Methylation synthetic lethality: Exploiting selective drug targets for cancer therapy.

In cancer, synthetic lethality refers to the drug-induced inactivation of one gene and the inhibition of another in cancer cells by a drug, resulting in the death of only cancer cells; however, this effect is not present in normal cells, leading to targeted killing of cancer cells. Recent intensive epigenetic research has revealed that aberrant epigenetic changes are more frequently observed than gene mutations in certain cancers. Recently, numerous studies have reported various methylation synthetic lethal combinations involving DNA damage repair genes, metabolic pathway genes, and paralogs with significant results in cellular models, some of which have already entered clinical trials with promising results. This review systematically introduces the advantages of methylation synthetic lethality and describes the lethal mechanisms of methylation synthetic lethal combinations that have recently demonstrated success in cellular models. Furthermore, we discuss the future opportunities and challenges of methylation synthetic lethality in targeted anticancer therapies.

Cognitive behavioral phenotyping of DSCAM heterozygosity as a model for autism spectrum disorder.

It is estimated that 1 in 36 children are affected by autism spectrum disorder (ASD) in the United States, which is nearly a twofold increase from a decade ago. Recent genetic studies have identified de novo loss-of-function (dnLoF) mutations in the Down Syndrome Cell Adhesion Molecule (DSCAM) as a strong risk factor for ASD. Previous research has shown that DSCAM ablation confers social interaction deficits and perseverative behaviors in mouse models. However, it remains unknown to what extent DSCAM underexpression captures the full range of behaviors, specifically cognitive phenotypes, presented in ASD. Here, we conducted a comprehensive cognitive behavioral phenotyping which revealed that loss of one copy of DSCAM , as in the DSCAM 2J +/- mice, displayed hyperactivity, increased anxiety, and motor coordination impairments. Additionally, hippocampal-dependent learning and memory was affected, including working memory, long-term memory, and contextual fear learning. Interestingly, implicit learning processes remained intact. Therefore, DSCAM LoF produces autistic-like behaviors that are similar to human cases of ASD. These findings further support a role for DSCAM dnLoF mutations in ASD and suggest DSCAM 2J +/- as a suitable model for ASD research. Summary Statement: Autism spectrum disorder represents a growing patient population. Loss of one copy of the DSCAM gene provides a promising mouse model that reproduces autistic-like behaviors for research and therapeutic testing.

The relationship between innate/adaptive immunity and gastrointestinal cancer : a multi-omics Mendelian randomization study.

BACKGROUND: Innate/adaptive immunity is the key to anti-tumor therapy. However, its causal relationship to Gastrointestinal (GI) cancer remains unclear. METHODS: Immunity genes were extracted from the MSigDB database. The Genome-wide association studies (GWAS) summary data of GI cancer were integrated with expression quantitative trait loci (eQTL) and DNA methylation quantitative trait loci (mQTL) associated with genes. Summary-data-based Mendelian randomization (SMR) and co-localization analysis were used to reveal causal relationships between genes and GI cancer. Two-sample MR analysis was used for sensitivity analysis. Single cell analysis clarified the enrichment of genes. RESULTS: Three-step SMR analysis showed that a putative mechanism, cg17294865 CpG site regulating HLA-DRA expression was negatively associated with gastric cancer risk. HLA-DRA was significantly differentially expressed in monocyte/macrophage and myeloid cells in gastric cancer. CONCLUSION: This study provides evidence that upregulating the expression level of HLA-DRA can reduce the risk of gastric cancer.

Lung transplantation, case anecdotes reconstruction for inadequate left atrial cuff on the donor side by aortic arch: A feasible case report.

Abnormalities in pulmonary vasculature or technical issues during lung procurement can lead to an insufficient left atrial (LA) cuff in donors. However, surgeons frequently need to reconfigure these less-than-ideal lungs for transplantation. This case report introduces a novel technique for such reconstruction. The patient was a 35-year-old male diagnosed with pneumoconiosis for over a year. Due to progressive worsening dyspnoea leading to respiratory failure on multiple occasions, he was deemed a candidate for lung transplantation. While obtaining the donor's lung, an inadvertent short cut of the LA cuff around the left inferior pulmonary vein orifice resulted in the residual vein retracting into the pulmonary hilum. To overcome this, we employed the aortic arch for reconstruction, enabling the successful completion of the lung transplantation. On post-transplantation day 2, extracorporeal membrane oxygenation was no longer required. Mechanical ventilation ceased after 13 days, with the subsequent removal of a tracheostomy. The patient spent 35 days in the intensive care unit and 58 days in the hospital. Post-transplantation complications included primary graft dysfunction, acute kidney failure, pneumothorax in the transplanted lung, the clots in the inferior vena cava, and pneumonia. Remarkably, over a year of follow-up (19 months after lung transplantation), the patient reported no adverse events and had successfully returned to work. In this case, the aortic arch is an alternative for reconstructing an insufficient LA cuff.

High-throughput sequencing-based analysis of the composition and diversity of the endophyte community in roots of Stellera chamaejasme.

Stellera chamaejasme (S. chamaejasme) is an important medicinal plant with heat-clearing, detoxifying, swelling and anti-inflammatory effects. At the same time, it is also one of the iconic plants of natural grassland degradation in northwest China, playing a key role in the invasion process. Plant endophytes live in healthy plant tissues and can synthesize substances needed for plant growth, induce disease resistance in host plants, and enhance plant resistance to environmental stress. Therefore, studying the root endophytes of S. chamaejasme is of great significance for mining beneficial microbial resources and biological prevention and control of S. chamaejasme. This study used Illumina MiSeq high-throughput sequencing technology to analyze the composition and diversity of endophytes in the roots of S. chamaejasme in different alpine grasslands (BGC, NMC and XGYZ) in Tibet. Research results show that the main phylum of endophytic fungi in the roots of S. chamaejasme in different regions is Ascomycota, and the main phyla of endophytic bacteria are Actinobacteria, Proteobacteria and Firmicutes (Bacteroidota). Overall, the endophyte diversity of the NMC samples was significantly higher than that of the other two sample sites. Principal coordinate analysis (PCoA) and permutational multivariate analysis of variance (PERMANOVA) results showed significant differences in the composition of endophytic bacterial and fungal communities among BGC, NMC and XGYZ samples. Co-occurrence network analysis of endophytes showed that there were positive correlations between fungi and some negative correlations between bacteria, and the co-occurrence network of bacteria was more complex than that of fungi. In short, this study provides a vital reference for further exploring and utilizing the endophyte resources of S. chamaejasme and an in-depth understanding of the ecological functions of S. chamaejasme endophytes.

Enhanced interactions among gut mycobiomes with the deterioration of glycemic control.

BACKGROUND: The gut mycobiome is closely linked to health and disease; however, its role in the progression of type 2 diabetes mellitus (T2DM) remains obscure. Here, a multi-omics approach was employed to explore the role of intestinal fungi in the deterioration of glycemic control. METHODS: 350 participants without hypoglycemic therapies were invited for a standard oral glucose tolerance test to determine their status of glycemic control. The gut mycobiome was identified through internal transcribed spacer sequencing, host genetics were determined by genotyping array, and plasma metabolites were measured with untargeted liquid chromatography mass spectrometry. FINDINGS: The richness of fungi was higher, whereas its dissimilarity was markedly lower, in participants with T2DM. Moreover, the diversity and composition of fungi were closely associated with insulin sensitivity and pancreatic ß-cell functions. With the exacerbation of glycemic control, the co-occurrence network among fungus taxa became increasingly complex, and the complexity of the interaction network was inversely associated with insulin sensitivity. Mendelian randomization analysis further demonstrated that the Archaeorhizomycetes class, Fusarium genus, and Neoascochyta genus were causally linked to impaired glucose metabolism. Furthermore, integrative analysis with metabolomics showed that increased 4-hydroxy-2-oxoglutaric acid, ketoleucine, lysophosphatidylcholine (20:3/0:0), and N-lactoyl-phenylalanine, but decreased lysophosphatidylcholine (O-18:2), functioned as key molecules linking the adverse effect of Fusarium genus on insulin sensitivity. CONCLUSIONS: Our study uncovers a strong association between disturbance in gut fungi and the progression of T2DM and highlights the potential of targeting the gut mycobiome for the management of T2DM. FUNDINGS: This study was supported by MOST and NSFC of China.

The role of Down syndrome cell adhesion molecule in Down syndrome.

Down syndrome (DS) is caused by the presence of an extra copy of the entire or a portion of human chromosome 21 (HSA21). This genomic alteration leads to elevated expression of numerous HSA21 genes, resulting in a variety of health issues in individuals with DS. Among the genes located in the DS "critical region" of HSA21, Down syndrome cell adhesion molecule (DSCAM) plays an important role in neuronal development. There is a growing body of evidence underscoring DSCAM's involvement in various DS-related disorders. This review aims to provide a concise overview of the established functions of DSCAM, with a particular focus on its implications in DS. We delve into the roles that DSCAM plays in DS-associated diseases. In the concluding section of this review, we explore prospective avenues for future research to further unravel DSCAM's role in DS and opportunities for therapeutic treatments.

Alistipes indistinctus-derived hippuric acid promotes intestinal urate excretion to alleviate hyperuricemia.

Hyperuricemia induces inflammatory arthritis and accelerates the progression of renal and cardiovascular diseases. Gut microbiota has been linked to the development of hyperuricemia through unclear mechanisms. Here, we show that the abundance and centrality of Alistipes indistinctus are depleted in subjects with hyperuricemia. Integrative metagenomic and metabolomic analysis identified hippuric acid as the key microbial effector that mediates the uric-acid-lowering effect of A. indistinctus. Mechanistically, A. indistinctus-derived hippuric acid enhances the binding of peroxisome-proliferator-activated receptor γ (PPARγ) to the promoter of ATP-binding cassette subfamily G member 2 (ABCG2), which in turn boosts intestinal urate excretion. To facilitate this enhanced excretion, hippuric acid also promotes ABCG2 localization to the brush border membranes in a PDZ-domain-containing 1 (PDZK1)-dependent manner. These findings indicate that A. indistinctus and hippuric acid promote intestinal urate excretion and offer insights into microbiota-host crosstalk in the maintenance of uric acid homeostasis.

Undersampling and cumulative class re-decision methods to improve detection of agitation in people with dementia.

Agitation is one of the most prevalent symptoms in people with dementia (PwD) that can place themselves and the caregiver's safety at risk. Developing objective agitation detection approaches is important to support health and safety of PwD living in a residential setting. In a previous study, we collected multimodal wearable sensor data from 17 participants for 600 days and developed machine learning models for detecting agitation in 1-min windows. However, there are significant limitations in the dataset, such as imbalance problem and potential imprecise labels as the occurrence of agitation is much rarer in comparison to the normal behaviours. In this paper, we first implemented different undersampling methods to eliminate the imbalance problem, and came to the conclusion that only 20% of normal behaviour data were adequate to train a competitive agitation detection model. Then, we designed a weighted undersampling method to evaluate the manual labeling mechanism given the ambiguous time interval assumption. After that, the postprocessing method of cumulative class re-decision (CCR) was proposed based on the historical sequential information and continuity characteristic of agitation, improving the decision-making performance for the potential application of agitation detection system. The results showed that a combination of undersampling and CCR improved F1-score and other metrics to varying degrees with less training time and data. Supplementary Information: The online version contains supplementary material available at 10.1007/s13534-023-00313-8.

SNR-enhanced signal delivery scheme with delta-sigma modulation in a four-mode fiber system.

This Letter proposes a scheme for optimizing the signal-to-noise ratio (SNR) of signal to improve the system performance by a 1 bit delta-sigma modulation (DSM) in a four-mode MDM system for mobile fronthaul. A 1 bit digitalized signal with an SNR of 60 dB from transmitter digital signal processing (Tx DSP) can be achieved. Based on this system, an experimental demonstration of the ultrahigh-order 1048576-QAM signal transmission over a 50 km strong-coupling few-mode fiber (FMF) is successfully realized. With DSP, the bit error rate (BER) of the received 1048576-QAM signals over four modes transmission is below the 20% soft-decision forward error correction (20% SD-FEC) threshold of 2.4 × 10-2. To the best of our knowledge, this is the first time that the combination of DSM technology and strong-coupling MDM system is achieved and that the highest-modulation order with DSM reported in MDM system is reached. This experimental demonstration of the proposed novel scheme in MDM system can provide an effective solution for ultra-large-capacity mobile fronthaul in the future.

Neuro-bone tissue engineering: emerging mechanisms, potential strategies, and current challenges.

The skeleton is a highly innervated organ in which nerve fibers interact with various skeletal cells. Peripheral nerve endings release neurogenic factors and sense skeletal signals, which mediate bone metabolism and skeletal pain. In recent years, bone tissue engineering has increasingly focused on the effects of the nervous system on bone regeneration. Simultaneous regeneration of bone and nerves through the use of materials or by the enhancement of endogenous neurogenic repair signals has been proven to promote functional bone regeneration. Additionally, emerging information on the mechanisms of skeletal interoception and the central nervous system regulation of bone homeostasis provide an opportunity for advancing biomaterials. However, comprehensive reviews of this topic are lacking. Therefore, this review provides an overview of the relationship between nerves and bone regeneration, focusing on tissue engineering applications. We discuss novel regulatory mechanisms and explore innovative approaches based on nerve-bone interactions for bone regeneration. Finally, the challenges and future prospects of this field are briefly discussed.

Lesson of urgent bilateral lobar lung transplantation for acute fibrinous and organizing pneumonia: a case report.

Background: Acute fibrinous and organizing pneumonia (AFOP) is one of acute expiratory diseases, which occurs rarely with a difficult diagnosis. AFOP is related to an idiopathic cause or autoimmune disease, drug use, infection, cancer, or transplantation. Variation of treatment depends on different institutions. To date, no evidence shows that lobar lung transplantation is applied in an urgent situation such as AFOP. Case Description: A 33-year-old female patient experienced fever, cough, and dyspnea four days prior to admission. She had no underlying health conditions. Initially, she received oxygen therapy and empiric antimicrobial treatment, but later developed pulmonary consolidation. Pathological examination confirmed the diagnosis of AFOP. Despite receiving standardized treatment involving extracorporeal membrane oxygenation (ECMO) and mechanical ventilation, the patient's respiratory function remained compromised. Consequently, an urgent lobar lung transplantation was performed. However, the patient encountered several challenges including carbapenem-resistant Pseudomonas aeruginosa pneumonia, exophytic granulation tissue, anastomotic stenosis, bronchopleural fistulae, anastomotic infections, septic shock, bacteremia, reperfusion syndrome, primary graft dysfunction, severe renal failure, and critical illness myopathy. Although the patient ultimately recovered and had a favorable survival outcome over 1-year post-discharge through multidisciplinary care, there are several key points to consider. Based on the findings from a systematic review, urgent transplantation may be a potential alternative treatment for AFOP. However, peri-transplantation programs should be enhanced, particularly regarding criteria selection, ECMO management, and the role of enhanced recovery after transplantation. Conclusions: The case demonstrates the feasibility of bilateral lobar lung transplantation in patients with AFOP, especially in an urgent situation.

Design, Synthesis, and Biological Evaluation of Trisubstituted Piperazine Derivatives as Noncovalent Severe Acute Respiratory Syndrome Coronavirus 2 Main Protease Inhibitors with Improved Antiviral Activity and Favorable Druggability.

The ongoing transmission of SARS-CoV-2 necessitates the development of additional potent antiviral agents capable of combating the current highly infectious variants and future coronaviruses. Here, we present the discovery of potent nonpeptide main protease (Mpro) inhibitors with prominent antiviral activity and improved pharmacokinetic properties. Three series of 1,2,4-trisubstituted piperazine derivatives were designed and synthesized, and the optimal GC-78-HCl demonstrated high enzyme-inhibitory potency (IC50 = 0.19 µM) and exhibited excellent antiviral activity (EC50 = 0.40 µM), reaching the same level as Nirmatrelvir (EC50 = 0.38 µM). Additionally, GC-78-HCl displayed potent antiviral activities against various SARS-CoV-2 variants as well as HCoV-OC43 and HCoV-229E, indicating its potential broad-spectrum anticoronaviral activity. Notably, the pharmacokinetic properties of GC-78-HCl were somewhat enhanced compared to those of the lead compound. Furthermore, the cocrystal and molecular docking elucidated the mechanism of action. In conclusion, we discovered a novel nonpeptidic Mpro inhibitor with promising antiviral activity and a favorable pharmacokinetic profile.

Researched Apps Used in Dementia Care for People Living With Dementia and Their Informal Caregivers: Systematic Review on App Features, Security, and Usability.

BACKGROUND: Studies have shown that mobile apps have the potential to serve as nonpharmacological interventions for dementia care, improving the quality of life of people living with dementia and their informal caregivers. However, little is known about the needs for and privacy aspects of these mobile apps in dementia care. OBJECTIVE: This review seeks to understand the landscape of existing mobile apps in dementia care for people living with dementia and their caregivers with respect to app features, usability testing, privacy, and security. METHODS: ACM Digital Library, Cochrane Central Register of Controlled Trials, Compendex, Embase, Inspec, Ovid MEDLINE, PsycINFO, and Scopus were searched. Studies were included if they included people with dementia living in the community, their informal caregivers, or both; focused on apps in dementia care using smartphones or tablet computers; and covered usability evaluation of the app. Records were independently screened, and 2 reviewers extracted the data. The Centre for Evidence-Based Medicine critical appraisal tool and Mixed Methods Appraisal Tool were used to assess the risk of bias in the included studies. Thematic synthesis was used, and the findings were summarized and tabulated based on each research aim. RESULTS: Overall, 44 studies were included in this review, with 39 (89%) published after 2015. In total, 50 apps were included in the study, with more apps developed for people living with dementia as end users compared with caregivers. Most studies (27/44, 61%) used tablet computers. The most common app feature was cognitive stimulation. This review presented 9 app usability themes: user interface, physical considerations, screen size, interaction challenges, meeting user needs, lack of self-awareness of app needs, stigma, technological inexperience, and technical support. In total, 5 methods (questionnaires, interviews, observations, logging, and focus groups) were used to evaluate usability. There was little focus on the privacy and security aspects, including data transfer and protection, of mobile apps for people living with dementia. CONCLUSIONS: The limitations of this review include 1 reviewer conducting the full-text screening, its restriction to studies published in English, and the exclusion of apps that lacked empirical usability testing. As a result, there may be an incomplete representation of the available apps in the field of dementia care. However, this review highlights significant concerns related to the usability, privacy, and security of existing mobile apps for people living with dementia and their caregivers. The findings of this review provide a valuable framework to guide app developers and researchers in the areas of privacy policy development, app development strategies, and the importance of conducting thorough usability testing for their apps. By considering these factors, future work in this field can be advanced to enhance the quality and effectiveness of dementia care apps. TRIAL REGISTRATION: PROSPERO CRD42020216141; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=216141. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1159/000514838.

The Drosophila homolog of APP promotes Dscam expression to drive axon terminal growth, revealing interaction between Down syndrome genes.

Down syndrome (DS) is caused by triplication of human chromosome 21 (HSA21). Although several HSA21 genes have been found to be responsible for aspects of DS, whether and how HSA21 genes interact with each other is poorly understood. DS patients and animal models present with a number of neurological changes, including aberrant connectivity and neuronal morphology. Previous studies have indicated that amyloid precursor protein (APP) and Down syndrome cell adhesion molecule (DSCAM) regulate neuronal morphology and contribute to neuronal aberrations in DS. Here, we report the functional interaction between the Drosophila homologs of these two genes, Amyloid precursor protein-like (Appl) and Dscam (Dscam1). We show that Appl requires Dscam to promote axon terminal growth in sensory neurons. Moreover, Appl increases Dscam protein expression post-transcriptionally. We further demonstrate that regulation of Dscam by Appl does not require the Appl intracellular domain or second extracellular domain. This study presents an example of functional interactions between HSA21 genes, providing insights into the pathogenesis of neuronal aberrations in DS.

Corrigendum to "Photocatalytic oxygen evolution and antibacterial biomimetic repair membrane for diabetes wound repair via HIF1-α pathway" [Mater. Today Bio 20 (2023) 100616].

[This corrects the article DOI: 10.1016/j.mtbio.2023.100616.].

Discovery of novel sulfonamide substituted indolylarylsulfones as potent HIV-1 inhibitors with better safety profiles.

Indolylarylsulfones (IASs) are classical HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) with a unique scaffold and possess potent antiviral activity. To address the high cytotoxicity and improve safety profiles of IASs, we introduced various sulfonamide groups linked by alkyl diamine chain to explore the entrance channel of non-nucleoside inhibitors binding pocket. 48 compounds were designed and synthesized to evaluate their anti-HIV-1 activities and reverse transcriptase inhibition activities. Especially, compound R10L4 was endowed with significant inhibitory activity towards wild-type HIV-1 (EC50(WT) = 0.007 µmol/L, SI = 30,930) as well as a panel of single-mutant strains exemplified by L100I (EC50 = 0.017 µmol/L, SI = 13,055), E138K (EC50 = 0.017 µmol/L, SI = 13,123) and Y181C (EC50 = 0.045 µmol/L, SI = 4753) which were superior to Nevirapine and Etravirine. Notably, R10L4 was characterized with significantly reduced cytotoxicity (CC50 = 216.51 µmol/L) and showed no remarkable in vivo toxic effects (acute and subacute toxicity). Moreover, the computer-based docking study was also employed to characterize the binding mode between R10L4 and HIV-1 RT. Additionally, R10L4 presented an acceptable pharmacokinetic profile. Collectively, these results deliver precious insights for next optimization and indicate that the sulfonamide IAS derivatives are promising NNRTIs for further development.

Epstein-Barr virus immediate-early protein Zta mediates the proliferation and migration of HER2-overexpressing cancer cells.

Epstein-Barr virus immediate-early protein Zta plays an active role in altering cellular gene expression, which may be fundamentally linked to the viral life cycle, cell cycle, cell growth, and differentiation. HER2 is associated with a wide variety of human cancers, and its knockdown significantly reverses the malignant features of HER2-positive cancers. The aim of this study was to investigate the potential role of Zta in regulating HER2 expression and phenotype changes of MDA-MB-453 cells. Our results indicate that ectopic expression of Zta resulted in downregulation of the HER2 protein in cancer cells (MDA-MB-453, SKBR-3, BT474, and SKOV-3). The Zta protein significantly decreased HER2 mRNA and protein expression in MDA-MB-453 cells in a dose-dependent manner. Mechanistically, Zta recognized and targeted the promoter of HER2 gene, reducing the transcriptional activity of the HER2 gene. Zta induced G0/G1 arrest of MDA-MB-453 cells, inhibiting their proliferation and migration activity. These data suggest that Zta may act as a transforming suppressor of the HER2 gene.

Paraventricular nucleus-central amygdala oxytocinergic projection modulates pain-related anxiety-like behaviors in mice.

AIMS: Anxiety disorders associated with pain are a common health problem. However, the underlying mechanisms remain poorly understood. We aimed to investigate the role of paraventricular nucleus (PVN)-central nucleus of the amygdala (CeA) oxytocinergic projections in anxiety-like behaviors induced by inflammatory pain. METHODS: After inflammatory pain induction by complete Freund's adjuvant (CFA), mice underwent elevated plus maze, light-dark transition test, and marble burying test to examine the anxiety-like behaviors. Chemogenetic, optogenetic, and fiber photometry recordings were used to modulate and record the activity of the oxytocinergic projections of the PVN-CeA. RESULTS: The key results are as follows: inflammatory pain-induced anxiety-like behaviors in mice accompanied by decreased activity of PVN oxytocin neurons. Chemogenetic activation of PVN oxytocin neurons prevented pain-related anxiety-like behaviors, whereas inhibition of PVN oxytocin neurons induced anxiety-like behaviors in naïve mice. PVN oxytocin neurons projected directly to the CeA, and microinjection of oxytocin into the CeA blocked anxiety-like behaviors. Inflammatory pain also decreased the activity of CeA neurons, and optogenetic activation of PVNoxytocin -CeA circuit prevented anxiety-like behavior in response to inflammatory pain. CONCLUSION: The results of our study suggest that oxytocin has anti-anxiety effects and provide novel insights into the role of PVNoxytocin -CeA projections in the regulation of anxiety-like behaviors induced by inflammatory pain.