bluuebunny/crossref_metadata_2025_split huggingface dataset:
Childhood meningitis in rural Gambia: 10 years of population-based surveillance
Authors: Ikumapayi Usman N , Hill Philip C , Hossain Ilias , Olatunji Yekini , Ndiaye Malick , Badji Henry , Manjang Ahmed , Salaudeen Rasheed , Ceesay Lamin , Adegbola Richard A , Greenwood Brian M , Mackenzie Grant A 
Published: March 2022

AbstractBackgroundThe introduction in many countries of conjugate vaccines against Haemophilus influenzae type-b, Streptococcus pneumoniae, and Neisseria meningitidis has led to significant reductions in acute bacterial meningitis (ABM) in children. However, recent population-based data on ABM in sub-Saharan Africa are limited.MethodsPopulation-based surveillance for meningitis was carried out in a rural area of The Gambia under demographic surveillance from 2008 to 2017, using standardised criteria for referral, diagnosis and investigation. We calculated incidence using population denominators.ResultsWe diagnosed 1,599 patients with suspected meningitis and collected cerebrospinal fluid (n=1,121) and/or blood (n=1,070) from 1,427 (88%) of cases. We detected 169 cases of ABM, 209 cases of non-bacterial meningitis and 1,049 cases of clinically suspected meningitis. The estimated average annual incidence of ABM was high at 145 per 100,000 population in the <2-month age group, 56 per 100,000 in the 2–23-month age group, but lower at 5 per 100,000 in the 5–14-year age group. The most common causes of ABM were Streptococcus pneumoniae (n=44), Neisseria meningitidis (n=42), and Gram-negative coliform bacteria (n=26). Eighteen of 22 cases caused by pneumococcal serotypes included in PCV13 occurred prior to vaccine introduction and four afterwards. The overall case fatality ratio for ABM was 29% (49/169) and highest in the <2-month age group 37% (10/27). The fatality rate was 8.6% (18/209) for non-bacterial meningitis cases.ConclusionsGambian children continue to experience substantial morbidity and mortality associated with suspected meningitis, especially acute bacterial meningitis. Such severely ill children in sub-Saharan Africa require improved diagnostics and clinical care.Summary of the articles main pointPopulation-based surveillance in a health demographic surveillance area in Gambia showed a high incidence and mortality in clinically suspected, acute-bacterial, and non-bacterial meningitis among children 14-years of age. Findings revealed potential gaps in the diagnosis of meningitis in The Gambia requiring urgent attention.
Describing a complex primary health care population in a learning health system to support future decision support and artificial intelligence initiatives
Authors: Kueper Jacqueline K. , Rayner Jennifer , Zwarenstein Merrick , Lizotte Daniel J. 
Published: March 2022

ABSTRACTIntroductionLearning health systems (LHS) use data to improve care. Descriptive epidemiology to reveal health states and needs of the LHS population is essential for informing LHS initiatives, including development of decision support tools. To properly characterize complex populations, both simple statistical and artificial intelligence techniques can be useful. We present the first large-scale description of the population served by one of the first primary care LHS in North America.ObjectivesOur objective is to describe sociodemographic, clinical, and health care use characteristics of adult primary care clients served by the Alliance for Healthier Communities, which provides team-based primary health care through Community Health Centres (CHCs) across Ontario, Canada.MethodsUsing electronic health record data from 2009-2019 for all CHCs, we perform table-based summaries for each characteristic; and apply unsupervised leaning techniques to explore patterns of common condition co-occurrence, care provider teams, and care frequency.ResultsOf the 221,047 eligible clients, those at CHCs that primarily serve those most at risk (homeless, mental health, addictions) tend to have more chronic conditions and social determinants of health, which are also prominent in clients with multimorbidity. Most care is provided by physician and nursing providers, with heterogeneous combinations of other provider types. A subset of clients have many issues addressed within single-visits and there is within- and between-client variability in care frequency. Example methodological considerations learned for future LHS initiatives include the need to carefully consider the level of analysis and associated implications for data quality and target population, heterogeneity in conditions and care characteristics, and non-uniform risk profiles across the care history.ConclusionsWe demonstrate the use of methods from statistics and artificial intelligence, applied with an epidemiological lens, to provide an overview of a complex primary care population. In addition to substantive findings, we discuss implications for future LHS initiatives.
Omicron-specific mRNA vaccine elicits potent immune responses in mice, hamsters, and nonhuman primates
Authors: Wu Yi , Shen Yanqiong , Wu Namei , Zhang Xinghai , Chen Shaohong , Yang Chang , Zhou Junhui , Wu Yan , Chen Da , Wang Li , Wang Yuye , Xu Jiejie , Liu Ke , Wang Chao , Zhang Huajun , Xia Ninuo , Chiu Sandra , Wang Yucai 
Published: March 2022

ABSTRACTSARS-CoV-2 has infected more than 400 million people around the globe and caused millions of deaths. Since its identification in November 2021, Omicron, a highly transmissible variant, has become the dominant variant in most countries. Omicron’s highly mutated spike protein, the main target of vaccine development, significantly compromises the immune protection from current vaccination. We develop an mRNA vaccine (SOmicron-6P) based on an Omicron-specific sequence. In mice, SOmicron-6P shows superior neutralizing antibodies inducing abilities to a clinically approved inactivated virus vaccine, a clinically approved protein subunit vaccine, and an mRNA vaccine (SWT-2P) with the same sequence of BNT162b2 RNA. Significantly, SOmicron-6P induces a 14.4∼27.7-fold and a 28.3∼50.3-fold increase of neutralizing activity against the pseudovirus of Omicron and authentic Omicron compared to SWT-2P, respectively. In addition, two doses SOmicron-6P significantly protects Syrian hamsters against challenge with SARS-CoV-2 Omicron variant and elicits high titers of nAbs in a dose-dependent manner in macaques. Our results suggest that SOmicron-6P offers advantages over current vaccines, and it will be helpful for those with weak immunity.
Structure of cyanobacterial photosystem I complexed with Cytochrome c6 and Ferredoxin at 1.97 Å resolution
Authors: Li Jiannan , Hamaoka Noriyuki , Makino Fumiaki , Kawamoto Akihiro , Lin Yuxi , Rögner Matthias , Nowaczyk Marc M. , Lee Young-Ho , Namba Keiichi , Gerle Christoph , Kurisu Genji 
Published: March 2022

AbstractPhotosystem I (PSI) is a light driven electron pump transferring electrons from Cytochrome c6 (Cyt c6) to Ferredoxin (Fd). An understanding of this electron transfer process is hampered by a paucity of structural detail concerning the binding of Fd and the bound Cyt c6. Here we describe the high resolution cryo-EM structure of Thermosynechococcus elongatus BP-1 PSI in complex with Fd and Cyt c6. In our structure Cyt c6 is loosely bound in a non-productive site on the periphery of the complex. Side chain interactions at the PSI:Fd interface are visualized in detail. The structure explains the properties of mutants of PsaE and PsaC and suggests a molecular switch for the dissociation of Fd upon reduction. Calorimetry-based thermodynamic analyses confirms a single binding site for Fd and demonstrates that PSI:Fd complexation is purely driven by entropy. A reaction cycle for the efficient transfer of electrons from Cyt c6 to Fd via PSI is proposed.
Tween-20 induces the structural remodelling of single lipid vesicles
Authors: Dresser Lara , Graham Sarah P. , Miller Lisa M. , Schaefer Charley , Conteduca Donato , Johnson Steven , Leake Mark C. , Quinn Steven D. 
Published: March 2022

AbstractThe interaction of Tween-20 with lipid membranes is crucial for a number of biotechnological applications including viral inactivation and membrane protein extraction, but the underlying mechanistic details have remained elusive. Evidence from ensemble assays supports a global model of Tween-20 induced membrane disruption that broadly encompasses association of the surfactant with the membrane surface, membrane fragmentation and the release of mixed micelles to solution, but whether this process involves intermediate and dynamic transitions between regimes is an open question. In search of the mechanistic origins of membrane disruption, increasing focus is put on identifying Tween-20 interactions with highly controllable model membranes. In light of this, and to unveil quantitative mechanistic details, we employed highly interdisciplinary biophysical approaches, including quartz-crystal microbalance with dissipation monitoring, steady-state and time-resolved fluorescence and FRET spectroscopy, dynamic light scattering, fluorescence correlation spectroscopy, wide-field single-vesicle imaging and scanning electron microscopy, to interrogate the interactions between Tween-20 and both freely-diffusing and surface-immobilized model-membrane vesicles. Using ultrasensitive sensing approaches, we discovered that Tween-20 leads to a stepwise and phase-dependent structural remodelling of sub-micron sized vesicles that includes permeabilization and swelling, even at detergent concentrations below the critical micellar concentration. These insights into the structural perturbation of lipid vesicles upon Tween-20 interaction highlight the impact on vesicle conformation prior to complete solubilization, and the tools presented may have general relevance for probing the interaction between lipid vesicles and a wide variety of disruptive agents.
Redundant PLETHORA activity promotes development of early embryonic cell lineages in Arabidopsis
Authors: Kerstens Merijn , Galinha Carla , Hofhuis Hugo , Nodine Michael , Scheres Ben , Willemsen Viola 
Published: March 2022

AbstractThe BABY BOOM/PLETHORA4 (BBM/PLT4) transcription factor has received much attention due to its ability to induce somatic and zygotic embryogenesis, two processes of pivotal importance in plant breeding. Loss of additional AINTEGUMENTA-LIKE/PLETHORA (AIL/PLT) genes, encoding members of the APETALA2 transcription factor family, causes embryo arrest and abortion, but whether BBM/PLT4 provides specific information for embryo development has remained unknown. Here, we reveal that AIL/PLT members are expressed in partially overlapping domains from their first appearance in the apical cell daughter of the zygote. Redundant early embryonic activity of BABY BOOM/PLT4 and PLT2 triggers development of the apical cell lineage and is required to initiate embryonic primordia. Furthermore, promoter swap experiments show that PLT1 and PLT3 expression in the expression domains of PLT2 and BABY BOOM/PLT4 is sufficient to rescue plt2 bbm double mutants. Our data indicate that generic AIL/PLT factors, involved in maintenance of stem cells, promotion of cell division and suppression of cell differentiation, provide the necessary information to initiate embryogenesis in Arabidopsis.
Chaperones facilitate heterologous expression of naturally evolved putative de novo proteins
Authors: Eicholt Lars A. , Aubel Margaux , Berk Katrin , Bornberg-Bauer Erich , Lange Andreas 
Published: March 2022

AbstractOver the past decade, evidence has accumulated that new protein coding genes can emerge de novo from previously non-coding DNA. Most studies have focused on large scale computational predictions of de novo protein coding genes across a wide range of organisms. In contrast, experimental data concerning the folding and function of de novo proteins is scarce. This might be due to difficulties in handling de novo proteins in vitro, as most are predicted to be short and disordered. Here we propose a guideline for the effective expression of eukaryotic de novo proteins in Escherichia coli.We used 11 sequences from Drosophila melanogaster and 10 from Homo sapiens, that are predicted de novo proteins from former studies, for heterologous expression. The candidate de novo proteins have varying secondary structure and disorder content. Using multiple combinations of purification tags, E. coli expression strains and chaperone systems, we were able to increase the number of solubly expressed putative de novo proteins from 30 % to 62 %. Our findings indicate that the best combination for expressing putative de novo proteins in E.coli is a GST-tag with T7 Express cells and co-expressed chaperones. We found that, overall, proteins with higher predicted disorder were easier to express.
The mitochondrion of Plasmodium falciparum generates essential acetyl-CoA for protein acetylation
Authors: Nair Sethu C. , Munro Justin T. , Mann Alexis , Llinás Manuel , Prigge Sean T. 
Published: March 2022

AbstractCoenzyme A (CoA) biosynthesis is an excellent target for antimalarial intervention. While most studies have focused on the use of CoA to produce acetyl-CoA in the apicoplast and the cytosol of malaria parasites, mitochondrial acetyl-CoA production is less well understood. In the current study, we performed metabolite labeling experiments to measure endogenous metabolites in Plasmodium falciparum lines with genetic deletions affecting mitochondrial dehydrogenase activity. Our results show that mitochondrial acetyl-CoA biosynthesis is essential for parasite growth and identify a catalytic redundancy between the two main ketoacid dehydrogenase enzymes, both of which are able to produce acetyl-CoA. The activity of these enzymes is dependent on the lipoate attachment enzyme LipL2, which is essential for parasite survival solely based on its role in supporting acetyl-CoA metabolism. We also find that acetyl-CoA produced in the mitochondrion is essential for the acetylation of histones and other proteins outside of the mitochondrion. Taken together, our results demonstrate that the mitochondrion is an essential de novo source of acetyl-CoA and is required for P. falciparum protein acetylation critical to parasite survival.
TBK1 phosphorylation activates LIR-dependent degradation of the inflammation repressor TNIP1
Authors: Zhou Jianwen , Rasmussen Nikoline Lander , Olsvik Hallvard Lauritz , Akimov Vyacheslav , Hu Zehan , Evjen Gry , Blagoev Blagoy , Lamark Trond , Johansen Terje , Dengjel Jörn 
Published: March 2022

AbstractLimitation of excessive inflammation due to selective degradation of pro-inflammatory proteins is one of the cytoprotective functions attributed to autophagy. In the current study, we highlight that selective autophagy also plays a vital role in promoting the establishment of a robust inflammatory response. Under inflammatory conditions, here TLR3-activation by poly(I:C) treatment, the inflammation repressor TNIP1 (TNFAIP3 interacting protein 1) is phosphorylated by TBK1 (Tank-binding kinase 1) activating a LIR motif that leads to the selective autophagy-dependent degradation of TNIP1, supporting expression of pro-inflammatory genes and proteins. Thus, similarly as in cancer, autophagy may play a dual role in controlling inflammation depending on the exact state and timing of the inflammatory response.SummaryAutophagy is well known for its anti-inflammatory effects. Here, we highlight that selective, autophagy-dependent degradation of the inflammation repressor TNIP1 supports pro-inflammatory gene and protein expression. Similarly as in cancer, autophagy appears to play a dual role in controlling inflammation.
Purifying selection enduringly acts on the sequence evolution of highly expressed proteins in Escherichia coli
Authors: Shibai Atsushi , Kotani Hazuki , Sakata Natsue , Furusawa Chikara , Tsuru Saburo 
Published: March 2022

AbstractThe evolutionary speed of a protein sequence is constrained by its expression level, with highly expressed proteins evolving relatively slowly. This negative correlation between expression levels and evolutionary rates (known as the E–R anticorrelation) has already been widely observed in past macroevolution between species from bacteria to animals. However, it remains unclear whether this seemingly general law also governs recent evolution, including past and de novo, within a species. However, the advent of genomic sequencing and high-throughput phenotyping, particularly for bacteria, has revealed fundamental gaps between the two evolutionary processes and has provided empirical data opposing the possible underlying mechanisms which are widely believed. These conflicts raise questions about the generalization of the E–R anticorrelation and the relevance of plausible mechanisms. To explore the ubiquitous impact of expression level on molecular evolution, and to test the relevance of the possible underlying mechanisms, we analyzed the genome sequences of 99 strains of Escherichia coli for microevolution in nature. We also analyzed genomic mutations accumulated under laboratory conditions as a model of de novo microevolution. Here, we show that the E–R anticorrelation is significant in both past and de novo microevolution in E. coli. Our data also confirmed ongoing purifying selection acting on highly expressed genes. Ongoing selection included codon-level purifying selection, supporting the relevance of the underlying mechanisms. However, their contributions to the constraints in recent evolution might be smaller than previously expected from past macroevolution.
Ligand-mediated structural dynamics of a mammalian pancreatic KATP channel
Authors: Sung Min Woo , Driggers Camden M. , Mostofian Barmak , Russo John D. , Patton Bruce L. , Zuckerman Daniel M. , Shyng Show-Ling 
Published: March 2022

AbstractRegulation of pancreatic KATP channels involves orchestrated interactions of channel subunits, Kir6.2 and SUR1, and their ligands. How ligand interactions affect channel conformations and activity is not well understood. To elucidate the structural correlates pertinent to ligand interactions and channel gating, we compared cryo-EM structures of channels in the presence and absence of pharmacological inhibitors and ATP, focusing on channel conformational dynamics. We found pharmacological inhibitors and ATP enrich a channel conformation in which the Kir6.2 cytoplasmic domain is closely associated with the transmembrane domain relative to one where the Kir6.2 cytoplasmic domain is extended away into the cytoplasm. This conformation change remodels a network of intra and inter-subunit interactions as well as both the ATP and PIP2 binding pockets. The structures resolved key contacts between the distal N-terminus of Kir6.2 and SUR1’s ABC module involving residues implicated in channel function. A SUR1 residue, K134, is identified to directly contribute to the PIP2 binding pocket. Molecular dynamics simulations revealed two Kir6.2 residues, K39 and R54, that mediate both ATP and PIP2 binding, suggesting a mechanism for competitive gating by ATP and PIP2.
Boundary work at the margins of politics and auditing: rationalising advertising probity in Ontario
Authors: Andon Paul , Free Clinton , Radcliffe Vaughan , Stein Mitchell 
Published: March 2022

PurposeThe authors examine how political players attempt to rationalise arguments for and against the expansion of auditing into governmental affairs, and how state audit authorities respond to politically motivated boundary work. This study is motivated by growing evidence of political involvement in attempts to both expand and undermine state audit oversight of government affairs.Design/methodology/approachThe authors present an interpreted history (covering relevant events from 1995 to 2016) of political rationales and associated boundary work that led to the expansion of the Office of the Auditor General of Ontario's (OAGO) mandate to audit government advertising campaigns for partisanship as well as attempts to modify this new audit remit over time.FindingsThe authors reveal substantive, formal and practical ways in which political players sought to rationalise/counter-rationalise expanding the OAGO's authority to the unfamiliar territory of advertising probity. The authors show how such justification claims ebb and flow in accordance with changeable political interests, and how state auditors react to the fraught nature of politically motivated boundary work.Originality/valueThe authors conceptualise important forms of rationalising rhetoric (which cannot be reduced to expressions of neoliberal government) that can be mobilised to deem state auditor authority legitimate in overseeing otherwise novel, unfamiliar and controversial government affairs. The authors also reveal a hitherto unrecognised resolve in state auditor responses to political intervention and shed further light on generalised forms of rationale that can underpin boundary work at the margins of accounting.
Information needs and seeking behaviors of Israeli citizens during the COVID-19 outbreak
Authors: Yavetz Gal , Aharony Noa , Sofer Yaen Yaacov 
Published: March 2022

PurposeThe aim of this study is to examine the information needs and information seeking behaviors of Israeli citizens during the outbreak of the coronavirus disease (COVID-19) in 2020, with an emphasis on the dissemination of digital information by government agencies.Design/methodology/approachThe research approach underlying this investigation is of the “case study” type, employing semi-structured, in-depth interviews conducted with 24 Israeli citizens regarding their perceptions and experiences with government information and government services during the first months of the coronavirus.FindingsThe findings of this study reveal that most participants indicated feelings of media fatigue as a result of increased exposure to news media and social media, to the point of experiencing information overload. Second, participants described feeling a lack of clear information and poor access to accurate health and official information at the outset of the COVID-19 crisis in Israel. Third, participants in the authors’ study noted that most of the information to which they were exposed about the virus came to them through communal connections such as friends and family, via social media and messaging apps like WhatsApp. In general, the participants expressed satisfaction with the quality and availability of the data and extensive information of government ministries on social networks, together with a lack of satisfaction due to difficulties in usage and a lack of clear information on traditional government websites.Originality/valueThe findings present the information acquisition and the experience of citizens in situations of national emergencies and crises, in a new light, through a focus on the dissemination of government, health and news information.