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Chemoarchitecture, the heterogeneous distribution of neurotransmitter transporter and receptor molecules, is a relevant component of structure-function relationships in the human brain. Here, we studied the organization of the receptome, a measure of interareal chemoarchitectural similarity, derived from positron-emission tomography imaging studies of 19 different neurotransmitter transporters and receptors. Nonlinear dimensionality reduction revealed three main spatial gradients of cortical chemoarchitectural similarity - a centro-temporal gradient, an occipito-frontal gradient, and a temporo-occipital gradient. In subcortical nuclei, chemoarchitectural similarity distinguished functional communities and delineated a striato-thalamic axis. Overall, the cortical receptome shared key organizational traits with functional and structural brain anatomy, with node-level correspondence to functional, microstructural, and diffusion MRI-based measures decreasing along a primary-to-transmodal axis. Relative to primary and paralimbic regions, unimodal and heteromodal regions showed higher receptomic diversification, possibly supporting functional flexibility., Competing Interests: BH, JH, BB, SE, JD, BM, SV No competing interests declared, (© 2023, Hänisch et al.)

Variant surface glycoprotein (VSG) coats bloodstream form Trypanosoma brucei parasites, and monoallelic VSG expression underpins the antigenic variation necessary for pathogenicity. One of thousands of VSG genes is transcribed by RNA polymerase I in a singular nuclear structure called the expression site body (ESB), but how monoallelic VSG transcription is achieved remains unclear. Using a localization screen of 153 proteins we found one, ESB-specific protein 1 (ESB1), that localized only to the ESB and is expressed only in VSG-expressing life cycle stages. ESB1 associates with DNA near the active VSG promoter and is necessary for VSG expression, with overexpression activating inactive VSG promoters. Mechanistically, ESB1 is necessary for recruitment of a subset of ESB components, including RNA polymerase I, revealing that the ESB has separately assembled subdomains. Because many trypanosomatid parasites have divergent ESB1 orthologues yet do not undergo antigenic variation, ESB1 probably represents an important class of transcription regulators., (© 2022. The Author(s).)

Aberrant alternative splicing is a hallmark of cancer, yet the underlying regulatory programs that control this process remain largely unknown. Here, we report a systematic effort to decipher the RNA structural code that shapes pathological splicing during breast cancer metastasis. We discovered a previously unknown structural splicing enhancer that is enriched near cassette exons with increased inclusion in highly metastatic cells. We show that the spliceosomal protein small nuclear ribonucleoprotein polypeptide A' (SNRPA1) interacts with these enhancers to promote cassette exon inclusion. This interaction enhances metastatic lung colonization and cancer cell invasion, in part through SNRPA1-mediated regulation of PLEC alternative splicing, which can be counteracted by splicing modulating morpholinos. Our findings establish a noncanonical regulatory role for SNRPA1 as a prometastatic splicing enhancer in breast cancer., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

When Alzheimer's disease (AD) disease-modifying therapies will be available, global healthcare systems will be challenged by a large-scale demand for clinical and biological screening. Validation and qualification of globally accessible, minimally-invasive, and time-, cost-saving blood-based biomarkers need to be advanced. Novel pathophysiological mechanisms (and related candidate biomarkers) - including neuroinflammation pathways (TREM2 and YKL-40), axonal degeneration (neurofilament light chain protein), synaptic dysfunction (neurogranin, synaptotagmin, α-synuclein, and SNAP-25) - may be integrated into an expanding pathophysiological and biomarker matrix and, ultimately, integrated into a comprehensive blood-based liquid biopsy, aligned with the evolving ATN + classification system and the precision medicine paradigm. Liquid biopsy-based diagnostic and therapeutic algorithms are increasingly employed in Oncology disease-modifying therapies and medical practice, showing an enormous potential for AD and other brain diseases as well. For AD and other neurodegenerative diseases, newly identified aberrant molecular pathways have been identified as suitable therapeutic targets and are currently investigated by academia/industry-led R&D programs, including the nerve-growth factor pathway in basal forebrain cholinergic neurons, the sigma1 receptor, and the GTPases of the Rho family. Evidence for a clinical long-term effect on cognitive function and brain health span of cholinergic compounds, drug candidates for repositioning programs, and non-pharmacological multidomain interventions (nutrition, cognitive training, and physical activity) is developing as well. Ultimately, novel pharmacological paradigms, such as quantitative systems pharmacology-based integrative/explorative approaches, are gaining momentum to optimize drug discovery and accomplish effective pathway-based strategies for precision medicine. This article is part of the special issue on 'The Quest for Disease-Modifying Therapies for Neurodegenerative Disorders'., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Identifying master regulators that drive pathologic gene expression is a key challenge in precision oncology. Here, we have developed an analytic framework, named PRADA, that identifies oncogenic RNA-binding proteins through the systematic detection of coordinated changes in their target regulons. Application of this approach to data collected from clinical samples, patient-derived xenografts, and cell line models of colon cancer metastasis revealed the RNA-binding protein RBMS1 as a suppressor of colon cancer progression. We observed that silencing RBMS1 results in increased metastatic capacity in xenograft mouse models, and that restoring its expression blunts metastatic liver colonization. We have found that RBMS1 functions as a posttranscriptional regulator of RNA stability by directly binding its target mRNAs. Together, our findings establish a role for RBMS1 as a previously unknown regulator of RNA stability and as a suppressor of colon cancer metastasis with clinical utility for risk stratification of patients. SIGNIFICANCE: By applying a new analytic approach to transcriptomic data from clinical samples and models of colon cancer progression, we have identified RBMS1 as a suppressor of metastasis and as a post-transcriptional regulator of RNA stability. Notably, RBMS1 silencing and downregulation of its targets are negatively associated with patient survival. See related commentary by Carter, p. 1261 . This article is highlighted in the In This Issue feature, p. 1241 ., (©2020 American Association for Cancer Research.)

Background: Sphingolipids are important components of cellular membranes and functionally associated with fundamental processes such as cell differentiation, neuronal signaling, and myelin sheath formation. Defects in the synthesis or degradation of sphingolipids leads to various neurological pathologies; however, the entire spectrum of sphingolipid metabolism disorders remains elusive., Methods: A combined approach of genomics and lipidomics was applied to identify and characterize a human sphingolipid metabolism disorder., Results: By whole-exome sequencing in a patient with a multisystem neurological disorder of both the central and peripheral nervous systems, we identified a homozygous p.Ala280Val variant in DEGS1, which catalyzes the last step in the ceramide synthesis pathway. The blood sphingolipid profile in the patient showed a significant increase in dihydro sphingolipid species that was further recapitulated in patient-derived fibroblasts, in CRISPR/Cas9-derived DEGS1-knockout cells, and by pharmacological inhibition of DEGS1. The enzymatic activity in patient fibroblasts was reduced by 80% compared with wild-type cells, which was in line with a reduced expression of mutant DEGS1 protein. Moreover, an atypical and potentially neurotoxic sphingosine isomer was identified in patient plasma and in cells expressing mutant DEGS1., Conclusion: We report DEGS1 dysfunction as the cause of a sphingolipid disorder with hypomyelination and degeneration of both the central and peripheral nervous systems., Trial Registration: Not applicable., Funding: Seventh Framework Program of the European Commission, Swiss National Foundation, Rare Disease Initiative Zurich.

Mammalian polyamines, including putrescine, spermidine, and spermine, are positively charged amines that are essential for all living cells including neoplastic cells. An increasing understanding of polyamine metabolism, its molecular functions, and its role in cancer has led to the interest in targeting polyamine metabolism as an anticancer strategy, as the metabolism of polyamines is frequently dysregulated in neoplastic disease. In addition, due to compensatory mechanisms, combination therapies are clinically more promising, as agents can work synergistically to achieve an effect beyond that of each strategy as a single agent. In this article, the nature of polyamines, their association with carcinogenesis, and the potential use of targeting polyamine metabolism in treating and preventing cancer as well as combination therapies are described. The goal is to review the latest strategies for targeting polyamine metabolism, highlighting new avenues for exploiting aberrant polyamine homeostasis for anticancer therapy and the mechanisms behind them. [ABSTRACT FROM AUTHOR]

Serotonin type 3 receptors (\(5-HT_3\)) are involved in learning, cognition and emotion, and have been implicated in various psychiatric phenotypes. However, their contribution to the pathomechanism of these disorders remains elusive. Three single nucleotide polymorphisms (SNPs) in the \(HTR3A\) and \(HTR3B\) genes (rs1062613, rs1176744 and rs3831455) have been associated with bipolar affective disorder (BPAD) in pilot studies, and all of them are of functional relevance. We performed a European multicenter study to confirm previous results and provide further evidence for the relevance of these SNPs to the etiology of neuropsychiatric disorders. This involved analysis of the distribution of the three SNPs among 1804 BPAD cases and 2407 healthy controls. A meta-analysis revealed a pooled odds ratio of 0.881 (P=0.009, 95% confidence intervals=0.802–0.968) for the non-synonymous functional SNP \(HTR3B\) p.Y129S (rs1176744), thereby confirming previous findings. In line with this, the three genome-wide association study samples BOMA (Bonn-Mannheim)-BPAD, WTCCC (Wellcome Trust Case Control Consortium)-BPAD and GAIN (Genetic Association Information Network)-BPAD, including >3500 patients and 5200 controls in total, showed an overrepresentation of the p.Y129 in patients. Remarkably, the meta-analysis revealed a P-value of 0.048 (OR=0.934, fixed effect model). We also performed expression analyses to gain further insights into the distribution of \(HTR3A\) and \(HTR3B\) mRNA in the human brain. \(HTR3A\) and \(HTR3B\) were detected in all investigated brain tissues with the exception of the cerebellum, and large differences in the A:B subunit ratio were observed. Interestingly, expression of the B subunit was most prominent in the brain stem, amygdalae and frontal cortex, regions of relevance to psychiatric disorders. In conclusion, the present study provides further evidence for the presence of impaired \(5-HT_3\) receptor function in BPAD.

The link between long COVID-19 and brain/cognitive impairments is concerning and may foster a worrisome worldwide emergence of novel cases of neurodegenerative diseases with aging. This review aims to update the knowledge, crosstalk, and possible intersections between the Post-COVID Syndrome (PCS) and Alzheimer's disease (AD). References included in this review were obtained from PubMed searches conducted between October 2023 and November 2023. PCS is a very heterogenous and poorly understood disease with recent evidence of a possible association with chronic diseases such as AD. However, more scientific data is required to establish the link between PCS and AD. [ABSTRACT FROM AUTHOR]

Background: Polycystic ovary syndrome (PCOS) is a prevalent endocrine disorder affecting women of reproductive ages. Our previous study has implicated a possible link between RNA editing and PCOS, yet the actual role of RNA editing, its association with clinical features, and the underlying mechanisms remain unclear. Methods: Ten RNA-Seq datasets containing 269 samples of multiple tissue types, including granulosa cells, T helper cells, placenta, oocyte, endometrial stromal cells, endometrium, and adipose tissues, were retrieved from public databases. Peripheral blood samples were collected from twelve PCOS and ten controls and subjected to RNA-Seq. Transcriptome-wide RNA-Seq data analysis was conducted to identify differential RNA editing (DRE) between PCOS and controls. The functional significance of DRE was evaluated by luciferase reporter assays and overexpression in human HEK293T cells. Dehydroepiandrosterone and lipopolysaccharide were used to stimulate human KGN granulosa cells to evaluate gene expression. Results: RNA editing dysregulations across multiple tissues were found to be associated with PCOS in public datasets. Peripheral blood transcriptome analysis revealed 798 DRE events associated with PCOS. Through weighted gene co-expression network analysis, our results revealed a set of hub DRE events in PCOS blood. A DRE event in the eukaryotic translation initiation factor 2-alpha kinase 2 (EIF2AK2:chr2:37,100,559) was associated with PCOS clinical features such as luteinizing hormone (LH) and the ratio of LH over follicle-stimulating hormone. Luciferase assays, overexpression, and knockout of RNA editing enzyme adenosine deaminase RNA specific (ADAR) showed that the ADAR-mediated editing cis-regulated EIF2AK2 expression. EIAF2AK2 showed a higher expression after dehydroepiandrosterone and lipopolysaccharide stimulation, triggering changes in the downstrean MAPK pathway. Conclusions: Our study presented the first evidence of cross-tissue RNA editing dysregulation in PCOS and its clinical associations. The dysregulation of RNA editing mediated by ADAR and the disrupted target EIF2AK2 may contribute to PCOS development via the MPAK pathway, underlining such epigenetic mechanisms in the disease. [ABSTRACT FROM AUTHOR]

Cellular senescence is a dynamic biological process triggered by sublethal cell damage and driven by specific changes in gene expression programs. We recently identified ANKRD1 (ankyrin repeat domain 1) as a protein strongly elevated after triggering senescence in fibroblasts. Here, we set out to investigate the mechanisms driving the elevated production of ANKRD1 in the early stages of senescence. Our results indicated that the rise in ANKRD1 levels after triggering senescence using etoposide (Eto) was the result of moderate increases in transcription and translation, and robust mRNA stabilization. Antisense oligomer (ASO) pulldown followed by mass spectrometry revealed a specific interaction of the RNA-binding protein RBMS1 with ANKRD1 mRNA that was confirmed by ribonucleoprotein immunoprecipitation analysis. RBMS1 abundance decreased in the nucleus and increased in the cytoplasm during Eto-induced senescence; in agreement with the hypothesis that RBMS1 may participate in post-transcriptional stabilization of ANKRD1 mRNA, silencing RBMS1 reduced, while overexpressing RBMS1 enhanced ANKRD1 mRNA half-life after Eto treatment. A segment proximal to the ANKRD1 coding region was identified as binding RBMS1 and conferring RBMS1-dependent increased expression of a heterologous reporter. We propose that RBMS1 increases expression of ANKRD1 during the early stages of senescence by stabilizing ANKRD1 mRNA. [ABSTRACT FROM AUTHOR]

Preeclampsia is one of the leading causes of maternal and fetal morbidity and mortality worldwide. Preeclampsia is linked to mitochondrial dysfunction as a contributing factor in its progression. This study aimed to develop a novel diagnostic model based on mitochondria-related genes(MRGs) for preeclampsia using machine learning and further investigate the association of the MRGs and immune infiltration landscape in preeclampsia. In this research, we analyzed GSE75010 database and screened 552 DE-MRGs between preeclampsia samples and normal samples. Enrichment assays indicated that 552 DE-MRGs were mainly related to energy metabolism pathway and several different diseases. Then, we performed LASSO and SVM-RFE and identified three critical diagnostic genes for preeclampsia, including CPOX, DEGS1 and SH3BP5. In addition, we developed a novel diagnostic model using the above three genes and its diagnostic value was confirmed in GSE44711, GSE75010 datasets and our cohorts. Importantly, the results of RT-PCR confirmed the expressions of CPOX, DEGS1 and SH3BP5 were distinctly increased in preeclampsia samples compared with normal samples. The results of the CIBERSORT algorithm revealed a striking dissimilarity between the immune cells found in preeclampsia samples and those found in normal samples. In addition, we found that the levels of SH3BP5 were closely associated with several immune cells, highlighting its potential involved in immune microenvironment of preeclampsia. Overall, this study has provided a novel diagnostic model and diagnostic genes for preeclampsia while also revealing the association between MRGs and immune infiltration. These findings offer valuable insights for further research and treatment of preeclampsia. [ABSTRACT FROM AUTHOR]

Recently, multi-voxel pattern analysis has verified that information can be removed from working memory (WM) via three distinct operations replacement, suppression, or clearing compared to information being maintained (Kim et al., 2020). While univariate analyses and classifier importance maps in Kim et al. (2020) identified brain regions that contribute to these operations, they did not elucidate whether these regions represent the operations similarly or uniquely. Using Leiden-community-detection on a sample of 55 humans (17 male), we identified four brain networks, each of which has a unique configuration of multi-voxel activity patterns by which it represents these WM operations. The visual network (VN) shows similar multi-voxel patterns for maintain and replace, which are highly dissimilar from suppress and clear, suggesting this network differentiates whether an item is held in WM or not. The somatomotor network (SMN) shows a distinct multi-voxel pattern for clear relative to the other operations, indicating the uniqueness of this operation. The default mode network (DMN) has distinct patterns for suppress and clear, but these two operations are more similar to each other than to maintain and replace, a pattern intermediate to that of the VN and SMN. The frontoparietal control network (FPCN) displays distinct multi-voxel patterns for each of the four operations, suggesting that this network likely plays an important role in implementing theseWMoperations. These results indicate that the operations involved in removing information fromWMcan be performed in parallel by distinct brain networks, each of which has a particular configuration by which they represent these operations. [ABSTRACT FROM AUTHOR]

Although located at the chromosome end, telomeres are an essential chromosome component that helps maintain genome integrity and chromosome stability from protozoa to mammals. The role of telomere proteins in chromosome end protection is conserved, where they suppress various DNA damage response machineries and block nucleolytic degradation of the natural chromosome ends, although the detailed underlying mechanisms are not identical. In addition, the specialized telomere structure exerts a repressive epigenetic effect on expression of genes located at subtelomeres in a number of eukaryotic organisms. This so-called telomeric silencing also affects virulence of a number of microbial pathogens that undergo antigenic variation/phenotypic switching. Telomere proteins, particularly the RAP1 homologs, have been shown to be a key player for telomeric silencing. RAP1 homologs also suppress the expression of Telomere Repeat-containing RNA (TERRA), which is linked to their roles in telomere stability maintenance. The functions of RAP1s in suppressing telomere recombination are largely conserved from kinetoplastids to mammals. However, the underlying mechanisms of RAP1-mediated telomeric silencing have many species-specific features. In this review, I will focus on Trypanosoma brucei RAP1's functions in suppressing telomeric/subtelomeric DNA recombination and in the regulation of monoallelic expression of subtelomere-located major surface antigen genes. Common and unique mechanisms will be compared among RAP1 homologs, and their implications will be discussed. [ABSTRACT FROM AUTHOR]

The brain is composed of disparate neural populations that communicate and interact with one another. Although fiber bundles, similarities in molecular architecture, and synchronized neural activity all reflect how brain regions potentially interact with one another, a comprehensive study of how all these interregional relationships jointly reflect brain structure and function remains missing. Here, we systematically integrate 7 multimodal, multiscale types of interregional similarity ("connectivity modes") derived from gene expression, neurotransmitter receptor density, cellular morphology, glucose metabolism, haemodynamic activity, and electrophysiology in humans. We first show that for all connectivity modes, feature similarity decreases with distance and increases when regions are structurally connected. Next, we show that connectivity modes exhibit unique and diverse connection patterns, hub profiles, spatial gradients, and modular organization. Throughout, we observe a consistent primacy of molecular connectivity modes—namely correlated gene expression and receptor similarity—that map onto multiple phenomena, including the rich club and patterns of abnormal cortical thickness across 13 neurological, psychiatric, and neurodevelopmental disorders. Finally, to construct a single multimodal wiring map of the human cortex, we fuse all 7 connectivity modes and show that the fused network maps onto major organizational features of the cortex including structural connectivity, intrinsic functional networks, and cytoarchitectonic classes. Altogether, this work contributes to the integrative study of interregional relationships in the human cerebral cortex. Brain connectivity can refer to physical neural fibers that link brain regions, synchronized fluctuations in neural activity, or similarities in local molecular composition. This study integrates seven connectivity blueprints to comprehensively characterize inter-regional relationships in the human cortex. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) has been proven to be highly reliant on arginine availability. Limiting arginine-rich foods or treating patients with arginine-depleting enzymes arginine deiminase (ADI) or arginase can suppress colon cancer. However, arginase and ADI are not the best drug candidates for CRC. Ornithine, the product of arginase, can enhance the supply of polyamine, which favors CRC cell growth, while citrulline, the product of ADI, faces the problem of arginine recycling due to the overexpression of argininosuccinate synthetase (ASS). Biosynthetic arginine decarboxylase (ADC), an enzyme that catalyzes the conversion of arginine to agmatine and carbon dioxide, may be a better choice as it combines both arginine depletion and suppression of intracellular polyamine synthesis via its product agmatine. ADC has anti-tumor potential yet has received much less attention than the other two arginine-depleting enzymes. In order to gain a better understanding of ADC, the preparation and the anti-cancer properties of this enzyme were explored in this study. When tested in vitro, ADC inhibited the proliferation of three colorectal cancer cell lines regardless of their ASS cellular expression. In contrast, ADC had a lesser cytotoxic effect on the human foreskin fibroblasts and rat primary hepatocytes. Further in vitro studies revealed that ADC induced S and G2/M phase cell-cycle arrest and apoptosis in HCT116 and LoVo cells. ADC-induced apoptosis in HCT116 cells followed the mitochondrial apoptotic pathway and was caspase-3-dependent. With all results obtained, we suggest that arginine is a potential target for treating colorectal cancer with ADC, and the anti-cancer properties of ADC should be more deeply investigated in the future. [ABSTRACT FROM AUTHOR]

The integration of high-temperature superconducting YBa2Cu3O6+x (YBCO) into flexible electronic devices has the potential to revolutionize the technology industry. The effective preparation of high-quality flexible YBCO films therefore plays a key role in this development. We present a novel approach for transferring water-sensitive YBCO films onto flexible substrates without any buffer layer. Freestanding YBCO film on a polydimethylsiloxane substrate is extracted by etching the Sr3Al2O6 sacrificial layer from the LaAlO3 substrate. In addition to the obtained freestanding YBCO thin film having a Tc of 89.1 K, the freestanding YBCO thin films under inward and outward bending conditions have Tc of 89.6 and 88.9 K, respectively. A comprehensive characterization involving multiple experimental techniques, including high-resolution transmission electron microscopy, scanning electron microscopy, Raman, and x-ray absorption spectroscopy, is conducted to investigate the morphology, structural, and electronic properties of the YBCO film before and after the extraction process where it shows the preservation of the structural and superconductive properties of the freestanding YBCO virtually in its pristine state. Further investigation reveals the formation of a YBCO passivated layer serves as a protective layer that effectively preserves the inner section of the freestanding YBCO during the etching process. This work plays a key role in actualizing the fabrication of flexible oxide thin films and opens up new possibilities for a diverse range of device applications involving thin-films and low-dimensional materials. [ABSTRACT FROM AUTHOR]

Hypomyelinating leukodystrophies (HLDs) represent a group of congenital rare diseases for which the responsible genes have been identified in recent studies. In this review, we briefly describe the genetic/molecular mechanisms underlying the pathogenesis of HLD and the normal cellular functions of the related genes and proteins. An increasing number of studies have reported genetic mutations that cause protein misfolding, protein dysfunction, and/or mislocalization associated with HLD. Insight into the mechanisms of these pathways can provide new findings for the clinical treatments of HLD. [ABSTRACT FROM AUTHOR]

Background: Neurosyphilis-associated cognitive and behavioral impairment— historically coined as "general paralysis of the insane"— share clinical and neuroradiological features with the neurodegenerative disease spectrum, in particular Alzheimer's disease (AD). Anatomopathological similarities have been extensively documented, i.e., neuronal loss, fibrillary alterations, and local amyloid-β deposition. Consequently, accurate classification and timely differential diagnosis may be challenging. Objective: To describe clinical, bio-humoral, brain MRI, FDG-PET, and amyloid-PET features in cases of neurosyphilis with an AD-like phenotypical presentation, as well as clinical outcome in terms of response to antibiotic therapy. Methods: We selected the studies comparing patients with AD and with neurosyphilis associated cognitive impairment, to investigate candidate biomarkers classifying the two neurological diseases. Results: The neuropsychological phenotype of general paralysis, characterized by episodic memory impairment and executive disfunction, substantially mimics clinical AD features. Neuroimaging often shows diffuse or medial temporal cortical atrophy, thus contributing to a high rate of misdiagnosis. Cerebrospinal fluid (CSF)-based analysis may provide supportive diagnostic value, since increased proteins or cells are often found in neurosyphilis, while published data on pathophysiological AD candidate biomarkers are controversial. Finally, psychometric testing using cross-domain cognitive tests, may highlight a wider range of compromised functions in neurosyphilis, involving language, attention, executive function, and spatial ability, which are atypical for AD. Conclusion: Neurosyphilis should be considered a potential etiological differential diagnosis of cognitive impairment whenever imaging, neuropsychological or CSF features are atypical for AD, in order to promptly start antibiotic therapy and delay or halt cognitive decline and disease progression. [ABSTRACT FROM AUTHOR]

Alzheimer's is a neurodegenerative disorder affecting the central nervous system and cognitive processes, explicitly impairing detailed mental analysis. Throughout this condition, the affected individual's cognitive abilities to process and analyze information gradually deteriorate, resulting in mental decline. In recent years, there has been a notable increase in endeavors aimed at identifying Alzheimer's disease and addressing its progression. Research studies have demonstrated the significant involvement of genetic factors, stress, and nutrition in developing this condition. The utilization of computer-aided analysis models based on machine learning and artificial intelligence has the potential to significantly enhance the exploration of various neuroimaging methods and non-image biomarkers. This study conducts a comparative assessment of more than 80 publications that have been published since 2017. Alzheimer's disease detection is facilitated by utilizing fundamental machine learning architectures such as support vector machines, decision trees, and ensemble models. Furthermore, around 50 papers that utilized a specific architectural or design approach concerning Alzheimer's disease were examined. The body of literature under consideration has been categorized and elucidated through the utilization of data-related, methodology-related, and medical-fostering components to illustrate the underlying challenges. The conclusion section of our study encompasses a discussion of prospective avenues for further investigation and furnishes recommendations for future research activities on the diagnosis of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Desmoplastic small round cell tumor (DSRCT) is a rare pediatric cancer caused by the EWSR1-WT1 fusion oncogene. Despite initial response to chemotherapy, DSRCT has a recurrence rate of over 80% leading to poor patient prognosis with a 5-year survival rate of only 15–25%. Owing to the rarity of DSRCT, sample scarcity is a barrier in understanding DSRCT biology and developing effective therapies. Utilizing a novel pair of primary and recurrent DSRCTs, we present the first map of DSRCT genomic breakpoints and the first comparison of gene expression alterations between primary and recurrent DSRCT. Our genomic breakpoint map includes the lone previously published DSRCT genomic breakpoint, the breakpoint from our novel primary/recurrent DSRCT pair, as well as the breakpoints of five available DSRCT cell lines and five additional DSRCTs. All mapped breakpoints were unique and most breakpoints included a 1–3 base pair microhomology suggesting microhomology-mediated end-joining as the mechanism of translocation fusion and providing novel insights into the etiology of DSRCT. Through RNA-sequencing analysis, we identified altered genes and pathways between primary and recurrent DSRCTs. Upregulated pathways in the recurrent tumor included several DNA repair and mRNA splicing-related pathways, while downregulated pathways included immune system function and focal adhesion. We further found higher expression of the EWSR1-WT1 upregulated gene set in the recurrent tumor as compared to the primary tumor and lower expression of the EWSR1-WT1 downregulated gene set, suggesting the EWSR1-WT1 fusion continues to play a prominent role in recurrent tumors. The identified pathways including upregulation of DNA repair and downregulation of immune system function may help explain DSRCT's high rate of recurrence and can be utilized to improve the understanding of DSRCT biology and identify novel therapies to both help prevent recurrence and treat recurrent tumors. [ABSTRACT FROM AUTHOR]

Arginine is a semi-essential amino acid that supports protein synthesis to maintain cellular functions. Recent studies suggest that arginine also promotes wound healing, cell division, ammonia metabolism, immune system regulation, and hormone biosynthesis—all of which are critical for tumor growth. These discoveries, coupled with the understanding of cancer cell metabolic reprogramming, have led to renewed interest in arginine deprivation as a new anticancer therapy. Several arginine deprivation strategies have been developed and entered clinical trials. The main principle behind these therapies is that arginine auxotrophic tumors rely on external arginine sources for growth because they carry reduced key arginine-synthesizing enzymes such as argininosuccinate synthase 1 (ASS1) in the intracellular arginine cycle. To obtain anticancer effects, modified arginine-degrading enzymes, such as PEGylated recombinant human arginase 1 (rhArg1-PEG) and arginine deiminase (ADI-PEG 20), have been developed and shown to be safe and effective in clinical trials. They have been tried as a monotherapy or in combination with other existing therapies. This review discusses recent advances in arginine deprivation therapy, including the molecular basis of extracellular arginine degradation leading to tumor cell death, and how this approach could be a valuable addition to the current anticancer arsenal. [ABSTRACT FROM AUTHOR]

Background: Identifying Kidney Renal Papillary Cell Carcinoma (KIRP) patients with high-risk, guiding individualized diagnosis and treatment of patients, and identifying effective prognostic targets are urgent problems to be solved in current research on KIRP. Methods: In this study, data of multi omics for patients with KIRP were collected from TCGA database, including mRNAs, lncRNAs, miRNAs, data of methylation, and data of gene mutations. Data of multi-omics related to prognosis of patients with KIRP were selected for each omics level. Further, multi omics data related to prognosis were integrated into cluster analysis based on ten clustering algorithms using MOVICS package. The multi omics-based cancer subtype (MOCS) were compared on biological characteristics, immune microenvironmental cell abundance, immune checkpoint, genomic mutation, drug sensitivity using R packages, including GSVA, clusterProfiler, TIMER, CIBERSORT, CIBERSORT-ABS, quanTIseq, MCPcounter, xCell, EPIC, GISTIC, and pRRophetic algorithms. Results: The top ten OS-related factors for KIRP patients were annotated. Patients with KIRP were divided into MOCS1, MOCS2, and MOCS3. Patients in the MOCS3 subtype were observed with shorter overall survival time than patients in the MOCS1 and MOCS2 subtypes. MOCS1 was negatively correlated with immune-related pathways, and we found global dysfunction of cancerrelated pathways among the three MOCS subtypes. We evaluated the activity profiles of regulons among the three MOCSs. Most of the metabolism-related pathways were activated in MOCS2. Several immune microenvironmental cells were highly infiltrated in specific MOCS subtype. MOCS3 showed a significantly lower tumor mutation burden. The CNV occurrence frequency was higher in MOCS1. As for treatment, we found that these MOCSs were sensitive to different drugs and treatments. We also analyzed single-cell data for KIRP. Conclusion: Based on a variety of algorithms, this study determined the risk classifier based on multi-omics data, which could guide the risk stratification and medication selection of patients with KIRP. [ABSTRACT FROM AUTHOR]

Alternative splicing represents an essential process that occurs widely in eukaryotes. In humans, most genes undergo alternative splicing to ensure transcriptome and proteome diversity reflecting their functional complexity. Over the last decade, aberrantly spliced transcripts due to mutations in cis- or trans-acting splicing regulators have been tightly associated with cancer development, largely drawing scientific attention. Although a plethora of single proteins, ribonucleoproteins, complexed RNAs, and short RNA sequences have emerged as nodal contributors to the splicing cascade, the role of RNA secondary structures in warranting splicing fidelity has been underestimated. Recent studies have leveraged the establishment of novel high-throughput methodologies and bioinformatic tools to shed light on an additional layer of splicing regulation in the context of RNA structural elements. This short review focuses on the most recent available data on splicing mechanism regulation on the basis of RNA secondary structure, emphasizing the importance of the complex RNA G-quadruplex structures (rG4s), and other specific RNA motifs identified as splicing silencers or enhancers. Moreover, it intends to provide knowledge on newly established techniques that allow the identification of RNA structural elements and highlight the potential to develop new RNA-oriented therapeutic strategies against cancer. [ABSTRACT FROM AUTHOR]

Nearly 35 million people worldwide live with Alzheimer's disease (AD). The prevalence of the disease is expected to rise two-fold by 2050. With only symptomatic treatment options available, it is essential to understand the developments and existing evidence that aims to target brain pathology and dementia outcomes. This scoping systematic review aimed to collate existing evidence of CT1812 for use in patients with AD and summarize the methodologies of ongoing trials. Adhering to PRISMA Statement 2020 guidelines, PubMed/MEDLINE, Embase, Cochrane, and ClinicalTrials.gov were systematically searched through up to 15 November 2022 by applying the following keywords: CT1812, Alzheimer's disease, dementia, and/or sigma-2 receptor. Three completed clinical trials were included along with three ongoing records of clinical trials. The three completed trials were in Phases I and II of testing. The sample size across all three trials was 135. CT1812 reached endpoints across the trials and obtained a maximum concentration in the cerebrospinal fluid with 97–98% receptor occupancy. The findings of this systematic review must be used with caution as the results, while mostly favorable so far, must be replicated in higher-powered, placebo-controlled Phase II–III trials. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is the third most common cancer in the world, with increasing morbidity and mortality. The current diagnosis and treatment plan rely on early detection and comprehensive treatment based on surgery. Still, most patients are in the middle and advanced stage at the time of diagnosis, and the therapeutic effect is very limited. Immunotherapy is a new cancer treatment method. The most commonly used are immune checkpoint inhibitors, specifically anti PD-1/PD-L1 interaction. However, immunotherapy has limitations, with its therapeutic effect closely related to the immune response in the tumor microenvironment. In recent years, the effect of arginine metabolism disorder on the occurrence and development of cancer and tumor immune regulation has attracted wide attention. Studies have confirmed that cancer cells cannot survive without arginine and arginine metabolites. In addition, arginine is essential for the proliferation, differentiation, and survival of tumor-infiltrating lymphocytes. High arginine levels can promote the anti-tumor immune response, thus increasing the effect of tumor immunotherapy. In this paper, the molecular mechanisms of arginine metabolism in the development and immune regulation of CRC are reviewed, with the authors hoping to provide potential evidence for the development of immunotherapy for CRC. [ABSTRACT FROM AUTHOR]

Inherited leukodystrophies are genetic disorders characterized by abnormal white matter in the central nervous system. Although individually rare, there are more than 400 distinct types of leukodystrophies with a cumulative incidence of 1 in 4500 live births. The pathophysiology of most leukodystrophies is poorly understood, there are treatments for only a few, and there is significant morbidity and mortality, suggesting a critical need for improvements in this field. A variety of animal, cell, and induced pluripotent stem cell-derived models have been developed for leukodystrophies, but with significant limitations in all models. Many leukodystrophies lack animal models, and extant models often show no or mixed recapitulation of key phenotypes. Zebrafish (Danio rerio) have become increasingly used as disease models for studying leukodystrophies due to their early onset of disease phenotypes and conservation of molecular and neurobiological mechanisms. Here, we focus on reviewing new zebrafish disease models for leukodystrophy or models with recent progress. This includes discussion of leukodystrophy with vanishing white matter disease, X-linked adrenoleukodystrophy, Zellweger spectrum disorders and peroxisomal disorders, PSAP deficiency, metachromatic leukodystrophy, Krabbe disease, hypomyelinating leukodystrophy-8/4H leukodystrophy, Aicardi-Goutières syndrome, RNASET2-deficient cystic leukoencephalopathy, hereditary diffuse leukoencephalopathy with spheroids-1 (CSF1R-related leukoencephalopathy), and ultra-rare leukodystrophies. Zebrafish models offer important potentials for the leukodystrophy field, including testing of new variants in known genes; establishing causation of newly discovered genes; and early lead compound identification for therapies. There are also unrealized opportunities to use humanized zebrafish models which have been sparsely explored., (© 2024 Japanese Society of Developmental Biologists.)

The compartmentalised eukaryotic cell demands accurate targeting of proteins to the organelles in which they function, whether membrane-bound (like the nucleus) or non-membrane-bound (like the nucleolus). Nucleolar targeting relies on positively charged localisation signals and has received rejuvenated interest since the widespread recognition of liquid-liquid phase separation (LLPS) as a mechanism contributing to nucleolus formation. Here, we exploit a new genome-wide analysis of protein localisation in the early-branching eukaryote Trypanosoma brucei to analyse general nucleolar protein properties. T. brucei nucleolar proteins have similar properties to those in common model eukaryotes, specifically basic amino acids. Using protein truncations and addition of candidate targeting sequences to proteins, we show both homopolymer runs and distributed basic amino acids give nucleolar partition, further aided by a nuclear localisation signal (NLS). These findings are consistent with phase separation models of nucleolar formation and physical protein properties being a major contributing mechanism for eukaryotic nucleolar targeting, conserved from the last eukaryotic common ancestor. Importantly, cytoplasmic ribosome proteins, unlike mitochondrial ribosome proteins, have more basic residues - pointing to adaptation of physicochemical properties to assist segregation. [ABSTRACT FROM AUTHOR]

Artificial intelligence (AI)‐assisted materials design and discovery methods can come to the aid of global concerns for introducing new efficient materials in different applications. Also, a sustainable clean future requires a transition to a low‐carbon economy that is material‐intensive. AI‐assisted methods advent as inexpensive and accelerated methods in the design of new materials for clean energies. Herein, the emerging research area of AI‐assisted material discovery with a focus on developing clean energies is discussed. The applications, advantages, and challenges of using AI in material discovery are discussed and the future perspective of using AI in clean energy is studied. This perspective paves the way for a better understanding of the future of AI applications in clean energies. [ABSTRACT FROM AUTHOR]

Clear cell renal cell carcinoma (ccRCC) is the most common subtype of renal carcinoma and is associated with poor prognosis and notorious for its immune dysfunction characteristic. SNRPA1 is a spliceosome component responsible for processing pre-mRNA into mRNA, while the biological effect of SNRPA1 in ccRCC remains elusive. The aim of this study was to decipher the effect of SNRPA1 on clinical effect and tumor immunity for ccRCC patients. Multi-databases were collected to evaluate the different expression, prognostic value, DNA methylation, tumor immune microenvironment, and drug sensitivity of SNRPA1 on ccRCC. IHC was utilized to validate the expression and prognostic value of SNRPA1 in ccRCC patients from the SMMU cohort. The knockout expression of SNRPA by sgRNA plasmid inhibited the cell proliferation, migration, and metastasis ability and significantly increased the sensitivity of sunitinib treatment. In addition, we explored the role of SNRPA1 in pan-cancer level. The results indicated that SNRPA1 was differentially expressed in most cancer types. SNRPA1 may significantly influence the prognosis of multiple cancer types, especially in ccRCC patients. Notably, SNRPA1 was significantly correlated with immune cell infiltration and immune checkpoint inhibitory genes. In addition, the aggressive and immune inhibitory effects shown in SNRPA1 overexpression and the effect of SNRPA1 on ccRCC cell line invasion, metastasis, and drug sensitivity in vitro were observed. Moreover, SNRPA1 was related to Myc, MTORC, G2M, E2F, and DNA repair pathways in various cancer types. In all, SNRPA1 may prove to be a new biomarker for prognostic prediction, effect tumor immunity, and drug susceptibility in ccRCC. [ABSTRACT FROM AUTHOR]

The protein structure field is experiencing a revolution. From the increased throughput of techniques to determine experimental structures, to developments such as cryo-EM that allow us to find the structures of large protein complexes or, more recently, the development of artificial intelligence tools, such as AlphaFold, that can predict with high accuracy the folding of proteins for which the availability of homology templates is limited. Here we quantify the effect of the recently released AlphaFold database of protein structural models in our knowledge on human proteins. Our results indicate that our current baseline for structural coverage of 48%, considering experimentally-derived or template-based homology models, elevates up to 76% when including AlphaFold predictions. At the same time the fraction of dark proteome is reduced from 26% to just 10% when AlphaFold models are considered. Furthermore, although the coverage of disease-associated genes and mutations was near complete before AlphaFold release (69% of Clinvar pathogenic mutations and 88% of oncogenic mutations), AlphaFold models still provide an additional coverage of 3% to 13% of these critically important sets of biomedical genes and mutations. Finally, we show how the contribution of AlphaFold models to the structural coverage of non-human organisms, including important pathogenic bacteria, is significantly larger than that of the human proteome. Overall, our results show that the sequence-structure gap of human proteins has almost disappeared, an outstanding success of direct consequences for the knowledge on the human genome and the derived medical applications. Author summary: Protein structures are key to understand many biological phenomena at the molecular scale: from the effects of genetic variation to how different proteins interact with each other to create molecular pathways that, together, have a biological function. Obtaining experimental structures, however, is extremely consuming in terms of both, time and resources. For this and other reasons, scientists have long worked to develop computational approaches that predict the structure of a protein using only its sequence as input. Recently, a group of scientists at Deepmind have developed AlphaFold2, a computational tool that is extremely accurate at this task. Moreover, they have used this tool to predict the structures of all human proteins. In this manuscript we provide an overview of the structural coverage of the human proteome before AlphaFold models were released and how much we have gained thanks to these models. We also show how the gain affects our understanding of human pathogenic variants, both germline and somatic. Finally, we provide evidence suggesting that the gain in non-human organisms is larger than for the human proteome, particularly in the case of bacteria. [ABSTRACT FROM AUTHOR]

Plectin, as the cytolinker and scaffolding protein, are widely expressed and abundant in many tissues, and has involved in various cellular activities contributing to tumorigenesis, such as cell adhesion, migration, and signal transduction. Due to the specific expression and differential localization of plectin in cancer, most researchers focus on the role of plectin in cancer, and it has emerged as a potent driver of malignant hallmarks in many human cancers, which provides the possibility for plectin to be widely used as a biomarker and therapeutic target in the early diagnosis and targeted drug delivery of the disease. However, there is still a lack of systematic review on the interaction molecules and mechanism of plectin. Herein, we summarized the structure, expression and function of plectin, and mainly focused on recent studies on the functional and physical interactions between plectin and its interacting molecules, shedding light on the potential of targeting plectin for cancer therapy., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Manfred Göthert, who had served Naunyn-Schmiedeberg's Arch Pharmacol as Managing Editor from 1998 to 2005, deceased in June 2019. His scientific oeuvre encompasses more than 20 types of presynaptic receptors, mostly on serotoninergic and noradrenergic neurones. He was the first to identify presynaptic receptors for somatostatin and ACTH and described many presynaptic receptors, known from animal preparations, also in human tissue. In particular, he elucidated the pharmacology of presynaptic 5-HT receptors. A second field of interest included ligand-gated and voltage-dependent channels. The negative allosteric effect of anesthetics at peripheral nACh receptors is relevant for the peripheral clinical effects of these drugs and modified the Meyer-Overton hypothesis. The negative allosteric effect of ethanol at NMDA receptors in human brain tissue occurred at concentrations found in the range of clinical ethanol intoxication. Moreover, the inhibitory effect of gabapentinoids on P/Q Ca2+ channels and the subsequent decrease in AMPA-induced noradrenaline release may contribute to their clinical effect. Another ligand-gated ion channel, the 5-HT3 receptor, attracted the interest of Manfred Göthert from the whole animal via isolated preparations down to the cellular level. He contributed to that molecular study in which 5-HT3 receptor subtypes were disclosed. Finally, he found altered pharmacological properties of 5-HT receptor variants like the Arg219Leu 5-HT1A receptor (which was also shown to be associated with major depression) and the Phe124Cys 5-HT1B receptor (which may be related to sumatriptan-induced vasospasm). Manfred Göthert was a brilliant scientist and his papers have a major impact on today's pharmacology. [ABSTRACT FROM AUTHOR]

The root of Saposhnikovia divaricata (Fangfeng) is commonly used in traditional Chinese medicine (TCM) for headache and neuroinflammation-related disease treatment. The mRNA expression of IL-6 and IL-1β were significantly inhibited after Fangfeng extract (FFE) treatment in LPS-induced BV-2 cells. Metatolome profiling indicated that dopamine, palmitic acid, corticosterone, and eicosapentaenoic acid metabolites could be regulated by FFE for LPS stimulated inflammation responses in BV-2 cells. The disturbed metabolic pathways include caffeine metabolism, mannose type O-glycan biosynthesis, arachidonic acid metabolism, and steroid biosynthesis. This study will enable us to identify potential protein targets and metabolite intermediates for FFE exerting its protective function in BV-2 cells, and it also provided a potential application of Fangfeng in neuroinflammation-related disease treatment. [ABSTRACT FROM AUTHOR]