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JOURNAL ARTICLE
Yasser Al-Sarraj, Rowaida Z Taha, Eman Al-Dous, Dina Ahram, Somayyeh Abbasi, Eman Abuazab, Hibah Shaath, Wesal Habbab, Khaoula Errafii, Yosra Bejaoui, Maryam AlMotawa, Namat Khattab, Yasmin Abu Aqel, Karim E Shalaby, Amina Al-Ansari, Marios Kambouris, Adel Abouzohri, Iman Ghazal, Mohammed Tolfat, Fouad Alshaban, Hatem El-Shanti, Omar M E Albagha
Introduction: Autism spectrum disorder (ASD) is characterized by aberrations in social interaction and communication associated with repetitive behaviors and interests, with strong clinical heterogeneity. Genetic factors play an important role in ASD, but about 75% of ASD cases have an undetermined genetic risk. Methods: We extensively investigated an ASD cohort made of 102 families from the Middle Eastern population of Qatar. First, we investigated the copy number variations (CNV) contribution using genome-wide SNP arrays...
2024: Frontiers in Genetics
#2
JOURNAL ARTICLE
Héctor Carbajal-Contreras, Adrian Rafael Murillo-de-Ozores, Germán Magaña-Avila, Alejandro Marquez-Salinas, Laurent Bourqui, Michelle Tellez-Sutterlin, Jessica P Bahena-Lopez, Eduardo Cortes-Arroyo, Sebastián González-Behn-Eschemburg, Alejandro Lopez-Saavedra, Norma Vazquez, David H Ellison, Johannes Loffing, Gerardo Gamba, María Castañeda-Bueno
Vasopressin regulates water homeostasis via the V2 receptor in the kidney at least in part through protein kinase A (PKA) activation. Vasopressin, through an unknown pathway, upregulates the activity and phosphorylation of the Na+-Cl- cotransporter (NCC) and Na+-K+-2Cl- cotransporter 2 (NKCC2) by Ste20-related Proline/Alanine rich Kinase (SPAK) and Oxidative Stress Responsive kinase 1 (OSR1), which are regulated by the With No Lysine (K) kinase (WNK) family. Phosphorylation of WNK4 at PKA consensus motifs may be involved...
December 14, 2023: American Journal of Physiology. Renal Physiology
#3
Liliana R Teixeira, Radha Akella, John M Humphreys, Haixia He, Elizabeth J Goldsmith
Previous observations showed that chloride and osmotic stress regulate the autophosphorylation and activity of the kinase domains of WNK1 and WNK3. Further, prior crystallography on the asymmetric dimeric of the unphosphorylated WNK1 kinase domain (WNK1/S382A, WNK1/SA) revealed conserved waters in the active site. Here we show by crystallography that PEG400 applied to crystals of dimeric WNK1/SA grown in space group P1 induces de-dimerization with a change in space group to P2 1 . Both the conserved waters, referred to here as conserved water network 1 (CWN1) and the chloride binding site are disrupted by PEG400...
August 31, 2023: bioRxiv
#4
JOURNAL ARTICLE
John M Humphreys, Liliana R Teixeira, Radha Akella, Haixia He, Ashari R Kannangara, Kamil Sekulski, John Pleinis, Joanna Liwocha, Jenny Jiou, Kelly A Servage, Kim Orth, Lukasz Joachimiak, Josep Rizo, Melanie H Cobb, Chad A Brautigam, Aylin R Rodan, Elizabeth J Goldsmith
Previous work has demonstrated that the WNK kinases 1 and 3 are direct osmosensors consistent with their established role in cell volume control. WNK kinases may also be regulated by hydrostatic pressure. Hydrostatic pressure applied to cells in culture with N2 gas or to Drosophila Malpighian tubules by centrifugation induces phosphorylation of downstream effectors of endogenous WNKs. In vitro, the autophosphorylation and activity of the unphosphorylated kinase domain of WNK3 (uWNK3) is enhanced to a lesser extent than in cells by 190 kPa applied with N2 gas...
August 16, 2023: Molecular Biology of the Cell
#5
JOURNAL ARTICLE
Wantao Liu, Xinan Li, Qiang Ma, Yongtong Zhu, Wenzhong Zhao, Yisheng Yang, Weiqiang Xiao, Daxiong Huang, Fengbo Cai, David Yiu Leung Chan, Shanchao Zhao, Qingjun Chu
BACKGROUND: Sertoli cell-only syndrome (SCOS) is the most serious pathological type of non-obstructive azoospermia. Recently, several genes related to SCOS have been identified, including FANCM, TEX14, NR5A1, NANOS2, PLK4, WNK3, and FANCA, but they cannot fully explain the pathogenesis of SCOS. This study attempted to explain spermatogenesis dysfunction in SCOS through testicular tissue RNA sequencing and to provide new targets for SCOS diagnosis and therapy. METHODS: We analyzed differentially expressed genes (DEGs) based on RNA sequencing of nine patients with SCOS and three patients with obstructive azoospermia and normal spermatogenesis...
June 9, 2023: Reproductive Biology and Endocrinology: RB&E
#6
JOURNAL ARTICLE
Nan Chen, Yushuang Liu, Hongyi Yu, Sihan Liu, Peng Xiao, Zhongyi Jia, Zhongling Zhang
Cullin 3 (CUL3), a member of Cullin-RING ubiquitin ligase family, regulates multiple intracellular pathways. CUL3 expression in peripheral immune cells is highly associated with the development of stroke, while little is known about the mechanism of how CUL3 participates in cerebral ischemia/reperfusion (I/R) injury. In this study, we showed that CUL3 was obviously upregulated in brain tissues of male rats received middle cerebral artery occlusion (MCAO) and reperfusion and oxygen-glucose deprivation/reoxygenation (OGD/R)-induced neurons...
January 30, 2023: Neuroscience
#7
JOURNAL ARTICLE
Julita Chlebowicz, Radha Akella, John M Humphreys, Haixia He, Ashari R Kannangara, Shuguang Wei, Bruce Posner, Elizabeth J Goldsmith
INTRODUCTION: WNK [with no lysine (K)] kinases are serine/threonine kinases associated with familial hyperkalemic hypertension (FHHt). WNKs are therapeutic targets for blood pressure regulation, stroke and several cancers including triple negative breast cancer and glioblastoma. Here, we searched for and characterized novel WNK kinase inhibitors. METHODS: We used a ~210,000-compound library in a high-throughput screen, re-acquisition and assay, commercial specificity screens and crystallography to identify WNK-isoform-selective inhibitors...
2023: Drug Design, Development and Therapy
#8
JOURNAL ARTICLE
Hyun Ju Yoon, Gi-Cheon Kim, Sejin Oh, Hakhyun Kim, Yong Keon Kim, Yunji Lee, Min Seo Kim, Gino Kwon, Yeon-Su Ok, Ho-Keun Kwon, Hyun Seok Kim
Immune checkpoint therapies, such as programmed cell death ligand 1 (PD-L1) blockade, have shown remarkable clinical benefit in many cancers by restoring the function of exhausted T cells. Hence, the identification of novel PD-L1 regulators and the development of their inhibition strategies have significant therapeutic advantages. Here, we conducted pooled shRNA screening to identify regulators of membrane PD-L1 levels in lung cancer cells targeting druggable genes and cancer drivers. We identified WNK lysine deficient protein kinase 3 (WNK3) as a novel positive regulator of PD-L1 expression...
November 10, 2022: Experimental & Molecular Medicine
#9
JOURNAL ARTICLE
Adya Saran Sinha, Tianying Wang, Miho Watanabe, Yasushi Hosoi, Eisei Sohara, Tenpei Akita, Shinichi Uchida, Atsuo Fukuda
The with-no-lysine (WNK) family of serine-threonine kinases and its downstream kinases of STE20/SPS1-related proline/alanine-rich kinase (SPAK) and oxidative stress-responsive kinase-1 (OSR1) may regulate intracellular Cl- homeostasis through phosphorylation of cation-Cl- co-transporters. WNK3 is expressed in fetal and postnatal brains, and its expression level increases during development. Its roles in neurons, however, remain uncertain. Using WNK3 knockout (KO) mice, we investigated the role of WNK3 in the regulation of the intracellular Cl- concentration ([Cl- ]i ) and the excitability of layer V pyramidal neurons in the medial prefrontal cortex (mPFC)...
2022: Frontiers in Molecular Neuroscience
#10
JOURNAL ARTICLE
Fang Liu, Haoyang Xu, Wei Ni, Yakun Wang, Xiaoyou Hong, Wei Li, Lingyun Yu, Chen Chen, Chengqing Wei, Xiaoli Liu, Xinping Zhu
DNA methylation plays a significant role in transducing external environmental signals to a cellular response in reptiles; however, whether the methylation patterns are conserved across species remains unclear. Here, we examined the genome-wide DNA methylation differentiation between male and female hatchling gonads of the temperature-dependent sex determination (TSD) Mauremys mutica (M. mutica) using methylation-dependent restriction-site associated DNA sequencing (MethylRAD-seq) to test differentially methylated genes underlying sexual development...
July 14, 2022: Biology of Reproduction
#11
JOURNAL ARTICLE
Sébastien Küry, Jinwei Zhang, Thomas Besnard, Alfonso Caro-Llopis, Xue Zeng, Stephanie M Robert, Sunday S Josiah, Emre Kiziltug, Anne-Sophie Denommé-Pichon, Benjamin Cogné, Adam J Kundishora, Le T Hao, Hong Li, Roger E Stevenson, Raymond J Louie, Wallid Deb, Erin Torti, Virginie Vignard, Kirsty McWalter, F Lucy Raymond, Farrah Rajabi, Emmanuelle Ranza, Detelina Grozeva, Stephanie A Coury, Xavier Blanc, Elise Brischoux-Boucher, Boris Keren, Katrin Õunap, Karit Reinson, Pilvi Ilves, Ingrid M Wentzensen, Eileen E Barr, Solveig Heide Guihard, Perrine Charles, Eleanor G Seaby, Kristin G Monaghan, Marlène Rio, Yolande van Bever, Marjon van Slegtenhorst, Wendy K Chung, Ashley Wilson, Delphine Quinquis, Flora Bréhéret, Kyle Retterer, Pierre Lindenbaum, Emmanuel Scalais, Lindsay Rhodes, Katrien Stouffs, Elaine M Pereira, Sara M Berger, Sarah S Milla, Ankita B Jaykumar, Melanie H Cobb, Shreyas Panchagnula, Phan Q Duy, Marie Vincent, Sandra Mercier, Brigitte Gilbert-Dussardier, Xavier Le Guillou, Séverine Audebert-Bellanger, Sylvie Odent, Sébastien Schmitt, Pierre Boisseau, Dominique Bonneau, Annick Toutain, Estelle Colin, Laurent Pasquier, Richard Redon, Arjan Bouman, Jill A Rosenfeld, Michael J Friez, Helena Pérez-Peña, Syed Raza Akhtar Rizvi, Shozeb Haider, Stylianos E Antonarakis, Charles E Schwartz, Francisco Martínez, Stéphane Bézieau, Kristopher T Kahle, Bertrand Isidor
PURPOSE: WNK3 kinase (PRKWNK3) has been implicated in the development and function of the brain via its regulation of the cation-chloride cotransporters, but the role of WNK3 in human development is unknown. METHOD: We ascertained exome or genome sequences of individuals with rare familial or sporadic forms of intellectual disability (ID). RESULTS: We identified a total of 6 different maternally-inherited, hemizygous, 3 loss-of-function or 3 pathogenic missense variants (p...
September 2022: Genetics in Medicine: Official Journal of the American College of Medical Genetics
#12
JOURNAL ARTICLE
Xueshan Zhao, Xiaodong Jin, Qiuning Zhang, Ruifeng Liu, Hongtao Luo, Zhen Yang, Yichao Geng, Shuangwu Feng, Chengcheng Li, Lina Wang, Xiaohu Wang, Qiang Li
BACKGROUND: The lncRNA H19 is believed to act as an oncogene in various types of tumors and is considered to be a therapeutic target and diagnostic marker. However, the role of the lncRNA H19 in regulating the radiosensitivity of non-small cell lung cancer (NSCLC) cells is unknown. METHODS: The expression profiles of lncRNAs in NSCLC were explored via transcriptome sequencing. CCK-8, EdU incorporation and clonogenic survival assays were conducted to evaluate the proliferation and radiosensitivity of NSCLC cells...
December 4, 2021: Cancer Cell International
#13
JOURNAL ARTICLE
Wee Meng Lim, Eunice W M Chin, Bor Luen Tang, Tingting Chen, Eyleen L K Goh
The activation of chloride (Cl- )permeable gamma (γ)-aminobutyric acid type A(GABAA ) receptors induces synaptic inhibition in mature and excitation in immature neurons. This developmental "switch" in GABA function controlled by its polarity depends on the postnatal decrease in intraneuronal Cl- concentration mediated by KCC2, a member of cation-chloride cotransporters (CCCs). The serine-threonine kinase WNK3 (With No Lysine [K]), is a potent regulator of all CCCs and is expressed in neurons. Here, we characterized the functions of WNK3 and its role in GABAergic signaling in cultured embryonic day 18 (E18) hippocampal neurons...
2021: Frontiers in Molecular Neuroscience
#14
REVIEW
Shihan Salihu, Nur Farah Meor Azlan, Sunday Solomon Josiah, Zhijuan Wu, Yun Wang, Jinwei Zhang
The circadian system plays an immense role in controlling physiological processes in our body. The suprachiasmatic nucleus (SCN) supervises this system, regulating and harmonising the circadian rhythms in our body. Most neurons present in the SCN are GABAergic neurons. Although GABA is considered the main inhibitory neurotransmitter of the CNS, recent studies have shown that excitatory responses were recorded in this area. These responses are enabled by an increase in intracellular chloride ions [Cl- ]i levels...
September 2021: Asian journal of pharmaceutical sciences
#15
JOURNAL ARTICLE
Pan Zhang, Olivia C Perez, Bruce R Southey, Jonathan V Sweedler, Amynah A Pradhan, Sandra L Rodriguez-Zas
Prolonged use of opioids can cause opioid-induced hyperalgesia (OIH). The impact of alternative splicing on OIH remains partially characterized. A study of the absolute and relative modes of action of alternative splicing further the understanding of the molecular mechanisms underlying OIH. Differential absolute and relative isoform profiles were detected in the trigeminal ganglia and nucleus accumbens of mice presenting OIH behaviors elicited by chronic morphine administration relative to control mice. Genes that participate in glutamatergic synapse (e...
October 1, 2021: Genes
#16
JOURNAL ARTICLE
Jie Zhu, Xiaolong Lin, Chen Chen, Helian Tan, Yanping Gao, Di Li, Gang Chen
With-no-lysine kinase 3 (WNK3) is a key regulator of chloride ion transport and neuronal survival in diverse cell types. WNK3 was previously found to regulate the activity of Na+ -K+ -2Cl- cotransporter-1 (NKCC1) in ischemia-associated brain damage. However, the role of WNK3 in traumatic brain injury (TBI) has not yet been studied. A weight-drop TBI model was established in Sprague-Dawley rats. Overexpression and specific inhibition were used to investigate the role of WNK3 in TBI via Western blot, immunofluorescence, neuronal apoptosis, brain water content, and neurological score analyses...
October 6, 2021: Neuroscience
#17
JOURNAL ARTICLE
Yaqi Fan, Fangfang Dai, Mengqin Yuan, Feiyan Wang, Nanhui Wu, Mingyuan Xu, Yun Bai, Yeqiang Liu
BACKGROUND: As the second most common malignancy in adults, papillary renal cell carcinoma (PRCC) has shown an increasing trend in both incidence and mortality. Effective treatment for advanced metastatic PRCC is still lacking. In this study, we aimed to establish competitive endogenous RNA (ceRNA) networks related to PRCC tumorigenesis, and analyze the specific role of differentially expressed ceRNA components and infiltrating immune cells in tumorigenesis. METHODS: CeRNA networks were established to identify the key ceRNAs related to PRCC tumorigenesis based on the 318 samples from The Cancer Genome Atlas database (TCGA), including 285 PRCC and 33 normal control samples...
November 2021: Cancer Medicine
#18
JOURNAL ARTICLE
Yue Wang, Bingbing Wu, Shengrong Long, QiangLiu, Guangyu Li
Background: The primary features of malignant glioma include high rates of mortality and recurrence, uncontrollable invasiveness, strong angiogenesis, and widespread hypoxia. The hypoxic microenvironment is an important factor affecting the malignant progression of glioma. However, the molecular mechanisms underlying glioma adaption in hypoxic microenvironments are poorly understood. Objective: The work presented in this paper focuses on the role of WNK3 gene in glioma invasion under hypoxic conditions...
January 1, 2021: Translational Neuroscience
#19
JOURNAL ARTICLE
Ya Zhang, Qin Guo, Gengru Jiang, Chong Zhang
Impaired endothelium-mediated vasodilation and/or increased sensitivity to vasoconstrictors lead to vascular smooth muscle cell (VSMC) dysfunction in individuals with diabetes. Diabetic nephropathy is associated with a considerably higher risk of cardiovascular disease and death than their nondiabetic counterparts. We studied the activity of Cullin 3 RING ubiquitin ligase (CRL3) and its substrates in mice using an intraperitoneal injection of streptozotocin (STZ) and db/db mice. The levels of CRL3 adaptors, including Kelch-like 2/3 (KLHL2/3) and Rho-related BTB domain-containing protein 1, were significantly decreased in the aortic tissues and heart of the STZ group, whereas the levels of Cullin 3 (CUL3) and its neddylated derivatives were substantially increased...
July 31, 2021: Archives of Biochemistry and Biophysics
#20
JOURNAL ARTICLE
Franca Anglani, Leonardo Salviati, Matteo Cassina, Matteo Rigato, Laura Gobbi, Lorenzo A Calò
Gordon's syndrome, known also as Pseudohypoaldosteronism type II is a rare inherited dominant form of low-renin hypertension associated with hyperkalemia and metabolic acidosis. Four genes related to the regulation of the NaCl co-symporter NCC have been discovered associated to Gordon phenotypes: WINK 1 and WINK4, which, along with WNK2 and WNK3, encode a family of WNK-kinases, and KLHL3 and CUL3 encoding respectively, Kelch-like 3 protein and cullin. Heterozygous mutations in these genes constitutively activate NCC leading to abnormally increased salt reabsorption and salt-sensitive hypertension...
June 5, 2021: Journal of Nephrology
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