Elife. 2024 May 3;12:RP89967. doi: 10.7554/eLife.89967.

ABSTRACT

The gain-of-function mutation in the TALK-1 K+ channel (p.L114P) is associated with maturity-onset diabetes of the young (MODY). TALK-1 is a key regulator of β-cell electrical activity and glucose-stimulated insulin secretion. The KCNK16 gene encoding TALK-1 is the most abundant and β-cell-restricted K+ channel transcript. To investigate the impact of KCNK16 L114P on glucose homeostasis and confirm its association with MODY, a mouse model containing the Kcnk16 L114P mutation was generated. Heterozygous and homozygous Kcnk16 L114P mice exhibit increased neonatal lethality in the C57BL/6J and the CD-1 (ICR) genetic background, respectively. Lethality is likely a result of severe hyperglycemia observed in the homozygous Kcnk16 L114P neonates due to lack of glucose-stimulated insulin secretion and can be reduced with insulin treatment. Kcnk16 L114P increased whole-cell β-cell K+ currents resulting in blunted glucose-stimulated Ca2+ entry and loss of glucose-induced Ca2+ oscillations. Thus, adult Kcnk16 L114P mice have reduced glucose-stimulated insulin secretion and plasma insulin levels, which significantly impairs glucose homeostasis. Taken together, this study shows that the MODY-associated Kcnk16 L114P mutation disrupts glucose homeostasis in adult mice resembling a MODY phenotype and causes neonatal lethality by inhibiting islet insulin secretion during development. These data suggest that TALK-1 is an islet-restricted target for the treatment for diabetes.

PMID:38700926 | DOI:10.7554/eLife.89967

J Mol Neurosci. 2024 May 3;74(2):51. doi: 10.1007/s12031-024-02228-0.

ABSTRACT

Alzheimer's disease (AD) is a neurodegenerative disorder and the most common cause of dementia. Programmed cell death (PCD) is mainly characterized by unique morphological features and energy-dependent biochemical processes. The predominant pathway leading to cell death in AD has not been thoroughly analyzed, although there is evidence of neuron loss in AD and numerous pathways of PCD have been associated with this process. A better understanding of the systems biology underlying the relationship between AD and PCD could lead to the development of new therapeutic approaches. To this end, publicly available transcriptome data were examined using bioinformatic methods such as differential gene expression and weighted gene coexpression network analysis (WGCNA) to find PCD-related AD biomarkers. The diagnostic significance of these biomarkers was evaluated using a logistic regression-based predictive model. Using these biomarkers, a multifactorial regulatory network was developed. Last, a drug repositioning study was conducted to propose new drugs for the treatment of AD targeting PCD. The development of 3PM (predictive, preventive, and personalized) drugs for the treatment of AD would be enabled by additional research on the effects of these drugs on this disease.

PMID:38700745 | DOI:10.1007/s12031-024-02228-0

Plant Cell. 2024 May 3:koae139. doi: 10.1093/plcell/koae139. Online ahead of print.

NO ABSTRACT

PMID:38700166 | DOI:10.1093/plcell/koae139

In Silico Pharmacol. 2024 Apr 30;12(1):36. doi: 10.1007/s40203-024-00208-1. eCollection 2024.

ABSTRACT

Depression is a common psychiatric comorbidity among patients with epilepsy (PWE), affecting more than a third of PWE. Management of depression may improve quality of life of epileptic patients. Unfortunately, available antidepressants worsen epilepsy by reducing the seizure threshold. This situation demands search of new safer target for combined directorate of epilepsy and comorbid depression. A system biology approach may be useful to find novel pathways/markers for the cure of both epilepsy and associated depression via analyzing available genomic and proteomic information. Hence, the system biology approach using curated 64 seed genes involved in temporal lobe epilepsy and mental depression was applied. The interplay of 600 potential proteins was revealed by the Disease Module Detection (DIAMOnD) Algorithm for the treatment of both epilepsy and comorbid depression using these seed genes. The gene enrichment analysis of seed and diamond genes through DAVID suggested 95 pathways. Selected pathways were refined based on their syn or anti role in epilepsy and depression. In conclusion, total 8 pathways and 27 DIAMOnD genes/proteins were finally deduced as potential new targets for modulation of selected pathways to manage epilepsy and comorbid depression.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s40203-024-00208-1.

PMID:38699778 | PMC:PMC11061056 | DOI:10.1007/s40203-024-00208-1

Natl Sci Rev. 2024 Jan 15;11(4):nwae011. doi: 10.1093/nsr/nwae011. eCollection 2024 Apr.

NO ABSTRACT

PMID:38699632 | PMC:PMC11065342 | DOI:10.1093/nsr/nwae011

Saudi Pharm J. 2024 Jun;32(6):102055. doi: 10.1016/j.jsps.2024.102055. Epub 2024 Mar 30.

ABSTRACT

Acute myeloid leukaemia (AML) is characterized by uncontrolled proliferation of myeloid progenitor cells and impaired maturation, leading to immature cell accumulation in the bone marrow and bloodstream, resulting in hematopoietic dysfunction. Chemoresistance, hyperactivity of survival pathways, and miRNA alteration are major factors contributing to treatment failure and poor outcomes in AML patients. This study aimed to investigate the impact of the pharmacological p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580 on the chemoresistance potential of AML stem cell line KG1a to the therapeutic drug daunorubicin (DNR). KG1a and chemosensitive leukemic HL60 cells were treated with increasing concentrations of DNR. Cell Titer-Glo®, flow cytometry, phosphokinase and protein arrays, Western blot technology, and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) were employed for assessment of cell viability, half-maximal inhibitory concentration (IC50) determination, apoptotic status detection, cell cycle analysis, apoptosis-related protein and gene expression monitoring. Confocal microscopy was used to visualize caspase and mitochondrial permeability transition pore (mPTP) activities. Exposed at various incubation times, higher DNR IC50 values were determined for KG1a cells than for HL60 cells, confirming KG1a cell chemoresistance potential. Exposed to DNR, late apoptosis induction in KG1a cells was enhanced after SB203580 pretreatment, defined as the combination treatment. This enhancement was confirmed by increased cleavage of poly(ADP-ribose) polymerase, caspase-9, caspase-3, and augmented caspase-3/-7 and mPTP activities in KG1a cells upon combination treatment, compared to DNR. Using phosphokinase and apoptosis protein arrays, the combination treatment decreased survival Akt phosphorylation and anti-apoptotic Bcl-2 expression levels in KG1a cells while increasing the expression levels of the tumor suppressor p53 and cyclin-dependent kinase inhibitor p21, compared to DNR. Cell cycle analysis revealed KG1a cell growth arrest in G2/M-phase caused by DNR, while combined treatment led to cell growth arrest in S-phase, mainly associated with cyclin B1 expression levels. Remarkably, the enhanced KG1a cell sensitivity to DNR after SB203580 pretreatment was associated with an increased upregulation of miR-328-3p and slight downregulation of miR-26b-5p, compared to DNR effect. Altogether, these findings could contribute to the development of a new therapeutic strategy by targeting the p38 MAPK pathway to improve treatment outcomes in patients with refractory or relapsed AML.

PMID:38699598 | PMC:PMC11063648 | DOI:10.1016/j.jsps.2024.102055

iScience. 2024 Apr 16;27(5):109752. doi: 10.1016/j.isci.2024.109752. eCollection 2024 May 17.

ABSTRACT

Breast cancers (BRCA) exhibit substantial transcriptional heterogeneity, posing a significant clinical challenge. The global transcriptional changes in a disease context, however, are likely mediated by few key genes which reflect disease etiology better than the differentially expressed genes (DEGs). We apply our network-based tool PathExt to 1,059 BRCA tumors across 4 subtypes to identify key mediator genes in each subtype. Compared to conventional differential expression analysis, PathExt-identified genes exhibit greater concordance across tumors, revealing shared and subtype-specific biological processes; better recapitulate BRCA-associated genes in multiple benchmarks, and are more essential in BRCA subtype-specific cell lines. Single-cell transcriptomic analysis reveals a subtype-specific distribution of PathExt-identified genes in multiple cell types from the tumor microenvironment. Application of PathExt to a TNBC chemotherapy response dataset identified subtype-specific key genes and biological processes associated with resistance. We described putative drugs that target key genes potentially mediating drug resistance.

PMID:38699227 | PMC:PMC11063905 | DOI:10.1016/j.isci.2024.109752

Transpl Int. 2024 Apr 18;37:12468. doi: 10.3389/ti.2024.12468. eCollection 2024.

ABSTRACT

Kidney organoids are an innovative tool in transplantation research. The aim of the present study was to investigate whether kidney organoids are susceptible for allo-immune attack and whether they can be used as a model to study allo-immunity in kidney transplantation. Human induced pluripotent stem cell-derived kidney organoids were co-cultured with human peripheral blood mononuclear cells (PBMC), which resulted in invasion of allogeneic T-cells around nephron structures and macrophages in the stromal cell compartment of the organoids. This process was associated with the induction of fibrosis. Subcutaneous implantation of kidney organoids in immune-deficient mice followed by adoptive transfer of human PBMC led to the invasion of diverse T-cell subsets. Single cell transcriptomic analysis revealed that stromal cells in the organoids upregulated expression of immune response genes upon immune cell invasion. Moreover, immune regulatory PD-L1 protein was elevated in epithelial cells while genes related to nephron differentiation and function were downregulated. This study characterized the interaction between immune cells and kidney organoids, which will advance the use of kidney organoids for transplantation research.

PMID:38699175 | PMC:PMC11064018 | DOI:10.3389/ti.2024.12468

Front Mol Biosci. 2024 Apr 18;11:1395220. doi: 10.3389/fmolb.2024.1395220. eCollection 2024.

ABSTRACT

Background: Dormant ribosomes are typically associated with preservation factors to protect themselves from degradation under stress conditions. Stm1/SERBP1 is one such protein that anchors the 40S and 60S subunits together. Several proteins and tRNAs bind to this complex as well, yet the molecular mechanisms remain unclear. Methods: Here, we reported the cryo-EM structures of five newly identified Stm1/SERBP1-bound ribosomes. Results: These structures highlighted that eIF5A, eEF2, and tRNA might bind to dormant ribosomes under stress to avoid their own degradation, thus facilitating protein synthesis upon the restoration of growth conditions. In addition, Ribo-seq data analysis reflected the upregulation of nutrient, metabolism, and external-stimulus-related pathways in the ∆stm1 strain, suggesting possible regulatory roles of Stm1. Discussion: The knowledge generated from the present work will facilitate in better understanding the molecular mechanism of dormant ribosomes.

PMID:38698775 | PMC:PMC11063288 | DOI:10.3389/fmolb.2024.1395220

Int J Biol Macromol. 2024 Apr 30:131923. doi: 10.1016/j.ijbiomac.2024.131923. Online ahead of print.

ABSTRACT

Recent advances in mass spectrometry (MS) yielding sensitive and accurate measurements along with developments in software tools have enabled the characterization of complex systems routinely. Thus, structural proteomics and cross-linking mass spectrometry (XL-MS) have become a useful method for structural modeling of protein complexes. Here we utilized commonly used XL-MS software tools to elucidate the protein interactions within a membrane protein complex containing FtsH, HflK, and HflC, over-expressed in E.coli. The MS data were processed using MaxLynx, MeroX, MS Annika, xiSEARCH, and XlinkX software tools. The number of identified inter- and intra-protein cross-links varied among software. Each interaction was manually checked using the raw MS and MS/MS data and distance restraints to verify inter- and intra-protein cross-links. A total of 37 inter-protein and 148 intra-protein cross-links were determined in the FtsH-HflK-HflC complex. The 59 of them were new interactions on the lacking region of recently published structures. These newly identified interactions, when combined with molecular docking and structural modeling, present opportunities for further investigation. The results provide valuable information regarding the complex structure and function to decipher the intricate molecular mechanisms underlying the FtsH-HflK-HflC complex.

PMID:38697437 | DOI:10.1016/j.ijbiomac.2024.131923

Int J Biol Macromol. 2024 Apr 30:131918. doi: 10.1016/j.ijbiomac.2024.131918. Online ahead of print.

ABSTRACT

Polygalacturonases (PGs) can modulate chemistry and mechanical properties of the plant cell wall through the degradation of pectins, one of its major constituents. PGs are largely used in food, beverage, textile, and paper industries to increase processes' performances. To improve the use of PGs, knowledge of their biochemical, structural and functional features is of prime importance. Our study aims at characterizing SmoPG1, a polygalacturonase from Selaginella moellendorffii, that belongs to the lycophytes. Transcription data showed that SmoPG1 was mainly expressed in S. moellendorffii shoots while phylogenetic analyses suggested that SmoPG1 is an exo-PG, which was confirmed by the biochemical characterization following its expression in heterologous system. Indeed, LC-MS/MS oligoprofiling using various pectic substrates identified galacturonic acid (GalA) as the main hydrolysis product. We found that SmoPG1 was most active on polygalacturonic acid (PGA) at pH 5, and that its activity could be modulated by different cations (Ca2+, Cu2+, Fe2+, Mg2+, Mn2+, Na2+, Zn2+). In addition, SmoPG1 was inhibited by green tea catechins, including (-)-epigallocatechin-3-gallate (EGCG). Docking analyses and MD simulations showed in detail amino acids responsible for the SmoPG1-EGCG interaction. Considering its expression yield and activity, SmoPG1 appears as a prime candidate for the industrial production of GalA.

PMID:38697418 | DOI:10.1016/j.ijbiomac.2024.131918

Bioresour Technol. 2024 Apr 30:130770. doi: 10.1016/j.biortech.2024.130770. Online ahead of print.

ABSTRACT

Ammonia inhibition is a common issue encountered in anaerobic digestion (AD) when treating nitrogen-rich substrates. This study proposed a novel approach, the electrodialysis-integrated AD (ADED) system, for in-situ recovery of ammonium (NH4+) while simultaneously enhancing AD performance. The ADED reactor was operated at two different NH4+-N concentrations (5,000 mg/L and 10,000 mg/L) to evaluate its performance against a conventional AD reactor. The results indicate that the ADED technology effectively reduced the NH4+-N concentration to below 2,000 mg/L, achieving this with a competitive energy consumption. Moreover, the ADED reactor demonstrated a 1.43-fold improvement in methane production when the influent NH4+-N was 5,000 mg/L, and it effectively prevented complete inhibition of methane production at the influent NH4+-N of 10,000 mg/L. The life cycle impact assessment reveals that ADED technology offers a more environmentally friendly alternative by recovering valuable fertilizer from the AD system.

PMID:38697366 | DOI:10.1016/j.biortech.2024.130770

Cell Genom. 2024 Apr 29:100421. doi: 10.1016/j.xgen.2023.100421. Online ahead of print.

ABSTRACT

Regular exercise has many physical and brain health benefits, yet the molecular mechanisms mediating exercise effects across tissues remain poorly understood. Here we analyzed 400 high-quality DNA methylation, ATAC-seq, and RNA-seq datasets from eight tissues from control and endurance exercise-trained (EET) rats. Integration of baseline datasets mapped the gene location dependence of epigenetic control features and identified differing regulatory landscapes in each tissue. The transcriptional responses to 8 weeks of EET showed little overlap across tissues and predominantly comprised tissue-type enriched genes. We identified sex differences in the transcriptomic and epigenomic changes induced by EET. However, the sex-biased gene responses were linked to shared signaling pathways. We found that many G protein-coupled receptor-encoding genes are regulated by EET, suggesting a role for these receptors in mediating the molecular adaptations to training across tissues. Our findings provide new insights into the mechanisms underlying EET-induced health benefits across organs.

PMID:38697122 | DOI:10.1016/j.xgen.2023.100421

Immunity. 2024 Apr 26:S1074-7613(24)00214-0. doi: 10.1016/j.immuni.2024.04.009. Online ahead of print.

ABSTRACT

Multimodal single-cell profiling methods can capture immune cell variations unfolding over time at the molecular, cellular, and population levels. Transforming these data into biological insights remains challenging. Here, we introduce a framework to integrate variations at the human population and single-cell levels in vaccination responses. Comparing responses following AS03-adjuvanted versus unadjuvanted influenza vaccines with CITE-seq revealed AS03-specific early (day 1) response phenotypes, including a B cell signature of elevated germinal center competition. A correlated network of cell-type-specific transcriptional states defined the baseline immune status associated with high antibody responders to the unadjuvanted vaccine. Certain innate subsets in the network appeared "naturally adjuvanted," with transcriptional states resembling those induced uniquely by AS03-adjuvanted vaccination. Consistently, CD14+ monocytes from high responders at baseline had elevated phospho-signaling responses to lipopolysaccharide stimulation. Our findings link baseline immune setpoints to early vaccine responses, with positive implications for adjuvant development and immune response engineering.

PMID:38697118 | DOI:10.1016/j.immuni.2024.04.009

Neuron. 2024 Apr 22:S0896-6273(24)00244-7. doi: 10.1016/j.neuron.2024.04.006. Online ahead of print.

ABSTRACT

Mutations in human nonsense-mediated mRNA decay (NMD) factors are enriched in neurodevelopmental disorders. We show that deletion of key NMD factor Upf2 in mouse embryonic neural progenitor cells causes perinatal microcephaly but deletion in immature neurons does not, indicating NMD's critical roles in progenitors. Upf2 knockout (KO) prolongs the cell cycle of radial glia progenitor cells, promotes their transition into intermediate progenitors, and leads to reduced upper-layer neurons. CRISPRi screening identified Trp53 knockdown rescuing Upf2KO progenitors without globally reversing NMD inhibition, implying marginal contributions of most NMD targets to the cell cycle defect. Integrated functional genomics shows that NMD degrades selective TRP53 downstream targets, including Cdkn1a, which, without NMD suppression, slow the cell cycle. Trp53KO restores the progenitor cell pool and rescues the microcephaly of Upf2KO mice. Therefore, one physiological role of NMD in the developing brain is to degrade selective TRP53 targets to control progenitor cell cycle and brain size.

PMID:38697111 | DOI:10.1016/j.neuron.2024.04.006

Plant Methods. 2024 May 3;20(1):60. doi: 10.1186/s13007-024-01193-4.

ABSTRACT

BACKGROUND: Despite major efforts over the last decades, the rising demands of the growing global population makes it of paramount importance to increase crop yields and reduce losses caused by plant pathogens. One way to tackle this is to screen novel resistant genotypes and immunity-inducing agents, which must be conducted in a high-throughput manner.

RESULTS: Colour-analyzer is a free web-based tool that can be used to rapidly measure the formation of lesions on leaves. Pixel colour values are often used to distinguish infected from healthy tissues. Some programs employ colour models, such as RGB, HSV or L*a*b*. Colour-analyzer uses two colour models, utilizing both HSV (Hue, Saturation, Value) and L*a*b* values. We found that the a* b* values of the L*a*b* colour model provided the clearest distinction between infected and healthy tissue, while the H and S channels were best to distinguish the leaf area from the background.

CONCLUSION: By combining the a* and b* channels to determine the lesion area, while using the H and S channels to determine the leaf area, Colour-analyzer provides highly accurate information on the size of the lesion as well as the percentage of infected tissue in a high throughput manner and can accelerate the plant immunity research field.

PMID:38698422 | DOI:10.1186/s13007-024-01193-4

J Nanobiotechnology. 2024 May 3;22(1):222. doi: 10.1186/s12951-024-02456-x.

ABSTRACT

BACKGROUND: Aging is a very complex physiological phenomenon, and sEVs are involved in the regulation of this mechanism. Serum samples from healthy individuals under 30 and over 60 years of age were collected to analyze differences in sEVs proteomics.

RESULTS: Based on PBA analysis, we found that sEVs from the serum of elderly individuals highly express TACSTD2 and identified a subpopulation marked by TACSTD2. Using ELISA, we verified the upregulation of TACSTD2 in serum from elderly human and aged mouse. In addition, we discovered that TACSTD2 was significantly increased in samples from tumor patients and had better diagnostic value than CEA. Specifically, 9 of the 13 tumor groups exhibited elevated TACSTD2, particularly for cervical cancer, colon cancer, esophageal carcinoma, liver cancer and thyroid carcinoma. Moreover, we found that serum sEVs from the elderly (especially those with high TACSTD2 levels) promoted tumor cell (SW480, HuCCT1 and HeLa) proliferation and migration.

CONCLUSION: TACSTD2 was upregulated in the serum of elderly individuals and patients with tumors, and could serve as a dual biomarker for aging and tumors.

PMID:38698420 | DOI:10.1186/s12951-024-02456-x

Nat Microbiol. 2024 May 2. doi: 10.1038/s41564-024-01680-3. Online ahead of print.

ABSTRACT

The detection of oral bacteria in faecal samples has been associated with inflammation and intestinal diseases. The increased relative abundance of oral bacteria in faeces has two competing explanations: either oral bacteria invade the gut ecosystem and expand (the 'expansion' hypothesis), or oral bacteria transit through the gut and their relative increase marks the depletion of other gut bacteria (the 'marker' hypothesis). Here we collected oral and faecal samples from mouse models of gut dysbiosis (antibiotic treatment and DSS-induced colitis) and used 16S ribosomal RNA sequencing to determine the abundance dynamics of oral bacteria. We found that the relative, but not absolute, abundance of oral bacteria increases, reflecting the 'marker' hypothesis. Faecal microbiome datasets from diverse patient cohorts, including healthy individuals and patients with allogeneic haematopoietic cell transplantation or inflammatory bowel disease, consistently support the 'marker' hypothesis and explain associations between oral bacterial abundance and patient outcomes consistent with depleted gut microbiota. By distinguishing between the two hypotheses, our study guides the interpretation of microbiome compositional data and could potentially identify cases where therapies are needed to rebuild the resident microbiome rather than protect against invading oral bacteria.

PMID:38698178 | DOI:10.1038/s41564-024-01680-3

Cell Death Discov. 2024 May 2;10(1):211. doi: 10.1038/s41420-024-01929-0.

ABSTRACT

Forkhead box protein M1 (FOXM1) is often overexpressed in human cancers and strongly associated with therapy resistance and less good patient survival. The chemotherapy options for patients with the most aggressive types of solid cancers remain very limited because of the acquired drug resistance, making the therapy less effective. NPM1 mutation through the inactivation of FOXM1 via FOXM1 relocalization to the cytoplasm confers more favorable treatment outcomes for AML patients, confirming FOXM1 as a crucial target to overcome drug resistance. Pharmacological inhibition of FOXM1 could be a promising approach to sensitize therapy-resistant cancers. Here, we explore a novel FOXM1 inhibitor STL001, a first-generation modification drug of our previously reported FOXM1 inhibitor STL427944. STL001 preserves the mode of action of the STL427944; however, STL001 is up to 50 times more efficient in reducing FOXM1 activity in a variety of solid cancers. The most conventional cancer therapies studied here induce FOXM1 overexpression in solid cancers. The therapy-induced FOXM1 overexpression may explain the failure or reduced efficacy of these drugs in cancer patients. Interestingly, STL001 increased the sensitivity of cancer cells to conventional cancer therapies by suppressing both the high-endogenous and drug-induced FOXM1. Notably, STL001 does not provide further sensitization to FOXM1-KD cancer cells, suggesting that the sensitization effect is conveyed specifically through FOXM1 suppression. RNA-seq and gene set enrichment studies revealed prominent suppression of FOXM1-dependent pathways and gene ontologies. Also, gene regulation by STL001 showed extensive overlap with FOXM1-KD, suggesting a high selectivity of STL001 toward the FOXM1 regulatory network. A completely new activity of FOXM1, mediated through steroid/cholesterol biosynthetic process and protein secretion in cancer cells was also detected. Collectively, STL001 offers intriguing translational opportunities as combination therapies targeting FOXM1 activity in a variety of human cancers driven by FOXM1.

PMID:38697979 | DOI:10.1038/s41420-024-01929-0

Life Sci. 2024 May 1:122679. doi: 10.1016/j.lfs.2024.122679. Online ahead of print.

NO ABSTRACT

PMID:38697877 | DOI:10.1016/j.lfs.2024.122679