bluuebunny/crossref_metadata_2025_split huggingface dataset:
Novel KCNQ4 variants in different functional domains confer genotype- and mechanism-based therapeutics in patients with nonsyndromic hearing loss
Authors: Lee Sang-Yeon , Choi Hyun Been , Park Mina , Choi Il Soon , An Jieun , Kim Ami , Kim Eunku , Kim Nahyun , Han Jin Hee , Kim Min young , Lee Seung min , Oh Doo-Yi , Kim Bong Jik , Yi Nayoung , Kim Nayoung, K. D. , Lee Chung , Park Woong-Yang , Koh Young Ik , Gee Heon Yung , Cho Hyun Sung , Kang Tong Mook , Choi Byung Yoon 
Published: July 2021

AbstractLoss-of-function variant in the gene encoding the KCNQ4 potassium channel causes autosomal dominant nonsyndromic hearing loss (DFNA2), and no effective pharmacotherapeutics have been developed to reverse channel activity impairment. Phosphatidylinositol 4,5-bisphosphate (PIP2), an obligatory phospholipid for maintaining KCNQ channel activity, confers differential pharmacological sensitivity of channels to KCNQ openers. Through whole-exome sequencing of DFNA2 families, we identified three novel KCNQ4 variants related to diverse auditory phenotypes in the proximal C-terminus (p.Arg331Gln), the C-terminus of the S6 segment (p.Gly319Asp), and the pore region (p.Ala271_Asp272del). Potassium currents in HEK293T cells expressing each KCNQ4 variant were recorded by patch-clamp, and functional recovery by PIP2 expression or KCNQ openers was examined. In the homomeric expression setting, the three novel KCNQ4 mutant proteins lost conductance and were unresponsive to KCNQ openers or PIP2 expression. Loss of p.Arg331Gln conductance was slightly restored by a tandem concatemer channel (WT-p.R331Q), and increased PIP2 expression further increased the concatemer current to the level of the WT channel. Strikingly, an impaired homomeric p.Gly319Asp channel exhibited hyperactivity when a concatemer (WT-p.G319D), with a negative shift in the voltage dependence of activation. Correspondingly, a KCNQ inhibitor and chelation of PIP2 effectively downregulated the hyperactive WT-p.G319D concatemer channel. Conversely, the pore-region variant (p.Ala271_Asp272del) was nonrescuable under any condition. Collectively, these novel KCNQ4 variants may constitute therapeutic targets that can be manipulated by the PIP2 level and KCNQ-regulating drugs under the physiological context of heterozygous expression. Our research contributes to the establishment of a genotype/mechanism-based therapeutic portfolio for DFNA2.
A longitudinal study of the antilipolytic effect of insulin in women following bariatric surgery
Authors: Kwok Kelvin Ho Man , Andersson Daniel P. , Rydén Mikael , Arner Peter 
Published: July 2021

AbstractInsulin resistance of glucose utilization is fully restored following BMI normalization after bariatric surgery. We investigated if this also pertains to insulin-induced effects on fatty acid handling. Forty-three women with obesity (OB) were investigated before and 2 years after Roux-en-Y gastric by-pass when BMI was <30 kg/m2 (PO) and compared with 26 never obese women (NO). The Adipo-IR index was used as measure of insulin antilipolytic sensitivity. Changes (delta) in circulating glycerol and fatty acid levels during hyperinsulinemic euglycemic clamp represented the insulin maximum antilipolytic effect. Overall fatty acid utilization was reflected by delta fatty acids minus 3 × delta glycerol. Adipo-IR was higher in OB than in NO and PO (p < 0.0001), the latter two groups having similar values. Insulin lowered glycerol levels by about 70% in all groups, but delta glycerol was 30% larger in PO than in NO (p = 0.04). Delta adds and adds utilization were similar in all groups. We conclude that women with obesity, whose BMI is normalized after bariatric surgery, have improved maximum in vivo antilipolytic effect of insulin above expected in absolute but not relative terms as regards glycerol changes, while the handling of circulating fatty acids is changed to the normal state.
Pharmacological and optical activation of TrkB in Parvalbumin interneurons regulate intrinsic states to orchestrate cortical plasticity
Authors: Winkel Frederike , Ryazantseva Maria , Voigt Mathias B. , Didio Giuliano , Lilja Antonia , Llach Pou Maria , Steinzeig Anna , Harkki Juliana , Englund Jonas , Khirug Stanislav , Rivera Claudio , Palva Satu , Taira Tomi , Lauri Sari E. , Umemori Juzoh , Castrén Eero 
Published: July 2021

AbstractElevated states of brain plasticity typical for critical periods of early postnatal life can be reinstated in the adult brain through interventions, such as antidepressant treatment and environmental enrichment, and induced plasticity may be critical for the antidepressant action. Parvalbumin-positive (PV) interneurons regulate the closure of developmental critical periods and can alternate between high and low plasticity states in response to experience in adulthood. We now show that PV plasticity states and cortical networks are regulated through the activation of TrkB neurotrophin receptors. Visual cortical plasticity induced by fluoxetine, a widely prescribed selective serotonin reuptake inhibitor (SSRI) antidepressant, was lost in mice with reduced expression of TrkB in PV interneurons. Conversely, optogenetic gain-of-function studies revealed that activation of an optically activatable TrkB (optoTrkB) specifically in PV interneurons switches adult cortical networks into a state of elevated plasticity within minutes by decreasing the intrinsic excitability of PV interneurons, recapitulating the effects of fluoxetine. TrkB activation shifted cortical networks towards a low PV configuration, promoting oscillatory synchrony, increased excitatory-inhibitory balance, and ocular dominance plasticity. OptoTrkB activation promotes the phosphorylation of Kv3.1 channels and reduces the expression of Kv3.2 mRNA providing a mechanism for the lower excitability. In addition, decreased expression and puncta of Synaptotagmin2 (Syt2), a presynaptic marker of PV interneurons involved in Ca2+-dependent neurotransmitter release, suggests lower inputs onto pyramidal neurons suppressing feed-forward inhibition. Together, the results provide mechanistic insights into how TrkB activation in PV interneurons orchestrates the activity of cortical networks and mediating antidepressant responses in the adult brain.
Fermitin family member 2 promotes melanoma progression by enhancing the binding of p-α-Pix to Rac1 to activate the MAPK pathway
Authors: Huang Shaobin , Deng Wuguo , Wang Peng , Yan Yue , Xie Chuanbo , Cao Xiaoling , Chen Miao , Zhang Changlin , Shi Dingbo , Dong Yunxian , Cheng Pu , Xu Hailin , Zhu Wenkai , Hu Zhicheng , Tang Bing , Zhu Jiayuan 
Published: July 2021

AbstractWe identified fermitin family member 2 (FERMT2, also known as kindlin-2) as a potential target in A375 cell line by siRNA library screening. Drugs that target mutant BRAF kinase lack durable efficacy in the treatment of melanoma because of acquired resistance, thus the identification of novel therapeutic targets is needed. Immunohistochemistry was used to identify kindlin-2 expression in melanoma samples. The interaction between kindlin-2 and Rac1 or p-Rac/Cdc42 guanine nucleotide exchange factor 6 (α-Pix) was investigated. Finally, the tumor suppressive role of kindlin-2 was validated in vitro and in vivo. Analysis of clinical samples and Oncomine data showed that higher levels of kindlin-2 predicted a more advanced T stage and M stage and facilitated metastasis and recurrence. Kindlin-2 knockdown significantly inhibited melanoma growth and migration, whereas kindlin-2 overexpression had the inverse effects. Further study showed that kindlin-2 could specifically bind to p-α-Pix(S13) and Rac1 to induce a switch from the inactive Rac1-GDP conformation to the active Rac1-GTP conformation and then stimulate the downstream MAPK pathway. Moreover, we revealed that a Rac1 inhibitor suppressed melanoma growth and metastasis and the combination of the Rac1 inhibitor and vemurafenib resulted in a better therapeutic outcome than monotherapy in melanoma with high kindlin-2 expression and BRAF mutation. Our results demonstrated that kindlin-2 promoted melanoma progression, which was attributed to specific binding to p-α-Pix(S13) and Rac1 to stimulate the downstream MAPK pathway. Thus, kindlin-2 could be a potential therapeutic target for treating melanoma.
Positive feedback regulation of lncRNA PVT1 and HIF2α contributes to clear cell renal cell carcinoma tumorigenesis and metastasis
Authors: Zhang Ming-xiao , Zhang Li-zhen , Fu Liang-min , Yao Hao-hua , Tan Lei , Feng Zi-hao , Li Jia-ying , Lu Jun , Pan Yi-hui , Shu Guan-nan , Li Peng-ju , Tang Yi-ming , Liao Zhuang-yao , Wei Jin-huan , Chen Wei , Guo Jian-ping , Luo Jun-hang , Chen Zhen-hua 
Published: July 2021

AbstractLong noncoding RNAs (lncRNAs) have been reported to exert important roles in tumors, including clear cell renal cell carcinoma (ccRCC). PVT1 is an important oncogenic lncRNA which has critical effects on onset and development of various cancers, however, the underlying mechanism of PVT1 functioning in ccRCC remains largely unknown. VHL deficiency-induced HIF2α accumulation is one of the major factors for ccRCC. Here, we identified the potential molecular mechanism of PVT1 in promoting ccRCC development by stabilizing HIF2α. PVT1 was significantly upregulated in ccRCC tissues and high PVT1 expression was associated with poor prognosis of ccRCC patients. Both gain-of-function and loss-of function experiments revealed that PVT1 enhanced ccRCC cells proliferation, migration, and invasion and induced tumor angiogenesis in vitro and in vivo. Mechanistically, PVT1 interacted with HIF2α protein and enhanced its stability by protecting it from ubiquitination-dependent degradation, thereby exerting its biological significance. Meanwhile, HIF2α bound to the enhancer of PVT1 to transactivate its expression. Furthermore, HIF2α specific inhibitor could repress PVT1 expression and its oncogenic functions. Therefore, our study demonstrates that the PVT1/ HIF2α positive feedback loop involves in tumorigenesis and progression of ccRCC, which may be exploited for anticancer therapy.
Exosomal miR-1260b derived from non-small cell lung cancer promotes tumor metastasis through the inhibition of HIPK2
Authors: Kim Dong Ha , Park Hyojeong , Choi Yun Jung , Kang Myoung-Hee , Kim Tae-Keun , Pack Chan-Gi , Choi Chang-Min , Lee Jae Cheol , Rho Jin Kyung 
Published: July 2021

AbstractTumor-derived exosomes (TEXs) contain enriched miRNAs, and exosomal miRNAs can affect tumor growth, including cell proliferation, metastasis, and drug resistance through cell-to-cell communication. We investigated the role of exosomal miR-1260b derived from non-small cell lung cancer (NSCLC) in tumor progression. Exosomal miR-1260b induced angiogenesis by targeting homeodomain-interacting protein kinase-2 (HIPK2) in human umbilical vein endothelial cells (HUVECs). Furthermore, exosomal miR-1260b or suppression of HIPK2 led to enhanced cellular mobility and cisplatin resistance in NSCLC cells. In patients with NSCLC, the level of HIPK2 was significantly lower in tumor tissues than in normal lung tissues, while that of miR-1260b was higher in tumor tissues. HIPK2 and miR-1260b expression showed an inverse correlation, and this correlation was strong in distant metastasis. Finally, the expression level of exosomal miR-1260b in plasma was higher in patients with NSCLC than in healthy individuals, and higher levels of exosomal miR-1260b were associated with high-grade disease, metastasis, and poor survival. In conclusion, exosomal miR-1260b can promote angiogenesis in HUVECs and metastasis of NSCLC by regulating HIPK2 and may serve as a prognostic marker for lung cancers.
Gene-drive suppression of mosquito populations in large cages as a bridge between lab and field
Authors: Hammond Andrew , Pollegioni Paola , Persampieri Tania , North Ace , Minuz Roxana , Trusso Alessandro , Bucci Alessandro , Kyrou Kyros , Morianou Ioanna , Simoni Alekos , Nolan Tony , Müller Ruth , Crisanti Andrea 
Published: July 2021

AbstractCRISPR-based gene-drives targeting the gene doublesex in the malaria vector Anopheles gambiae effectively suppressed the reproductive capability of mosquito populations reared in small laboratory cages. To bridge the gap between laboratory and the field, this gene-drive technology must be challenged with vector ecology.Here we report the suppressive activity of the gene-drive in age-structured An. gambiae populations in large indoor cages that permit complex feeding and reproductive behaviours.The gene-drive element spreads rapidly through the populations, fully supresses the population within one year and without selecting for resistance to the gene drive. Approximate Bayesian computation allowed retrospective inference of life-history parameters from the large cages and a more accurate prediction of gene-drive behaviour under more ecologically-relevant settings.Generating data to bridge laboratory and field studies for invasive technologies is challenging. Our study represents a paradigm for the stepwise and sound development of vector control tools based on gene-drive.
Heatstroke predictions by machine learning, weather information, and an all-population registry for 12-hour heatstroke alerts
Authors: Ogata Soshiro , Takegami Misa , Ozaki Taira , Nakashima Takahiro , Onozuka Daisuke , Murata Shunsuke , Nakaoku Yuriko , Suzuki Koyu , Hagihara Akihito , Noguchi Teruo , Iihara Koji , Kitazume Keiichi , Morioka Tohru , Yamazaki Shin , Yoshida Takahiro , Yamagata Yoshiki , Nishimura Kunihiro 
Published: July 2021

AbstractThis study aims to develop and validate prediction models for the number of all heatstroke cases, and heatstrokes of hospital admission and death cases per city per 12 h, using multiple weather information and a population-based database for heatstroke patients in 16 Japanese cities (corresponding to around a 10,000,000 population size). In the testing dataset, mean absolute percentage error of generalized linear models with wet bulb globe temperature as the only predictor and the optimal models, respectively, are 43.0% and 14.8% for spikes in the number of all heatstroke cases, and 37.7% and 10.6% for spikes in the number of heatstrokes of hospital admission and death cases. The optimal models predict the spikes in the number of heatstrokes well by machine learning methods including non-linear multivariable predictors and/or under-sampling and bagging. Here, we develop prediction models whose predictive performances are high enough to be implemented in public health settings.
Rewiring of the ubiquitinated proteome determines ageing in C. elegans
Authors: Koyuncu Seda , Loureiro Rute , Lee Hyun Ju , Wagle Prerana , Krueger Marcus , Vilchez David 
Published: July 2021

AbstractAgeing is driven by a loss of cellular integrity1. Given the major role of ubiquitin modifications in cell function2, here we assess the link between ubiquitination and ageing by quantifying whole-proteome ubiquitin signatures in Caenorhabditis elegans. We find a remodelling of the ubiquitinated proteome during ageing, which is ameliorated by longevity paradigms such as dietary restriction and reduced insulin signalling. Notably, ageing causes a global loss of ubiquitination that is triggered by increased deubiquitinase activity. Because ubiquitination can tag proteins for recognition by the proteasome3, a fundamental question is whether deficits in targeted degradation influence longevity. By integrating data from worms with a defective proteasome, we identify proteasomal targets that accumulate with age owing to decreased ubiquitination and subsequent degradation. Lowering the levels of age-dysregulated proteasome targets prolongs longevity, whereas preventing their degradation shortens lifespan. Among the proteasomal targets, we find the IFB-2 intermediate filament4 and the EPS-8 modulator of RAC signalling5. While increased levels of IFB-2 promote the loss of intestinal integrity and bacterial colonization, upregulation of EPS-8 hyperactivates RAC in muscle and neurons, and leads to alterations in the actin cytoskeleton and protein kinase JNK. In summary, age-related changes in targeted degradation of structural and regulatory proteins across tissues determine longevity.
Rapid and stable mobilization of CD8+ T cells by SARS-CoV-2 mRNA vaccine
Authors: Oberhardt Valerie , Luxenburger Hendrik , Kemming Janine , Schulien Isabel , Ciminski Kevin , Giese Sebastian , Csernalabics Benedikt , Lang-Meli Julia , Janowska Iga , Staniek Julian , Wild Katharina , Basho Kristi , Marinescu Mircea Stefan , Fuchs Jonas , Topfstedt Fernando , Janda Ales , Sogukpinar Oezlem , Hilger Hanna , Stete Katarina , Emmerich Florian , Bengsch Bertram , Waller Cornelius F. , Rieg Siegbert , Sagar  , Boettler Tobias , Zoldan Katharina , Kochs Georg , Schwemmle Martin , Rizzi Marta , Thimme Robert , Neumann-Haefelin Christoph , Hofmann Maike 
Published: July 2021

AbstractSARS-CoV-2 spike mRNA vaccines1–3 mediate protection from severe disease as early as ten days after prime vaccination3, when neutralizing antibodies are hardly detectable4–6. Vaccine-induced CD8+ T cells may therefore be the main mediators of protection at this early stage7,8. The details of their induction, comparison to natural infection, and association with other arms of vaccine-induced immunity remain, however, incompletely understood. Here we show on a single-epitope level that a stable and fully functional CD8+ T cell response is vigorously mobilized one week after prime vaccination with bnt162b2, when circulating CD4+ T cells and neutralizing antibodies are still weakly detectable. Boost vaccination induced a robust expansion that generated highly differentiated effector CD8+ T cells; however, neither the functional capacity nor the memory precursor T cell pool was affected. Compared with natural infection, vaccine-induced early memory T cells exhibited similar functional capacities but a different subset distribution. Our results indicate that CD8+ T cells are important effector cells, are expanded in the early protection window after prime vaccination, precede maturation of other effector arms of vaccine-induced immunity and are stably maintained after boost vaccination.
Spanish electoral archive. SEA database
Authors: Pérez Virgilio , Aybar Cristina , Pavía Jose M. 
Published: July 2021

AbstractThis paper introduces the SEA database (acronym for Spanish Electoral Archive). SEA brings together the most complete public repository available to date on Spanish election outcomes. SEA holds all the results recorded from the electoral processes of General (1979–2019), Regional (1989–2021), Local (1979–2019) and European Parliamentary (1987–2019) elections held in Spain since the restoration of democracy in the late 70 s, in addition to other data sets with electoral content. The data are offered for free and is presented in a homogeneous and friendly format. Most of the databases are available for download with data from various electoral levels, including from the ballot box level. This paper details how the information is organized, what the main variables are on offer for each election, which processes were applied to the data for their homogenization, and discusses future areas of work. This data has many applications, for example, as inputs in election prediction models and in ecological inference algorithms, to study determinants of turnout or voting, or for defining marketing strategies.
Nature-inspired wax-coated jute bags for reducing post-harvest storage losses
Authors: Odokonyero Kennedy , Gallo Adair , Mishra Himanshu 
Published: July 2021

AbstractPost-harvest storage of grains is crucial for food and feed reserves and facilitating seeds for planting. Ironically, post-harvest losses continue to be a major food security threat in the developing world, especially where jute bags are utilized. While jute fabrics flaunt mechanical strength and eco-friendliness, their water-loving nature has proven to be their Achilles heel. Increased relative humidity and/or precipitation wets jute, thereby elevating the moisture content of stored seeds and causing fungal growth. This reduces seed longevity, viability, and nutritional value. To address this crucial weakness of jute bags, we followed a nature-inspired approach to modify their surface microtexture and chemical make-up via alkali and wax treatments, respectively. The resulting wax-coated jute bags (WCJBs) exhibited significant water-repellency to simulated rainfall and airborne moisture compared to control jute bags (CJBs). A 2 months-long seed storage experiment with wheat (Triticum aestivum) grains exposed to 55%, 75%, and 98% relative humidity environments revealed that the grains stored in the WCJBs exhibited 7.5–4% lesser (absolute) moisture content than those in the CJBs. Furthermore, WCJBs-stored grains exhibited a 35–12% enhancement in their germination efficacy over the controls. This nature-inspired engineering solution could contribute towards reducing post-harvest losses in the developing world, where jute bags are extensively utilized for grain storage.
Multi-step ahead thermal warning network for energy storage system based on the core temperature detection
Authors: Li Marui , Dong Chaoyu , Yu Xiaodan , Xiao Qian , Jia Hongjie 
Published: July 2021

AbstractThe energy storage system is an important part of the energy system. Lithium-ion batteries have been widely used in energy storage systems because of their high energy density and long life. However, the temperature is still the key factor hindering the further development of lithium-ion battery energy storage systems. Both low temperature and high temperature will reduce the life and safety of lithium-ion batteries. In actual operation, the core temperature and the surface temperature of the lithium-ion battery energy storage system may have a large temperature difference. However, only the surface temperature of the lithium-ion battery energy storage system can be easily measured. The estimation method of the core temperature, which can better reflect the operation condition of the lithium-ion battery energy storage system, has not been commercialized. To secure the thermal safety of the energy storage system, a multi-step ahead thermal warning network for the energy storage system based on the core temperature detection is developed in this paper. The thermal warning network utilizes the measurement difference and an integrated long and short-term memory network to process the input time series. This thermal early warning network takes the core temperature of the energy storage system as the judgment criterion of early warning and can provide a warning signal in multi-step in advance. This detection network can use real-time measurement to predict whether the core temperature of the lithium-ion battery energy storage system will reach a critical value in the following time window. And the output of the established warning network model directly determines whether or not an early emergency signal should be sent out. In the end, the accuracy and effectiveness of the model are verified by numerous testing.