics of more than two variables, whose time evolutions are given by the Nambu bracket, a generalization of the canonical Poisson bracket. Nambu dynamics can always be represented in the form of noncanonical Hamiltonian dynamics by defining the noncanonical Poisson bracket by means of the Nambu bracket. For the time evolution to be consistent, the Nambu bracket must satisfy the fundamental identity, while the noncanonical Poisson bracket must satisfy the Jacobi identity. However, in many degrees of freedom systems, it is well known that the fundamental identity does not hold. In the present paper we show that, even if the fundamental identity is violated, the Jacobi identity for the corresponding noncanonical Hamiltonian dynamics could hold. As an example we evaluate these identities for a semiclassical system of two coupled oscillators.
COVID-19 stressors, wellbeing and health behaviours: a cross-sectional study
Authors: Bell L M , Smith R , van de Venter E C , Shuttleworth C , Wilson K , Lycett D
Published: June 2021

Background

Following the implementation of pandemic response measures, concerns arose regarding the impact for population health and wellbeing.

Methods

This study reports findings from a survey (N = 2510) conducted in Warwickshire (UK) during August and September 2020, and for the first time investigates behaviours which may worsen or mitigate the association between COVID-19-related stressors and wellbeing.

Results

Increased stressors were associated with lower mental wellbeing and higher loneliness. Participants with a mental health condition reported lower wellbeing, as did younger groups, women and participants not in employment. To cope with restrictions, more participants engaged in healthier behaviours over unhealthy behaviours, and relaxing reduced the association between stressors and poor wellbeing. Some participants reported increasing alcohol and unhealthy dietary behaviours to cope with restrictions, however, these behaviours did not mitigate the impact of COVID-19 stressors and were instead negatively associated with wellbeing. Around half of participants helped neighbours during the pandemic, a behaviour positively associated with wellbeing particularly among older adults.

Conclusion

These findings contribute understanding about how various positive and negative health behaviours may mitigate or worsen the impact of COVID-19 on wellbeing, and how public health interventions may effectively target behaviours and groups in similar populations.
Bicortical Short C2 Pars Screw Fixation for High-Riding Vertebral Artery Provided Sufficient Biomechanical Stability
Authors: Shao Minghao , Dai Yuan , Zhu Wei , Yu Jian , Lyu Feizhou
Published: June 2021

Study Design.

Finite element analysis.

Objective.

To determine and compare the biomechanical stability of the bicortical short C2 pars screw fixation for high-riding vertebral artery (HRVA) with the C2 pedicle screw and C2 translaminar screw fixation in finite element models.

Summary of Background Data.

Fixation of C2 is technically demanding in the case of HRVA. However, there is no consensus on the alternative technique for the C2 screw fixation for HRVA in the literature.

Methods.

A finite element model of the upper cervical spine (C0-C2) with HRVA had been developed. C1 pedicle screw was applied at C1 by using notching technique. Bicortical short C2 pars screws, C2 pedicle screws, and C2 translaminar screws were used in each model. Then a vertical load of 50 N and a 1.5 Nm torque were applied to the C0 to simulate flexion, extension, lateral bending, and axial rotation respectively.

Results.

Compared with C2 pedicle screw fixation, the bicortical short C2 pars screw fixation increased the range of motion by −1.45%, 2.13%, 62.0%, and 22.0% under flexion, extension, lateral bending, and axial rotation, respectively. However, the C2 translaminar screw fixation increased the range of motion by 43.6%, 17.8%, 423.4%, and 19.9%, respectively. In terms of the peak von Mises stress, compared with C2 pedicle screw fixation, bicortical short C2 pars screw decreased 46.1%, 41.6%, 71.3%, and −12.5% under flexion, extension, lateral bending, and axial rotation, respectively; C2 translaminar screw decreased −2.66%, −4.87%, 73.0%, and −10.1%, respectively.

Conclusion.

For a patient with HRVA, bicortical short C2 pars screw fixation provides sufficient stability and exhibited a smaller von Mises distribution on the screw-rod construct, indicating it could be an effective C2 internal fixation method for HRVA to promote C1-C2 stability and avoid the vertebral artery injury.

Level of Evidence: N/A
Effects of the Prone Position on Regional Neutrophilic Lung Inflammation According to 18F-FDG Pet in an Experimental Ventilator-Induced Lung Injury Model
Authors: Nakahashi Susumu , Imai Hiroshi , Shimojo Nobutake , Magata Yasuhiro , Einama Takahiro , Hayakawa Mineji , Wada Takeshi , Morimoto Yuji , Gando Satoshi
Published: June 2021

Ventilator-induced lung injury (VILI) can be life-threatening and it is important to prevent the development of VILI. It remains unclear whether the prone position affects neutrophilic inflammation in the lung regions in vivo, which plays a crucial role in the pathogenesis of VILI. This study aimed to assess the relationship between the use of the prone position and the development of VILI-associated regional neutrophilic lung inflammation. Regional neutrophilic lung inflammation and lung aeration during low tidal volume mechanical ventilation were assessed using in vivo 2-deoxy-2-[(18)F] fluoro-D-glucose (18F-FDG) positron emission tomography and computed tomography in acutely experimentally injured rabbit lungs (lung injury induced by lung lavage and excessive ventilation). Direct comparisons were made among three groups: control, supine, and prone positions. After approximately 7 h, tissue-normalized 18F-FDG uptake differed significantly between the supine and prone positions (SUP: 0.038 ± 0.014 vs. PP: 0.029 ± 0.008, P = 0.038), especially in the ventral region (SUP: 0.052 ± 0.013 vs. PP: 0.026 ± 0.007, P = 0.003). The use of the prone position reduced lung inhomogeneities, which was demonstrated by the correction of the disproportionate rate of voxel gas over the given lung region. The progression of neutrophilic inflammation was affected by the interaction between the total strain (for aeration) and the inhomogeneity. The prone position is effective in slowing down the progression of VILI-associated neutrophilic inflammation. Under low-tidal-volume ventilation, the main drivers of its effect may be homogenization of lung tissue and that of mechanical forces.
“Raising HOPE”: Improved Outcomes for HIV/HCV-coinfected Liver Transplant Recipients in the Direct-acting Antiviral Era
Authors: Cotter Thomas G. , Wang Jennifer , Lieber Sarah R. , Odenwald Matthew A. , Rich Nicole E. , Marrero Jorge A. , Singal Amit G. , Mitchell Mack C. , Aronsohn Andrew , Charlton Michael , Fung John
Published: June 2021

Background.

The 2013 HIV Organ Policy Equity Act has increased liver transplantation (LT) in HIV+ patients; however, transplant centers may remain reluctant to perform LT in HIV/hepatitis C virus (HCV)-coinfected patients due to inferior outcomes. We aimed to assess how direct-acting antivirals (DAAs) have impacted HIV+/HCV+-coinfected LT recipient outcomes.

Methods.

national data including 70 125 adult LT recipients between 2008 and 2019 were analyzed. Kaplan-Meier survival analysis and Cox proportional hazards model were used to analyze outcomes.

Results.

LT for HIV+ individuals increased in the DAA era from 28 in 2014 to 64 in 2019 (23 had HIV+/HCV+ coinfection). In the pre-DAA era, HIV+/HCV+-coinfected LT recipients had an increased risk of graft failure compared with HIV−/HCV−-uninfected LT recipients (hazard ratio [HR], 1.85; P < 0.001). In contrast, there was no difference in graft failure between HIV+/HCV+-coinfected versus HIV−/HCV−-uninfected LT recipients in the DAA era (HR, 1.24; P = 0.308). Among coinfected LT recipients in the DAA era, 1- and 3-y cumulative graft survivals were 88.6% and 81.7% compared with 76.3% and 58.0% in the pre-DAA era, respectively (P = 0.006). In Cox analysis, HCV coinfection was not associated with graft failure (HR, 1.00; 95% confidence interval, 0.53-1.89) among HIV+ LT recipients in the DAA era (n = 271). Black and Hispanic populations accounted for almost half of HIV+/HCV+ LTs in the DAA era.

Conclusions.

HIV+/HCV+-coinfected LT recipient outcomes have improved significantly in the DAA era. Our results should offer reassurance to transplant centers and encourage timely transplantation referral of HIV patients with decompensated cirrhosis, including patients coinfected with HCV.
Mind the replication gap
Authors: Mocanu Camelia , Chan Kok-Lung
Published: June 2021

Unlike bacteria, mammalian cells need to complete DNA replication before segregating their chromosomes for the maintenance of genome integrity. Thus, cells have evolved efficient pathways to restore stalled and/or collapsed replication forks during S-phase, and when necessary, also to delay cell cycle progression to ensure replication completion. However, strong evidence shows that cells can proceed to mitosis with incompletely replicated DNA when under mild replication stress (RS) conditions. Consequently, the incompletely replicated genomic gaps form, predominantly at common fragile site regions, where the converging fork-like DNA structures accumulate. These branched structures pose a severe threat to the faithful disjunction of chromosomes as they physically interlink the partially duplicated sister chromatids. In this review, we provide an overview discussing how cells respond and deal with the under-replicated DNA structures that escape from the S/G2 surveillance system. We also focus on recent research of a mitotic break-induced replication pathway (also known as mitotic DNA repair synthesis), which has been proposed to operate during prophase in an attempt to finish DNA synthesis at the under-replicated genomic regions. Finally, we discuss recent data on how mild RS may cause chromosome instability and mutations that accelerate cancer genome evolution.
Analysis of fracture deformation field and energy evolution of granite after high confining pressure cyclic load pre-damage
Authors: Yang Dongjie , Hu Jianhua , Wen Guanping , Zeng Pingping
Published: June 2021

Considering the recent developments of deep mining, investigating the rock properties under high ground stress periodic load is highly demanded. Studies show that these characteristics are important factors affecting the long-term steadiness of rock. However, the mechanical properties of rock mass without macro failure after cyclic load should be studied. In the present study, granite in a mine is considered as the research object. A rock pre-damage experiment is conducted with the same cycles under different confining pressures and constant cycle upper and lower limit loads. The pre-damaged rock sample is subjected to a uniaxial compression test, and a high-speed charge couple device camera is used to record the speckle field image of the sample surface during the whole loading process. The digital speckle techniques are used to analyse the image of the pre-damaged sample, the deformation field of the specimen surface, the displacement dislocation value of the localized deformation area and the deformation energy value of the specimen surface. The results show that for the same cycle times, the confining pressure is less than 80 MPa, which has a weakening effect on the rock's axial strength. As the confining pressure approaches 120 MPa, the pre-damaged rock uniaxial peak strength increases. The characteristics of displacement dislocation energy evolution of the localized deformation bound are divided into three stages (pre-peak stage, peak point and post-peak stage). After pre-damage under the same cycle times and different confining pressure conditions, the deformation field evolution of rock is relatively consistent.
A Wronskian method for elastic waves propagating along a tube
Authors: Chapman C. J. , Sorokin S. V.
Published: June 2021

A technique involving the higher Wronskians of a differential equation is presented for analysing the dispersion relation in a class of wave propagation problems. The technique shows that the complicated transcendental-function expressions which occur in series expansions of the dispersion function can, remarkably, be simplified to low-order polynomials exactly, with explicit coefficients which we determine. Hence simple but high-order expansions exist which apply beyond the frequency and wavenumber range of widely used approximations based on kinematic hypotheses. The new expansions are hypothesis-free, in that they are derived rigorously from the governing equations, without approximation. Full details are presented for axisymmetric elastic waves propagating along a tube, for which stretching and bending waves are coupled. New approximate dispersion relations are obtained, and their high accuracy confirmed by comparison with the results of numerical computations. The weak coupling limit is given particular attention, and shown to have a wide range of validity, extending well into the range of strong coupling.
The dilution effect behind the scenes: testing the underlying assumptions of its mechanisms through quantifying the long-term dynamics and effects of a pathogen in multiple host species
Authors: Garrido Mario , Halle Snir , Flatau Ron , Cohen Carmit , Navarro-Castilla Álvaro , Barja Isabel , Hawlena Hadas
Published: June 2021

Disentangling the mechanisms that mediate the relationships between species diversity and disease risk has both theoretical and applied implications. We employed a model system of rodents and their
Mycoplasma
pathogens, in which an extreme negative diversity–disease relationship was demonstrated, to test the assumptions underlying three mechanisms that may explain this field pattern. Through quantifying the long-term dynamics and effects of the pathogen in its three host species, we estimated the between-host differences in pathogen spreading and transmission potentials, and host recovery potential and vulnerability to infection. The results suggest that one of the hosts is a pathogen amplifier and the other two hosts function as diluters. Considering the similarity in infection success and intensity among hosts, and the failure to detect any pathogen-induced damage, we could not validate the assumption underlying the hypotheses that diluters reduce the overall transmission or increase the mortality of infected hosts in the system. Instead, the results demonstrate that diluters clear the infection faster than amplifiers, supporting the possibility that the addition of diluters to the community may reduce the overall number of infected hosts through this mechanism. This study highlights the contribution of experimental studies that simultaneously explore different aspects of host–pathogen interactions in multiple hosts, in diversity–disease research.
The transition from hunting–gathering to agriculture in Nubia: dental evidence for and against selection, population continuity and discontinuity
Authors: Irish Joel D. , Usai Donatella
Published: June 2021

Some researchers posit population continuity between Late Palaeolithic hunter–gatherers of the late Pleistocene and Holocene agriculturalists from Lower (northern) Nubia, in northeast Africa. Substantial craniodental differences in these time-successive groups are suggested to result fromin situevolution. Specifically, these populations are considered a model example for subsistence-related selection worldwide in the transition to agriculture. Others question continuity, with findings indicating that the largely homogeneous Holocene populations differ significantly from late Pleistocene Lower Nubians. If the latter are representative of the local populace, post-Pleistocene discontinuity is implied. So who was ancestral to the Holocene agriculturalists? Dental morphological analyses of 18 samples (1075 individuals), including one dated to the 12th millennium BCE from Al Khiday, near the Upper Nubian border, may provide an answer. It is the first Late Palaeolithic sample (n= 55) recovered within the region in approximately 50 years. Using the Arizona State University Dental Anthropology System to record traits and multivariate statistics to estimate biological affinities, Al Khiday is comparable to several Holocene samples, yet also highly divergent from contemporaneous Lower Nubians. Thus, population continuity is indicated after all, but with late Pleistocene Upper—rather than Lower Nubians as originally suggested—assuming dental traits are adequate proxies for ancient DNA.
Streptacidiphilus fuscans sp. nov., a novel actinobacterium isolated from the root of pumpkin (Cucurbita moschata)
Authors: Yu Bing , Han Chuanyu , Zhao Junwei , Zhang Yuting , Shan Qiqi , Wu Yan , Ju Hanxun , Xiang Wensheng , Wang Xiangjing
Published: June 2021

A novel acidophilic actinobacterium, designated strain NEAU-YB345T, was isolated from a pumpkin root collected from Mudanjiang, Heilongjiang Province, northeast PR China. Based on 16S rRNA gene sequence similarity and chemotaxonomic and morphological properties, the isolate was assigned to the genus

Streptacidiphilus

, with the high 16S rRNA gene sequence similarities to

Streptacidiphilus melanogenes

JCM 16224T (99.2 %),

Streptacidiphilus anmyonensis

JCM 16223T (99.1 %) and

Streptacidiphilus jiangxiensis

JCM 12277T (98.7 %). Its cell wall contained ll-diaminopimelic acid as the major diamino acid. Rhamnose, ribose, glucose and galactose were the detected sugars from the whole-cell hydrolysates. The phospholipid profile consisted of diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol, phosphatidylinositol mannoside and an unidentified phospholipid. The menaquinones were MK-9(H8) and MK-9(H6). Major fatty acids were C16 : 0, iso-C16 : 0, iso-C15 : 0 and anteiso-C15 : 0. Phylogenetic analysis using 16S rRNA gene and whole-genome sequences placed the strain in distinct clades but within the genus

Streptacidiphilus

. The DNA G+C content was 71.2 mol%. Based on DNA–DNA relatedness and physiological and biochemical data, the isolate could be distinguished from its closest relatives. Therefore, strain NEAU-YB345T represents a novel species of the genus

Streptacidiphilus

, for which the name Streptacidiphilus fuscans sp. nov. is proposed. The type strain is NEAU-YB345T (=CCTCC AA 2020030T=JCM 33976T).
Dementia is strongly associated with medial temporal atrophy even after accounting for neuropathologies
Authors: Woodworth Davis C. , Sheikh-Bahaei Nasim , Scambray Kiana A. , Phelan Michael J. , Perez-Rosendahl Mari , Corrada María M. , Kawas Claudia H. , Sajjadi S. Ahmad ,   for the Alzheimer’s Disease Neuroimaging Initiative
Published: June 2021

Objective

Brain atrophy is associated with degenerative neuropathologies as well as clinical status of dementia. Whether dementia influences atrophy independent of neuropathologies is not known. In this study, we examined the pattern of atrophy associated with dementia while accounting for the most common dementia-related neuropathologies.

Methods

We used data from National Alzheimer’s Coordinating Center (NACC, N=129) and Alzheimer’s Disease Neuroimaging Initiative (ADNI, N=47) participants with suitable in-vivo 3D-T1w MRI and autopsy data. We determined dementia status at visit closest to MRI. We examined the following dichotomized neuropathological variables: Alzheimer’s disease neuropathology, hippocampal sclerosis, Lewy Bodies, cerebral amyloid angiopathy, atherosclerosis. Voxel-based morphometry (VBM) identified areas associated with dementia after accounting for neuropathologies. Identified regions of interest were further analyzed. We used multiple linear regression models adjusted for neuropathologies and demographic variables.

Results

We found strong associations for dementia with volumes of the hippocampus, amygdala, and parahippocampus (semi-partial correlations≥0.28, P<0.0001 for all regions in NACC; semi-partial correlations≥0.35, P≤0.01 for hippocampus and parahippocampus in ADNI). Dementia status accounted for more unique variance in atrophy in these structures (∼8%) compared with neuropathological variables; the only exception was hippocampal sclerosis which accounted for more variance in hippocampal atrophy (10%).

Conclusion

Even after accounting for the most common neuropathologies, dementia still had among the strongest correlations with atrophy of medial temporal lobe structures. This suggests that atrophy of the medial temporal lobe is most related to clinical status of dementia as opposed to Alzheimer’s or other neuropathologies.
The importance of time post-vaccination in determining the decrease in vaccine efficacy against SARS-CoV-2 variants of concern
Authors: On Yinon Bar , Noor Elad , Gottlieb Noam , Sigal Alex , Milo Ron
Published: June 2021

With the development of high-efficacy vaccines against SARS-CoV-2, an urgent open question is whether currently available vaccines protect with similar efficacy against infection with SARS-CoV-2 variants of concern (VOC). Recent reports quantifying the extent by which VOC can evade vaccine immunity resulted in a range of estimates for the same VOC, which makes them difficult to interpret. One possible explanation for the discrepancies between different studies is an inconsistency in terms of the time post-vaccination of the sampled population. Here we present a model based on the observed correlation between antibody neutralization levels and vaccine efficacy, which demonstrates the impact of time post-vaccination on the comparison of the vaccine efficacy for VOC versus non-VOC infections. Our model predicts and exemplifies several possible consequences for vaccine efficacy in VOC infections: 1) a delay in the onset of vaccine efficacy against VOC; 2) a transient increase in susceptibility to breakthrough infection with VOC compared to non-VOC as a function of time after vaccination. We review preliminary data indicating that such phenomena are observed in studies of the B.1.1.7 and B.1.351 variants. We find that ignoring the strong dependence on the time post-vaccination can lead to contradictory reports of relative efficacy against VOC versus non-VOC, with implications on mitigation strategies against VOC and the design of vaccine efficacy studies.
CHA2DS2-VASc score on admission to predict mortality in COVID-19 patients: A meta-analysis
Authors: Sarkar Prattay Guha , Kumar Amit , Bandyopadhyay Debdutta
Published: June 2021

Background

CHA2DS2-VASc score is used in non-valvular AF patients to predict thromboembolic risk. Recent studies have tried to evaluate CHA2DS2-VASc score on admission in COVID-19 patients to predict mortality.

Methods

We conducted a literature search on 14 April 2021 to retrieve all published studies, pre-prints and grey literature related to the predictive power of CHA2DS2-VASc score in COVID-19 patients of admission and mortality. Screening of studies and data extraction was done by two authors independently. We used the Quality in Prognosis Studies (QUIPS) tool for the methodological quality assessment of the included studies.

Results

Five studies involving 5,941 patients reported the predictive value of CHA2DS2-VASc score for mortality in COVID-19 patients. The pooled sensitivity (SEN), specificity (SPE) and area under curve were 0.72 (95% CI 0.63-0.79), 0.74 (95% CI 0.67-0.81) and 0.80 (95% CI 0.76-0.83).

Conclusions

CHA2DS2-VASc score at admission has good predictive value for mortality in patients with COVID-19 infection and can help clinicians identify potentially severe cases early. Early initiation of effective management in these cases may help in reducing overall mortality due to COVID-19.

Trial registry

We prospectively registered this meta-analysis on PROSPERO database (Reg number: CRD42021248398).
Brain atrophy progression in Parkinson’s disease is shaped by connectivity and local vulnerability
Authors: Tremblay Christina , Rahayel Shady , Vo Andrew , Morys Filip , Shafiei Golia , Markello Ross D. , Gan-Or Ziv , Misic Bratislav , Dagher Alain
Published: June 2021

Atrophy in multiple brain regions has been reported in the early stages of Parkinson’s Disease, but there have been few longitudinal studies. How intrinsic properties of the brain, such as anatomical connectivity, local cell type distribution and gene expression combine to determine the pattern of disease progression remains unknown. One hypothesis proposes that the disease stems from prion-like propagation of misfolded alpha-synuclein via the connectome that might cause varying degrees of tissue damage based on local properties.

Here we used MRI data from the Parkinson Progression Markers Initiative to test this model by mapping the progression of brain atrophy over one, two and four years and relating it to brain structural and functional connectivity, cell type expression and gene ontology enrichment analyses. In this longitudinal study, we derived atrophy progression maps for the three time points using deformation-based morphometry applied to T1-weighted MRI from 74 de novo Parkinson’s Disease patients (50 Men: 24 Women) and 157 healthy control participants (115 Men: 42 Women). After regressing out the expected age and sex effects associated with normal aging, we found that atrophy significantly progressed over two and four years in the caudate, nucleus accumbens, hippocampus, and the temporal, parietal, occipital and posterior cingulate cortex. This progression was shaped by both structural and functional brain connectivity. Also, the progression of atrophy was more pronounced in regions with a higher expression of genes related to synapses and was related to the prevalence of oligodendrocytes and endothelial cells.

In sum, we demonstrate that the progression of atrophy in Parkinson’s Disease is in line with the prion-like propagation hypothesis of alpha-synuclein and provide evidence that synapses may be especially vulnerable to synucleinopathy. In addition to identifying vulnerable brain regions, this study reveals different factors that may be implicated in the neurotoxic mechanisms leading to progression in Parkinson’s Disease.
High throughput sequencing based detection of SARS-CoV-2 prevailing in wastewater of Pune, West India
Authors: Dharmadhikari Tanmay , Rajput Vinay , Yadav Rakeshkumar , Boaragaonkar Radhika , Panse Dayanand , Kamble Sanjay , Dastager Syed , Dharne Mahesh
Published: June 2021

Given a large number of SARS-CoV-2 infected individuals, clinical detection has proved challenging. The wastewater-based epidemiological paradigm would cover the clinically escaped asymptomatic individuals owing to the faecal shedding of the virus. We hypothesised using wastewater as a valuable resource for analysing SARS-CoV-2 mutations circulating in the wastewater of Pune region (Maharashtra; India), one of the most affected during the covid-19 pandemic. We conducted a case study in open wastewater drains from December 2020-March 2021 to assess the presence of SARS-CoV-2 nucleic acid and further detect mutations using ARTIC protocol of MinION sequencing. The analysis revealed 108 mutations across six samples categorised into 40 types of mutations. We report the occurrence of mutations associated with B.1.617 lineage in March-2021 samples, simultaneously also reported as a Variant of Concern (VoC) responsible for the rapid increase in infections. The study also revealed four mutations; S:N801, S:C480R, NSP14:C279F and NSP3:L550del not currently reported from wastewater or clinical data in India but reported in the world. Further, a novel mutation NSP13:G206F mapping to NSP13 region was observed from wastewater. Notably, S:P1140del mutation was observed in December 2020 samples while it was reported in February 2021 from clinical data, indicating the instrumentality of wastewater data in early detection. This is the first study in India to conclude that wastewater-based epidemiology to identify mutations associated with SARS-CoV-2 virus from wastewater as an early warning indicator system.
The role of nature conservation and commercial farming in psychological distress among rural Ugandans
Authors: Pienkowski Thomas , Keane Aidan , Kinyanda Eugene , Knizek Birthe Loa , Asiimwe Caroline , Muhanguzi Geoffrey , Milner-Gulland E.J.
Published: June 2021

Mental illness is a leading contributor to the global burden of disease, but there is limited understanding of how it is influenced by socio-ecological context, particularly in the global south. We asked how interactions with ecological systems influence stressors associated with psychological distress in a rural Ugandan case study. We conducted and thematically analyzed 45 semi-structured interviews with residents of Nyabyeya Parish, Masindi District. Our results suggest that poverty and food insecurity were the primary reported causes of “thinking too much” and related idioms of psychological distress. The expansion of commercial agriculture may have been associated with the contraction of subsistence farming, reportedly exacerbating poverty and food insecurity among poorer households but contributing incomes to wealthier ones. Furthermore, households bordering a conservation area reported that crop losses from wildlife contributed to food insecurity. However, forest resources were important safety nets for those facing poverty and food insecurity. Our study suggests how two globally prevalent land uses – commercial agriculture and nature conservation – may influence social determinants of psychological distress in our study area. Psychological distress does not necessarily imply mental disorder. Nonetheless, exploring socially-mediated interactions with ecosystems may help explain the etiology of psychological distress. Furthermore, we suggest opportunities to manage socio-ecological systems to support mental health, such as promoting equitable access and control of livelihood resources. We also highlight co-benefits and trade-offs between global sustainability goals that could be managed for mental health, and why these should be recognized in the anticipated ‘New Deal for Nature.’

Highlights

Food insecurity and poverty were major stressors reportedly causing psychological distress, characterized as “thinking too much.”

Complex interactions between conservation, commercial agriculture, and poverty influenced psychological distress.

Commercial agriculture displaced subsistence farming, exacerbating poverty and food security among poorer households.

Conserved forests were both home to crop-raiding wildlife and sources of income and food, affecting poverty and food insecurity.

Mental health needs to be included in assessments of the role of the ecosystems in public health.
The ChAdOx1 vectored vaccine, AZD2816, induces strong immunogenicity against SARS-CoV-2 Beta (B.1.351) and other variants of concern in preclinical studies
Authors: Spencer Alexandra J , Morris Susan , Ulaszewska Marta , Powers Claire , Kailath Reshma , Bissett Cameron , Truby Adam , Thakur Nazia , Newman Joseph , Allen Elizabeth R , Rudiansyah Indra , Liu Chang , Dejnirattisai Wanwisa , Mongkolsapaya Juthathip , Davies Hannah , Donnellan Francesca R , Pulido David , Peacock Thomas P. , Barclay Wendy S. , Bright Helen , Ren Kuishu , Screaton Gavin , McTamney Patrick , Bailey Dalan , Gilbert Sarah C , Lambe Teresa
Published: June 2021

There is an ongoing global effort to design, manufacture, and clinically assess vaccines against SARS-CoV-2. Over the course of the ongoing pandemic a number of new SARS-CoV-2 virus isolates or variants of concern (VoC) have been identified containing mutations in key proteins. In this study we describe the generation and preclinical assessment of a ChAdOx1-vectored vaccine (AZD2816) which expresses the spike protein of the Beta VoC (B.1.351). We demonstrate that AZD2816 is immunogenic after a single dose. When AZD2816 is used as a booster dose in animals primed with a vaccine encoding the original spike protein (ChAdOx1 nCoV-19/ [AZD1222]), high titre binding and neutralising antibodies against Beta (B.1.351), Gamma (P.1) and Delta (B.1.617.2) are induced. In addition, a strong and polyfunctional T cell response was measured in these booster regimens. These data support the ongoing clinical development and testing of this new variant vaccine.
The Lipid Droplet Knowledge Portal: A resource for systematic analyses of lipid droplet biology
Authors: Mejhert Niklas , Gabriel Katlyn R. , Krahmer Natalie , Kuruvilla Leena , Chitraju Chandramohan , Boland Sebastian , Jang Dong-Keun , von Grotthuss Marcin , Costanzo Maria C. , Flannick Jason , Burtt Noël P. , Farese Robert V. , Walther Tobias C.
Published: June 2021

Lipid droplets (LDs) are organelles of cellular lipid storage with fundamental roles in energy metabolism and cell membrane homeostasis. There has been an explosion of research into the biology of LDs, in part due to their relevance in diseases of lipid storage, such as atherosclerosis, obesity, type 2 diabetes mellitus, and hepatic steatosis. Consequently, there is an increasing need for a resource that combines large datasets from systematic analyses of LD biology. Here we integrate high-confidence, systematically generated data on studies of LDs in the framework of an online platform named the Lipid Droplet Knowledge Portal. This scalable and interactive portal includes comprehensive datasets, across a variety of cell types, for LD biology, including transcriptional profiles of induced lipid storage, organellar proteomics, genome-wide screen phenotypes, and ties to human genetics. This new resource is a powerful platform that can be utilized to uncover new determinants of lipid storage.

HIGHLIGHTS

■ The LD-Portal is a resource combining datasets from systematic analyses in LD biology

■ The LD-Portal allows users to query genetic, proteomic, and phenotypic aspects of LD biology

■ The LD-Portal can be used to discover new facets of lipid storage and LD biology

■ A crucial function of MSRB3 is uncovered in cholesterol ester storage in LDs
A novel immunopeptidomic-based pipeline for the generation of personalized oncolytic cancer vaccines
Authors: Feola Sara , Chiaro Jacopo , Martins Beatriz , Russo Salvatore , Fusciello Manlio , Ylösmäki Erkko , Hamdan Firas , Feodoroff Michaela , Antignani Gabriella , Viitala Tapani , Pesonen Sari , Grönholm Mikaela , Branca Rui M M , Lehtiö Janne , Cerullo Vincenzo
Published: June 2021

Beside the isolation and identification of MHC-I restricted peptides from the surface of cancer cells, one of the challenges is eliciting an effective anti-tumor CD8+ T cell mediated response as part of therapeutic cancer vaccine. Therefore, the establishment of a solid pipeline for the downstream selection of clinically relevant peptides and the subsequent creation of therapeutic cancer vaccines are of utmost importance. Indeed, the use of peptides for eliciting specific anti-tumor adaptive immunity is hindered by two main limitations: the efficient selection of the most optimal candidate peptides and the use of a highly immunogenic platform to combine with the peptides to induce effective tumor-specific adaptive immune responses. Here, we describe for the first time a streamlined pipeline for the generation of personalized cancer vaccines starting from the isolation and selection of the most immunogenic peptide candidates expressed on the tumor cells and ending in the generation of efficient therapeutic oncolytic cancer vaccines. This immunopeptidomics-based pipeline was carefully validated in a murine colon tumor model CT26. Specifically, we used state-of-the-art immunoprecipitation and mass spectrometric methodologies to isolate >8000 peptide targets from the CT26 tumor cell line. The selection of the target candidates was then based on two separate approaches: RNAseq analysis and the HEX software. The latter is a tool previously developed by Chiaro et al. (1), able to identify tumor antigens similar to pathogen antigens, in order to exploit molecular mimicry and tumor pathogen cross-reactive T-cells in cancer vaccine development. The generated list of candidates (twenty-six in total) was further tested in a functional characterization assay using interferon-γ ELISpot (Enzyme-Linked Immunospot), reducing the number of candidates to six. These peptides were then tested in our previously described oncolytic cancer vaccine platform PeptiCRAd, a vaccine platform that combines an immunogenic oncolytic adenovirus (OAd) coated with tumor antigen peptides. In our work, PeptiCRAd was successfully used for the treatment of mice bearing CT26, controlling the primary malignant lesion and most importantly a secondary, non-treated, cancer lesion. These results confirmed the feasibility of applying the described pipeline for the selection of peptide candidates and generation of therapeutic oncolytic cancer vaccine, filling a gap in the field of cancer immunotherapy, and paving the way to translate our pipeline into human therapeutic approach.
Systematic multi-omics cell line profiling uncovers principles of Ewing sarcoma fusion oncogene-mediated gene regulation
Authors: Orth Martin F. , Surdez Didier , Marchetto Aruna , Grossetête Sandrine , Gerke Julia S. , Zaidi Sakina , Alonso Javier , Sastre Ana , Baulande Sylvain , Sill Martin , Cidre-Aranaz Florencia , Ohmura Shunya , Kirchner Thomas , Hauck Stefanie M. , Reischl Eva , Gymrek Melissa , Pfister Stefan M. , Strauch Konstantin , Delattre Olivier , Grünewald Thomas G. P.
Published: June 2021

Cell lines have been essential for major discoveries in cancer including Ewing sarcoma (EwS). EwS is a highly aggressive pediatric bone or soft-tissue cancer characterized by oncogenic EWSR1-ETS fusion transcription factors converting polymorphic GGAA-microsatellites (mSats) into neo-enhancers. However, further detailed mechanistic evaluation of gene regulation in EwS have been hindered by the limited number of well-characterized cell line models. Here, we present the Ewing Sarcoma Cell Line Atlas (ESCLA) comprising 18 EwS cell lines with inducible EWSR1-ETS knockdown that were profiled by whole-genome-sequencing, DNA methylation arrays, gene expression and splicing arrays, mass spectrometry-based proteomics, and ChIP-seq for EWSR1-ETS and histone marks. Systematic analysis of these multi-dimensional data illuminated hundreds of new potential EWSR1-ETS target genes, the nature of EWSR1-ETS-preferred GGAA-mSats, and potential indirect modes of EWSR1-ETS-mediated gene regulation. Moreover, we identified putative co-regulatory transcription factors and heterogeneously regulated EWSR1-ETS target genes that may have implications for the clinical heterogeneity of EwS. Collectively, our freely available ESCLA constitutes an extremely rich resource for EwS research and highlights the power of leveraging multidimensional and comprehensive datasets to unravel principles of heterogeneous gene regulation by dominant fusion oncogenes.
Locally secreted BiTEs complement CAR T cells by enhancing solid tumor killing
Authors: Yin Yibo , Rodriguez Jesse L. , Li Nannan , Thokala Radhika , Nasrallah MacLean P. , Hu Li , Zhang Logan , Zhang Jiasi Vicky , Kainth Devneet , Haddad Leila , Johns Emily X. , Long Yu , Liang Hongsheng , Qi Jiping , Zhang Xiangtong , Binder Zev A. , Lin Zhiguo , O’Rourke Donald M.
Published: June 2021

Bispecific T-cell engagers (BiTEs) are bispecific antibodies that redirect T cells to target antigen-expressing tumors. BiTEs can be secreted by T cells through genetic engineering and perform anti-tumor activity. We hypothesized that BiTE-secreting T cells could be a valuable T cell-directed therapy in solid tumors, with distinct properties in mono- or multi-valent strategies incorporating chimeric antigen receptor (CAR) T cells. Glioblastomas represent a good model for solid tumor heterogeneity and represent a significant therapeutic challenge. We detected expression of tumor-associated epidermal growth factor receptor (EGFR), EGFR variant III (EGFRvIII), and interleukin-13 receptor alpha 2 (IL13Rα2) on glioma tissues and glioma cancer stem cells. These antigens formed the basis of a multivalent approach, using a conformation-specific tumor-related EGFR targeting antibody (806) and Hu08, an IL13Rα2-targeting antibody, as the scFvs to generate new BiTE molecules. Compared with 806CAR T cells and Hu08CAR T cells, BiTE T cells demonstrated prominent activation, cytokine production, and cytotoxicity in response to target-positive gliomas. Superior response activity was also demonstrated in BiTE secreting bivalent targeting T cells compared with bivalent targeting CAR T cells, which significantly delayed tumor growth in a glioma mouse model. In summary, BiTEs secreted by mono- or multi- valent targeting T cells have potent anti-tumor activity in vitro and in vivo with significant sensitivity and specificity, demonstrating a promising strategy in solid tumor therapy.
An Efficient and Cost-effective Purification Methodology for SaCas9 Nuclease
Authors: Teng Allen C.T. , Tavassoli Marjan , Shrestha Suja , Lindsay Kyle , Ivakine Evgueni , Cohn Ronald , Santerre J. Paul , Gramolini Anthony O.
Published: June 2021

With an ever-increasing demand for laboratory-grade Cas9 proteins by many groups advancing the use of CRISPR technology, a more efficient and scalable process for generating the proteins, coupled with rapid purification methods is in urgent demand. Here, we introduce a modified methodology for rapid purification of active SaCas9 protein within 24 hours. The product has over 90% protein purity. The simplicity and cost-effectiveness of such methodology will enable general labs to produce a sizable amount of Cas9 proteins, further accelerating the advancement of CRISPR/Cas9-based research.
Analysis of cell-mediated immunity in people with long COVID
Authors: Montes Nerea , Domènech Èlia , Guerrero Sílvia , Oliván-Blázquez Bárbara , Magallón-Botaya Rosa
Published: June 2021

Introduction

The objective of this study is to analyse the specific immune response against SARS-CoV-2 in those affected by Long Covid (LC), attributable to T cells (cell-mediated immunity) and to carry out a parallel analysis of the humoral response and lymphocyte typing.

Methodology

Descriptive cross-sectional study of 74 patients with LC for at least 4 months since diagnosis. The collected data were: information on the COVID-19 episode and the persistent symptoms, medical history and a specific cell-mediated immunity to SARS-CoV-2 through flow cytometry, assessing the release of interferon-gamma (IFN-Ɣ) by T4 lymphocytes, T8 lymphocytes and NK cells. Descriptive and comparative analyses were carried out.

Results

Patients with LC had negative serology for Covid-19 in 89% of cases but 96% showed specific cellular immunity to SARS-CoV-2 an average of 9.5 months after infection: 89% of this response corresponded to T8 lymphocytes, 58% to NK cells, and 51% to T4 lymphocyte (20% negligibly positive). Most of them had altered immune cell typing and we found that T4 lymphocyte counts were low in 34% of cases and NK cell high in 64%. Macrophage populations were detected in the peripheral blood of 7% of them. Patients displayed a higher percentage of illnesses related to &[Prime]abnormal&[Prime] immune responses, either preceding SARS-CoV-2 infection (43%) or following it in 23% of cases.

Conclusion

The immune system appears to have an important involvement in the development of LC and viral persistence could be the cause or consequence of it. Further analysis with a control group should be performed.