bluuebunny/crossref_metadata_2025 huggingface dataset:
Milk casein prevents inactivation effect of black tea galloylated theaflavins on SARS-CoV-2 in vitro
Authors: Ohgitani Eriko , Shin-Ya Masaharu , Ichitani Masaki , Kobayashi Makoto , Takihara Takanobu , Saito Motoki , Kinugasa Hitoshi , Mazda Osam
Published: September 2021

Repeated emergence of highly contagious and potentially immune-evading variant SARS-CoV-2 is posing global health and socioeconomical threats. For suppression of the spread of the virus infection among people, a procedure to inactivate virus in saliva may be useful, because saliva of infected persons is the major origin of droplets and aerosols that mediate viral transmission to nearby persons. We previously reported that SARS-CoV-2 is rapidly and remarkably inactivated by treatment in vitro with tea including green tea, roasted green tea, oolong tea and black tea. Tea catechin-derived compounds including theaflavins (TFs) with (a) galloyl moiety(ies) showed this activity. Although black tea is popularly consumed worldwide, a lot of people consume it with sugar, milk, lemon juice, and so on. But it has not been determined whether these ingredients may influence the inactivation effect of black tea against SARS-CoV-2. Moreover, it has not been revealed whether black tea is capable of inactivating variant viruses such as delta variant. Here we examined the effect of black tea on some variants in the presence or absence of sugar, milk, and lemon juice in vitro. Black tea and galloylated TFs remarkably inactivated alpha, gamma, delta and kappa variants. Intriguingly, an addition of milk but not sugar and lemon juice totally prevented black tea from inactivating alpha and delta variant viruses. The suppressive effect was also exerted by milk casein. These results suggest the possibility that intake of black tea without milk by infected persons may result in inactivation of the virus in saliva and attenuation of spread of SARS-CoV-2 to nearby persons through droplets. Clinical studies are required to investigate this possibility.
Comprehensive Assessment of Smoking and Sex Related Effects in Publicly Available Gene Expression Data
Authors: Flynn Emily , Chang Annie , Nugent Bridget M. , Altman Russ
Published: September 2021

Smoking greatly reduces life expectancy in both men and women, but with different patterns of morbidity. After adjusting for smoking history, women have higher risk of respiratory effects and diabetes from smoking, while men show greater mortality from smoking-related cancers. While many smoking-related sex differences have been documented, the underlying molecular mechanisms are not well understood. To date, identification of sex differences in response to smoking has been limited to a small number of studies and the resulting smoking-related effects require further validation. Publicly available gene expression data present a unique opportunity to examine molecular-level sex and smoking effects across many tissues and studies. We performed a systematic search to identify smoking-related studies from healthy tissue samples and found 31 separate studies as well as an additional group of overlapping studies that in total span 2,177 samples and 12 tissues. These samples and studies were overall male-biased. In smoking, while effects appeared to be somewhat tissue-specific and largely autosomal, we identified a small number of genes that were consistently differentially expressed across tissues, including AHRR and GZMH. We also identified one gene, AKR1C3, encoding an aldo-keto reductase, which showed strong opposite direction, smoking-related effects in blood and airway epithelium, with higher expression in airway epithelium and lower expression in blood of smokers versus non-smokers. By contrast, at similar significance thresholds, sex-related effects were entirely sex chromosomal and consistent across tissues, providing evidence of stronger effects of smoking than sex on autosomal expression. Due to sample size limitations, we only examined interaction effects in the largest study, where we identified 30 genes with sex differential effects in response to smoking, only one of which, CAPN9, replicated in a held-out analysis. Overall these results present a comprehensive analysis of smoking-related effects across tissues and an initial examination of sex differential smoking effects in public gene expression data.
Results from a conservation initiative for parrotfishes in the Colombian Caribbean
Authors: López-Angarita Juliana , Restrepo Orjuela María del Pilar , Peña Katherine Guzmán , Escobar Dairo
Published: September 2021

Parrotfish (Family Scaridae) are a family of herbivorous fishes crucial to coral reef health, particularly for Caribbean reefs due to their declining coral cover. However, despite parrotfish are fully protected in some countries, they are still heavy fished in most of their Caribbean range. The consequences of this targeted fishery in the Colombian Caribbean are not fully understood due to a lack of local conservation and management resources. This research aimed to evaluate and enhance the conservation status and protection of parrotfish among local communities in the National Natural Park Corales del Rosario and San Bernardo. Underwater visual census surveys (UVC) were undertaken to evaluate reef fish community structure, and participatory education campaigns and activities were carried out with local communities to raise awareness about parrotfish ecology and their functional role in conserving Caribbean coral reef ecosystems of Colombia. UVC showed parrotfish to be dominant in the fish community, yet there was evidence of exploitation of large adults by selective fishing. Conflicts exist between the community and environmental authorities because fishing regulations are not clear, and the level of enforcement is insufficient. Parrotfish are sold to tourists, as ‘red snapper’ to fulfil high seafood demand since commercially valuable fish are now scarce. However, following intensive awareness-raising activities developed as part of this study, the community has started to recognize the vital ecological role of parrotfish in coral reef systems, and are suggesting a redrafting of fishing legislation by the environmental authorities, in order to recognise and incorporate the traditional fishing rights of human communities living within the MPA. Lobbying for the protection of parrotfish and inclusion of local communities in decision-making will take time, but this research represents the crucial first steps towards sustainable practice and cooperative alliances in the Colombian Caribbean.
3D U-Net improves automatic brain extraction for isotropic rat brain MRI data
Authors: Hsu Li-Ming , Wang Shuai , Walton Lindsay , Wang Tzu-Wen Winnie , Lee Sung-Ho , Shih Yen-Yu Ian
Published: September 2021

Brain extraction is a critical pre-processing step in brain magnetic resonance imaging (MRI) analytical pipelines. In rodents, this is often achieved by manually editing brain masks slice-by-slice, a time-consuming task where workloads increase with higher spatial resolution datasets. We recently demonstrated successful automatic brain extraction via a deep-learning-based framework, U-Net, using 2D convolutions. However, such an approach cannot make use of the rich 3D spatial-context information from volumetric MRI data. In this study, we advanced our previously proposed U-Net architecture by replacing all 2D operations with their 3D counterparts and created a 3D U-Net framework. We trained and validated our model using a recently released CAMRI rat brain database acquired at isotropic spatial resolution, including T2-weighted turbo-spin-echo structural MRI and T2*-weighted echo-planar-imaging functional MRI. The performance of our 3D U-Net model was compared with existing rodent brain extraction tools, including Rapid Automatic Tissue Segmentation (RATS), Pulse-Coupled Neural Network (PCNN), SHape descriptor selected External Regions after Morphologically filtering (SHERM), and our previously proposed 2D U-Net model. 3D U-Net demonstrated superior performance in Dice, Jaccard, Hausdorff distance, and sensitivity. Additionally, we demonstrated the reliability of 3D U-Net under various noise levels, evaluated the optimal training sample sizes, and disseminated all source codes publicly, with a hope that this approach will benefit rodent MRI research community.

Significant methodological contribution

We proposed a deep-learning-based framework to automatically identify the rodent brain boundaries in MRI. With a fully 3D convolutional network model, 3D U-Net, our proposed method demonstrated improved performance compared to current automatic brain extraction methods, as shown in several qualitative metrics (Dice, Jaccard, PPV, SEN, and Hausdorff). We trust that this tool will avoid human bias and streamline pre-processing steps during 3D high resolution rodent brain MRI data analysis. The software developed herein has been disseminated freely to the community.
Selective Display of a Chemoattractant Agonist on Cancer Cells Activates the Formyl Peptide Receptor 1 on Immune Cells
Authors: Sikorski Eden L. , Wehr Janessa , Ferraro Noel J. , Pires Marcos M. , Thévenin Damien
Published: September 2021

Current immunotherapeutics often work by directing components of the immune system to recognize biomarkers on the surface of cancer cells to generate an immune response. However, variable changes in biomarker distribution and expression can result in uneven patient response. The development of a more universal tumor-homing strategy has the potential to improve selectivity and extend therapy to cancers with decreased expression or absence of specific biomarkers. Here, we designed a bifunctional agent that exploits the inherent acidic microenvironment of most solid tumors to selectively graft the surface of cancer cells with a formyl peptide receptor ligand (FPRL). Our approach is based on the pH(Low) Insertion Peptide (pHLIP), a unique peptide that selectively targets tumorsin vivoby anchoring onto cancer cells in a pH-dependent manner. We establish that selectively remodeling cancer cells with a pHLIP-based FPRL activates formyl peptide receptors on recruited immune cells, potentially initiating an immune response towards tumors.
TT-Mars: Structural Variants Assessment Based on Haplotype-resolved Assemblies
Authors: Yang Jianzhi , Chaisson Mark
Published: September 2021

Variant benchmarking is a critical component of method development and evaluating the accuracy of studies of genetic variation. Currently, the best approach to evaluate the accuracy of a callset is the comparison against a well curated gold standard. In repetitive regions of the genome it may be difficult to establish what is the truth for a call, for example when different alignment scoring metrics provide equally supported but different variant calls in on the same data. Here we provide an alternative approach, TT-Mars, that takes advantage of the recent production of high-quality haplotype-resolved genome assemblies by evaluating variant calls based on how well their call reflects the content of the assembly, rather than comparing calls themselves. We used TT-Mars to assess callsets from different SV discovery methods on multiple human genome samples and demonstrated that it is capable at accurately classifying true positive and false positive SVs. On the HG002 personal genome, TT-Mars recapitulates 96.0%-99.6% of the validations made using the Genome in a Bottle gold standard callset evaluated by truvari, and evaluates an additional 121-10,966 variants across different callsets. Furthermore, with a group of high-quality assemblies, TT-Mars can evaluate performance of SV calling algorithms as a distribution rather than a point estimate. We also compare TT-Mars against the long-read based validation tool, VaPoR, and when assembly-based variant calls produced by dipcall are used as a gold standard. Compared with VaPoR, TT-Mars analyzes more calls on a long read callset by assessing more short variant calls (< 100 bases), while requiring smaller input. Compared with validation using dipcall variants, TT-Mars analyzes 1,497-2,229 more calls on long read callsets and has favorable results when candidate calls are fragmented into multiple calls in alignments. TT-Mars is available at https://github.com/ChaissonLab/TT-Mars.git with accompanying assembly data and corresponding liftover files.
MARS: a tool for haplotype-resolved population-based structural variation detection
Authors: Zhang Lu , Sidow Arend , Zhou Xin
Published: September 2021

Motivation

Linked-reads enables genome-wide phased diploid assemblies. These haplotype-resolved assemblies allow us to genotype structural variants (SVs) with a high sensitivity and be able to further phase them. Yet, existing SV callers are designed for haploid genome assemblies only, and there is no tool to call SV from a large population of diploid assemblies which can define and refine SVs from a global view.

Results

We introduce MARS (Multiple Alignment-based Refinement of Svs) in linked-reads for the detection of the most common SV types - indels from diploid genome assemblies of a large population. We evaluated SVs from MARS based on Mendelian law of inheritance and PacBio HiFi reads and it achieved a high validation rate around 73%-87% for indels that we have selected from 34 assembled samples.

Availability

Source code and documentation are available on https://github.com/maiziex/MARS.

Contact

maizie.zhou@vanderbilt.edu

Supplementary information

Supplementary data are available at Bioinformatics online.
Overall vertical transmission of HCV, transmission net of clearance, and timing of transmission
Authors: Ades A E , Gordon Fabiana , Scott Karen , Collins Jeannie , Thorne Claire , Pembrey Lucy , Chappell Elizabeth , Mariné-Barjoan Eugènia , Butler Karina , Indolfi Giuseppe , Gibb Diana M , Judd Ali
Published: September 2021

Background

It is widely accepted that the risk of HCV vertical transmission (VT) is 5-6% in mono-infected women, and that 25-40% of HCV infection clears spontaneously within 5 years. However, VT and clearance rates have not been estimated from the same datasets, and there is a lack of information on VT rates “net” of clearance.

Methods

We re-analysed data on 1749 children in 3 prospective cohorts to obtain coherent estimates of overall VT rate and VT rates “net” of clearance at different ages. Clearance rates were used to impute the proportion of uninfected children who had been infected and then cleared before testing negative. The proportion of transmission early in utero, late in utero and at delivery was estimated from data on the proportion of RNA positives in samples tested within three days of birth, and differences between elective caesarean and non-elective caesarean deliveries.

Findings

Overall VT rates were 7.2% (95% credible interval 5.6-8.9) in mothers who were HIV negative and 12.1% (8.6-16.8) in HIV-co-infected women. The corresponding rates net of clearance at 5 years were 2.4% (1.1-4.1) and 4.1% (1.7-7.3). We estimated that 24.8% (12.1-40.8) of infections occur early in utero, 66.0% (42.5-83.3) later in utero, and 9.3% (0.5-30.6) during delivery.

Conclusion

Overall VT rates are about 24% higher than previously assumed, but the risk of infection persisting beyond age 5 years is about 38% lower. The results can inform design of trials of to prevent or treat pediatric HCV infection, and strategies to manage children exposed in utero.

Key points

Taking account of infections that would have cleared spontaneously before detection, the rate of HCV vertical transmission is 7.2% (95%CrI 5.6-8.9) in mono-infected women, but transmission “net” of clearance is 3.1% (1.8-4.4) at 3 years, and 2.4% (1.1-4.1) at 5.
Is there an association between daytime napping, cognitive function and brain volume? A Mendelian randomisation study in the UK Biobank
Authors: Paz Valentina , Dashti Hassan S. , Garfield Victoria
Published: September 2021

Daytime napping has been associated with cognitive function and brain health in observational studies. However, it remains elusive whether these associations are causal. Using Mendelian randomisation (MR), we studied the relationship between habitual daytime napping and cognitive/structural brain outcomes. Data were from UK Biobank (UKB) (maximum n= 378 932; mean age= 57 years). Our exposure (daytime napping) was instrumented using 92 previously identified genome-wide, independent genetic variants (single-nucleotide polymorphisms, SNPs). Our cognitive outcomes were reaction time and visual memory; our neuroimaging outcomes were total brain volume and hippocampal volume (cm3). Inverse-variance weighted (IVW) MR was implemented, with sensitivity analyses including MR-Egger and the Weighted Median Estimator for horizontal pleiotropy. We also tested different daytime napping instruments (47 SNPs, 86 SNPs and 17 SNPs) to ensure the robustness of our results. Our main MR analysis (IVW) showed an association between genetic liability to habitual daytime napping and larger total brain volume (unstandardised ß=15.80 cm3, 95% confidence interval (CI)=0.25; 31.34), but not hippocampal volume (ß=-0.03 cm3, 95%CI=-0.13; 0.06). No associations were found between daytime napping and reaction time (expß=1.01, 95%CI=1.00; 1.03), or visual memory (expß=0.99, 95%CI=0.94; 1.05). Additional analyses with 47 SNPs (adjusted for excessive daytime sleepiness), 86 SNPs (excluding sleep apnoea) and 17 SNPs (no sample overlap with UKB) were largely consistent with our main findings. MR-Egger and Weighted Median Estimator approaches showed no evidence of horizontal pleiotropy. Overall, we observed evidence of an association between genetically-instrumented daytime napping and larger total brain volume, but no evidence of an association between habitual daytime napping and hippocampal volume, reaction time or visual memory. Future studies could focus on the associations between napping and other cognitive/brain outcomes, as well as replication of these findings using other datasets and methods.

Key Messages

Daytime napping has been linked with cognitive function and brain health in observational studies, but whether these links are causal remains elusive.

Using Mendelian randomisation, we investigated the potential causal role of habitual daytime napping on cognitive and neuroimaging outcomes.

We observed evidence of a modest causal association between habitual daytime napping and larger total brain volume, but not enough evidence to support associations with hippocampal volume, reaction time or visual memory.
A brief analysis of the COVID-19 death data in Malaysia
Authors: Arifin Wan Nor , Musa Kamarul Imran , Hanis Tengku Muhammad , Rodzlan Hasani Wan Shakira , Che Nawi Che Muhammad Nur Hidayat , Ershad Ahmad Khan Erwan , Suliman Mohd Azmi , Termizi Sahrol Azmi , Ab Aziz Wira Alfatah
Published: September 2021

In December 2019, the first cases of Coronavirus Disease 2019 (COVID-19) were detected in Wuhan, China. Since then, COVID-19 begun to spread rapidly all over the world. On March 11, 2020, the World Health Organisation declared COVID-19 a pandemic. As of September 7, 2021, there were over 220 million confirmed COVID-19 cases globally, with more than 4.6 million deaths. Malaysia reported 2,067,327 confirmed cases with 22,743 deaths. Given the severity of the pandemic, the Ministry of Health Malaysia has stepped up in its efforts in handling the pandemic locally by sharing the COVID-19 related data on the GitHub, enabling transparent data sharing. This enables timely data analysis and quick decision to better understand the COVID-19 situation in this country. This article aims to provide a quick analysis of the death and vaccination data provided by the Malaysian Ministry of Health and to provide useful insight into the analysis.
SARS-CoV-2 nucleocapsid antigen in urine of hospitalized patients with Covid-19
Authors: Veyrenche N , Pisoni A , Debiesse S , Bollore K , Bedin AS , Makinson A , Niel C , Alcocer-Cordellat C , Mondain AM , Le Moing V , Van de Perre P , Tuaillon E
Published: September 2021

Introduction

SARS-CoV-2 nucleocapsid antigen (N-Ag) can be detected in the blood of patients with Covid-19. In this study, we used a highly sensitive and specific nucleocapsid-Ag assay to explore the presence of N-Ag in urine during the course of Covid-19, and explore its relationship with the severity of the disease.

Material and Methods

Urine and blood samples were collected from 82 patients with a SARS-CoV-2 infection proven by PCR and included in the COVIDotheque. We explored the presence of N-Ag in urine and blood using the AAZ N-Ag test, studied the kinetics of the marker according to the time since the onset of symptoms and evaluated the association between N-Ag levels, clinical severity and inflammation.

Results

In the first and second weeks of Covid-19, hospitalized patients tested positive for urinary N-Ag (81.25% and 71.79%, respectively) and blood N-Ag (93.75% and 94.87%, respectively). N-Ag levels in urine and blood were moderately correlated with the number of days after the onset of symptoms (r=-0.43, p<0.0001; r=-0.55 p<0.0001, respectively). The follow up of seven SARS-CoV-2 infected patients confirmed the waning of N-Ag in urine and blood over the course of the disease. High urinary N-Ag levels were associated with the absence of SARS-CoV-2 nucleocapsid-IgG (N-IgG), admission in intensive care units, high C-reactive protein levels, lymphopenia, eosinopenia, and high lactate dehydrogenase (LDH).

Conclusion

Our study demonstrate that N-Ag is present in the urine of patients hospitalized in the early phase of Covid-19. As a direct marker of SARS-CoV-2, urinary N-Ag reflects the dissemination of viral compounds in the body. Urine N-Ag is a promising marker to predict adverse evolution of SARS-CoV-2 infections.
Initial Analysis of Viral Dynamics and Circulating Viral Variants During the mRNA-1273 Phase 3 COVE Trial
Authors: Pajon Rolando , Paila Yamuna D. , Girard Bethany , Dixon Groves , Kacena Katherine , Baden Lindsey R. , Sahly Hana M. El , Essink Brandon , Mullane Kathleen M , Frank Ian , Denhan Douglas , Kerwin Edward , Zhao Xiaoping , Ding Baoyu , Deng Weiping , Tomassini Joanne E , Zhou Honghong , Leav Brett , Schödel Florian
Published: September 2021

This analysis assessed the impact of mRNA-1273 vaccination on the viral dynamics of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in the ongoing Coronavirus Efficacy (COVE) trial. mRNA-1273 vaccination significantly reduced SARS-CoV-2 viral copy number (95% confidence interval [CI]) by 100-fold on the day of diagnosis (4.1 [3.4-4.8] versus placebo (6.2 [6.0-6.4] log10 copies/ml). Median times to undetectable viral copies were 4 days for mRNA-1273 and 7 for placebo. Vaccination also reduced the burden of disease and infection scores. Vaccine efficacies (95% CI) during the trial against SARS-CoV-2 variants circulating in the US were 82.4% (40.4%-94.8%) for Epsilon and Gamma, and 81.2% (36.1%-94.5%) for the Epsilon variants. The detection of other respiratory viruses during the trial was similar between groups. In those who became SARS-CoV-2 infected, the reduction of viral load after mRNA-1273 vaccination is potentially correlated to the risk of transmission, which has not been assessed in this study.
How a Positive COVID-19 diagnosis affects the physical, social and psychological wellbeing of people in the United Arab Emirates? An Explorative Qualitative Study
Authors: AlKuwaiti Mouza , Hamada Bayan Abu , AlJeneibi Noof , Paulo Marília Silva , Elbarazi Iffat
Published: September 2021

Purpose

Exploring the effect of COVID-19 diagnosis on the individual has not been explored through an exploratory qualitative approach. This study aims to explore the physical, social, and psychological impact of the diagnosis on the individual through online interviews.

Method

A qualitative study approach using online interviews was conducted. A sample of 30 participants of different age groups, gender, and nationalities were interviewed to explore the impact of a positive COVID-19 diagnosis on their physical, mental, social, psychological health, and lifestyle practices. An interview guide was created based on coping strategy model and conceptual framework of coping strategies. All interviews were recorded then transcribed after obtaining written consent from participants. Ethics approval was obtained from the United Arab Emirates Social Science Ethics Committee. NVIVO software was used for thematic analysis based on both identified coping models to highlight the most important feelings and emotions, family support, and changes in lifestyle that may impact the COVID-19 patient and family. Researchers identified the themes separately and then verified themes in one meeting.

Results

Major themes include the physical effects, social effects, psychological effects, spiritual effects, and lifestyle effects. Emerging themes include coping mechanisms, trust in authorities and health care system, appreciation of the role of the government, conspiracy theories, and media roles. Those who had a positive infection towards the end of 2020 and in 2021 described having fewer negative emotions and better psychological resilience.

Conclusion

The findings of this study indicate that people diagnosed with COVID-19 have perceived a very good support in terms of their physical health from the government and health authorities, but require social, psychological, and educational support during the infection period and post-recovery.
Risk of cardiovascular disease after a diagnosis of common psychiatric disorders: a matched cohort study of disease susceptibility and progression trajectory in the UK Biobank
Authors: Han Xin , Zeng Yu , Shang Yannan , Hu Yao , Hou Can , Yang Huazhen , Chen Wenwen , Ying Zhiye , Sun Yajing , Qu Yuanyuan , Wang Junren , Zhang Wei , Fang Fang , Valdimarsdóttir Unnur A. , Song Huan
Published: September 2021

Background

Whether associations between psychiatric disorders and cardiovascular diseases (CVDs) can be modified by disease susceptibility and the temporal pattern of these associated CVDs remain unknown.

Methods

We conducted a matched cohort study of UK Biobank including 35,227 patients with common psychiatry disorders (anxiety, depression, and stress-related disorders) between 1997 and 2019, together with 176,135 sex- and birth year-individually matched unexposed individuals.

Results

The mean age at the index date was 51.76 years, and 66.0% of participants were females. During a mean follow-up of 11.94 years, we observed an elevated risk of CVD among patients with studied psychiatry disorders, compared with matched unexposed individuals (hazard ratios [HRs]=1.16, 95% confidence interval [CI]: 1.14-1.19), especially during the first six months of follow-up (HR=1.59 [1.42-1.79]). To assess the modification role of disease susceptibility, we stratified analyses by family history of CVD and by CVD PRS, which obtained similar estimates between subgroups with different susceptibilities to CVD. We conducted trajectory analysis to visualize the temporal pattern of CVDs after common psychiatry disorders, identifying primary hypertension, acute myocardial infarction, and stroke as three main intermediate steps leading to further increased risk of other CVDs.

Conclusions

The association between common psychiatry disorders and subsequent CVD is not modified by predisposition to CVD. Hypertension, acute myocardial infarction, and stroke are three initial CVDs linking psychiatric disorders to other CVD squeals, highlighting a need of timely intervention on these targets to prevent further CVD squeals among all individuals with common psychiatric disorders.
Mutational signature profiling classifies subtypes of clinically different mismatch repair deficient tumors with a differential immunogenic response potential
Authors: Giner-Calabuig Mar , De Leon Seila , Wang Julian , Fehlmann Tara D , Ukaegbu Chinedu , Gibson Joanna , Fernandez Miren Alustiza , Pico Maria-Dolores , Alenda Cristina , Herraiz Maite , Carrillo-Palau Marta , Salces Inmaculada , Reyes Josep , Ortega Silvia P , Obrador Antònia , Cecchini Michael , Syngal Sapna , Stoffel Elena , Ellis Nathan A , Sweasy Joann , Jover Rodrigo , Llor Xavier , Xicola Rosa M
Published: September 2021

Background

Mismatch repair (MMR) deficiency is the hallmark of tumors from Lynch syndrome (LS), sporadicMLH1hypermethylated, and Lynch-like syndrome (LLS), but there is a lack of understanding of the variability in their mutational profiles based on clinical phenotypes. The aim of this study was to perform a molecular characterization to identify novel features that can impact tumor behavior and clinical management.

Methods

We tested 105 MMR-deficient colorectal cancer tumors (25 LS, 35 LLS, and 45 sporadic) for global exome microsatellite instability, cancer mutational signatures, mutational spectrum and neoepitope load.

Results

78% of tumors showed high contribution of MMR-deficient mutational signatures, high level of global exome microsatellite instability, loss of MLH1/PMS2 protein expression and included sporadic tumors. 22% of tumors showed weaker features of MMR deficiency, 73% lost MSH2/MSH6 expression and included half of LS and LLS tumors. Remarkably, 9% of all tumors lacked global exome microsatellite instability. Lastly, HLA-B07:02 could be triggering the neoantigen presentation in tumors that show the strongest contribution of MMR-deficient tumors.

Conclusions

Next-generation sequencing approaches allow for a granular molecular characterization of MMR-deficient tumors, which can be essential to properly diagnose and treat patients with these tumors in the setting of personalized medicine.
M-Phase oscillations in PP1 activity are essential for accurate progression through mammalian oocyte meiosis
Authors: Camlin Nicole J. , Venkatachalam Ilakkiya , Evans Janice P.
Published: September 2021

Tightly controlled fluctuations in kinase and phosphatase activity play important roles in regulating M-Phase transitions. Protein Phosphatase 1 (PP1) is one of these phosphatases, with oscillations in PP1 activity driving mitotic M-Phase. Evidence from a variety of experimental systems also points to roles in meiosis. Here we report that PP1 is important for M-Phase transitions through mouse oocyte meiosis. We employed a unique small-molecule approach to inhibit or activate PP1 at distinct phases of mouse oocyte meiosis. These studies show that temporal control of PP1 activity is essential for G2/M transition, metaphase I/anaphase I transition, and the formation of a normal metaphase II oocyte. Our data also reveal that inappropriate activation of PP1 is more deleterious at G2/M transition than at prometaphase I-to-metaphase I, and that an active pool of PP1 during prometaphase is vital for metaphase I/anaphase I transition and metaphase II chromosome alignment. Taken together, these results establish that loss of oscillations in PP1 activity causes a range of severe meiotic defects, pointing to essential roles for PP1 in female fertility, and more broadly, M-Phase regulation.

Summary statement

Altering the normal cyclical activity of the phosphatase PP1 in oocytes causes a range of severe meiotic defects, pointing to essential roles for PP1 in M-Phase entry, progression, and exit.
Key features of the genetic architecture and evolution of host-microbe interactions revealed by high-resolution genetic mapping of the mucosa-associated gut microbiome in hybrid mice
Authors: Doms Shauni , Fokt Hanna , Rühlemann Malte Christoph , Chung Cecilia J. , Künstner Axel , Ibrahim Saleh , Franke Andre , Turner Leslie M. , Baines John F.
Published: September 2021

Determining the forces that shape diversity in host-associated bacterial communities is critical to understanding the evolution and maintenance of metaorganisms. To gain deeper understanding of the role of host genetics in shaping gut microbial traits, we employed a powerful genetic mapping approach using inbred lines derived from the hybrid zone of two incipient house mouse species. Further, we uniquely performed our analysis on microbial traits measured at the gut mucosal interface, which is in more direct contact with host cells and the immune system. A high number of mucosa-associated bacterial taxa have significant heritability estimates; heritabilities are greater for 16S rRNA transcript-compared to gene copy-based traits, and interestingly, are positively correlated with cospeciation rate estimates. Genomewide association mapping identifies 443 loci influencing 123 taxa, with narrow genomic intervals pinpointing promising candidate genes and pathways. Importantly, we identified an enrichment of candidate genes associated with several human diseases, including inflammatory bowel disease, and functional categories including innate immunity and G-protein-coupled receptors. These results highlight key features of the genetic architecture of mammalian host-microbe interactions and how they diverge as new species form.
Molecular insights into the inhibition of glutamate dehydrogenase (GDH) by the dicarboxylic acid metabolites
Authors: Godsora Barsa Kanchan Jyotshna , Prakash Prem , Punekar Narayan S. , Bhaumik Prasenjit
Published: September 2021

Glutamate dehydrogenase (GDH) is a salient metabolic enzyme which catalyzes the NAD+ - or NADP+-dependent reversible conversion of α-ketoglutarate (AKG) to L-glutamate; and thereby connects the carbon and nitrogen metabolism cycles in all living organisms. The function of GDH is extensively regulated by both metabolites (citrate, succinate, etc.) and non-metabolites (ATP, NADH, etc.) but sufficient molecular evidences are lacking to rationalize the inhibitory effects by the metabolites. We have expressed and purified NADP+-dependent Aspergillus terreus GDH (AtGDH) in recombinant form. Succinate, malonate, maleate, fumarate and tartrate independently inhibit the activity of AtGDH to different extents. The crystal structures of AtGDH complexed with the dicarboxylic acid metabolites and the coenzyme NADPH have been determined. Although AtGDH structures are not complexed with substrate; surprisingly, they acquire super closed conformation like previously reported for substrate and coenzyme bound catalytically competent Aspergillus niger GDH (AnGDH). These dicarboxylic acid metabolites partially occupy the same binding pocket as substrate; but interact with varying polar interactions and the coenzyme NADPH binds to the Domain-II of AtGDH. The low inhibition potential of tartrate as compared to other dicarboxylic acid metabolites is due to its weaker interactions of carboxylate groups with AtGDH. Our results suggest that the length of carbon skeleton and positioning of the carboxylate groups of inhibitors between two conserved lysine residues at the GDH active site might be the determinants of their inhibitory potency. Molecular details on the dicarboxylic acid metabolites bound AtGDH active site architecture presented here would be applicable to GDHs in general.
Unidirectional Single-File Transport of Full-Length Proteins Through a Nanopore
Authors: Yu Luning , Kang Xinqi , Li Fanjun , Mehrafrooz Behzad , Makhamreh Amr , Fallahi Ali , Foster Joshua C. , Aksimentiev Aleksei , Chen Min , Wanunu Meni
Published: September 2021

Nanopore sensors could revolutionize single-molecule proteomics by providing a means for identification of known proteins through fingerprinting or by de novo sequencing. However, the complex chemical and physical properties of proteins present multiple challenges to the conventional nanopore sensing method, predominantly, the single-file threading of a protein chain into a nanopore and its transport through it. Herein we describe a general approach for realizing unidirectional transport of full-length proteins through nanopores. We show that the combination of a chemically resistant biological nanopore platform and a high concentration guanidinium chloride buffer enables protein unfolding and unidirectional transport through a pore, propelled by an electroosmotic effect that largely owes to the guanidinium chloride presence. The uniform and slow (~10 µs/amino acid) single-file transport, when combined with supervised machine learning of the electrical current signatures obtained, allows us to use to discern the protein threading orientation and identity. In conjunction with a method for tail-modification of native proteins and higher-resolution nanopores, our approach could offer a path towards direct single-molecule protein fingerprinting without the requirement of a motor enzyme.
Comprehensive analysis of mutational signatures in pediatric cancers
Authors: Thatikonda Venu , Islam S. M. Ashiqul , Jones Barbara C. , Gröbner Susanne N. , Warsow Gregor , Hutter Barbara , Huebschmann Daniel , Fröhling Stefan , Blattner-Johnson Mirjam , Jones David T.W. , Alexandrov Ludmil B. , Pfister Stefan M. , Jäger Natalie
Published: September 2021

Analysis of mutational signatures can reveal the underlying molecular mechanisms of the processes that have imprinted the somatic mutations found in a cancer genome. Here, we present a pan-cancer mutational signatures analysis of single base substitutions (SBS) and small insertion and deletions (ID) in pediatric cancers encompassing 537 whole genome sequenced tumors from 20 molecularly defined cancer subtypes. We identified only a small number of mutational signatures active in pediatric cancers when compared to the previously analyzed adult cancers. Further, we report a significant difference in the proportion of pediatric tumors which show homologous recombination repair defect signature SBS3 compared to prior analyses. Correlating genomic alterations with signature activities, we identified an association of TP53 mutation status with substitution signatures SBS2, SBS8, SBS13 and indel signatures ID2 and ID9, as well as chromothripsis associated with SBS8, SBS40 and ID9. This analysis provides a systematic overview of COSMIC v.3 SBS and ID mutational signatures active across pediatric cancers, which is highly relevant for understanding tumor biology as well as enabling future research in defining biomarkers of treatment response.
Identification of distinct characteristics of antibiofilm peptides and prospection of diverse sources for efficacious sequences
Authors: Bose Bipasa , Downey Taylor , Ramasubramanian Anand K. , Anastasiu David C.
Published: September 2021

A majority of microbial infections are associated with biofilms. Targeting biofilms is considered an effective strategy to limit microbial virulence while minimizing the development of antibiotic resistance. Towards this need, antibiofilm peptides are an attractive arsenal since they are bestowed with properties orthogonal to small molecule drugs. In this work, we developed machine learning models to identify the distinguishing characteristics of known antibiofilm peptides, and to mine peptide databases from diverse habitats to classify new peptides with potential antibiofilm activities. Additionally, we used the reported minimum inhibitory/eradication concentration (MBIC/MBEC) of the antibiofilm peptides to create a regression model on top of the classification model to predict the effectiveness of new antibiofilm peptides. We used a positive dataset containing 242 antibiofilm peptides, and a negative dataset which, unlike previous datasets, contains peptides that are likely to promote biofilm formation. Our model achieved a classification accuracy greater than 98% and harmonic mean of precision-recall (F1) and Matthews correlation coefficient (MCC) scores greater than 0.90; the regression model achieved an MCC score greater than 0.81. We utilized our classification-regression pipeline to evaluate 135,015 peptides from diverse sources and identified antibiofilm peptide candidates that are efficacious against preformed biofilms at micromolar concentrations. Structural analysis of the top 37 hits revealed a larger distribution of helices and coils than sheets. Sequence alignment of these hits with known antibiofilm peptides revealed that, while some of the hits showed relatively high sequence similarity with known peptides, some others did not indicate the presence of antibiofilm activity in novel sources or sequences. Further, some of the hits had previously recognized therapeutic properties or host defense traits suggestive of drug repurposing applications. Taken together, this work demonstrates a newin silicioapproach to predicting antibiofilm efficacy, and identifies promising new candidates for biofilm eradication.
The relationships between women’s reproductive factors: a Mendelian randomization analysis
Authors: Prince Claire , Sharp Gemma C , Howe Laura D , Fraser Abigail , Richmond Rebecca C
Published: September 2021

Background

Women’s reproductive factors include their age at menarche and menopause, the age at which they start and stop having children, and the number of children they have. Studies that have linked these factors with disease risk have largely investigated individual reproductive factors and have not considered the genetic correlation and total interplay that may occur between them. This study aimed to investigate the nature of the relationships between eight female reproductive factors.

Methods

We used data from the UK Biobank and genetic consortia with data available for the following reproductive factors: age at menarche, age at menopause, age at first birth, age at last birth, number of births, being parous, age at first sex and lifetime number of sexual partners. Linkage disequilibrium score regression (LDSC) was performed to investigate the genetic correlation between reproductive factors. We then applied Mendelian randomization (MR) methods to estimate the causal relationships between these factors. Sensitivity analyses were used to investigate directionality of the effects, test for evidence of pleiotropy and account for sample overlap.

Results

LDSC indicated that most reproductive factors are genetically correlated (rg range: |0.06 – 0.94|), though there was little evidence for genetic correlations between lifetime number of sexual partners and age at last birth, number of births and ever being parous (rg < 0.01). MR revealed potential causal relationships between many reproductive factors, including later age at menarche (1 SD increase) leading to a later age at first sexual intercourse (Beta (B)=0.09 SD, 95% confidence intervals (CI)=0.06,0.11), age at first birth (B=0.07 SD, CI=0.04,0.10), age at last birth (B=0.06 SD, CI=0.04,0.09) and age at menopause (B=0.06 SD, CI=0.03,0.10). Later age at first birth was found to lead to a later age at menopause (B=0.21 SD, CI=0.13,0.29), age at last birth (B=0.72 SD, CI=0.67,0.77) and a lower number of births (B=-0.38 SD, CI=-0.44,-0.32).

Conclusion

This study presents evidence that women’s reproductive factors are genetically correlated and causally related. Future studies examining the health sequelae of reproductive factors should consider a woman’s entire reproductive history, including the causal interplay between reproductive factors.
World Science against COVID-19: Gender and Geographical Distribution of Research
Authors: González-Álvarez Julio
Published: September 2021

In just a year and a half, an enormous volume of scientific research has been generated throughout the world to study a virus/disease that turned into a pandemic. All the articles on COVID-19 or SARS-CoV-2 included in the SCI-EXPANDED database (Web of Science), signed by more than a third of a million of authorships, were analyzed. Gender could be identified in 92% of the authorships. Women represent 40% of all authors, a similar proportion as first authors, but just 30% as last/senior authors. The pattern of collaboration shows an interesting finding: when a woman signs as a first or last/senior author, the article byline approximates gender parity

According to the corresponding address, the USA shares 22.8% of all world articles, followed by China (14.4%), Italy (7.8%), the UK (5.8%), India (4.2%), Spain (3.8%), Germany (3.6%), France (2.9%), Turkey (2.5%), and Canada (2.4%).

Despite their short lives, the papers received an average of 11 citations. The high impact of papers from China is striking (25.1 citations; the UK, 12.4 citations; the USA, 11.3 citations), presumably because the disease emerged in China, and the first publications (very cited) came from there.
Metabolic snapshot of plasma samples reveals new pathways implicated in SARS-CoV-2 pathogenesis
Authors: Albóniga Oihane E. , Jimйnez Daniel , Sбnchez-Conde Matilde , Vizcarra Pilar , Ron Raquel , Herrera Sabina , Martнnez-Sanz Javier , Moreno Elena , Moreno Santiago , Barbas Coral , Serrano-Villar Sergio
Published: September 2021

Despite of the scientific and human efforts to understand COVID-19, there are questions still unanswered. Variations in the metabolic reaction to SARS-CoV-2 infection could explain the striking differences in the susceptibility to infection and the risk of severe disease. Here, we used untargeted metabolomics to examine novel metabolic pathways related to SARS-CoV-2 susceptibility and COVID-19 clinical severity using capillary electrophoresis coupled to a time-of-flight mass spectrometer (CE-TOF-MS) in plasma samples. We included 27 patients with confirmed COVID-19 early after symptom onset who were prospectively followed and 29 healthcare workers heavily exposed to SARS-CoV-2 but with low susceptibility to infection (‘nonsusceptible’). We found that the metabolite profile was predictive of the study group. We identified a total of 55 metabolites as biomarkers of SARS-CoV-2 susceptibility or COVID-19 clinical severity. We report the discovery of new plasma biomarkers for COVID-19 that provide mechanistic explanations for the clinical consequences of SARS-CoV-2, including mitochondrial and liver dysfunction as a consequence of hypoxemia (citrulline, citrate, and BAIBA), energy production and amino acid catabolism (L-glycine, L-alanine, L-serine, L-proline, L-aspartic acid and L-histidine), endothelial dysfunction and thrombosis (citrulline, L-ADMA, 2-AB, and Neu5Ac), and we found interconnections between these pathways. In summary, in this first report of the metabolomic profile of individuals with severe COVID-19 and SARS-CoV-2 susceptibility by CE-MS, we define several metabolic pathways implicated in SARS-CoV-2 susceptibility and COVID-19 clinical progression that could be developed as biomarkers of COVID-19.
Simultaneous measurement of pole figure and residual stress for polycrystalline thin films: ω–φ′ compensated grazing-incidence diffraction in side-inclination mode
Authors: Wang Xiaodong
Published: September 2021

A new grazing-incidence diffraction (GID) measurement geometry between in plane and out of plane is proposed. It is improved from the previous ω–φ compensated GID in side-inclination mode for measurement of residual stress in polycrystalline thin films [Wang & van Riessen (2017). Powder Diffr.
32, S9–S15]. Instead of keeping a constant azimuthal direction of the incident beam on the thin film sample, the current proposed variation maintains a constant azimuthal direction of the scattering vector projection on the thin film sample. The variation is named `ω–φ′ compensated GID in side-inclination mode' and enables d-spacing measurements along the same azimuthal direction. An Excel spreadsheet is included for readers to plan the measurement and to calculate the residual stress for the planned sample azimuthal direction. Anisotropic residual stresses of a polycrystalline NiFe thin film on an Si 001 substrate are measured by combining this method with phi rotations. Highly automated data analysis templates are developed using DIFFRAC.TOPAS v7 launch mode to calculate residual stress for all planned azimuthal directions sequentially. A pole figure file in simple text format is also generated from the same data set using DIFFRAC.TOPAS v7 launch mode, and can be directly imported into DIFFRAC.TEXTURE v4.1 for further texture analysis. Corrections for the incident-beam refraction have been implemented in both data analysis models.