Developmental Stage and Cellular Context Determine Oncogenic and Molecular Outcomes of Mutation in Hematopoiesis.

Mutations in the histone methyltransferase EZH2, particularly the Y641 hotspot mutation, have been implicated in hematologic malignancies, yet the effect of timing and cellular context on their oncogenic potential has remained unknown. In this study, we utilized a conditional allele with tissue-specific Cre drivers to investigate the effects of mutations at various stages of development, with a focus on the hematopoietic system. We found that ubiquitous heterozygous expression at birth, or conditional expression in hematopoietic or mesenchymal stem cells, led to decreased survival due to hematopoietic defects and bone marrow failure, with no evidence of malignancy.

Mechanosensitive channels TMEM63A and TMEM63B mediate lung inflation-induced surfactant secretion.

Pulmonary surfactant is a lipoprotein complex lining the alveolar surface to decrease the surface tension and facilitate inspiration. Surfactant deficiency is often seen in premature infants and in children and adults with respiratory distress syndrome. Mechanical stretch of alveolar type 2 epithelial (AT2) cells during lung expansion is the primary physiological factor that stimulates surfactant secretion; however, it is unclear whether there is a mechanosensor dedicated to this process.

Death-seq identifies regulators of cell death and senolytic therapies.

Selectively ablating damaged cells is an evolving therapeutic approach for age-related disease. Current methods for genome-wide screens to identify genes whose deletion might promote the death of damaged or senescent cells are generally underpowered because of the short timescales of cell death as well as the difficulty of scaling non-dividing cells. Here, we establish "Death-seq," a positive-selection CRISPR screen optimized to identify enhancers and mechanisms of cell death.

Malnutrition and visceral obesity predicted adverse short-term and long-term outcomes in patients undergoing proctectomy for rectal cancer.

Background: To the best of our knowledge, no previous studies have explored the relationship between visceral obesity and malnutrition. Therefore, this study has aimed to investigate the association between them in patients with rectal cancer.

Methods: Patients with rectal cancer who underwent proctectomy were included.

Case report: Muscle involvement in a Chinese patient with -related disorder.

The gene encodes tRNA nucleotidyltransferase 1, which catalyzes the addition of cytosine-cytosine-adenosine (CCA) to the ends of cytoplasmic and mitochondrial tRNAs. The most common clinical phenotype associated with is autosomal recessive sideroblastic anemia with B-cell immunodeficiency, periodic fever, and developmental delay (SIFD). Muscle involvement has rarely been reported in -related disorders.

The influence of three-dimensional structure on naïve T cell homeostasis and aging.

A breakdown in cellular homeostasis is thought to drive naïve T cell aging, however the link between naïve T cell homeostasis and aging in humans is poorly understood. To better address this, we developed a lymphoid organoid system that maintains resting naïve T cells for more than 2 weeks, in conjunction with high CD45RA expression. Deep phenotypic characterization of naïve T cells across age identified reduced CD45RA density as a hallmark of aging.

Design, Synthesis and Structure-Activity Relationship Studies of Meridianin Derivatives as Novel JAK/STAT3 Signaling Inhibitors.

Hyperactivation of Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling is an attractive therapeutic target for tumor therapy. Herein, forty-eight novel meridianin derivatives were designed and synthesized, and their antitumor activity was evaluated in vitro both for activity optimization and structure-activity relationship (SAR) study. The results indicated that most derivatives exhibited significantly improved antitumor activity, especially for compound .

A new phenotype of syndromic retinitis pigmentosa with myopathy is caused by mutations in retinol dehydrogenase 11.

Retinol dehydrogenase 11 (RDH11) is an 11-cis-retinol dehydrogenase that has a well-characterized, albeit auxiliary role in the retinoid cycle. Diseases caused by mutations in the RDH11 gene are very rare, and only one affected family with eye and intelligence involvement has been reported. In the present study, we describe the clinical and genetic findings in a Chinese patient with retinitis pigmentosa (RP), juvenile cataracts, intellectual disability, and myopathy.

Habitual tea consumption and 5-year incident metabolic syndrome among older adults: a community-based cohort study.

Background: The effect of tea consumption on metabolic syndrome (MetS) remains controversial. The objective of this study is to examine the prospective association of tea consumption with 5-year incident MetS among aged population in China.

Methods: This analysis included 3005 Chinese adults aged 60 years or older who were free of MetS at baseline examination.

Phenotype and Genotype Study of Chinese -Related α-Dystroglycanopathy.

Objective: Alpha-dystroglycanopathy (α-DGP) is a subtype of muscular dystrophy caused by defects in the posttranslational glycosylation of α-dystroglycan (α-DG). Our study aimed to summarize the clinical and genetic features of -related α-DGP in a cohort of patients in China.

Methods: Pedigrees, clinical data, and laboratory tests of patients diagnosed with -related α-DGP were analyzed retrospectively.

Potential Biomolecules Capable of Assessing Risk of Osteoporotic Fracture: A Scoping Review.

Osteoporosis as a systemic chronic skeletal disease is characterized by low bone mineral density and increased risk to osteoporotic fractures. Osteoporosis is prevalent in the middle-aged and elderly population, especially in the postmenopausal women. With population aging, osteoporosis has become a world-wide serious public health problem.

Downregulation of c-Myc expression confers sensitivity to CHK1 inhibitors in hematologic malignancies.

Checkpoint kinase 1 inhibitors (CHK1i) have shown impressive single-agent efficacy in treatment of certain tumors, as monotherapy or potentiators of chemotherapy in clinical trials, but the sensitive tumor types and downstream effectors to dictate the therapeutic responses to CHK1i remains unclear. In this study we first analyzed GDSC (Genomics of Drug Sensitivity in Cancer) and DepMap database and disclosed that hematologic malignancies (HMs) were relatively sensitive to CHK1i or CHK1 knockdown. This notion was confirmed by examining PY34, a new and potent in-house selective CHK1i, which exhibited potent anti-HM effect in vitro and in vivo, as single agent.

The effect of candesartan on chronic stress induced imbalance of glucose homeostasis.

Objective: To explore whether chronic stress induces imbalance of glucose homeostasis, and to investigate the possible involvement of the renin-angiotensin system (RAS).

Methods: Male Sprague-Dawley rats were divided into four groups: control, chronic stress, chronic stress plus low dose candesartan (an angiotensin II receptor-1 blocker, ARB, 5 mg/kg/d, i.p.

Controlled induction and targeted elimination of p16-expressing chondrocytes in cartilage explant culture.

Cellular senescence is a phenotypic state that contributes to age-related diseases through the secretion of matrix-degrading and inflammatory molecules. An emerging therapeutic strategy for osteoarthritis (OA) is to selectively eliminate senescent cells by initiating apoptosis. This study establishes a cartilage explant model of senescence induction and senolytic clearance using expression as a biomarker of senescence.

Cells exhibiting strong promoter activation in vivo display features of senescence.

The activation of cellular senescence throughout the lifespan promotes tumor suppression, whereas the persistence of senescent cells contributes to aspects of aging. This theory has been limited, however, by an inability to identify and isolate individual senescent cells within an intact organism. Toward that end, we generated a murine reporter strain by "knocking-in" a fluorochrome, tandem-dimer Tomato (tdTom), into exon 1α of the locus.

Engineering NiO/NiFe LDH Intersection to Bypass Scaling Relationship for Oxygen Evolution Reaction via Dynamic Tridimensional Adsorption of Intermediates.

Oxygen evolution reaction (OER) is a pivotal reaction in many technologies for renewable energy, such as water splitting, metal-air batteries, and regenerative fuel cells. However, this reaction is known to be kinetically sluggish and proceeds at rather high overpotential due to the universal scaling relationship, namely, the adsorption energies of intermediates are linearly correlated and cannot be optimized simultaneously. Several approaches have been proposed to break the scaling relationship by introducing additional active sites; however, positive experimental results are still absent.

Utility of GDF-15 as a diagnostic biomarker in gastric cancer: an investigation combining GEO, TCGA and meta-analysis.

It was recently suggested that growth differentiation factor-15 (GDF-15) is associated with gastric cancer (GC) carcinogenesis. However, the diagnostic potential of GDF-15 for GC remains unclear. To address this issue, we obtained RNA sequencing and microarray data from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases, and searched PubMed, Google Scholar and Web of Science for relevant literature.

Identifying the Key Role of Pyridinic-N-Co Bonding in Synergistic Electrocatalysis for Reversible ORR/OER.

For many regenerative electrochemical energy-conversion systems, hybrid electrocatalysts comprising transition metal (TM) oxides and heteroatom-doped (e.g., nitrogen-doped) carbonaceous materials are promising bifunctional oxygen reduction reaction/oxygen evolution reaction electrocatalysts, whose enhanced electrocatalytic activities are attributed to the synergistic effect originated from the TM-N-C active sites.

Modest Oxygen-Defective Amorphous Manganese-Based Nanoparticle Mullite with Superior Overall Electrocatalytic Performance for Oxygen Reduction Reaction.

Manganese-based oxides have exhibited high promise as noncoinage alternatives to Pt/C for catalyzing oxygen reduction reaction (ORR) in basic solution and a mix of Mn valence is believed to be vital in achieving optimum ORR performance. Here, it is proposed that, distinct from the most studied perovskites and spinels, Mn-based mullites with equivalent molar ratio of Mn and Mn provide a unique platform to maximize the role of Mn valence in facile ORR kinetics by introducing modest content of oxygen deficiency, which is also beneficial to enhanced catalytic activity. Accordingly, amorphous mullite SmMn O nanoparticles with finely tuned concentration of oxygen vacancies are synthesized via a versatile top-down approach and the modest oxygen-defective sample with an Mn /Mn ratio of 1.

An oncogenic Ezh2 mutation induces tumors through global redistribution of histone 3 lysine 27 trimethylation.

B cell lymphoma and melanoma harbor recurrent mutations in the gene encoding the EZH2 histone methyltransferase (EZH2), but the carcinogenic role of these mutations is unclear. Here we describe a mouse model in which the most common somatic Ezh2 gain-of-function mutation (EZH2(Y646F) in human; Ezh2(Y641F) in mouse) is conditionally expressed. Expression of Ezh2(Y641F) in mouse B cells or melanocytes caused high-penetrance lymphoma or melanoma, respectively.

Tissue-Specific Effects of Reduced β-catenin Expression on Adenomatous Polyposis Coli Mutation-Instigated Tumorigenesis in Mouse Colon and Ovarian Epithelium.

Adenomatous polyposis coli (APC) inactivating mutations are present in most human colorectal cancers and some other cancers. The APC protein regulates the β-catenin protein pool that functions as a co-activator of T cell factor (TCF)-regulated transcription in Wnt pathway signaling. We studied effects of reduced dosage of the Ctnnb1 gene encoding β-catenin in Apc-mutation-induced colon and ovarian mouse tumorigenesis and cell culture models.

Excess centrosomes disrupt endothelial cell migration via centrosome scattering.

Supernumerary centrosomes contribute to spindle defects and aneuploidy at mitosis, but the effects of excess centrosomes during interphase are poorly understood. In this paper, we show that interphase endothelial cells with even one extra centrosome exhibit a cascade of defects, resulting in disrupted cell migration and abnormal blood vessel sprouting. Endothelial cells with supernumerary centrosomes had increased centrosome scattering and reduced microtubule (MT) nucleation capacity that correlated with decreased Golgi integrity and randomized vesicle trafficking, and ablation of excess centrosomes partially rescued these parameters.