bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterising the vegetation-rainfall relationship in the Northeast Himalaya, India
Authors: Sarania Bidyut , Guttal Vishwesha , Tamma Krishnapriya 
Published: October 2021

AbstractEcosystems are complex systems and are characterised by positive and negative feedbacks between the abiotic and biotic components. The response of an ecosystem to its environment can be determined by examining state diagrams, which are plots of the state variable as a function of the environmental driver. For instance, tree cover as a function of rainfall is widely used to characterise vegetation patterns. Previous studies have shown that tree cover shows bimodal distributions for intermediate rainfall regimes in Africa and South America. In this study, we construct a vegetation state diagram – by plotting vegetation cover as a function of mean annual rainfall – for Northeast India, which is part of the Eastern Himalaya and the Indo-Burma biodiversity hotspot. We use remotely sensed satellite data of Enhanced Vegetation Index (EVI) as a proxy for vegetation cover. We obtain Mean Annual Precipitation (MAP) from the CHIRPS data (Climate Hazards Group InfraRed Precipitation with Station data). We find that EVI increases monotonically as a function of MAP in the range 1000-2000 mm, after which it plateaus. The 1000 to 2000 mm MAP corresponds to the vegetation transitional zone (1200-3700 m), whereas >2000 MAP region covers the greater extent of the tropical forest (<1200 m) of NEI. In other words, we find no evidence for bimodality in tree cover or vegetation states at coarser scales in North Eastern India. Our characterisation of the state diagram for vegetation in northeast India is important to understand response to ongoing change in rainfall patterns.
Untwisted α-synuclein Filaments formed in the Presence of Lipid Vesicles
Authors: Dasari Anvesh K. R. , Dillard Lucas , Hojjatian Alimohammad , Sengupta Urmi , Kayed Rakez , Taylor Kenneth A. , Borgnia Mario J. , Lim Kwang Hun 
Published: October 2021

AbstractAccumulation of filamentous aggregates of α-synuclein is a pathological hallmark of several neurodegenerative diseases including Parkinson’s disease (PD). Interaction between α-synuclein and lipids has been shown to play a critical role in aggregation of α-synuclein. Most structural studies have, however, been focused on α-synuclein filaments formed in the absence of lipids. Here, we report structural investigation of α-synuclein filaments assembled under the quiescent conditions in the presence of anionic lipid vesicles using electron microscopy (EM) including cryo-EM. Our transmission electron microscopy (TEM) analyses reveal that α-synuclein forms curly protofilaments at an early stage of aggregation. The flexible protofilaments were then converted to long filaments after a longer incubation of 30 days. More detailed structural analyses using cryo-EM reveal that the long filaments adopt untwisted structures with different diameters, which have not been observed in previous α-synuclein filaments formed in vitro. The untwisted filaments are rather similar to straight filaments with no observable twist that are extracted from patients with dementia with Lewy bodies. Our structural studies highlight the conformational diversity of α-synuclein filaments, requiring additional structural investigation of not only more ex vivo α-synuclein filaments, but also in vitro α-synuclein filaments formed in the presence of diverse co-factors to better understand the molecular basis of diverse molecular conformations of α-synuclein filaments.
Systematic Discovery of Antibacterial and Antifungal Bacterial Toxins
Authors: Nachmias Nimrod , Dotan Noam , Fraenkel Rina , Rocha Marina Campos , Kluzek Monika , Shalom Maor , Rivitz Arbel , Shamash-Halevy Naama , Cahana Inbar , Deouell Noam , Klein Jacob , Schlezinger Neta , Tzarum Netanel , Oppenheimer-Shaanan Yaara , Levy Asaf 
Published: October 2021

AbstractMicrobes employ toxins to kill competing microbes or eukaryotic host cells. Polymorphic toxins are proteins that encode C-terminal toxin domains. Here, we developed a computational approach to discover novel toxin domains of polymorphic toxins within 105,438 microbial genomes. We validated nine short novel toxins (“PTs”) that cause bacterial or yeast cell death. The novel PTs are encoded by ∼2.2% of the sequenced bacteria, including numerous pathogens. We also identified five cognate immunity genes (“PIMs”) that neutralize the toxins. Intriguingly, we observed an antifungal effect of the PTs against various pathogenic fungi. The toxins likely act as enzymes that cause severe damage to cell shape, membrane, and DNA. Finally, we solved the 3D structure of two PTs in complex with their PIMs, and showed that they function as novel DNAses. The new potent toxins likely play key roles in inter-microbial competition and can be utilized in various clinical and biotechnological applications.
Diverse chemical functionalization of nucleobases within long RNAs using sulfinate salts
Authors: Gomez Anastassia , Bassi Tiziano , Grayson Leah , Vantourout Julien , Toor Navtej 
Published: October 2021

AbstractWe have devised a single pot, low-cost method to modify RNA with sulfinate salts that can directly add almost any desired functional group to nucleobases under mild aqueous conditions. This chemistry modifies the Hoogsteen edge of RNA and DNA nucleobases. It can be applied to RNA or DNA of any size, as well as to individual nucleotides. Existing methods of RNA modification have relatively limited applicability due to constraints on the size of the RNA and the lack of diversity of possible modifications. We have been able to add azide groups for click reactions directly onto the nucleobases of RNA utilizing sulfinate salts. C-H bonds on the nucleobase aromatic rings serve as the sites of attachment, with C-H being replaced with C-R, where R is the azide-containing linker. With the addition of azide functional groups, the modified RNA can easily be reacted with any alkyne-labeled compound of interest, including fluorescent dyes as shown in this work. This methodology enables the exploration of diverse chemical groups on RNA that can potentially confer protection from nucleases, allow for efficient delivery of nucleic acids into cells, or act as new tools for the investigation of nucleic acid structure and function.
Oral Lisinopril Raises Tissue Levels of ACE2, the SARS-CoV-2 Receptor, in Healthy Male and Female Mice
Authors: Brooks Steven D. , Smith Rachel L. , Moreira Aline da Silva , Ackerman Hans C. 
Published: October 2021

ABSTRACTAngiotensin-converting enzyme 2 (ACE2) is the established cellular receptor for SARS-CoV-2. However, it is unclear whether ACE1 inhibitors (e.g., lisinopril) or angiotensin receptor blockers (e.g., losartan) alter tissue ACE2 expression. This study sought to determine whether lisinopril or losartan, as monotherapies or in combination, change tissue levels of ACE2 in healthy male and female mice.Mice received lisinopril (10 mg/kg/day), losartan (10 mg/kg/day), or both for 21 days via drinking water. A control group received water without drug. ACE2 protein index (ACE2 protein / total protein) was determined on small intestine, lung, kidney, and brain. Oral lisinopril increased ACE2 protein index across all tissues (p < 0.0001 vs control). In contrast, the combination of lisinopril plus losartan did not increase ACE2 levels in any tissue (p = 0.89 vs control) and even decreased tissue expression of the Ace2 gene (p < 0.001 vs control). Tissue ACE2 remained elevated in mice 21 days after cessation of lisinopril (p = 0.02). Across both cohorts, plasma ACE2 did not correlate with ACE2 protein index in any tissue. A sex difference was observed: kidney ACE2 levels were higher in males than females (p < 0.0001).Oral lisinopril increases ACE2, the cellular receptor for SARS-CoV-2, in tissues that are relevant to the transmission and pathogenesis of COVID-19. Remarkably, the addition of losartan prevented lisinopril-induced increases in ACE2 across tissues. These results suggest that ACE inhibitors and angiotensin receptor blockers interact to determine tissue levels of ACE2.
Dynamic Brain Network States during Suspenseful Film Viewing
Authors: Bezdek Matthew A. , Keilholz Shella D. , Schumacher Eric H. 
Published: October 2021

AbstractStudies of brain activity evoked by naturalistic stimuli have found narrative suspense produces reliable patterns of activation consistent with increased attention to the narrative and decreased processing of non-narrative stimuli (Bezdek et al., 2015). Yet the progression of brain states (i.e. patterns of activity levels across the whole brain) at suspense peaks and how they differ from suspense valleys or resting state scans has not previously been investigated. We used a fast fMRI acquisition sequence to measure sub-second brain states at peaks and valleys of narrative suspense and during rest. We found five brain states that occur during suspenseful film viewing, four of which differ in their frequency near suspense peaks compared to valleys. The pattern of results is consistent with the theoretical view that suspense captures and focuses attentional processing, triggering subsequent cognitive processing of narrative events.
Discovery of Potent Triple Inhibitors of Both SARS-CoV-2 Proteases and Human Cathepsin L
Authors: Meewan Ittipat , Kattoula Jacob , Kattoula Julius Y. , Skinner Danielle , Fajtová Pavla , Giardini Miriam A. , Woodworth Brendon , McKerrow James H. , de Siqueira-Neto Jair Lage , O’Donoghue Anthony J. , Abagyan Ruben 
Published: October 2021

AbstractThere are currently no FDA approved inhibitors of SARS-CoV-2 viral proteases with specific treatment for post-exposure of SARS-CoV-2. Here, we discovered inhibitors containing thiuram disulfide or dithiobis-(thioformate) tested against three key proteases in SARS CoV-2 replication including SARS CoV-2 Main Protease (Mpro), SARS CoV-2 Papain Like Protease (PLpro), and human cathepsin L. The use of thiuram disulfide and dithiobis-(thioformate) covalent inhibitor warheads was inspired by disulfiram, a currently prescribed drug commonly used to treat chronic alcoholism that at the present time is in Phase 2 clinical trials against SARS-CoV-2. At the maximal allowed dose, disulfiram is associated with adverse effects. Our goal was to find more potent inhibitors that target both viral proteases and one essential human protease to reduce the dosage and minimize the adverse effects associated with these agents. We found that compounds coded as RI175, JX 06, and RI172 are the most potent inhibitors from an enzymatic assay against SARS-CoV-2 Mpro, SARS-CoV-2 PLpro, and human cathepsin L with IC50s of 330, 250 nM, and 190 nM about 4.5, 17, and 11.5-fold more potent than disulfiram, respectively. The identified protease inhibitors in this series were also tested against SARS CoV-2 in a cell-based and toxicity assay and were shown to have similar or greater antiviral effect than disulfiram. The identified triple protease inhibitors and their derivatives are promising candidates for treatment of the Covid-19 virus and related variants.
Expert annotation and life-cycle transcriptomics of transcription factors in rust fungi (Pucciniales) highlight the role of cold shock proteins in dormancy exit
Authors: Louet Clémentine , Blot Carla , Shelest Ekaterina , Guerillot Pamela , Pétrowski Jérémy , Frey Pascal , Duplessis Sébastien 
Published: October 2021

AbstractFungi of the order Pucciniales are obligate plant biotrophs causing rust diseases. They exhibit a complex life cycle with the production of up to five spore types, infection of two unrelated hosts and an overwintering stage. Transcription factors (TFs) are key regulators of gene expression in eukaryote cells. In order to better understand genetic programs expressed during major transitions of the rust life cycle, we surveyed the complement of TFs in fungal genomes with an emphasis on Pucciniales. We found that despite their large gene numbers, rust genomes have a reduced repertoire of TFs compared to other fungi. The proportions of C2H2 and Zinc cluster - two of the most represented TF families in fungi-indicate differences in their evolutionary relationships in Pucciniales and other fungal taxa. The cold shock protein (CSP) family showed a striking expansion in Pucciniomycotina with specific duplications in the order Pucciniales. The survey of expression profiles collected by transcriptomics along the life cycle of the poplar rust fungus revealed TF genes related to major biological transitions, e.g. response to environmental cues and host infection. Particularly, poplar rust CSPs were strongly expressed in basidia produced after the overwintering stage suggesting a possible role in dormancy exit. Expression during transition from dormant telia to basidia confirmed the specific expression of the three poplar rust CSP genes. Their heterologous expression in yeast improved cell growth after cold stress exposure, strengthening their implication in dormancy exit. This study addresses for the first time TF involved in developmental transition in the rust life cycle opening perspectives to further explore molecular regulation in the biology of the Pucciniales.
Two type II phosphatidylinositol 4-kinases function sequentially in tubule-mediated cargo delivery from early endosomes to melanosomes
Authors: Zhu Yueyao , Li Shuixing , Jaume Alexa , Jani Riddhi Atul , Delevoye Cédric , Raposo Graça , Marks Michael S. 
Published: October 2021

ABSTRACTMelanosomes are pigment cell-specific lysosome-related organelles in which melanin pigments are synthesized and stored. Melanosome maturation requires delivery of melanogenic cargoes via tubular transport carriers that emanate from early endosomes and that require BLOC-1 for their formation. Here we show that phosphatidylinositol-4-phosphate (PtdIns4P) and the type II PtdIns-4-kinases (PI4KIIα and PI4KIIβ) support BLOC-1-dependent tubule formation to regulate melanosome biogenesis. Depletion of either PI4KIIα or PI4KIIβ with shRNAs in melanocytes reduced melanin content and misrouted BLOC-1-dependent cargoes to late endosomes/lysosomes. Genetic epistasis, cell fractionation, and quantitative live-cell imaging analyses show that PI4KIIα and PI4KIIβ function sequentially and non-redundantly downstream of BLOC-1 during tubule elongation towards melanosomes by generating local pools of PtdIns4P. The data show that both type II PtdIns-4-kinases are necessary for efficient BLOC-1-dependent tubule elongation and subsequent melanosome contact and content delivery during melanosome biogenesis. The independent functions of PtdIns-4-kinases in tubule extension are downstream of likely redundant functions in BLOC-1-dependent tubule initiation.SUMMARYContents are delivered to maturing melanosomes from early endosomal intermediates through tubular transport carriers. Zhu et al show that two type II phosphatidylinositol kinases, PI4KIIα and PI4KIIβ, sequentially generate phosphatidylinositol-4-phosphate during tubule initiation and elongation for ultimate melanosome content delivery.
Contribution of rsaC, a small non-coding RNA, towards the pathogenicity of Staphylococcus aureus in a mouse systemic infection model
Authors: Panthee Suresh , Hamamoto Hiroshi , Paudel Atmika , Ohgi Suguru , Sekimizu Kazuhisa 
Published: October 2021

AbstractUnderstanding how a pathogen responds to the host stimuli and succeeds in causing disease is crucial for developing a novel treatment approach against the pathogen. Transcriptomic analysis facilitated by RNA-Seq technologies is used to examine bacterial responses at the global level. However, the ability to understand pathogen behavior inside the host tissues is hindered by much lower pathogen biomass than host tissue. Recently, we succeeded in establishing a method to enrich Staphylococcus aureus cells from infected organs. In this research, we analyzed the small non-coding RNA (sRNA) transcriptome of S. aureus inside the host and found that rsaC was among the highly expressed sRNAs. Furthermore, by gene disruption and complementation, we demonstrated that rsaC was required for full pathogenicity of S. aureus in a murine model. Besides, we found that ΔrsaC showed a difference in gene expression depending on the oxygen and host stress. The findings of this study suggest rsaC acts as a novel virulence factor in S. aureus and might facilitate the adaptation of staphylococci within the host.ImportanceDrug-resistant Staphylococcus aureus is among the pathogen for which new treatment options are urgently needed. However, limited understanding of S. aureus pathogenesis in the host has hindered unearthing potential strategies to treat the infections. Here, based on the in vivo transcriptomic analysis, we present the identification of a small non-coding RNA (sRNA) rsaC as a novel virulence factor of S. aureus. Furthermore, we performed transcriptomic analysis of the rsaC disrupted mutant and identified different pathways, possibly controlled by rsaC, during aerobic, anaerobic, and in vivo conditions. These findings contribute to reveal the role of sRNA rsaC and broadens our understanding of the adaptation of S. aureus to host environments.
Comparative effectiveness of allocation strategies of COVID-19 vaccines and antivirals against emerging SARS-CoV-2 variants of concern in East Asia and Pacific region
Authors: Leung Kathy , Jit Mark , Leung Gabriel M , Wu Joseph T 
Published: October 2021

AbstractBackgroundWe aimed to evaluate the impact of various allocation strategies of COVID-19 vaccines and antiviral such that the pandemic exit strategy could be tailored to risks and preferences of jurisdictions in the East Asia and Pacific region (EAP) to improve its efficiency and effectiveness.MethodsVaccine efficacies were estimated from the titre distributions of 50% plaque reduction neutralization test (PRNT50), assuming that PRNT50 titres of primary vaccination decreased by 2-10 folds due to antibody waning and emergence of VOCs, and an additional dose of vaccine would increase PRNT50 titres by 3- or 9-fold. We then used an existing SARS-CoV-2 transmission model to assess the outcomes of vaccine allocation strategies with and without the use of antivirals for symptomatic patients in Japan, Hong Kong and Vietnam.FindingsIncreasing primary vaccination coverage was the most important contributing factor in reducing the total and peak number of COVID-19 hospitalizations, especially when population vaccine coverage or vaccine uptake among older adults was low. Providing antivirals to 50% of symptomatic infections only further reduced total and peak hospitalizations by 10-13%. The effectiveness of an additional dose of vaccine was highly dependent on the immune escape potential of VOCs and antibody waning, but less dependent on the boosting efficacy of the additional dose.InterpretationIncreasing primary vaccination coverage should be prioritised in the design of allocation strategies of COVID-19 vaccines and antivirals in the EAP region. Heterologous vaccination with any available vaccine as the additional dose could be considered when planning pandemic exit strategies tailored to the circumstances of EAP jurisdictions.FundingHealth and Medical Research Fund, General Research Fund, AIR@InnoHK
Factors affecting the mental health of pregnant women using UK maternity services during the COVID-19 pandemic: A qualitative interview study
Authors: McKinlay A R , Fancourt D , Burton A 
Published: October 2021

AbstractBackgroundPeople using maternity services in the United Kingdom (UK) have faced significant changes brought on by the COVID-19 pandemic and social distancing regulations. We focused on the experiences of pregnant women using UK maternity services during the pandemic and the impact of social distancing rules on their mental health and wellbeing.MethodsWe conducted 23 qualitative semi-structured interviews from June 2020 to August 2021, with women from across the UK who experienced a pregnancy during the pandemic. Nineteen women in the study carried their pregnancy to term and four women experienced a miscarriage during the pandemic. Interviews took place remotely over video or telephone call, discussing topics such as mental health during pregnancy and use of UK maternity services. We used reflexive thematic analysis to analyse interview transcripts.ResultsWe generated six higher order themes: (1) Some pregnancy discomforts alleviated by social distancing measures, (2) The importance of relationships that support coping and adjustment, (3) Missed pregnancy and parenthood experiences, (4) The mental health consequences of birth partner and visitor restrictions, (5) Maternity services under pressure, and (6) Lack of connection with staff. Many participants felt a sense of loss over a pregnancy experience that differed so remarkably to what they had expected because of the pandemic. Supportive relationships were important to help cope with pregnancy and pandemic-related changes; but feelings of isolation were compounded for some participants because opportunities to build social connections through face-to-face parent groups were unavailable. Participants also described feeling alone due to restrictions on partners being present when accessing UK maternity services.ConclusionsOur findings highlight some of the changes that may have affected pregnant women’s mental health during the COVID-19 pandemic. Reduced social support and being unable to have a partner or support person present during maternity service use were the greatest concerns reported by women in this study, as this absence removed a protective buffer in times of uncertainty and distress. This suggests that the availability of a birth partner or support person must be prioritised wherever possible to protect the mental health of women experiencing pregnancy and miscarriage in times of pandemics.
Novel torin1-sensitive phosphorylation sites on the metabolic regulator AMPK revealed by label-free mass spectrometry
Authors: Smiles William J. , Ovens Ashley J. , Yu Dingyi , Ling Naomi X.Y. , Morrison Kaitlin R. , Hoque Ashfaqul , Scott John W. , Galic Sandra , Langendorf Christopher G. , Kemp Bruce E. , Peterson Janni , Oakhill Jonathan S. 
Published: October 2021

AbstractAMPK and mTORC1 are nutrient-sensitive protein kinases that form a fundamental negative feedback loop that governs cell growth and proliferation. AMPK is an αβγ heterotrimer that is directly phosphorylated by mTORC1 on α2S345to suppress AMPK activity and promote cell proliferation under nutrient stress conditions. Using mass spectrometry, we generated precise phosphorylation profiles of all 12 AMPK complexes expressed in proliferating human cells. Of the 18 phosphorylation sites detected, seven were sensitive to pharmacological mTORC1 inhibition, including four in the AMPK γ2 isoform NH2-terminal domain and α2S377which is located in the nucleotide-sensing motif. In particular, β1S182and β2S184were found to be mTORC1 substratesin vitroand near-maximally or substantially phosphorylated under cellular growth conditions. βS182phosphorylation was elevated in α1-containing complexes, relative to α2, an effect partly attributable to the non-conserved α-subunit serine/threonine-rich loop. While mutation of β1S182to a non-phosphorylatable Ala had no effect on basal and ligand-stimulated AMPK activity, β2-S184A mutation increased nuclear AMPK activity and enhanced cell proliferation under nutrient stress. We conclude that mTORC1 governs the nuclear activity of AMPK to regulate transcription factors involved in metabolism and cell survival during nutrient shortage.