Notes

BDNF regulates GABAAR trafficking and also associated cognitive functions by means of autophagic unsafe effects of p62.
The microbiota profile of children changes with age. To investigate the differences in the gut microbiota profile of 1- and 4-year-old children, we collected fecal samples and sequenced the V3-V4 hypervariable region of the 16S rRNA gene via high-throughput DNA sequencing. From phylum to species level, the microbiota underwent significant changes with age. The abundance of phyla Proteobacteria and Actinobacteria declined with age, whereas phyla Firmicutes and Bacteroidetes increased with age and dominated the gut microbiota of 4-year-olds. The intestinal environment of children at age four is closer to maturity. Hence, the abundance of Bifidobacterium significantly decreased in the gut of 4-year-olds, whereas Akkermansia muciniphila increased from 0.14% in 1-year-olds to 4.25% in 4-year-olds. The functional change in gut microbiota is consistent with changes in infant food, as microbiota participating in amino acid and vitamin metabolism were enriched in 1-year-olds, whereas microbiota involved in lipid metabolism increased with age.Prominin 1 (PROM1) is one of a few clinically relevant progenitor markers in human alcoholic hepatitis (AH) and hepatocellular carcinoma (HCC), and mouse liver tumor initiating stem cell-like cells (TICs). However, the origin, fate and functions of PROM1+ cells in AH and HCC are unknown. Here we show by genetic lineage tracing that PROM1+ cells are derived in part from hepatocytes in AH and become tumor cells in mice with diethyl nitrosamine (DEN)-initiated, Western alcohol diet-promoted liver tumorigenesis. Our RNA sequencing analysis of mouse PROM1+ cells, reveals transcriptomic landscapes indicative of their identities as ductular reaction progenitors (DRPs) and TICs. Indeed, single-cell RNA sequencing reveals two subpopulations of Prom1+ Afp- DRPs and Prom1+ Afp+ TICs in the DEN-WAD model. Integrated bioinformatic analysis identifies Discodin Domain Receptor 1 (DDR1) as a uniquely upregulated and patient-relevant gene in PROM1+ cells in AH and HCC. Translational relevance of DDR1 is supported by its marked elevation in HCC which is inversely associated with patient survival. Further, knockdown of Ddr1 suppresses the growth of TICs and TIC-derived tumor growth in mice. These results suggest the importance of PROM1+ cells in the evolution of liver cancer and DDR1 as a potential driver of this process.
We sought to delineate the genotypic and phenotypic spectrum of female and male individuals with X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome).

Twenty-five individuals (15 males, 10 females) with causative variants in MSL3 were ascertained through exome or genome sequencing at ten different sequencing centers.

We identified multiple variant types in MSL3 (ten nonsense, six frameshift, four splice site, three missense, one in-frame-deletion, one multi-exon deletion), most proven to be de novo, and clustering in the terminal eight exons suggesting that truncating variants in the first five exons might be compensated by an alternative MSL3 transcript. Three-dimensional modeling of missense and splice variants indicated that these have a deleterious effect. The main clinical findings comprised developmental delay and intellectual disability ranging from mild to severe. Autism spectrum disorder, muscle tone abnormalities, and macrocephaly were common as well as hearing impairment and gastrointestinal problems. Hypoplasia of the cerebellar vermis emerged as a consistent magnetic resonance image (MRI) finding. Females and males were equally affected. Using facial analysis technology, a recognizable facial gestalt was determined.

Our aggregated data illustrate the genotypic and phenotypic spectrum of X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). Our cohort improves the understanding of disease related morbidity and allows us to propose detailed surveillance guidelines for affected individuals.
Our aggregated data illustrate the genotypic and phenotypic spectrum of X-linked, MSL3-related disorder (Basilicata-Akhtar syndrome). Our cohort improves the understanding of disease related morbidity and allows us to propose detailed surveillance guidelines for affected individuals.AML is a genetically heterogeneous disease and understanding how different co-occurring mutations cooperate to drive leukemogenesis will be crucial for improving diagnostic and therapeutic options for patients. selleck inhibitor MIR142 mutations have been recurrently detected in IDH-mutated AML samples. Here, we have used a mouse model to investigate the interaction between these two mutations and demonstrate a striking synergy between Mir142 loss-of-function and IDH2R140Q, with only recipients of double mutant cells succumbing to leukemia. Transcriptomic analysis of the non-leukemic single and leukemic double mutant progenitors, isolated from these mice, suggested a novel mechanism of cooperation whereby Mir142 loss-of-function counteracts aberrant silencing of Hoxa cluster genes by IDH2R140Q. Our analysis suggests that IDH2R140Q is an incoherent oncogene, with both positive and negative impacts on leukemogenesis, which requires the action of cooperating mutations to alleviate repression of Hoxa genes in order to advance to leukemia. This model, therefore, provides a compelling rationale for understanding how different mutations cooperate to drive leukemogenesis and the context-dependent effects of oncogenic mutations.Preclinical knowledge of dysregulated pathways and potential biomarkers for urological cancers has undergone limited translation into the clinic. Moreover, the low approval rate of new anticancer drugs and the heterogeneous drug responses in patients indicate that current preclinical models do not always reflect the complexity of malignant disease. Patient-derived tumour models used in preclinical uro-oncology research include 3D culture systems, organotypic tissue slices and patient-derived xenograft models. Technological innovations have enabled major improvements in the capacity of these tumour models to reproduce the clinical complexity of urological cancers. Each type of patient-derived model has inherent advantages and limitations that can be exploited, either alone or in combination, to gather specific knowledge on clinical challenges and address unmet clinical needs. Nevertheless, few opportunities exist for patients with urological cancers to benefit from personalized therapeutic approaches. Clinical validation of experimental data is needed to facilitate the translation and implementation of preclinical knowledge into treatment decision making.High-risk prostate cancer is a heterogeneous disease that lacks clear consensus on its ideal management. Historically, non-surgical treatment was the preferred strategy, and several studies demonstrated improved survival among men with high-risk disease managed with the combination of radiotherapy and androgen deprivation therapy (ADT) compared with ADT alone. However, practice trends in the past 10-15 years have shown increased use of radical prostatectomy with pelvic lymph node dissection for primary management of high-risk, localized disease. Radical prostatectomy, as a primary monotherapy, offers the potential benefits of avoiding ADT, reducing rates of symptomatic local recurrence, enabling full pathological tumour staging and potentially reducing late adverse effects such as secondary malignancy compared with radiation therapy. Retrospective studies have reported wide variability in short-term (pathological) and long-term (oncological) outcomes of radical prostatectomy. Surgical monotherapy continues to be appropriate for selected patients, whereas in others the best treatment strategy probably involves a multimodal approach. Appropriate risk stratification utilizing clinical, pathological and potentially also genomic risk data is imperative in the initial management of men with prostate cancer. However, data from ongoing and planned prospective trials are needed to identify the optimal management strategy for men with high-risk, localized prostate cancer.CD1d-dependent type I NKT cells, which are activated by lipid antigen, are known to play important roles in innate and adaptive immunity, as are a portion of type II NKT cells. However, the heterogeneity of NKT cells, especially NKT-like cells, remains largely unknown. Here, we report the profiling of NKT (NK1.1+CD3e+) cells in livers from wild type (WT), Jα18-deficient and CD1d-deficient mice by single-cell RNA sequencing. Unbiased transcriptional clustering revealed distinct cell subsets. The transcriptomic profiles identified the well-known CD1d-dependent NKT cells and defined two CD1d-independent NKT cell subsets. In addition, validation of marker genes revealed the differential organ distribution and landscape of NKT cell subsets during liver tumor progression. More importantly, we found that CD1d-independent Sca-1-CD62L+ NKT cells showed a strong ability to secrete IFN-γ after costimulation with IL-2, IL-12 and IL-18 in vitro. Collectively, our findings provide a comprehensive characterization of NKT cell heterogeneity and unveil a previously undefined functional NKT cell subset.There is considerable interest in understanding the genetics of erectile dysfunction (ED). Since early twin studies that suggested a genetic component to ED, multiple candidate gene studies have identified genetic variants that may be associated with ED. Genome-wide association studies (GWAS) have overcome some of the criticism of the candidate gene approach. Two recent GWAS studies have identified loci near SIM1 that may be associated with ED and have renewed interest in the leptin melanocortin signaling pathway. We review the current literature on the genetic basis of ED by highlighting several candidate genes and genetic variants associated with ED.Human and animal behaviour exhibits complex but regular patterns over time, often referred to as expressions of personality. Yet it remains unclear what personality really is is it just the behavioural patterns themselves, something in the brain, in the genes or perhaps all of these? Here we offer a set of causal hypotheses about the role of personality, integrating psychological and neuroscientific approaches to personality in a testable framework. These hypotheses clarify the causal and constitutive relations that personality has with genes, environment, brain, mind and behaviour, and we suggest specific experiments that can adjudicate amongst the different hypotheses. We focus on a set of models that propose that personality is instantiated in the brain, distally caused by genes and environment and, in turn, causing the overt behaviours from which it is often inferred. We argue that articulating and testing such models will be essential in a mature science of personality.Exportin 1 (XPO1), also known as chromosome region maintenance protein 1, plays a crucial role in maintaining cellular homeostasis via the regulated export of a range of cargoes, including proteins and several classes of RNAs, from the nucleus to the cytoplasm. Dysregulation of this protein plays a pivotal role in the development of various solid and haematological malignancies. Furthermore, XPO1 is associated with resistance to several standard-of-care therapies, including chemotherapies and targeted therapies, making it an attractive target of novel cancer therapies. Over the years, a number of selective inhibitors of nuclear export have been developed. However, only selinexor has been clinically validated. The novel mechanism of action of XPO1 inhibitors implies a different toxicity profile to that of other agents and has proved challenging in certain settings. Nonetheless, data from clinical trials have led to the approval of the XPO1 inhibitor selinexor (plus dexamethasone) as a fifth-line therapy for patients with multiple myeloma and as a monotherapy for patients with relapsed and/or refractory diffuse large B cell lymphoma.
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