bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of vaccination in reducing Hospital expenses, Mortality and Average length of stay among COVID-19 patients – a retrospective cohort study from India
Authors: Ramakrishnan Madhumathi , Subbarayan Prakash
Published: June 2021

Background & Aim

WHO listed vaccine hesitancy among the top 10 global threats to health and there are very few reports highlighting vaccine benefits against COVID-19. The aim of this study was to study the impact of vaccination on reducing the average length of stay (ALOS), intensive care unit (ICU) requirement, mortality and cost of the treatment among COVID-19 patients.

Methods

In this retrospective cohort study all the patients above 45 years who underwent treatment for COVID-19 were included. The data of patients treated pan India during the period March & April 2021 with the diagnosis of COVID-19, under health insurance cover, were extracted to study parameters like the ALOS, mortality, ICU requirement, total hospital expenses incurred and the vaccination status.

Results

Among 3820 patients with COVID-19, 3301 (86.4%) were unvaccinated while 519 (13.6%) were vaccinated. Among the unvaccinated the mean (s.d) ALOS was 7 days. Fourteen days after second dose of vaccination this was significantly less (p=0.01) at 4.9. The mean total hospital expense among the unvaccinated was Rs. 277850. Fourteen days after second dose of vaccination this was further less (p=0.001) at Rs. 217850. Among the unvaccinated population 291/3301 (8.8%) required ICU and this was significantly less (p=0.03) at 31/519 (6%) among the vaccinated. Among those who received two doses of vaccination it was further less at 1/33 (3%). The mortality among unvaccinated patients was 16/3301 (0.5%) while there was no mortality among the vaccinated. Among those who received two doses of vaccination there was a 66% relative risk reduction in ICU stay and 81% relative risk reduction in mortality.

Conclusions

There was a significant reduction in ALOS, ICU requirement, mortality & treatment cost in patients who had completed two doses of vaccination. These findings may be used in motivating public and promoting vaccination drive.
Factors affecting the transmission of SARS-CoV-2 in school settings
Authors: Yuan Haokun , Reynolds Connor , Ng Sydney , Yang Wan
Published: June 2021

Background

Several studies have reported SARS-CoV-2 outbreaks in schools, with a wide range of secondary attack rate (SAR; range: 0-100%). We aimed to examine key risk factors to better understand SARS-CoV-2 transmission in schools.

Methods

We collected records of 39 SARS-CoV-2 school outbreaks globally published through July 2021 and compiled information on hypothesized risk factors. We utilized the directed acyclic graph (DAG) to conceptualize risk mechanisms, used logistic regression to examine each risk-factor group, and further built multi-risk models.

Results

The best-fit model showed that the intensity of concurrent community transmission (adjusted odds ratio [aOR]: 1.2, 95% CI: 1.17 – 1.24, for each increase of 1 case per 10,000 persons per week), individualism (aOR: 1.72, 95% CI: 1.19 – 2.5, above vs. below the median) were associated higher risk, whereas preventive measures (aOR: 0.22, 95% CI: 0.17 – 0.29, distancing and masking vs. none) and higher population immunity (aOR: 0.28, 95% CI: 0.22 – 0.35) were associated with lower risk of SARS-CoV-2 transmission in schools. Compared to students in pre-schools, the aOR was 0.35 (95% CI: 0.23 – 0.54) for students in primary schools and 1.3 (95% CI: 0.9 – 1.88) for students in high schools.

Conclusions

Preventive measures in schools (e.g. social distancing and mask-wearing) and communal efforts to lower transmission and increase vaccination uptake (i.e. vaccine-induced population immunity) in the community should be taken to collectively reduce transmission and protect children in schools. Flexible reopening policies may be considered for different levels of schools given their risk differences.
New insights from the combined discrimination of modern/ancient genome-wide shared alleles and haplotypes: Differentiated demographic history reconstruction of Tai-Kadai and Sinitic people in South China
Authors: Wang Mengge , He Guanglin , Zou Xing , Chen Pengyu , Wang Zheng , Tang Renkuan , Yang Xiaomin , Chen Jing , Yang Meiqing , Li Yingxiang , Liu Jing , Wang Fei , Zhao Jing , Guo Jianxin , Hu Rong , Wei Lan-Hai , Chen Gang , Yeh Hui-Yuan , Wang Chuan-Chao
Published: June 2021

Southern China was a region with mixed rice-millet farming during the Middle Neolithic period and also suggested to be the homeland of Tai-Kadai-speaking (TK) people. The archaeological evidence of animal and plant domestication has demonstrated that southern Chinese rice agriculturalists dispersed from the Yangtze River basin with the dissemination of TK, Austroasiatic (AA), Austronesian (AN) and Hmong-Mien (HM) languages. However, the formations of the inland TK-speaking people, central/southern Han Chinese and their relationships with Neolithic farmers from the Yangtze and Yellow Rivers (YR) basins are far from clear due to the limited sampling of South China. Here, we revealed the spatiotemporal demographic history of southern China by analyzing newly generated genome-wide data of 70 southeastern mainland TK speakers including Dong, Gelao and Bouyei and 45 southwestern Han Chinese together with comprehensive modern/ancient reference datasets. Southwest Han Chinese and Gelao demonstrated a closer genomic affinity to Neolithic YR farmers, while inland TKs (Dong and Bouyei) demonstrated a closer genomic affinity to coastal TK/AN-speaking islanders and Neolithic Yangtze farmers and their descendants. The shared genetic drift between inland TK/AN speaker highlighted a common origin of AN/TK groups, which may be descended from Tanshishan people or their predecessors (Xitoucun). Additionally, we found that inland TK/Sinitic could be modelled as an admixture of ancestral northern East Asian (ANEA) and ancestral southern East Asian (ASEA) sources with different proportions, in which the ANEA was phylogenetically closer to Neolithic millet farmers deriving from the YR Basin and the ASEA was phylogenetically closer to Coastal Neolithic-to-modern southern East Asians. Finally, we discovered genetic differentiation among TK people from southern China and Southeast Asia and obvious substructures between northern and southern inland Chinese TK people. The observed patterns of the spatiotemporal distribution of the northern and southern East Asian lineages in Central/southern China were also compatible with the scenario of bi-directional gene flow events from ANEA and ASEA. Conclusively, multiple lines of genomic evidence indicated millet farmers deriving from the YR basin and rice farmers deriving from the Yangtze River basin substantially contributed to the present-day mainland TK speakers and Central/southern Han Chinese, and formed the modern dual genetic admixture profile.
Dysphagic disorder in a cohort of COVID-19 patients: evaluation and evolution
Authors: Glotta Andrea , Galli Anna , Biggiogero Maira , Bona Giovanni , Saporito Andrea , Mauri Romano , Ceruti Samuele
Published: June 2021

Background

COVID-19 is a multisystem disease complicated by respiratory failure requiring sustanined mechanical ventilation (MV). Prolongued oro-tracheal intubation is associated to an increased risk of dysphagia and bronchial aspiration. Purpose of this study was to investigate swallowing disorders in critically ill COVID-19 patients.

Methods

This was a retrospective study analysing a consecutive cohort of COVID-19 patients admitted to the Intensive Care Unit (ICU) of our Hospital. Data concerning dysphagia were collected according to the Gugging Swallowing Screen (GUSS) and related to demographic characteristics, clinical data, ICU Length-Of-Stay (LOS) and MV parameters.

Results

From March 2 to April 30 2020, 31 consecutive critically ill COVID-19 patients admitted to ICU were evaluated by speech and language therapists (SLT). Twenty-five of them were on MV (61% through endotracheal tube and 19% through tracheostomy); median MV lenght was 11 days. Seventeen (54.8%) patients presented dysphagia; a correlation was found between first GUSS severity stratification and MV days (p < 0.001), ICU LOS (p < 0.001), age (p = 0.03) and tracheostomy (p = 0.042). No other correlations were found. At 16 days, 90% of patients had fully recovered; a significant improvement was registered especially during the first week (p < 0.001).

Conclusion

Compared to non-COVID-19 patiens, a higher rate of dysphagia was reported in COVID-19 patients, with a more rapid and complete recovery. A systematic early SLT evaluation of COVID-19 patients on MV may thus be useful to prevent dysphagia-related complications.
Integration of molecular inflammatory interactome analyses reveals dynamics of circulating cytokines and extracellular vesicle long non-coding RNAs and mRNAs in heroin addicts during acute and protracted withdrawal
Authors: Zhang Zunyue , Wu Hongjin , Peng Qingyan , Xie Zhenrong , Chen Fengrong , Ma Yuru , Zhang Yizhi , Zhou Yong , Yang Jiqing , Chen Cheng , Li Shaoyou , Zhang Yongjin , Wang Yuan , Xu Yu , Luo Huayou , Zhu Mei , Kuang Yiqun , Yu Juehua , Wang Kunhua
Published: June 2021

Heroin addiction and withdrawal influence multiple physiological functions, including immune responses, but the mechanism remains largely elusive. The objective of this study was to investigate the molecular inflammatory interactome, particularly the cytokines and transcriptome regulatory network in heroin addicts undergoing withdrawal, compared to healthy controls (HCs). Twenty-seven cytokines were simultaneously assessed in 41 heroin addicts, including 20 at the acute withdrawal (AW) stage and 21 at the protracted withdrawal (PW) stage, and 38 age- and gender-matched HCs. Disturbed T-helper(Th)1/Th2, Th1/Th17, and Th2/Th17 balances, characterized by reduced interleukin (IL)-2, elevated IL-4, IL-10, and IL-17A, but normal TNF-α, were present in the AW subjects. These imbalances were mostly restored to the baseline at the PW stage. However, the cytokines TNF-α, IL-2, IL-7, IL-10, and IL-17A remained dysregulated. This study also profiled exosomal long non-coding RNA (lncRNA) and mRNA in the plasma of heroin addicts, constructed co-expression gene regulation networks, and identified lncRNA- mRNA-pathway pairs specifically associated with alterations in cytokine profiles and Th1/Th2/Th17 imbalances. Altogether, a large amount of cytokine and exosomal lncRNA/mRNA expression profiling data relating to heroin withdrawal was obtained, providing a useful experimental and theoretical basis for further understanding of the pathogenic mechanisms of withdrawal symptoms in heroin addicts.
A Continuous Bayesian Model for the Stimulation COVID-19 Epidemic Dynamics
Authors: Xu Zhaobin , Zhang Hongmei , Niu Yonggang
Published: June 2021

It is of great theoretical and application value to accurately forecast the spreading dynamics of COVID-19 epidemic. We first proposed and established a Bayesian model to predict the epidemic spreading behavior. In this model, the infection probability matrix is estimated according to the individual contact frequency in certain population group. This infection probability matrix is highly correlated with population geographic distribution, population age structure and so on. This model can effectively avoid the prediction malfunction by using the traditional ordinary differential equation methods such as SIR (susceptible, infectious and recovered) model and so on. Meanwhile, it would forecast the epidemic distribution and predict the epidemic hot spots geographically at different time. According to the results revealed by Bayesian model, the effect of population geographical distribution should be considered in the prediction of epidemic situation, and there is no simple derivation relationship between the threshold of group immunity and the virus reproduction number R0. If we further consider the virus mutation effect and the antibody attenuation effect, with a large global population spatial distribution, it will be difficult for us to eliminate Covid-19 in a short time even with vaccination endeavor. Covid-19 may exist in human society for a long time, and the epidemic caused by re-infection is characterized by a wild-geometric && low-probability distribution with no epidemic hotspots.
The molecular basis of extensively drug-resistant Salmonella Typhi isolates from pediatric septicemia patients
Authors: Kim Chanmi , Latif Iqra , Neupane Durga P. , Lee Gi Young , Kwon Ryan S. , Batool Alia , Ahmed Qasim , Qamar Muhammad Usman , Song Jeongmin
Published: June 2021

Sepsis is a syndromic response to infections and is becoming an emerging threat to the public health sector, particularly in developing countries. Salmonella Typhi (S. Typhi), the cause of typhoid fever, is one primary cause of pediatric sepsis in typhoid endemic areas. Extensively drug-resistant (XDR) S. Typhi is more common among pediatric patients, which is responsible for over 90% of the reported XDR typhoid cases, but the majority of antibiotic resistance studies available have been carried out using S. Typhi isolates from adult patients. Here, we characterized XDR S. Typhi isolates from a medium size cohort of pediatric typhoid patients to determine their antibiotic-resistance-related gene signatures associated with common treatment options to typhoid fever patients. This study informs the molecular basis of antibiotic-resistance among recent S. Typhi isolates from pediatric septicemia patients, therefore providing insights into the development of molecular detection methods and control strategies for XDR S. Typhi.
Detecting Flavobacterial Fish Pathogens in the Environment Using High-Throughput Community Analysis
Authors: Testerman Todd , Beka Lidia , McClure Emily Ann , Reichley Stephen R. , King Stacy , Welch Timothy J. , Graf Joerg
Published: June 2021

Diseases caused by the fish pathogensFlavobacterium columnareandFlavobacterium psychrophilumare major contributors of preventable losses in the aquaculture industry. The persistent and difficult to control infections caused by these bacteria make timely intervention and prophylactic elimination of pathogen reservoirs important measures to combat these disease-causing agents. In the present study, we present two independent assays for detecting these pathogens in a range of environmental samples. Natural water samples were inoculated withF. columnareandF. psychrophilumcells, and pathogen levels were detected using Illumina MiSeq sequencing and droplet digital PCR. Both detection methods accurately identified pathogen-positive samples and showed good agreement in quantifying each pathogen. Additionally, the real-world application of these approaches was demonstrated using environmental samples collected at a rainbow trout aquaculture facility. These results show that both methods can serve as useful tools for surveillance efforts in aquaculture facilities, where the early detection of these flavobacterial pathogens may direct preventative measures to reduce disease occurrence.

Importance

Early detection of a deadly disease outbreak in a population can be the difference between mass fatality or mitigated effects. In the present study, we evaluated and compared two techniques for detecting economically impactful aquaculture pathogens. We demonstrate that one of these techniques, 16S rRNA gene sequencing using Illumina MiSeq technology, provides the ability to accurately detect two fish pathogens,F. columnareandF. psychrophilum, while simultaneously profiling the native microbial community. The second technique, droplet digital PCR, is commonly used for pathogen detection, and the results obtained using the assays we designed with this method served to validate those obtained using the MiSeq method. These two methods offer distinct advantages. The MiSeq method pairs pathogen detection and microbial community profiling to answer immediate and long-term fish health concerns, while droplet digital PCR method provides fast and highly sensitive detection that is useful for surveillance and rapid clinical responses.
I will teach you here or there, I will try to teach you anywhere: perceived supports and barriers for emergency remote teaching during COVID-19 pandemic
Authors: Donham Cristine , Barron Hillary A. , Alkhouri Jourjina , Kumarath Maya Changaran , Alejandro Wesley , Menke Erik , Kranzfelder Petra
Published: June 2021

Background

Due to the COVID-19 pandemic, many universities moved to emergency remote teaching (ERT). This allowed institutions to continue their instruction despite not being in person. However, ERT is not without consequences. For example, students may have inadequate technological supports, such as reliable internet and computers. Students may also have poor learning environments at home and may need to find added employment to support their families. Additionally, there were consequences to faculty. It has been shown that female instructors are more disproportionately impacted in terms of mental health issues and increased domestic labor.

This research aims to investigate instructors’ and students’ perceptions of their transition to ERT. Specifically, we wanted to:

Identify supports and barriers during the transition to ERT

Compare instructors experiences with the student experiences

Explore these supports and barriers within the context of social presence, teaching presence, and/or cognitive presence during ERT as well as how these supports and barriers relate to scaffolding in emergency remote courses

Design

Using grounded theory techniques, we applied two-cycle, qualitative analyses to assess the instructor transcripts. In first-cycle analysis, we used open coding to develop initial ideas from the data. We then used second cycle coding to generate categories with definitions and criteria agreed upon during discussion-based consensus building. Finally, these categories and descriptions were used to code student survey data.

Analyses/Interpretations

Instructors identified twice as many barriers as supports in their teaching during the transition to ERT and identified casual and formal conversations with colleagues as valuable supports. Emerging categories for barriers consisted of academic integrity concerns as well as technological difficulties. Similarly, students identified more barriers than supports in their learning during the transition to ERT. More specifically, students described pre-existing course structure, classroom technology, and community as best supporting their learning. Barriers that challenged student learning included classroom environment, student availability, and student emotion and comfort.

Contribution

Together, this research will help us understand supports and barriers to teaching and learning during the transition to ERT. This understanding can help us better plan and prepare for future emergencies, particularly at MSIs, where improved communication and increased access to resources for both students and instructors are key.
Constitutive IFNα protein production in bats
Authors: Bondet Vincent , Le Baut Maxime , Le Poder Sophie , Lécu Alexis , Petit Thierry , Wedlarski Rudy , Duffy Darragh , Le Roux Delphine
Published: June 2021

Bats are the only mammals with self-powered flight and account for 20% of all extant mammalian diversity. In addition, they harbor many emerging and reemerging viruses, including multiple coronaviruses, several of which are highly pathogenic in other mammals, but cause no disease in bats. How this relationship between bats and viruses exists is not yet fully understood. Existing evidence supports a specific role for the innate immune system, in particular type I interferon (IFN) responses, a major component of antiviral immunity. Previous studies in bats have shown that components of the IFN pathway are constitutively activated at the transcriptional level. In this study, we tested the hypothesis that the type I IFN response in bats is also constitutively activated at the protein level. For this we utilized highly sensitive Single Molecule (Simoa) digital ELISA assays, previously developed for humans that we adapted to bat samples. We prospectively sampled four non-native chiroptera species from French zoos. We identified a constitutive expression of IFNα protein in the circulation of healthy bats, and concentrations that are physiologically active in humans. Expression levels differed according to the species examined, but was not associated with age, sex, or health status suggesting constitutive IFNα protein expression independent of disease. These results confirm a unique IFN response in bat species that may explain their ability to coexist with multiple viruses in the absence of pathology. These results may help to manage potential zoonotic viral reservoirs and potentially identify new anti-viral strategies.
Molecular Determinants of Ligand Residence in Galectin
Authors: Koneru Jaya Krishna , Sinha Suman , Mondal Jagannath
Published: June 2021

The recognition of carbohydrates by lectins play key roles in diverse cellular processes such as cellular adhesion, proliferation and apoptosis which makes it a promising therapeutic target against cancers. One of the most functionally active lectins, galectin-3 is distinctively known for its specific binding affinity towards β-galactoside. Despite the prevalence of high-resolution crystallographic structures, the mechanistic basis and the molecular determinants of the sugar recognition process by galectin-3 are currently elusive. Here we address this question by capturing the complete dynamical binding process of human galectin-3 with its native ligand N-acetyllactosamine (LacNAc) and one of its synthetic derivatives by unbiased Molecular Dynamics simulation. In our simulations, both the natural ligand LacNAc and its synthetic derivative, initially solvated in water, diffuse around the protein and eventually recognise the designated binding site at the S-side of galectin-3, in crystallographic precision and identifies key metastable intermediate ligand-states around the galectin on their course to eventual binding. The simulations highlight that the origin of the experimentally observed multi-fold efficacy of synthetically designed ligand-derivative over its native natural ligand LacNAc lies in the derivative’s relatively longer residence time in the bound pocket. A kinetic analysis demonstrates that the LacNAc-derivative would be more resilient compared to the parent ligand against unbinding from the protein binding site. In particular, the analysis identifies that interactions of the binding pocket residues Trp181, Arg144 and Arg162 with the tetrafuorophenyl ring of the derivative as the key determinant for the synthetic ligand to latch into the pocket.

Graphical Abstract
Natural history of Camponotus renggeri and Camponotus rufipes (Hymenoptera: Formicidae) in an Atlantic Forest reserve, Brazil
Authors: Pereira-Romeiro Miguel Piovesana , Vanin Gabriel Tofanelo , Azevedo-Silva Marianne , Mori Gustavo Maruyama
Published: June 2021

Widespread species face a wide variety of environmental challenges and their morphology, behavior, and natural history may change across their range. However, not rarely, natural history research is restricted to one or few locations. That is the case for Camponotus renggeri and C. rufipes. Both species occur across South America in different ecosystems, but most research on these species is restricted to the Brazilian savanna, known as Cerrado. Here, we describe the foraging area, nesting habits, and activity schedule of C. renggeri and C. rufipes in an Atlantic Forest reserve in SE Brazil. C. renggeri foraged exclusively during nighttime and C. rufipes remained active throughout the day, but with little intensity during daylight hours. Most nests of both species were composed of dry straw, and average foraging areas were 0.91 m2 for C. renggeri and 1.79 m2 for C. rufipes. Inferred intraspecific foraging areas of nearby nests overlapped, especially for C. renggeri. Our findings reinforces the importance of natural history and what it adds to our knowledge on the ecology and behavior of C. renggeri and C. rufipes in Atlantic Forest.
MungeSumstats: A Bioconductor package for the standardisation and quality control of many GWAS summary statistics
Authors: Murphy Alan E , Skene Nathan G
Published: June 2021

Genome-wide association studies (GWAS) summary statistics have popularised and accelerated genetic research. However, a lack of standardisation of the file formats used has proven problematic when running secondary analysis tools or performing meta-analysis studies. To address this issue, we have developed MungeSumstats, a Bioconductor R package for the standardisation and quality control of GWAS summary statistics. MungeSumstats can handle the most common summary statistic formats, including variant call format (VCF) producing a reformatted, standardised, tabular summary statistic file, VCF or R native data object.

Contact

Alan Murphy:a.murphy@imperial.ac.uk, Nathan Skene:n.skene@imperial.ac.uk

Availability and implementation

MungeSumstats is available on Bioconductor (v 3.13) and can also be found on Github at:https://neurogenomics.github.io/MungeSumstats

Supplementary information

The analysis deriving the most common summary statistic formats is available at:https://al-murphy.github.io/SumstatFormats
FACT-mediated maintenance of chromatin integrity during transcription is essential for mammalian stem cell viability
Authors: Goswami Imon , Sandlesh Poorva , Stablewski Aimee , Toshkov Ilya , Safina Alfiya F , Magnitov Mikhail , Wang Jianmin , Gurova Katerina
Published: June 2021

Preservation of nucleosomes during replication has been extensively studied, while the maintenance of nucleosomes during transcription has gotten less attention. The histone chaperone FACT is involved in transcription elongation, although whether it disassembles or assembles nucleosomes during this process is still unclear. We deleted the FACT subunit in adult mice to clarify the function of FACT in mammals. FACT loss was lethal due to the loss of the earliest progenitors in bone marrow and intestine, while mor differentiated cells were not affected. Using cells isolated from several tissues, we showed that FACT loss was lethal only for stem cells but not cells differentiated in vitro. FACT depletion led to increased chromatin accessibility in a transcription-dependent manner, suggesting that nucleosomes are lost during transcription in the absence of FACT. The most prominent response to the loss of nucleosomes was the activation of interferon signaling and the accumulation of immunocytes in sensitive organs. FACT maintained chromatin integrity during transcription in mammalian adult stem cells, suggesting that chromatin transcription in these cells is different from more differentiated cells.
A CRISPR-del-based pipeline for complete gene knockout in human diploid cells
Authors: Komori Takuma , Hata Shoji , Mabuchi Akira , Genova Mariya , Harada Tomoki , Fukuyama Masamitsu , Chinen Takumi , Kitagawa Daiju
Published: June 2021

The advance of CRISPR/Cas9 technology has enabled us easily to generate gene knockout cell lines by introducing insertion/deletion mutations (indels) at the target site via the error-prone non-homologous end joining repair system. Frameshift-promoting indels can disrupt gene functions by generation of a premature stop codon. However, there is growing evidence that targeted genes are not always knocked-out by the indel-based gene disruption. In this study, we established a pipeline of CRISPR-del, which induces a large chromosomal deletion by cutting two different target sites, to perform “complete” gene knockout efficiently in non-transformed human diploid RPE1 cells. By optimizing several procedures, the CRISPR-del pipeline allowed us to generate knockout cell lines harboring bi-allelic large chromosomal deletions in a high-throughput manner. Quantitative analyses show that the frequency of gene deletion with this approach is much higher than that of conventional CRISPR-del methods. The lengths of the deleted genomic regions demonstrated in this study are longer than those of 95% of the human protein-coding genes. Furthermore, the pipeline enables the generation of a model cell line having a bi-allelic cancer-associated chromosomal deletion. Overall, these data lead us to propose that the CRISPR-del pipeline is a high-throughput approach for performing “complete” gene knockout in RPE1 cells.
Inhibiting adenine synthesis attenuates glioblastoma cell stemness and temozolomide resistance
Authors: Singh Simranjit X. , Yang Rui , Roso Kristen , Hansen Landon J. , Du Changzheng , Chen Lee H. , Greer Paula K. , Pirozzi Christopher J. , He Yiping
Published: June 2021

Glioblastoma (GBM) is a lethal brain cancer exhibiting high levels of drug resistance, a feature partially imparted by tumor cell stemness. Recent work shows that homozygousMTAPdeletion, a genetic alteration occurring in about half of all GBMs, promotes stemness in GBM cells. Exploiting MTAP loss-conferred deficiency in adenine salvage, we demonstrate that transient adenine blockade via treatment with L-Alanosine (ALA), an inhibitor ofde novoadenine synthesis, attenuates stemness ofMTAP-deficient GBM cells. This ALA-induced reduction in stemness is accompanied by compromised mitochondrial function, highlighted by diminished spare respiratory capacity. Direct pharmacological inhibition of mitochondrial respiration recapitulates the effect of ALA on GBM cell stemness, suggesting ALA targets stemness partially via affecting mitochondrial function. Finally, in agreement with diminished stemness and compromised mitochondrial function, we show that ALA sensitizes GBM cells to temozolomide (TMZ)in vitroand in an orthotopic GBM model. Collectively, these results identify critical roles of adenine supply in maintaining mitochondrial function and stemness of GBM cells, highlight a critical role of mitochondrial function in sustaining GBM stemness, and implicate adenine synthesis inhibition as a complementary approach for treatingMTAP-deleted GBMs.
Heterogeneous ‘cell types’ can improve performance of deep neural networks
Authors: Doty Briar , Mihalas Stefan , Arkhipov Anton , Piet Alex
Published: June 2021

Deep convolutional neural networks (CNNs) are powerful computational tools for a large variety of tasks (Goodfellow, 2016). Their architecture, composed of layers of repeated identical neural units, draws inspiration from visual neuroscience. However, biological circuits contain a myriad of additional details and complexity not translated to CNNs, including diverse neural cell types (Tasic, 2018). Many possible roles for neural cell types have been proposed, including: learning, stabilizing excitation and inhibition, and diverse normalization (Marblestone, 2016; Gouwens, 2019). Here we investigate whether neural cell types, instantiated as diverse activation functions in CNNs, can assist in the feed-forward computational abilities of neural circuits. Our heterogeneous cell type networks mix multiple activation functions within each activation layer. We assess the value of mixed activation functions by comparing image classification performance to that of homogeneous control networks with only one activation function per network. We observe that mixing activation functions can improve the image classification abilities of CNNs. Importantly, we find larger improvements when the activation functions are more diverse, and in more constrained networks. Our results suggest a feed-forward computational role for diverse cell types in biological circuits. Additionally, our results open new avenues for the development of more powerful CNNs.
Adapting macroecology to microbiology: using occupancy modelling to assess functional profiles across metagenomes
Authors: Hilts Angus S. , Hunjan Manjot S. , Hug Laura A.
Published: June 2021

Metagenomic sequencing provides information on the metabolic capacities and taxonomic affiliations for members of a microbial community. When assessing metabolic functions in a community, missing genes in pathways can occur in two ways: the genes may legitimately be missing from the community whose DNA was sequenced, or the genes were missed during shotgun sequencing or failed to assemble, and thus the metabolic capacity of interest is wrongly absent from the sequence data. Here, we borrow and adapt occupancy modelling from macroecology to provide mathematical context to metabolic predictions from metagenomes. We review the five assumptions underlying occupancy modelling through the lens of microbial community sequence data. Using the methane cycle, we apply occupancy modelling to examine the presence and absence of methanogenesis and methanotrophy genes from nearly 10,000 metagenomes spanning global environments. We determine that methanogenesis and methanotrophy are positively correlated across environments, and note that the lack of available standardized metadata for most metagenomes is a significant hindrance to large-scale statistical analyses. We present this adaptation of macroecology’s occupancy modelling to metagenomics as a tool for assessing presence/absence of traits in environmental microbiological surveys. We further initiate a call for stronger metadata standards to accompany metagenome deposition, to enable robust statistical approaches in the future.
RNA at the surface of phase-separated condensates impacts their size and number
Authors: Cochard Audrey , Navarro Marina Garcia-Jove , Kashida Shunnichi , Kress Michel , Weil Dominique , Gueroui Zoher
Published: June 2021

Membrane-less organelles, by localizing and regulating complex biochemical reactions, are ubiquitous functional subunits of intracellular organization. They include a variety of nuclear and cytoplasmic ribonucleoprotein (RNP) condensates, such as nucleoli, P-bodies, germ granules and stress granules. While is it now recognized that specific RNA and protein families are critical for the biogenesis of RNP condensates, how these molecular constituents determine condensate size and morphology is unknown. To circumvent the biochemical complexity of endogenous RNP condensates, the use of programmable tools to reconstitute condensate formation with minimal constituents can be instrumental. Here we report a methodology to form RNA-containing condensates in living cells with controlled RNA and protein composition. Our bioengineered condensates are made of ArtiGranule scaffolds undergoing liquid-liquid phase separation in cells and programmed to specifically recruit a unique RNA species. We found that RNAs localized on condensate surface, either as isolated RNA molecules or as a homogenous corona of RNA molecules around the condensate. This simplified system allowed us to demonstrate that the size of the condensates scales with RNA surface density, the higher the RNA density is, the smaller and more frequent the condensates are. Our observations suggest a mechanism based on physical constraints, provided by RNAs localized on condensate surface, that limit condensate growth and coalescence.
Mechanisms of DNA repair have evolved to minimise the probability of nonsense mutations
Authors: Powell George , Long Helen S , Versluys Thomas M M , Mallon Ann-Marie , Lindgren Cecilia M , Simon Michelle M
Published: June 2021

Variation in sequence mutability has important implications for evolutionary models and predicting disease occurrence, and is driven in part by evolutionary divergence in mechanisms of DNA repair. The aim of this study was twofold: first, to assess the effect of local sequence context on substitution rates in the mouse lineage; second, to investigate the relationship between sequence mutability and selection. We show that the 7-mer context (i.e three bases either side of the base of interest) explains more variation in substitution rates between chromosomes in the mouse lineage than either the 3-mer, 5-mer, or 9-mer contexts. Furthermore, we also show that 7-mer substitutions with the potential to cause nonsense mutations when they occur in translated sequences occur at a lower rate across the genome than 7-mer substitutions with the potential to cause synonymous mutations. We propose that mechanisms of DNA repair have evolved to prioritise substitutions that are more likely to be deleterious to fitness.
Linking plant growth promoting arbuscular mycorrhizal colonization with bacterial plant sulfur supply
Authors: Gahan Jacinta , Schmalenberger Achim
Published: June 2021

Sulfur (S) exists in organically bound complexes (∼95%), predominantly as sulfonates, and are not directly plant available. Specific soil bacteria can mobilise sulfonates but very little is known about these bacteria in the hyphosphere. Since mycorrhizal fungi support growth of the majority of land plants, hyphosphere desulfonating bacteria may be of substantial benefit to the plant host. This study analysed the effect of AM inoculation withRhizophagus irregularis(formerG. intraradices,Glomus) and a mix of six AM species (Mixed) on PGP, microbial communities and sulfonate mobilising bacteria withL. perenne,Agrostis stoloniferaandPlantago lanceolataas plant hosts in bi-compartmental microcosms andA. stoloniferain PGP pot experiments. AM inoculation significantly increased plant growth, percentage root colonisation and the quantity of cultivable desulfonating bacteria in the hyphosphere over pre-inoculated soil for all plants. Community analysis via PCR-DGGE revealed significantly different bacterial and fungal communities post inoculation. Analysis of the sulfonate mobilisingasfAgene revealed a significantly altered community and novel bacterial isolates with this important functional ability post-inoculation. The results demonstrate that AM inoculation increased plant biomass yield, AM root colonisation and altered bacterial and fungal community dynamics in the hyphosphere. AM inoculated microcosms had an increased abundance of desulfonating bacteria that may be beneficial for plant-S supply.

Research highlights

Inoculation with AM fungi was shown to promote plant growth and harbour larger populations of sulfonate mobilising bacteria.

Post-inoculation hyphospheric bacterial and saprotrophic fungal communities were shown to differ significantly in composition and abundance.

Analysis of sulfonate mobilising bacteria revealed novel presumptive species in possession of theasfAgene associated with AM hyphae.

AM inoculation was shown to significantly impact theasfApositive bacterial community composition.
Extracting Phylogenetic Information of Human Mitochondrial DNA by Linear Autoencoder
Authors: Shimazaki Takuto , Nishimoto Kazuki , Niioka Hirohiko , Miyake Jun
Published: June 2021

We used a linear autoencoder (LAE) and its learning dynamics to analyze the high-order structure of human mitochondrial DNA (mtDNA). A total of 360 complete human mtDNA sequences were collected from the MITOMAP database and transformed into 1024-dimensional vectors of pentanucleotide frequencies. We compressed those into a three-dimensional (3D) coordinates by an LAE at each step of training by gradient descent with respect to the quadratic error function. Along the time axis of training epochs, the compressed 3D coordinates were gradually clustered and separated in accordance with the order of the genetic distance in the phylogenetic tree of human mtDNA haplogroups. This suggests that there is an association between the learning dynamics of LAE and the high-dimensional structure of human mtDNA sequences, similar to that of phylogenetic analysis and evolutionary pathways: the five clusters eventually contained only a single haplogroup of L0, M, N, R, and U, while the L3 cluster contained a small number of M members and The packing was comparable to that realized in learning dynamics similar to genetic classification and evolutionary pathways by LAE in principal component analysis (PCA), but somewhat denser than PCA.
PrISM: Precision for Integrative Structural Models
Authors: Ullanat Varun , Kasukurthi Nikhil , Viswanath Shruthi
Published: June 2021

Motivation

A single precision value is currently reported for an integrative model. However, precision may vary for different regions of an integrative model owing to varying amounts of input information.

Results

We develop PrISM (Precision for Integrative Structural Models), to efficiently identify high and low-precision regions for integrative models.

Availability

PrISM is written in Python and available under the GNU General Public License v3.0 at https://github.com/isblab/prism; benchmark data used in this paper is available at doi:10.5281/zenodo.6241200.

Contact

shruthiv@ncbs.res.in

Supplementary information

Supplementary data are available at Bioinformatics online.
Climatic niche conservatism shapes the ecological assembly of Hawaiian arthropod communities
Authors: Lim Jun Ying , Patiño Jairo , Noriyuki Suzuki , Simmari Luis Cayetano , Gillespie Rosemary G. , Krehenwinkel Henrik
Published: June 2021

Spatial variation in climatic conditions along elevation gradients provides an important backdrop by which communities assemble and diversify. Lowland habitats tend to be connected through time, whereas highlands can be continuously or periodically isolated, conditions that have been hypothesized to promote high levels of species endemism. This tendency is expected to be accentuated among taxa that show niche conservatism within a given climatic envelope. While species distribution modeling approaches have allowed extensive exploration of niche conservatism among target taxa, a broad understanding of the phenomenon requires sampling of entire communities. Species-rich groups such as arthropods are ideal case studies for understanding ecological and biodiversity dynamics along elevational gradients given their important functional role in many ecosystems, but community-level studies have been limited due to their tremendous diversity. Here, we develop a novel semi-quantitative metabarcoding approach that combines specimen counts and size-sorting to characterize arthropod community-level diversity patterns along two elevational gradients across two volcanoes on the island of Hawai‘i. We find that arthropod communities between the two transects become increasingly distinct compositionally at higher elevations. Resistance surface approaches suggest that climatic differences between sampling localities are an important driver in shaping beta-diversity patterns, though the relative importance of climate varies across taxonomic groups. Nevertheless, the climatic niche position of OTUs between transects was highly correlated, suggesting that climatic filters shape the colonization between adjacent volcanoes. Taken together, our results highlight climatic niche conservatism as an important factor shaping ecological assembly along elevational gradients and suggest topographic complexity as an important driver of diversification.
Efficient Generative Modelling of Protein Structure Fragments using a Deep Markov Model
Authors: Thygesen Christian B. , Al-Sibahi Ahmad Salim , Steenmanns Christian S. , Moreta Lys S. , Sørensen Anders B. , Hamelryck Thomas
Published: June 2021

Fragment libraries are often used in protein structure prediction, simulation and design as a means to significantly reduce the vast conformational search space. Current state-of-the-art methods for fragment library generation do not properly account for aleatory and epistemic uncertainty, respectively due to the dynamic nature of proteins and experimental errors in protein structures. Additionally, they typically rely on information that is not generally or readily available, such as homologous sequences, related protein structures and other complementary information. To address these issues, we developed BIFROST, a novel take on the fragment library problem based on a Deep Markov Model architecture combined with directional statistics for angular degrees of freedom, implemented in the deep probabilistic programming language Pyro. BIFROST is a probabilistic, generative model of the protein backbone dihedral angles conditioned solely on the amino acid sequence. BIFROST generates fragment libraries with a quality on par with current state-of-the-art methods at a fraction of the run-time, while requiring considerably less information and allowing efficient evaluation of probabilities.
Similar neuronal imprint and absence of cross-seeded partner fibrils in α-synuclein aggregates from MSA and Parkinson’s disease brains
Authors: Laferrière Florent , Claverol Stéphane , Bezard Erwan , De Giorgi Francesca , Ichas François
Published: June 2021

Aggregated alpha-synuclein (α-syn) is a principal constituent of Lewy bodies (LBs) and glial cytoplasmic inclusions (GCIs) observed respectively inside neurons in Parkinson’s disease (PD) and oligodendrocytes in multiple system atrophy (MSA). Yet, the cellular origin, the pathophysiological role, and the mechanism of formation of these inclusions bodies (IBs) remain to be elucidated. It has recently been proposed that α-syn IBs eventually cause the demise of the host cell by virtue of the cumulative sequestration of partner proteins and organelles. In particular, the hypothesis of a local cross-seeding of other fibrillization-prone proteins like tau or TDP-43 has also been put forward. We submitted sarkosyl-insoluble extracts of post-mortem brain tissue from PD, MSA and control subjects to a comparative proteomic analysis to address these points. Our studies indicate that: i) α-syn is by far the most enriched protein in PD and MSA extracts compared to controls; ii) PD and MSA extracts share a striking overlap of their sarkosyl-insoluble proteomes, consisting of a vast majority of mitochondrial and neuronal synaptic proteins, and (iii) other fibrillization-prone protein candidates possibly cross-seeded by α-syn are neither found in PD nor MSA extracts. Thus, our results (i) support the idea that pre-assembled building blocks originating in neurons serve to the formation of GCIs in MSA, (ii) show no sign of amyloid cross-seeding in either synucleinopathy, and (iii) point to the sequestration of mitochondria and of neuronal synaptic components in both LBs and GCIs.
Desiccation-induced fibrous condensation of CAHS protein from an anhydrobiotic tardigrade
Authors: Yagi-Utsumi Maho , Aoki Kazuhiro , Watanabe Hiroki , Song Chihong , Nishimura Seiji , Satoh Tadashi , Yanaka Saeko , Ganser Christian , Tanaka Sae , Schnapka Vincent , Goh Ean Wai , Furutani Yuji , Murata Kazuyoshi , Uchihashi Takayuki , Arakawa Kazuharu , Kato Koichi
Published: June 2021

Anhydrobiosis is one of the most extensively studied forms of cryptobiosis that is induced in certain organisms as a response to desiccation. Anhydrobiotic species has been hypothesized to produce substances that can protect their biological components and/or cell membranes without water. In extremotolerant tardigrades, highly hydrophilic and heat-soluble protein families, cytosolic abundant heat-soluble (CAHS) proteins, have been identified, which are postulated to be integral parts of the tardigrades’ response to desiccation. However, the molecular mechanisms underlying these protein functions remain to be fully elucidated. In this study, we perfomed in vitro and in vivo characterizations of the self-assembling property of CAHS1 protein, a major isoform of CAHS proteins from Ramazzottius varieornatus, using a series of spectroscopic and microscopic techniques. Our in vitro observations showed that CAHS1 proteins homo-oligomerized via the C-terminal α-helical region and formed a hydrogel as their concentration increased, and that these molecular assembling processes were reversible. Furthermore, our in vivo observations demonstrated that the overexpressed CAHS1 proteins formed condensates under desiccation-mimicking conditions. These data strongly suggested that, upon drying, the CAHS1 proteins form oligomers and eventually underwent sol-gel transition in tardigrade cytosols. Thus, it is proposed that the CAHS1 proteins form the cytosolic fibrous condensates, which presumably have variable mechanisms for the desiccation tolerance of tardigrades. These findings provide insights into the protective mechanisms involved in the anhydrobiosis of tardigrades.