bluuebunny/crossref_metadata_2025 huggingface dataset:
The toxic natural product tutin causes epileptic seizures in mice by activating calcineurin
Authors: Han Qing-Tong , Yang Wan-Qi , Zang Caixia , Zhou Linchao , Zhang Chong-Jing , Bao Xiuqi , Cai Jie , Li Fangfei , Shi Qinyan , Wang Xiao-Liang , Qu Jing , Zhang Dan , Yu Shi-Shan
Published: March 2023

Tutin, an established toxic natural product that causes epilepsy in rodents, is often used as a tool to develop animal model of acute epileptic seizures. However, the molecular target and toxic mechanism of tutin were unclear. In this study, for the first time, we conducted experiments to clarify the targets in tutin-induced epilepsy using thermal proteome profiling. Our studies showed that calcineurin (CN) was a target of tutin, and that tutin activated CN, leading to seizures. Binding site studies further established that tutin bound within the active site of CN catalytic subunit. CN inhibitor and calcineurin A (CNA) knockdown experiments in vivo proved that tutin induced epilepsy by activating CN, and produced obvious nerve damage. Together, these findings revealed that tutin caused epileptic seizures by activating CN. Moreover, further mechanism studies found that N-methyl-D-aspartate (NMDA) receptors, gamma-aminobutyric acid (GABA) receptors and voltage- and Ca2+- activated K+ (BK) channels might be involved in related signaling pathways. Our study fully explains the convulsive mechanism of tutin, which provides new ideas for epilepsy treatment and drug development.
Toripalimab combined with lenvatinib and GEMOX is a promising regimen as first-line treatment for advanced intrahepatic cholangiocarcinoma: a single-center, single-arm, phase 2 study
Authors: Shi Guo-Ming , Huang Xiao-Yong , Wu Dong , Sun Hui-Chuan , Liang Fei , Ji Yuan , Chen Yi , Yang Guo-Huan , Lu Jia-Cheng , Meng Xian-Long , Wang Xin-Ying , Sun Lei , Ge Ning-Ling , Huang Xiao-Wu , Qiu Shuang-Jian , Yang Xin-Rong , Gao Qiang , He Yi-Feng , Xu Yang , Sun Jian , Ren Zheng-Gang , Fan Jia , Zhou Jian
Published: March 2023

Advanced intrahepatic cholangiocarcinoma (ICC) has a dismal prognosis. Here, we report the efficacy and safety of combining toripalimab, lenvatinib, and gemcitabine plus oxaliplatin (GEMOX) as first-line therapy for advanced ICC. Thirty patients with pathologically confirmed advanced ICC received intravenous gemcitabine (1 g/m2) on Days 1 and 8 and oxaliplatin (85 mg/m2) Q3W for six cycles along with intravenous toripalimab (240 mg) Q3W and oral lenvatinib (8 mg) once daily for one year. The expression of programmed death-ligand 1 (PD-L1) and genetic status was investigated in paraffin-embedded tissues using immunohistochemistry and whole-exome sequencing (WES) analysis. The primary endpoint was the objective response rate (ORR). Secondary outcomes included safety, overall survival (OS), progression-free survival (PFS), disease control rate (DCR) and duration of response (DoR). As of July 1, 2022, the median follow-up time was 23.5 months, and the ORR was 80%. Twenty-three patients achieved partial response, and one achieved complete response. Patients (21/30) with DNA damage response (DDR)-related gene mutations showed a higher ORR, while patients (14/30) with tumor area positivity ≥1 (PD-L1 staining) showed a trend of high ORR, but without significant difference. The median OS, PFS, and DoR were 22.5, 10.2, and 11.0 months, respectively. The DCR was 93.3%. Further, 56.7% of patients experienced manageable grade ≥3 adverse events (AEs), commonly neutropenia (40.0%) and leukocytopenia (23.3%). In conclusion, toripalimab plus lenvatinib and GEMOX are promising first-line regimens for the treatment of advanced ICC. A phase-III, multicenter, double-blinded, randomized study to validate our findings was approved by the National Medical Products Administration (NMPA, No. 2021LP01825).

Trial registration Clinical trials: NCT03951597.
Kidney fibrosis: from mechanisms to therapeutic medicines
Authors: Huang Rongshuang , Fu Ping , Ma Liang
Published: March 2023

Chronic kidney disease (CKD) is estimated to affect 10–14% of global population. Kidney fibrosis, characterized by excessive extracellular matrix deposition leading to scarring, is a hallmark manifestation in different progressive CKD; However, at present no antifibrotic therapies against CKD exist. Kidney fibrosis is identified by tubule atrophy, interstitial chronic inflammation and fibrogenesis, glomerulosclerosis, and vascular rarefaction. Fibrotic niche, where organ fibrosis initiates, is a complex interplay between injured parenchyma (like tubular cells) and multiple non-parenchymal cell lineages (immune and mesenchymal cells) located spatially within scarring areas. Although the mechanisms of kidney fibrosis are complicated due to the kinds of cells involved, with the help of single-cell technology, many key questions have been explored, such as what kind of renal tubules are profibrotic, where myofibroblasts originate, which immune cells are involved, and how cells communicate with each other. In addition, genetics and epigenetics are deeper mechanisms that regulate kidney fibrosis. And the reversible nature of epigenetic changes including DNA methylation, RNA interference, and chromatin remodeling, gives an opportunity to stop or reverse kidney fibrosis by therapeutic strategies. More marketed (e.g., RAS blockage, SGLT2 inhibitors) have been developed to delay CKD progression in recent years. Furthermore, a better understanding of renal fibrosis is also favored to discover biomarkers of fibrotic injury. In the review, we update recent advances in the mechanism of renal fibrosis and summarize novel biomarkers and antifibrotic treatment for CKD.
Functional and structural diversification of incomplete phosphotransferase system in cellulose-degrading clostridia
Authors: Xu Tao , Tao Xuanyu , He Hongxi , Kempher Megan L , Zhang Siping , Liu Xiaochun , Wang Jun , Wang Dongyu , Ning Daliang , Pan Chongle , Ge Honghua , Zhang Nannan , He Yong-Xing , Zhou Jizhong
Published: March 2023

Carbohydrate utilization is critical to microbial survival. The phosphotransferase system (PTS) is a well-documented microbial system with a prominent role in carbohydrate metabolism, which can transport carbohydrates through forming a phosphorylation cascade and regulate metabolism by protein phosphorylation or interactions in model strains. However, those PTS-mediated regulated mechanisms have been underexplored in non-model prokaryotes. Here, we performed massive genome mining for PTS components in nearly 15,000 prokaryotic genomes from 4,293 species and revealed a high prevalence of incomplete PTSs in prokaryotes with no association to microbial phylogeny. Among these incomplete PTS carriers, a group of lignocellulose degrading clostridia was identified to have lost PTS sugar transporters and carry a substitution of the conserved histidine residue in the core PTS component, HPr (histidine-phosphorylatable phosphocarrier). Ruminiclostridium cellulolyticum was then selected as a representative to interrogate the function of incomplete PTS components in carbohydrate metabolism. Inactivation of the HPr homolog reduced rather than increased carbohydrate utilization as previously indicated. In addition to regulating distinct transcriptional profiles, PTS associated CcpA (Catabolite Control Protein A) homologs diverged from previously described CcpA with varied metabolic relevance and distinct DNA binding motifs. Furthermore, the DNA binding of CcpA homologs is independent of HPr homolog, which is determined by structural changes at the interface of CcpA homologs, rather than in HPr homolog. These data concordantly support functional and structural diversification of PTS components in metabolic regulation and bring novel understanding of regulatory mechanisms of incomplete PTSs in cellulose-degrading clostridia.
Do environmental effects indexed by parental genetic variation influence common psychiatric symptoms in childhood?
Authors: Jami Eshim S. , Hammerschlag Anke R. , Sallis Hannah M. , Qiao Zhen , Andreassen Ole A. , Magnus Per M. , Njølstad Pål R. , Havdahl Alexandra , Pingault Jean-Baptiste , Evans David M. , Munafò Marcus R. , Ystrom Eivind , Bartels Meike , Middeldorp Christel
Published: March 2023

Parental genes may indirectly influence offspring psychiatric outcomes through the environment that parents create for their children. These indirect genetic effects, also known as genetic nurture, could explain individual differences in common internalising and externalising psychiatric symptoms during childhood. Advanced statistical genetic methods leverage data from families to estimate the overall contribution of parental genetic nurture effects. This study included up to 10,499 children, 5990 mother–child pairs, and 6,222 father–child pairs from the Norwegian Mother Father and Child Study. Genome-based restricted maximum likelihood (GREML) models were applied using software packages GCTA and M-GCTA to estimate variance in maternally reported depressive, disruptive, and attention-deficit hyperactivity disorder (ADHD) symptoms in 8-year-olds that was explained by direct offspring genetic effects and maternal or paternal genetic nurture. There was no strong evidence of genetic nurture in this sample, although a suggestive paternal genetic nurture effect on offspring depressive symptoms (variance explained (V) = 0.098, standard error (SE) = 0.057) and a suggestive maternal genetic nurture effect on ADHD symptoms (V = 0.084, SE = 0.058) was observed. The results indicate that parental genetic nurture effects could be of some relevance in explaining individual differences in childhood psychiatric symptoms. However, robustly estimating their contribution is a challenge for researchers given the current paucity of large-scale samples of genotyped families with information on childhood psychiatric outcomes.
An epigenetic mechanism for differential maturation of amygdala–prefrontal connectivity in childhood socio-emotional development
Authors: Skyberg Amalia M. , Newman Benjamin T. , Graves Andrew J. , Goldstein Alison M. , Brindley Samantha R. , Kim Minah , Druzgal T. Jason , Connelly Jessica J. , Morris James P.
Published: March 2023

Functional connectivity between the amygdala and the medial prefrontal cortex (mPFC) has been identified as a neural substrate of emotion regulation that undergoes changes throughout development, with a mature profile typically emerging at 10 years of age. Maternal bonding in childhood has been shown to buffer amygdala reactivity and to influence the trajectory of amygdala–mPFC coupling. The oxytocinergic system is critical in the development of social behavior and maternal bonding. Early-life parental care influences the methylation status of the oxytocin receptor (OXTRm) in animal models and humans, and higher OXTRm is associated with lower amygdala–PFC functional connectivity in adults. Using a neuroimaging-epigenetic approach, we investigated saliva-derived OXTRm as a biological marker of structural and functional connectivity maturation in 57 typically developing children (P < 0.05). We utilized seed-based connectivity analysis during a novel abstract movie paradigm and find that higher levels of OXTRm are associated with a more adult-like functional connectivity profile. Concurrently, more adult-like functional connectivity was associated with higher reported self-control and more diffusion streamlines between the amygdala and mPFC. OXTRm mediates the association between structural and functional connectivity with higher levels of OXTRm being associated with more streamlines. Lastly, we also find that lower OXTRm blunts the association between amygdala–mPFC connectivity and future internalizing behaviors in early adolescence. These findings implicate OXTRm as a biological marker at the interface of the social environment and amygdala–mPFC connectivity in emotional and behavioral regulation. Ultimately, identification of neurobiological markers may lead to earlier detection of children at risk for socio-emotional dysfunction.
Shared genetic liability for alcohol consumption, alcohol problems, and suicide attempt: Evaluating the role of impulsivity
Authors: Stephenson Mallory , Lannoy Séverine , Edwards Alexis C.
Published: March 2023

Heavy drinking and diagnosis with alcohol use disorder (AUD) are consistently associated with risk for suicide attempt (SA). Though the shared genetic architecture among alcohol consumption and problems (ACP) and SA remains largely uncharacterized, impulsivity has been proposed as a heritable, intermediate phenotype for both alcohol problems and suicidal behavior. The present study investigated the extent to which shared liability for ACP and SA is genetically related to five dimensions of impulsivity. Analyses incorporated summary statistics from genome-wide association studies of alcohol consumption (N = 160,824), problems (N = 160,824), and dependence (N = 46,568), alcoholic drinks per week (N = 537,349), suicide attempt (N = 513,497), impulsivity (N = 22,861), and extraversion (N = 63,030). We used genomic structural equation modeling (Genomic SEM) to, first, estimate a common factor model with alcohol consumption, problems, and dependence, drinks per week, and SA included as indicators. Next, we evaluated the correlations between this common genetic factor and five factors representing genetic liability to negative urgency, positive urgency, lack of premeditation, sensation-seeking, and lack of perseverance. Common genetic liability to ACP and SA was significantly correlated with all five impulsive personality traits examined (rs = 0.24–0.53, ps < 0.002), and the largest correlation was with lack of premeditation, though supplementary analyses suggested that these findings were potentially more strongly influenced by ACP than SA. These analyses have potential implications for screening and prevention: Impulsivity can be comprehensively assessed in childhood, whereas heavy drinking and suicide attempt are quite rare prior to adolescence. Our findings provide preliminary evidence that features of impulsivity may serve as early indicators of genetic risk for alcohol problems and suicidality.
Mouse mutants in schizophrenia risk genes GRIN2A and AKAP11 show EEG abnormalities in common with schizophrenia patients
Authors: Herzog Linnea E. , Wang Lei , Yu Eunah , Choi Soonwook , Farsi Zohreh , Song Bryan J. , Pan Jen Q. , Sheng Morgan
Published: March 2023

Schizophrenia is a heterogeneous psychiatric disorder with a strong genetic basis, whose etiology and pathophysiology remain poorly understood. Exome sequencing studies have uncovered rare, loss-of-function variants that greatly increase risk of schizophrenia [1], including loss-of-function mutations in GRIN2A (aka GluN2A or NR2A, encoding the NMDA receptor subunit 2A) and AKAP11 (A-Kinase Anchoring Protein 11). AKAP11 and GRIN2A mutations are also associated with bipolar disorder [2], and epilepsy and developmental delay/intellectual disability [1, 3, 4], respectively. Accessible in both humans and rodents, electroencephalogram (EEG) recordings offer a window into brain activity and display abnormal features in schizophrenia patients. Does loss of Grin2a or Akap11 in mice also result in EEG abnormalities? We monitored EEG in heterozygous and homozygous knockout Grin2a and Akap11 mutant mice compared with their wild-type littermates, at 3- and 6-months of age, across the sleep/wake cycle and during auditory stimulation protocols. Grin2a and Akap11 mutants exhibited increased resting gamma power, attenuated auditory steady-state responses (ASSR) at gamma frequencies, and reduced responses to unexpected auditory stimuli during mismatch negativity (MMN) tests. Sleep spindle density was reduced in a gene dose-dependent manner in Akap11 mutants, whereas Grin2a mutants showed increased sleep spindle density. The EEG phenotypes of Grin2a and Akap11 mutant mice show a variety of abnormal features that overlap considerably with human schizophrenia patients, reflecting systems-level changes caused by Grin2a and Akap11 deficiency. These neurophysiologic findings further substantiate Grin2a and Akap11 mutants as genetic models of schizophrenia and identify potential biomarkers for stratification of schizophrenia patients.
Maternal perinatal depression and child brain structure at 2-3 years in a South African birth cohort study
Authors: Pellowski Jennifer A. , Wedderburn Catherine J. , Groenewold Nynke A. , Roos Annerine , Subramoney Sivenesi , Hoffman Nadia , Fouche Jean-Paul , Joshi Shantanu H. , Woods Roger P. , Narr Katherine L. , Zar Heather J. , Donald Kirsten A. , Stein Dan J.
Published: March 2023

Maternal perinatal depression is associated with risk of adverse child developmental outcomes and differences in offspring brain structure. Evidence from low- and middle-income countries is lacking as is an investigation of antenatal, postnatal, and persistent depression in the same sample. In a South African birth cohort, we investigated the effect of antenatal and postpartum maternal depressive symptoms on offspring brain structure at 2–3 years of age. Magnetic resonance imaging was performed, extracting cortical thickness and surface areas in frontal cortex regions of interest and subcortical volumes using FreeSurfer software. Maternal depressive symptoms were measured using the Edinburgh Postpartum Depression Scale and the Beck Depression Inventory II antenatally and at 6–10 weeks, 6 months, 12 months, and 18 months postpartum and analyzed dichotomously and continuously. Linear regressions were used controlling for child age, sex, intracranial volume, maternal education, age, smoking, alcohol use and HIV. 146 children were included with 38 (37%) exposed to depressive symptoms antenatally and 44 (35%) exposed postnatally. Of these, 16 (13%) were exposed to both. Postpartum, but not antenatal, depressive symptoms were associated with smaller amygdala volumes in children (B = −74.73, p = 0.01). Persistent maternal depressive symptoms across pregnancy and postpartum were also independently associated with smaller amygdala volumes (B = −78.61, p = 0.047). Differences in amygdala volumes among children exposed to postnatal as well as persistent maternal depressive symptomatology underscore the importance of identifying women at-risk for depression during the entire perinatal period.
Quinpirole ameliorates nigral dopaminergic neuron damage in Parkinson’s disease mouse model through activating GHS-R1a/D2R heterodimers
Authors: Tang Ting-ting , Bi Ming-xia , Diao Mei-ning , Zhang Xiao-yi , Chen Ling , Xiao Xue , Jiao Qian , Chen Xi , Yan Chun-ling , Du Xi-xun , Jiang Hong
Published: March 2023

Growth hormone secretagogue receptor 1a (GHS-R1a) is an important G protein-coupled receptor (GPCR) that regulates a variety of functions by binding to ghrelin. It has been shown that the dimerization of GHS-R1a with other receptors also affects ingestion, energy metabolism, learning and memory. Dopamine type 2 receptor (D2R) is a GPCR mainly distributed in the ventral tegmental area (VTA), substantia nigra (SN), striatum and other brain regions. In this study we investigated the existence and function of GHS-R1a/D2R heterodimers in nigral dopaminergic neurons in Parkinson’s disease (PD) models in vitro and in vivo. By conducting immunofluorescence staining, FRET and BRET analyses, we confirmed that GHS-R1a and D2R could form heterodimers in PC-12 cells and in the nigral dopaminergic neurons of wild-type mice. This process was inhibited by MPP+ or MPTP treatment. Application of QNP (10 μM) alone significantly increased the viability of MPP+-treated PC-12 cells, and administration of quinpirole (QNP, 1 mg/kg, i.p. once before and twice after MPTP injection) significantly alleviated motor deficits in MPTP-induced PD mice model; the beneficial effects of QNP were abolished by GHS-R1a knockdown. We revealed that the GHS-R1a/D2R heterodimers could increase the protein levels of tyrosine hydroxylase in the SN of MPTP-induced PD mice model through the cAMP response element binding protein (CREB) signaling pathway, ultimately promoting dopamine synthesis and release. These results demonstrate a protective role for GHS-R1a/D2R heterodimers in dopaminergic neurons, providing evidence for the involvement of GHS-R1a in PD pathogenesis independent of ghrelin.
Sequential targeting of PARP with carboplatin inhibits primary tumour growth and distant metastasis in triple-negative breast cancer
Authors: Beniey Michèle , Hubert Audrey , Haque Takrima , Cotte Alexia Karen , Béchir Nelly , Zhang Xiaomeng , Tran-Thanh Danh , Hassan Saima
Published: March 2023

Background

Patients with triple-negative breast cancer (TNBC) develop early recurrence. While PARP inhibitors (PARPi) have demonstrated potential in BRCA1/2-mutant (BRCAMUT) TNBC, durable responses will likely be achieved if PARPi are used in combination. It is plausible that sequential administration of a potent PARPi like talazoparib in combination with carboplatin can enhance primary tumour and metastasis inhibition in BRCAMUT and BRCA1/2 wild-type (BRCAWT) TNBCs, and decrease toxicity.

Methods

We evaluated the impact of the concurrent combination of talazoparib and carboplatin on cell survival in 13 TNBC cell lines. We compared the concurrent and sequential combination upon fork replication, migration and invasion. We also used three orthotopic xenograft models to evaluate primary tumour growth, distant metastasis, and toxicity.

Results

Concurrent talazoparib and carboplatin was synergistic in 92.3% of TNBC cell lines, independent of BRCA1/2-mutation status. The sequential combination decreased fork speed in normal cells, but not in TNBC cells. The talazoparib-first sequential combination resulted in a strong reduction in migration (70.4%, P < 0.0001), invasion (56.9%, P < 0.0001), lung micrometastasis (56.4%, P < 0.0001), and less toxicity in a BRCAWT model.

Conclusion

The sequential combination of talazoparib and carboplatin is an effective approach to inhibit micrometastatic disease, providing rationale for the use of this combination in early TNBC patients.
STOML2 restricts mitophagy and increases chemosensitivity in pancreatic cancer through stabilizing PARL-induced PINK1 degradation
Authors: Qin Cheng , Wang Yuanyang , Zhao Bangbo , Li Zeru , Li Tianyu , Yang Xiaoying , Zhao Yutong , Wang Weibin
Published: March 2023

Pancreatic cancer remains one of the most lethal diseases with a relatively low 5-year survival rate, and gemcitabine-based chemoresistance occurs constantly. Mitochondria, as the power factory in cancer cells, are involved in the process of chemoresistance. The dynamic balance of mitochondria is under the control of mitophagy. Stomatin-like protein 2 (STOML2) is located in the mitochondrial inner membrane and is highly expressed in cancer cells. In this study, using a tissue microarray (TMA), we found that high STOML2 expression was correlated with higher survival of patients with pancreatic cancer. Meanwhile, the proliferation and chemoresistance of pancreatic cancer cells could be retarded by STOML2. In addition, we found that STOML2 was positively related to mitochondrial mass and negatively related to mitophagy in pancreatic cancer cells. STOML2 stabilized PARL and further prevented gemcitabine-induced PINK1-dependent mitophagy. We also generated subcutaneous xenografts to verify the enhancement of gemcitabine therapy induced by STOML2. These findings suggested that STOML2 regulated the mitophagy process through the PARL/PINK1 pathway, thereby reducing the chemoresistance of pancreatic cancer. STOML2-overexpression targeted therapy might be helpful for gemcitabine sensitization in the future.
Targeting oxeiptosis-mediated tumor suppression: a novel approach to treat colorectal cancers by sanguinarine
Authors: Pallichankandy Siraj , Thayyullathil Faisal , Cheratta Anees Rahman , Subburayan Karthikeyan , Alakkal Ameer , Sultana Mehar , Drou Nizar , Arshad Muhammad , Tariq Saeed , Galadari Sehamuddin
Published: March 2023

Oxeiptosis is a recently identified reactive oxygen species (ROS)-sensitive, caspase independent, non-inflammatory regulated cell death pathway. The activation of Kelch-like ECH-associated protein 1-Phosphoglycerate mutase 5-Apoptosis inducing factor mitochondria associated 1 (KEAP1-PGAM5-AIFM1) pathway is the key signaling event in the execution of oxeiptosis. In the present study, we demonstrate that sanguinarine (SNG), a quaternary benzophenanthridine alkaloid, induces oxeiptosis in human colorectal cancer (CRC) cells via ROS, specifically hydrogen peroxide (H2O2)-dependent activation of KEAP1-PGAM5-AIFM1 signaling axis. Whilst, knockdown of KEAP1, PGAM5, and AIFM1 largely abolishes SNG-induced oxeiptosis, hence reinforcing the importance of the role of this pathway in the SNG-mediated cytotoxicity. Moreover, extracellular addition of H2O2 sensitizes SNG-induced oxeiptosis in CRC cells, while removal of intracellular ROS by ROS scavengers, not only alleviated the overproduction of ROS caused by SNG, but also reversed the biochemical events associated with oxeiptosis. Finally, in vivo study demonstrates that SNG effectively reduces the tumor growth in HT-29 xenograft mouse model through features associated with oxeiptosis. This study highlights oxeiptosis as a novel tumor suppressive mechanism and further investigation of the role of oxeiptosis in cancer treatment is warranted.
Dual roles of TRIM3 in colorectal cancer by retaining p53 in the cytoplasm to decrease its nuclear expression
Authors: Han Yang , Lu Su , Song Chenlong , Xuan Yi , Zhang Meng , Cai Hong
Published: March 2023

Colorectal cancer is a very heterogeneous disease caused by the interaction of genetic and environmental factors. P53, as a frequent mutation gene, plays a critical role in the adenoma-carcinoma transition during the tumorous pathological process. Our team discovered TRIM3 as a tumor-associated gene in CRC by high-content screening techniques. TRIM3 demonstrated both tumor-suppressive and tumorigenic features in cell experiments dependent on the cell status of wild or mutant p53. TRIM3 could directly interact with the C terminus of p53 (residues 320 to 393), a common segment of wtp53 and mutp53. Moreover, TRIM3 could exert different neoplastic features by retaining p53 in the cytoplasm to decrease its nuclear expression in a wtp53 or mutp53-dependent pathway. Chemotherapy resistance develops in nearly all patients with advanced CRC and seriously limits the therapeutic efficacies of anticancer drugs. TRIM3 could reverse the chemotherapy resistance of oxaliplatin in mutp53 CRC cells by degradation of mutp53 in the nuclei to downregulate the multidrug resistance gene. Therefore, TRIM3 could be a potential therapeutic strategy to improve the survival of CRC patients with mutp53.
Downregulation of Sox8 mediates monosodium urate crystal-induced autophagic impairment of cartilage in gout arthritis
Authors: Xiao Lu , Lin Shudian , Xu WenChao , Sun Erwei
Published: March 2023

The deposition of monosodium urate (MSU) crystals in arthritic joints of gout seriously damages cartilage. This study aimed to investigate whether MSU crystal-induced cartilage impairment was related to autophagic signaling. mRNAs of cartilage from MSU-induced gouty arthritis rat model were sequenced. MSU crystal-treated human chondrocytes were used to evaluate the function of Sox8. The recombinant Sox8 lentiviral vector (lenti-Sox8) was applied to upregulate the expression of Sox8. Transfection of the mRFP-GFP-LC3 plasmid was evaluated by confocal microscopy. The autophagic vacuoles were stained with monodansylcadaverine and examined by flow cytometry. The morphology of autophagosomes was observed by transmission electron microscopy. The ratio of LC3-II/I in the presence or absence of bafilomycin A1 and the expression levels of Beclin1, Sox8, p-PI3K, PI3K, p-AKT, AKT, p-mTOR, and mTOR were detected by Western blot. In vivo, the effect of Sox8 on cartilage of acute gouty model rats was evaluated by safranin-O/fast green staining and Western blot. The expression of Sox8 was significantly downregulated both in vivo and in vitro. In chondrocytes, MSU crystals reduced the expression of Sox8, inhibited the PI3K/AKT/mTOR signaling pathway, and increased the level of autophagy. Overexpression of Sox8 notably inhibited MSU crystal-induced autophagy by rescuing the phosphorylation levels in the PI3K/AKT/mTOR signaling pathway. In vivo, overexpression of Sox8 remarkably alleviated cartilage damage in acute gouty model rats. These results indicate that downregulation of Sox8 plays an important role in MSU-induced chondrocyte autophagy by modulating PI3K/AKT/mTOR signaling, and overexpression of Sox8 may serve as a novel therapy to prevent the impairment of cartilage in gout arthritis.
JMJD1C promotes smooth muscle cell proliferation by activating glycolysis in pulmonary arterial hypertension
Authors: Zhang Chen , Sun Yue , Guo Yingying , Xu Jingjing , Zhao Haiyan
Published: March 2023

Pulmonary arterial hypertension (PAH) is a chronic disorder characterized by hyperproliferation of pulmonary arterial smooth muscle cells (PASMCs). JMJD1C, a member of the Jumonji domain containing C (JMJC) histone demethylase family, contributes to cardiovascular dysfunction. However, the role of JMJD1C in PAH remains unknown. Mice were exposed to hypoxia to mimic several features associated with PAH clinically. We found that JMJD1C was highly expressed in the lungs of mice after hypoxia exposure. JMJD1C knockdown ameliorated hypoxia-induced right ventricular remodeling and thickening of the pulmonary arterial wall. PASMC hyperproliferation and resistance to apoptosis in mice exposed to hypoxia were suppressed by JMJD1C inhibition. We demonstrated that JMJD1C silencing reduced glycolytic enzymes (HK2, PGK1 and LDHA) and lactate overaccumulation in the lungs of mice exposed to hypoxia. In vitro, hypoxia-induced hyperproliferation and activated glycolytic processes in mouse PASMCs were impaired by JMJD1C knockdown. In addition, the activation of STAT3 signaling by hypoxia was suppressed by JMJD1C silencing both in vivo and in vitro. The overexpression of STAT3 reversed the inhibitory effect of JMJD1C depletion on proliferation and glycolysis in PASMCs under hypoxia. Thus, JMJD1C induces glycolytic processes by activating STAT3 signaling to promote PASMC proliferation and pulmonary vascular remodeling, suggesting the potential role of JMJD1C in regulating the metabolic program and vascular remodeling in PAH.
Two sporadic cases of childhood-onset Hailey-Hailey disease with superimposed mosaicism
Authors: Asahina Yasuhiko , Tahara Umi , Aoki Satomi , Nakabayashi Kazuhiko , Tateishi Chiharu , Hayashi Daisuke , Amagai Masayuki , Tsuruta Daisuke , Kubo Akiharu
Published: March 2023

A prenatal second-hit genetic change that occurs on the wild-type allele in an embryo with a congenital pathogenic variant allele results in mosaicism of monoallelic and biallelic defect of the gene, which is called superimposed mosaicism. Superimposed mosaicism of Hailey-Hailey disease (HHD) has been demonstrated in one familial case. Here, we report two unrelated HHD cases with superimposed mosaicism: a congenital monoallelic pathogenic variant of ATP2C1, followed by a postzygotic copy-neutral loss of heterozygosity. Uniquely, neither patient had a family history of HHD at the time of presentation. In the first case, the congenital pathogenic variant had occurred de novo. In the second case, the father had the pathogenic variant but had not yet developed skin symptoms. Our cases showed that superimposed mosaicism in HHD can lack a family history and that genetic analysis is crucial to classify the type of mosaicism and evaluate the risk of familial occurrence.
Exome sequencing in individuals with congenital anomalies of the kidney and urinary tract (CAKUT): a single-center experience
Authors: Riedhammer Korbinian M. , Ćomić Jasmina , Tasic Velibor , Putnik Jovana , Abazi-Emini Nora , Paripovic Aleksandra , Stajic Natasa , Meitinger Thomas , Nushi-Stavileci Valbona , Berutti Riccardo , Braunisch Matthias C. , Hoefele Julia
Published: March 2023

Individuals with congenital anomalies of the kidney and urinary tract (CAKUT) show a broad spectrum of malformations. CAKUT can occur in an isolated fashion or as part of a syndromic disorder and can lead to end-stage kidney failure. A monogenic cause can be identified in ~12% of affected individuals. This study investigated a single-center CAKUT cohort analyzed by exome sequencing (ES). Emphasis was placed on the question whether diagnostic yield differs between certain CAKUT phenotypes (e.g., bilateral kidney affection, unilateral kidney affection or only urinary tract affection). 86 unrelated individuals with CAKUT were categorized according to their phenotype and analyzed by ES to identify a monogenic cause. Prioritized variants were rated according to the recommendations of the American College of Medical Genetics and Genomics and the Association for Clinical Genomic Science. Diagnostic yields of different phenotypic categories were compared. Clinical data were collected using a standardized questionnaire. In the study cohort, 7/86 individuals had a (likely) pathogenic variant in the genes PAX2, PBX1, EYA1, or SALL1. Additionally, in one individual, a 17q12 deletion syndrome (including HNF1B) was detected. 64 individuals had a kidney affection, which was bilateral in 36. All solved cases (8/86, 9%) had bilateral kidney affection (diagnostic yield in subcohort: 8/36, 22%). Although the diagnostic yield in CAKUT cohorts is low, our single-center experience argues, that, in individuals with bilateral kidney affection, monogenic burden is higher than in those with unilateral kidney or only urinary tract affection.
Evaluation of care with intravitreal aflibercept treatment for UK patients with diabetic macular oedema: DRAKO study 24-month real-world outcomes
Authors: Sivaprasad Sobha , Ghanchi Faruque , Kelly Simon P. , Kotagiri Ajay , Talks James , Scanlon Peter , McGoey Hellen , Nolan Andrew , Saddiq Moneeb , Napier Jackie
Published: March 2023

Background/ Objectives

DRAKO (NCT02850263) was a 24-month, prospective, observational, multi-centre cohort study that enrolled patients diagnosed with diabetic macular oedema (DMO) including central involvement. The study aimed to evaluate standard of care intravitreal aflibercept (IVT-AFL) treatment in the UK. This analysis describes the 12-month outcomes for patients with prior anti–vascular endothelial growth factor (VEGF) treatment for DMO other than IVT-AFL (C2), and 2-year outcomes for both anti-VEGF treatment–naïve patients (C1) and C2 patients.

Methods

Study eyes were treated with IVT-AFL as per local standard of care. Mean changes in best-corrected visual acuity (BCVA) in ETDRS letters and central subfield thickness (CST) were stratified by baseline factors. Changes in diabetic retinopathy assessments, glycated haemoglobin A1c levels and vision-related quality of life (QoL) were evaluated alongside numbers of injections administered and safety outcomes.

Results

For C1, mean (SD) changes from baseline in BCVA of +0.7 (12.7) letters and CST of –123.3 (104.3) µm were observed at Month 24. For C2, mean (SD) changes from baseline for BCVA of + 0.2 (10.2) letters and –0.3 (13.0) letters, and CST of –79.1 (137.6) µm and −91.6 (132.9) µm, were observed at 12 and 24 months, respectively. In Year 2, C1 and C2 patients received a mean of 3.7 and 4.3 injections, respectively.

Conclusions

Year 2 results indicate that IVT-AFL is an effective treatment for DMO in real-world UK clinical practice, despite relatively low injection numbers. The high baseline visual acuity and QoL scores were maintained and there was further improvement in anatomical outcomes.
Ultrathin Descemet Stripping Automated Endothelial Keratoplasty (UT-DSAEK) versus Descemet Membrane Endothelial Keratoplasty (DMEK)—a systematic review and meta-analysis
Authors: Hurley Daire J. , Murtagh Patrick , Guerin Marc
Published: March 2023

Background/Objectives

Endothelial keratoplasty (EK) is a commonly performed transplant procedure used in the treatment of corneal endothelial dysfunction. The aim of this systematic review and meta-analysis is to evaluate the differences in visual acuity outcomes, endothelial cell density (ECD) and complications between two forms of EK, ultrathin Descemet stripping automated endothelial keratoplasty (UT-DSAEK) and Descemet membrane endothelial keratoplasty (DMEK).

Methods

A literature search of MEDLINE, Embase and Cochrane Library was conducted to identify studies reporting comparative results of UT-DSAEK versus DMEK. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was used for search strategy. Of 141 titles, 7 studies met the inclusion criteria; best corrected visual acuity (BCVA) (LogMAR), ECD (cells/mm2), and complications were compared, with all statistical analysis performed using Review Manager.

Results

A total of 362 eyes were included for analysis. DMEK resulted in significantly better BCVA at 3 months (0.14 vs 0.22,p = 0.003), 6 months (0.08 vs 0.18,p = 0.005) and 1 year post-op (0.07 vs 0.14,p = 0.0005). UT-DSAEK resulted in significantly lower total complications (25.2% vs 57.3%,p = 0.0001) and rates of re-bubbling (11.0% vs 33.7%,p = 0.004). No differences were found in ECD between the two procedures (1541 vs 1605,p = 0.77).

Conclusions

DMEK results in superior visual acuity rates with quicker recovery. However, UT-DSAEK has a more favourable complication profile, particularly regarding lower rates of re-bubbling. Both are valuable options in the treatment of corneal endothelial disease and choice of procedure may depend on surgical expertise.
Frequency of coexistent eye diseases and cognitive impairment or dementia: a systematic review and meta-analysis
Authors: Xu Ying , Phu Jack , Aung Htein Linn , Hesam-Shariati Negin , Keay Lisa , Tully Phillip J. , Booth Andrew , Anderson Craig S. , Anstey Kaarin J. , Peters Ruth
Published: March 2023

Objective

We aim to quantify the co-existence of age-related macular degeneration (AMD), glaucoma, or diabetic retinopathy (DR) and cognitive impairment or dementia.

Method

MEDLINE, EMBASE, PsycINFO and CINAHL were searched (to June 2020). Observational studies reporting incidence or prevalence of AMD, glaucoma, or DR in people with cognitive impairment or dementia, and of cognitive impairment or dementia among people with AMD, glaucoma, or DR were included.

Results

Fifty-six studies (57 reports) were included but marked by heterogeneities in the diagnostic criteria or definitions of the diseases, study design, and case mix. Few studies reported on the incidence. Evidence was sparse but consistent in individuals with mild cognitive impairment where 7.7% glaucoma prevalence was observed. Prevalence of AMD and DR among people with cognitive impairment ranged from 3.9% to 9.4% and from 11.4% to 70.1%, respectively. Prevalence of AMD and glaucoma among people with dementia ranged from 1.4 to 53% and from 0.2% to 25.9%, respectively. Prevalence of DR among people with dementia was 11%. Prevalence of cognitive impairment in people with AMD, glaucoma, and DR ranged from 8.4% to 52.4%, 12.3% to 90.2%, and 3.9% to 77.8%, respectively, and prevalence of dementia in people with AMD, glaucoma and DR ranged from 9.9% to 62.6%, 2.5% to 3.3% and was 12.5%, respectively.

Conclusions

Frequency of comorbid eye disease and cognitive impairment or dementia varied considerably. While more population-based estimations of the co-existence are needed, interdisciplinary collaboration might be helpful in the management of these conditions to meet healthcare needs of an ageing population.

Trial registration

PROSPERO registration: CRD42020189484.
Y chromosome-linked variation affects locomotor activity in male Drosophila melanogaster and is robust to differences in thermal environment
Authors: Layh Sean , Nagarajan-Radha Venkatesh , Lemos Bernardo , Dowling Damian K.
Published: March 2023

Although containing genes important for sex determination, genetic variation within the Y chromosome was traditionally predicted to contribute little to the expression of sexually dimorphic traits. This prediction was shaped by the assumption that the chromosome harbours few protein-coding genes, and that capacity for Y-linked variation to shape adaptation would be hindered by the chromosome’s lack of recombination and holandric inheritance. Consequently, most studies exploring the genotypic contributions to sexually dimorphic traits have focused on the autosomes and X chromosome. Yet, several studies have now demonstrated that the Y chromosome harbours variation affecting male fitness, moderating the expression of hundreds of genes across the nuclear genome. Furthermore, emerging results have shown that expression of this Y-linked variation may be sensitive to environmental heterogeneity, leading to the prediction that Y-mediated gene-by-environment interactions will shape the expression of sexually dimorphic phenotypes. We tested this prediction, investigating whether genetic variation across six distinct Y chromosome haplotypes affects the expression of locomotor activity, at each of two temperatures (20 and 28 °C) in male fruit flies (Drosophila melanogaster). Locomotor activity is a sexually dimorphic trait in this species, previously demonstrated to be under intralocus sexual conflict. We demonstrate Y haplotype effects on male locomotor activity, but the rank order and magnitude of these effects were unaltered by differences in temperature. Our study contributes to a growing number of studies demonstrating Y-linked effects moderating expression of traits evolving under sexually antagonistic selection, suggesting a role for the Y chromosome in shaping outcomes of sexual conflict.
Quantitative genetics of breeding coloration in sand lizards; genic capture unlikely to maintain additive genetic variance
Authors: Lindsay Willow R. , Bererhi Badreddine , Ljungström Gabriella , Wapstra Erik , Olsson Mats
Published: March 2023

Sexual selection on fitness-determining traits should theoretically erode genetic variance and lead to low heritability. However, many sexually selected traits maintain significant phenotypic and additive genetic variance, with explanations for this “lek paradox” including genic capture due to condition-dependence, and breaks on directional selection due to environmental sources of variance including maternal effects. Here we investigate genetic and environmental sources of variance in the intrasexually selected green badge of the sand lizard (Lacerta agilis). The badge functions as a cue to male fighting ability in this species, and male–male interactions determine mate acquisition. Using animal models on a pedigree including three generations of males measured over an extensive 9-year field study, we partition phenotypic variance in both badge size and body condition into additive genetic, maternal, and permanent environmental effects experienced by an individual over its lifespan. Heritability of badge size was 0.33 with a significant estimate of underlying additive genetic variance. Body condition was strongly environmentally determined in this species and did not show either significant additive genetic variance or heritability. Neither badge size nor body condition was responsive to maternal effects. We propose that the lack of additive genetic variance and heritability of body condition makes it unlikely that genic capture mechanisms maintain additive genetic variance for badge size. That said, genic capture was originally proposed for male traits under female choice, not agonistic selection. If developmental pathways generating variance in body condition, and/or the covarying secondary sex trait, differ between inter- and intrasexual selection, or the rate at which their additive genetic variance or covariance is depleted, future work may show whether genic capture is largely restricted to intersexual selection processes.
Tyrosyl-tRNA synthetase has a noncanonical function in actin bundling
Authors: Ermanoska Biljana , Asselbergh Bob , Morant Laura , Petrovic-Erfurth Maria-Luise , Hosseinibarkooie Seyyedmohsen , Leitão-Gonçalves Ricardo , Almeida-Souza Leonardo , Bervoets Sven , Sun Litao , Lee LaTasha , Atkinson Derek , Khanghahi Akram , Tournev Ivaylo , Callaerts Patrick , Verstreken Patrik , Yang Xiang-Lei , Wirth Brunhilde , Rodal Avital A. , Timmerman Vincent , Goode Bruce L. , Godenschwege Tanja A. , Jordanova Albena
Published: March 2023

Dominant mutations in tyrosyl-tRNA synthetase (YARS1) and six other tRNA ligases cause Charcot-Marie-Tooth peripheral neuropathy (CMT). Loss of aminoacylation is not required for their pathogenicity, suggesting a gain-of-function disease mechanism. By an unbiased genetic screen inDrosophila, we link YARS1 dysfunction to actin cytoskeleton organization. Biochemical studies uncover yet unknown actin-bundling property of YARS1 to be enhanced by a CMT mutation, leading to actin disorganization in theDrosophilanervous system, human SH-SY5Y neuroblastoma cells, and patient-derived fibroblasts. Genetic modulation of F-actin organization improves hallmark electrophysiological and morphological features in neurons of flies expressing CMT-causing YARS1 mutations. Similar beneficial effects are observed in flies expressing a neuropathy-causing glycyl-tRNA synthetase. Hence, in this work, we show that YARS1 is an evolutionary-conserved F-actin organizer which links the actin cytoskeleton to tRNA-synthetase-induced neurodegeneration.
Genomic diversity of non-diarrheagenic fecal Escherichia coli from children in sub-Saharan Africa and south Asia and their relatedness to diarrheagenic E. coli
Authors: Hazen Tracy H. , Michalski Jane M. , Tennant Sharon M. , Rasko David. A.
Published: March 2023

Escherichia coli is a frequent member of the healthy human gastrointestinal microbiota, as well as an important human pathogen. Previous studies have focused on the genomic diversity of the pathogenic E. coli and much remains unknown about the non-diarrheagenic E. coli residing in the human gut, particularly among young children in low and middle income countries. Also, gaining additional insight into non-diarrheagenic E. coli is important for understanding gut health as non-diarrheagenic E. coli can prevent infection by diarrheagenic bacteria. In this study we examine the genomic diversity of non-diarrheagenic fecal E. coli from male and female children with or without diarrhea from countries in sub-Saharan Africa and south Asia as part of the Global Enteric Multicenter Study (GEMS). We find that these E. coli exhibit considerable genetic diversity as they were identified in all E. coli phylogroups and an Escherichia cryptic clade. Although these fecal E. coli lack the characteristic virulence factors of diarrheagenic E. coli pathotypes, many exhibit remarkable genomic similarity to previously described diarrheagenic isolates with differences attributed to mobile elements. This raises an important question of whether these non-diarrheagenic fecal E. coli may have at one time possessed the mobile element-encoded virulence factors of diarrheagenic pathotypes or may have the potential to acquire these virulence factors.
Ozone exposure disrupts insect sexual communication
Authors: Jiang Nan-Ji , Chang Hetan , Weißflog Jerrit , Eberl Franziska , Veit Daniel , Weniger Kerstin , Hansson Bill S. , Knaden Markus
Published: March 2023

Insect sexual communication often relies upon sex pheromones. Most insect pheromones, however, contain carbon-carbon double bonds and potentially degrade by oxidation. Here, we show that frequently reported increased levels of Anthropocenic ozone can oxidize all described male-specific pheromones of Drosophila melanogaster, resulting in reduced amounts of pheromones such as cis-Vaccenyl Acetate and (Z)−7-Tricosene. At the same time female acceptance of ozone-exposed males is significantly delayed. Interestingly, groups of ozone-exposed males also exhibit significantly increased levels of male-male courtship behaviour. When repeating similar experiments with nine other drosophilid species, we observe pheromone degradation and/or disrupted sex recognition in eight of them. Our data suggest that Anthropocenic levels of ozone can extensively oxidize double bonds in a variety of insect pheromones, thereby leading to deviations in sexual recognition.