bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analysis of humoral immunity against emerging SARS-CoV-2 variants: a population-based prevalence study in Yokohama, Japan
Authors: Goto Atsushi , Miyakawa Kei , Nakayama Izumi , Yagome Susumu , Xu Juan , Kaneko Makoto , Ohtake Norihisa , Kato Hideaki , Ryo Akihide 
Published: March 2022

AbstractBackgroundLittle is known about the population prevalence of antibodies against emerging immune escape variants of SARS-CoV-2.MethodsA population-based prevalence study was conducted in Yokohama City, the most populous municipality of Japan. Quantitative measurements of immunoglobulin G against SARS-CoV-2 spike protein (SP-IgG) and qualitative measurements of neutralization antibodies against the Omicron BA.1 and BA.2 variants were performed.ResultsOf 6,000 randomly selected residents aged 20–74, 1,277 participated in the study during a period from January 30 to February 28, 2022. Of them, 3% had prior diagnosis of COVID-19, 96% received at least two-doses of SARS-CoV-2 vaccines, and 94% were positive for SP-IgG. The positive rates of neutralizing antibodies were 28% to Omicron BA.1 and BA.2 variants in a random sample of 10% of participants (n=123) and 100% to BA.1 and BA.2 among participants who received the third vaccination at least 7 days before (n=66).ConclusionsIn this population-based prevalence study in Japan, most had SP-IgG antibodies but the overall neutralizing antibody positive rate was 28% against the Omicron BA.1 and BA.2 variants. The population-level insufficient humoral immunity against the Omicron variants may explain the outbreak of COVID-19 during this period in Japan.
Damaging missense variants inIGF1Rimplicate a role for IGF-1 resistance in the aetiology of type 2 diabetes
Authors: Gardner Eugene J. , Kentistou Katherine A. , Stankovic Stasa , Lockhart Samuel , Wheeler Eleanor , Day Felix R. , Kerrison Nicola D. , Wareham Nicholas J. , Langenberg Claudia , O’Rahilly Stephen , Ong Ken K. , Perry John R. B. 
Published: March 2022

AbstractType 2 diabetes (T2D) is a chronic metabolic disorder with a significant genetic component. While large-scale population studies have identified hundreds of common genetic variants associated with T2D susceptibility, the role of rare (minor allele frequency < 0.1%) protein coding variation is less clear. To this end, we performed a gene burden analysis of 18,691 genes in 418,436 (n=32,374 T2D cases) individuals sequenced by the UK Biobank (UKBB) study to assess the impact of rare genetic variants on T2D risk. Our analysis identified T2D associations at exome-wide significance (P < 6.9×10-7) with rare, damaging variants within previously identified genes includingGCK, GIGYF1, HNF1A, andTNRC6B. In addition, individuals with rare, damaging missense variants in the genesZEB2(N=31 carriers; OR=5.5 [95% CI=2.5-12.0]; p=6.4×10-7),MLXIPL(N=245; OR=2.3 [1.6-3.2]; p=3.2×10-7), andIGF1R(N=394; OR=2.4 [1.8-3.2]; p=1.3×10-10) have higher risk of T2D. Carriers of damaging missense variants withinIGF1Rwere also shorter (-2.2cm [-1.8-2.7]; p=1.2×10-19) and had higher circulating protein levels of insulin-like growth factor-1 (IGF-1; 2.3 nmol/L [1.7-2.9] p=2.8×10-14), indicating relative IGF-1 resistance. A likely causal role of IGF-1 resistance on T2D was further supported by Mendelian randomisation analyses using common variants. Our results increase our understanding of the genetic architecture of T2D and highlight a potential therapeutic benefit of targeting the Growth Hormone/IGF-1 axis.
Monitoring of the SARS-CoV-2 Omicron BA.1/BA.2 variant transition in the Swedish population reveals higher viral quantity in BA.2 cases
Authors: Lentini Antonio , Pereira Antonio , Winqvist Ola , Reinius Björn 
Published: March 2022

AbstractThroughout the SARS-CoV-2 pandemic, multiple waves of variants of concern have swept across populations, leading to a chain of new and yet more contagious lineages dominating COVID-19 cases. Here, we tracked the remarkably rapid shift from Omicron BA.1 to BA.2 sub-variant dominance in the Swedish population during January–March 2022. By analysis of 174,933 clinical nasopharyngeal swab samples using a custom variant-typing RT-PCR assay, we uncover nearly two-fold higher levels of viral RNA in cases with Omicron BA.2. Importantly, increased viral load in the upper pharynx upon BA.2 infection may provide part of the explanation why Omicron BA.2 is more transmissible and currently outcompetes the BA.1 variant across populations.
Epigenetic modulators link mitochondrial redox homeostasis to cardiac function
Authors: Elbeck Zaher , Hossain Mohammad Bakhtiar , Siga Humam , Oskolkov Nikolay , Karlsson Fredrik , Lindgren Julia , Walentinsson Anna , Remedios Cristobal Dos , Koppenhöfer Dominique , Jarvis Rebecca , Bürli Roland , Jamier Tanguy , Franssen Elske , Firth Mike , Degasperi Andrea , Bendtsen Claus , Dudek Jan , Kohlhaas Michael , Nickel Alexander G. , Lund Lars H. , Maack Christoph , Végvári Ákos , Betsholtz Christer 
Published: March 2022

AbstractExcessive production of reactive oxygen species (ROS) is characteristic of numerous diseases, but most studies in this area have not considered the impact of endogenous antioxidative defenses. Here, utilizing multi-omics, we demonstrate that in cardiomyocytes mitochondrial isocitrate dehydrogenase (IDH2) constitutes a major antioxidant defense. In both male and female mice and humans the paradoxical reduction in expression of IDH2 associated with heart failure is compensated for by an increase in the enzyme’s activity. We describe extensive mutual regulation of the antioxidant activities of IDH2 and NRF2 by a network involving 2-oxoglutarate and L2-hydroxyglutarate and mediated in part through unconventional hydroxymethylation of cytosine residues present in introns. Conditional targeting of ROS in a murine model of heart failure improves cardiac function. Together, these insights may explain why previous attempts to treat heart failure with antioxidants have been unsuccessful and open new approaches to personalizing and, thereby, improving such treatment.Graphical abstractHighlightsParadoxical downregulation of mitochondrial isocitrate dehydrogenase (IDH2) in response to oxidative stress leads to the discovery of a robust antioxidative defense in the heart.An antioxidative loop involving IDH2 coordinates other antioxidative defenses, such as NRF2.This loop produces epigenetic modifications that link oxidative stress to mitochondrial function.The conclusion that enhancing antioxidative capacity improves cardiac function only when the endogenous capacity is insufficient opens new approaches to individualized treatment of patients with heart failure.
Phase transitions of a SEC14-like condensate at Arabidopsis plasma membranes regulate root growth
Authors: Liu Chen , Mentzelopoulou Andriani , Papagavriil Fotini , Ramachandran Prashanth , Perraki Artemis , Claus Lucas , Barg Sebastian , Dörmann Peter , Jaillais Yvon , Johnen Philipp , Russinova Eugenia , Gizeli Electra , Schaaf Gabriel , Moschou Panagiotis Nikolaou 
Published: March 2022

AbstractProtein function can be modulated by phase transitions in their material properties, which can range from liquid-to solid-like; yet the mechanisms that drive these transitions and whether they are important for physiology are still unknown. Using the model plant Arabidopsis, we show that developmental robustness is reinforced by phase transitions of the plasma membrane–bound lipid-binding protein SEC14-like. Using imaging, genetics, andin vitroreconstitution experiments, we show that SEC14-like undergoes liquid-like phase separation in the root stem cells. Outside the stem cell niche, SEC14-like associates with the caspase-like protease separase and conserved microtubule motors at unique polar plasma membrane interfaces. In these interfaces, SEC14-like undergoes abrupt processing by separase, which promotes its liquid-to-solid transition. The SEC14-like liquid-to-solid transition is important for root developmental robustness, as lines expressing an uncleavable SEC14-like variant or mutants of separase, and associated microtubule motors show similar developmental phenotypes. Furthermore, the processed and solidified but not the liquid form of SEC14-like interacts with the polar protein PINFORMED2 at the plasma membrane and perhaps other polar proteins of the PINFORMED family. This work demonstrates that robust development can involve abrupt liquid-to-solid transitions mediated by proteolysis at unique plasma membrane interfaces.
ALS sensitive spinal motor neurons enter a degenerative downward spiral of impaired splicing and proteostasis
Authors: Iannitelli Dylan E. , Tan Albert , Nguyen Emma , Babu Asha , Elorza Setiembre Delfina , Joseph Tyler , Zaaijer Sophie , An Disi , Ward Michael , Mazzoni Esteban O. 
Published: March 2022

AbstractDespite clear therapeutic potential, the mechanisms that confer differential neuronal sensitivity are not well understood. During Amyotrophic Lateral Sclerosis (ALS), sensitive spinal motor neurons (SpMN) die while a subset of rostral cranial motor neurons (CrMN) survive. In this work, we optimized a protocol to differentiate CrMNs and SpMNs from human induced pluripotent stem cells (iPSCs) by direct programming and positional patterning. Human iCrMNs are more resistant than iSpMNs to proteotoxic stress and rely on the proteasome to maintain proteostasis. iCrMNs better prevent mislocalization of TDP43 from the nucleus, a hallmark of ALS progression. iSpMNs contain more splicing defects than iCrMNs in response to ALS-related stress with genes involved in splicing and proteostasis maintenance. Therefore, iCrMNs resist ALS at two levels, preventing protein accumulation and reducing splicing defects in response to TDP43 nuclear depletion. Thus, ALS-sensitive iSpMNs appear to enter a downward spiral compromising their ability to maintain proteostasis and splicing.
Modulation of RNA binding properties of the RNA helicase UPF1 by its activator UPF2
Authors: Xue Guangpu , Maciej Vincent D. , de Amorim Alexandrina Machado , Pak Melis , Jayachandran Uma , Chakrabarti Sutapa 
Published: March 2022

AbstractThe NMD helicase UPF1 is a prototype of the superfamily 1 (SF1) of RNA helicases that bind RNA with high affinity and translocate on it in an ATP-dependent manner. Previous studies showed that UPF1 has a low basal catalytic activity that is greatly enhanced upon binding of its interaction partner, UPF2. Activation of UPF1 by UPF2 entails a large conformational change that switches the helicase from an RNA-clamping mode to an RNA-unwinding mode. The ability of UPF1 to bind RNA was expected to be unaffected by this activation mechanism. Here we show, using a combination of biochemical and biophysical methods, that binding of UPF2 to UPF1 drastically reduces the affinity of UPF1 for RNA, leading to a release of the bound RNA. Although UPF2 is capable of binding RNA in vitro, our results suggest that dissociation of the UPF1-RNA complex is not a consequence of direct competition in RNA binding but rather an allosteric effect that is likely mediated by the conformational change induced by binding of the helicase to its activator. We discuss these results in light of transient interactions forged during mRNP assembly, particularly in the UPF1-dependent mRNA decay pathways.
Structure of the connexin-43 gap junction channel in a putative closed state
Authors: Qi Chao , Acosta-Gutierrez Silvia , Lavriha Pia , Othman Alaa , Lopez-Pigozzi Diego , Bayraktar Erva , Schuster Dina , Picotti Paola , Zamboni Nicola , Bortolozzi Mario , Gervasio Francesco L. , Korkhov Volodymyr M. 
Published: March 2022

AbstractGap junction channels (GJCs) mediate intercellular communication by connecting two neighboring cells and enabling direct exchange of ions and small molecules. Cell coupling via connexin-43 (Cx43) GJCs is important in a wide range of cellular processes in health and disease1-3, yet the structural basis of Cx43 function and regulation has not been determined until now. Here we describe the structure of a human Cx43 GJC solved by cryo-EM and single particle analysis at 2.26 Å resolution. The pore region of Cx43 GJC features several lipid-like densities per Cx43 monomer, located close to a putative lateral access site at the monomer boundary. We found a previously undescribed conformation on the cytosolic side of the pore, formed by the N-terminal domain and the transmembrane helix 2 of Cx43 and stabilized by a small molecule. Structures of the Cx43 GJC and hemichannels in nanodiscs reveal a similar gate arrangement. The features of the Cx43 GJC and hemichannel cryo-EM maps and the channel properties revealed by molecular dynamics simulations suggest that the captured states of Cx43 are consistent with a closed state.
SWEET11 and SWEET12 transporters function in tandem to modulate sugar flux in Arabidopsis: An account of the underlying unique structure–function relationship
Authors: Fatima Urooj , Balasubramaniam D. , Khan Wajahat Ali , Kandpal Manu , Vadassery Jyothilakshmi , Arockiasamy Arulandu , Senthil-Kumar Muthappa 
Published: March 2022

AbstractSugar will eventually be exported transporters (SWEETs) have been identified as a unique class of sugar efflux transporters in all biological kingdoms. AtSWEET11 and AtSWEET12 in Arabidopsis act synergistically to perform distinct physiological roles, particularly in apoplasmic phloem loading, seed filling, and sugar level alteration at the site of pathogen infection. Plasma membrane-localized AtSWEET11 and AtSWEET12 transporters exclusively facilitate sucrose transport along the concentration gradient. This article examines the sucrose binding pocket of AtSWEET11 and AtSWEET12 using docking studies, and how they act synergistically in various functions throughout plant development and during abiotic and biotic stresses. Further, we highlight the phylogenetic and the in-silico analyses of AtSWEET11 and AtSWEET12 orthologs from 39 economically important plant species that could provide new platforms for future studies on sugar allocation mechanisms across the different plant families. In-depth understanding of these transporters and their molecular regulatory mechanisms could be harnessed for crop improvement and crop protection.
Dynamic interaction of BcsD subunit in type I bacterial cellulose synthase
Authors: Kondo Tatsuya , Nakamura Yui , Nojima Shingo , Yao Min , Imai Tomoya 
Published: March 2022

AbstractCellulose is a promising biological material for supporting sustainable human life. This natural polymer is synthesized by cellulose synthase, a protein complex in the cell membrane. Cellulose synthase in bacteria is a hetero-subunit complex, and its subunit organization varies widely depending on the species. In the type I bacterial cellulose synthase complex, the BcsD (bacterial cellulose synthase D) protein is believed to play an important role in producing cellulose with long slender fiber morphology and high crystallinity, given the phenotype of the bcsD-deficient mutant and the specific existence of the type I operon in bacterial species synthesizing crystalline cellulose microfibrils such as Acetobacter. In this study, we successfully established a heterogeneously expressed Bcs protein in Escherichia coli as an experimental model and conducted biochemical studies for the BcsD protein and the other three major subunits of bacterial cellulose synthase, BcsA, BcsB, and BcsC. It has been shown that the BcsD protein interacts with the functionally required minimal subunits of the BcsAB complex, as well as the BcsC protein. Furthermore, it was shown that BcsD interacts with the BcsAB complex in two modes: direct protein-protein interactions and indirect interactions through the product cellulose. The former and latter modes represent the basal and active states of the type I bacterial cellulose synthase, respectively. This dynamic behavior of the BcsD protein is important for the type I bacterial cellulose synthase complex to regulate the crystallization process of cellulose.
CRISPR-induced exon skipping of β-catenin reveals tumorigenic mutants driving distinct subtypes of liver cancer
Authors: Mou Haiwei , Yue Junjiayu , Jin Ying , Wang Zhikai , Gao Ya , Janowitz Tobias , Meyer Hannah V. , Kucukural Alper , Wilkinson John E , Ozata Deniz M. , Beyaz Semir 
Published: March 2022

AbstractCRISPR/Cas9-driven cancer modeling studies are based on disruption of tumor suppressor genes (TSGs) by small insertions or deletions (indels) that lead to frame-shift mutations. In addition, CRISPR/Cas9 is widely used to define the significance of cancer oncogenes and genetic dependencies in loss-of function studies. However, how CRISPR/Cas9 influences gain-of-function oncogenic mutations is elusive. Here, we demonstrate that single guide RNA targeting exon 3 of β-catenin results in exon skipping and generates gain-of-function isoforms in vivo. CRISPR/Cas9-mediated exon skipping of β-catenin induces liver tumor formation in synergy with YAPS127A in mice. We define two distinct exon skipping-induced tumor subtypes with different histological and transcriptional features. Notably, ectopic expression of two exon-skipped β-catenin transcript isoforms together with YAPS127A phenocopies the two distinct subtypes of liver cancer. Moreover, we identify similar β-catenin exon skipping events in hepatocellular carcinoma (HCC) patients. Collectively, our findings advance our understanding of β-catenin-related tumorigenesis and reveal that CRISPR/Cas9 can be repurposed, in vivo, to study gain-of-function mutations of oncogenes in cancer.
Solution structure of NPSL2, a regulatory element in the oncomiR-1 RNA
Authors: Liu Yaping , Munsayac Aldrex , Hall Ian , Keane Sarah C. 
Published: March 2022

AbstractThe miR-17~92a polycistron, also known as oncomiR-1, is commonly overexpressed in multiple cancers and has several oncogenic properties. OncomiR-1 encodes six constituent microRNAs (miRs), each enzymatically processed with different efficiencies. However, the structural mechanism that regulates this differential processing remains unclear. Chemical probing of oncomiR-1 revealed that the Drosha cleavage sites of pri-miR-92a are sequestered in a four-way junction. NPSL2, an independent stem loop element, is positioned just upstream of pri-miR-92a and sequesters a crucial part of the sequence that constitutes the basal helix of pri-miR-92a. Disruption of the NPSL2 hairpin structure could promote the formation of a pri-miR-92a structure that is primed for processing by Drosha. Thus, NPSL2 is predicted to function as a structural switch, regulating pri-miR-92a processing. Here, we determined the solution structure of NPSL2 using solution NMR spectroscopy. This is the first high-solution structure of an oncomiR-1 element. NPSL2 adopts a hairpin structure with a large, but highly structured, apical and internal loops. The 10-bp apical loop contains a pH-sensitive A+·C mismatch. Additionally, several adenosines within the apical and internal loops have elevated pKa values. The protonation of these adenosines can stabilize the NPSL2 structure through electrostatic interactions. Our study provides fundamental insights into the secondary and tertiary structure of an important RNA hairpin proposed to regulate miR biogenesis.
Local 5-HT signal bi-directionally regulates the coincidence time window of associative learning
Authors: Zeng Jianzhi , Li Xuelin , Zhangren Zimo , Lv Mingyue , Wang Yipan , Tan Ke , Xia Xiju , Wan Jinxia , Jing Miao , Yang Yang , Li Yan , Li Yulong 
Published: March 2022

AbstractTemporal coincidence between the conditioned stimulus (CS) and unconditioned stimulus (US) is essential for associative learning across species. Despite its ubiquitous presence, the mechanism that may regulate this time window duration remains unclear yet. Using olfactory associative learning in Drosophila as a model, we find that suppressing or promoting serotonin (5-HT) signal could respectively shorten or prolong the coincidence time window of odor-shock associative learning and synaptic plasticity in mushroom body (MB) Kenyon cells (KCs). Capitalizing on GPCR-activation based (GRAB) sensors for 5-HT and acetylcholine (ACh), we characterized the in vivo 5-HT dynamics in MB lobes during odor and shock stimulations and further dissected this microcircuit. Interestingly, local KC-released ACh activates nicotinic receptors on the dorsal paired medial (DPM) neuron, and in turn the DPM neuron releases 5-HT to inhibit the ACh signal via the 5-HT1a receptor. Finally, we demonstrated that the DPM-mediated serotonergic feedback circuit is sufficient and necessary to regulate the coincidence time window. This work provides a model for studying the temporal contingency of environmental events and their causal relationship.
A note on the correspondence between horizontal and vertical price transmission
Authors: Kinnucan Henry W. 
Published: March 2022

AbstractHorizontal (vertical) elasticities of price transmission in a competitive market can be positive or negative in sign depending on whether observed changes in market prices are triggered by shifts in the supply or demand for the commodity or by changes in trade (marketing) costs. These facts suggest estimates of horizontal (vertical) elasticities of price transmission obtained from empirical models that exclude trade (marketing) costs will suffer from attenuation bias. The attenuation bias is apt to cause inferences about market efficiency to be more pessimistic than is warranted.
Preparation and physiochemical properties of enzymatically modified octenyl succinate starch
Authors: Chen Xingyu , Hu Zhongshan , Chen Da , Feng Tao 
Published: March 2022

AbstractThe high viscosity and low solubility of octenyl succinate starch (OSAS) in water often lead to low reaction efficiency and uneven distribution of OSA groups, which can be solved by subjecting OSA starch to enzymatic digestion. Waxy corn starch is used to produce OSAS. The molecular weight of enzymolysis modified octenyl succinate starches (E‐OSAS) decreased with the addition of enzyme, and the substitution of enzymatically digested OSAS was larger than that of OSAS. As the addition of pullulanase increased, the substitution of E‐OSAS tended to increase and the apparent viscosity decreased significantly. The smaller its particle size and polydispersity index (PDI), the larger the absolute value of the zeta potential. E40‐OSAS with the smallest particle size and best homogeneity and stability had the smallest weight average molecular weight (1.38 × 106 g/mol), the smallest number average molecular weight (1.37 × 105 g/mol), and the largest degree of substitution of 0.019. The E‐OSAS has not been investigated deeply enough, and the enzymatic treatment by pullulanase is not much studied, so this study is of great importance to provide some basis for the research of new microcapsules.Practical ApplicationThis work aims to provide wall materials with lower viscosity and better encapsulation properties for the food industry. Waxy corns starch is used to manufacture OSAS. This wall material is a partly biodegradable material that is hydrophilic on the outside and hydrophobic on the inside, and its preparation process is in line with the concept of green chemistry.