Comprehensive Multi-omics Analysis Reveals Mitochondrial Stress as a Central Biological Hub for Spaceflight Impact.

Spaceflight is known to impose changes on human physiology with unknown molecular etiologies. To reveal these causes, we used a multi-omics, systems biology analytical approach using biomedical profiles from fifty-nine astronauts and data from NASA's GeneLab derived from hundreds of samples flown in space to determine transcriptomic, proteomic, metabolomic, and epigenetic responses to spaceflight. Overall pathway analyses on the multi-omics datasets showed significant enrichment for mitochondrial processes, as well as innate immunity, chronic inflammation, cell cycle, circadian rhythm, and olfactory functions. Importantly, NASA's Twin Study provided a platform to confirm several of our principal findings. Evidence of altered mitochondrial function and DNA damage was also found in the urine and blood metabolic data compiled from the astronaut cohort and NASA Twin Study data, indicating mitochondrial stress as a consistent phenotype of spaceflight.

Boosting Osmotic Energy Harvesting from Organic Solutions by Ultrathin Covalent Organic Framework Membranes.

Extracting osmotic energy from waste organic solutions via reverse electrodialysis represents a promising approach to reuse such industrial wastes and helps to mitigate the ever-growing energy needs. Herein, a molecularly thin membrane of covalent organic frameworks is engineered via interfacial polymerization to investigate its ion transport behavior in organic solutions. Interestingly, a significant deviation from linearity between ion conductance and reciprocal viscosity is observed, attributed to the nanoscale confinement effect on intermolecular interactions. This finding suggests a potential strategy to modulate the influence of apprarent viscosity on transmembrane transport. The osmotic energy harvesting of the ultrathin membrane in organic systems was studied, achieving an unprecedented output power density of over 84.5 W m-2 at a 1000-fold salinity gradient with a benign conversion efficiency and excellent stability. These findings provide a meaningful stepping stone for future studies seeking to fully leverage the potentials of organic systems in energy harvesting applications.

Mitochondria: An Emerging Unavoidable Link in the Pathogenesis of Periodontitis Caused by Porphyromonas gingivalis.

Porphyromonas gingivalis (P. gingivalis) is a key pathogen of periodontitis. Increasing evidence shows that P. gingivalis signals to mitochondria in periodontal cells, including gingival epithelial cells, gingival fibroblast cells, immune cells, etc. Mitochondrial dysfunction affects the cellular state and participates in periodontal inflammatory response through the aberrant release of mitochondrial contents. In the current review, it was summarized that P. gingivalis induced mitochondrial dysfunction by altering the mitochondrial metabolic state, unbalancing mitochondrial quality control, prompting mitochondrial reactive oxygen species (ROS) production, and regulating mitochondria-mediated apoptosis. This review outlines the impacts of P. gingivalis and its virulence factors on the mitochondrial function of periodontal cells and their role in periodontitis.

Anomalous Mechanical and Electrical Interplay in a Covalent Organic Framework Monolayer Membrane.

Ion transport through nanoconfinement, driven by both electrical and mechanical forces, has drawn ever-increasing attention, due to its high similarity to stress-sensitive ion channels in biological systems. Previous studies have reported only pressure-induced enhancement in ion conductance in low-permeable systems such as nanotubes, nanoslits, or single nanopores. This enhancement is generally explained by the ion accumulation caused by the capacitive effect in low-permeable systems. Here, we fabricate a highly permeable COF monolayer membrane to investigate ion transport behavior driven by both electrical and mechanical forces. Our results show an anomalous conductance reduction activated by external mechanical force, which is contrary to the capacitive effect-dominated conductance enhancement observed in low-permeable nanopores or channels. Through simulations, we uncovered a distinct electrical-mechanical interplay mechanism that depends on the relative rate between the ion diffusion from the boundary layer to the membrane surface and the ion transport through the membrane. The high pore density of the COF monolayer membrane reduces the charge accumulation caused by the capacitive effect, resulting in fewer accumulated ions near the membrane surface. Additionally, the high membrane permeability greatly accelerates the dissipation of the accumulated ions under mechanical pressure, weakening the effect of the capacitive layer on the streaming current. As a result, the ions accumulated on the electrodes, rather than in the capacitive layer, dominating the streaming current and giving rise to a distinct electrical-mechanical interplay mechanism compared to that in low-permeable nanopores or channels. Our study provides new insights into the interplay between electrical and mechanical forces in ultra-permeable systems.

Follicular fluid progesterone downregulated HPGD and COX2 in granulosa cells via suppressing NF-ĸB in endometriosis†.

Increasing evidences showed that ovulatory dysfunction, possibly caused by luteinized unruptured follicular follicle syndrome (LUFS), is one of the reasons for endometriosis-related infertility. The present study was conducted to explore the potential effect of elevated progesterone in follicular fluid (FF) on ovulation in endometriosis. A prospective study including 50 ovarian endometriosis patients and 50 control patients with matched pairs design was conducted with alterations in FF and peritoneal fluid (PF) components identified by metabolomics analyses and differentially expressed genes in granulosa cells (GCs) identified by transcriptome analysis. Patients with endometriosis exhibited a significantly higher progesterone level in serum, FF, and PF. Granulosa cells from endometriosis patients revealed decreased expression of HPGD, COX-2, and suppressed NF-ĸB signaling. Similarly, progesterone treatment in vitro downregulated HPGD and COX2 expression and suppressed NF-ĸB signaling in granulosa tumor-like cell line KGN (Bena Culture Collection, China) and primarily cultured GCs, as manifested by decreased expressions of IL1R1, IRAK3, reduced pIĸBα/IĸBα ratio, and nucleus translocation of p65. On the contrary, TNF-α treatment increased expression of IL1R1, IRAK3, pIĸBα, p65, and HPGD in GCs. One potential p65 binding site was identified in the promoter region of HPGD by chromatin immunoprecipitation. In conclusion, we found that intrafollicular progesterone might downregulate HPGD and COX-2 in GCs via suppressing the NF-ĸB signaling pathway, shedding light on the mechanism underlying the endometriosis-related ovulatory dysfunction.

Murine cytomegalovirus localization and uveitic cell infiltration might both contribute to trabecular meshwork impairment in Posner-Schlossman syndrome: Evidence from an open-angle rat model.

As a special type of glaucoma, Posner-Schlossman syndrome (PSS) is characterized by elevated intraocular pressure (IOP) and anterior uveitis. Cytomegalovirus (CMV) anterior chamber infection has now been considered the leading cause of PSS. We used murine CMV (MCMV) intracameral injection to establish a rat model manifested in IOP elevation and mild anterior uveitis, much like PSS; viral localization and gene expression at various time points and inflammatory cell infiltration derived from innate and adaptive immunity were investigated, as well as pathogenetic changes of the trabecular meshwork (TM). The IOP and uveitic manifestations peaked at 24 h post-infection (p.i.) and returned to normal after 96 h; the iridocorneal angle remained open consistently. At 24 h p.i., leucocytes gathered at the chamber angle. Maximum transcription of MCMV immediate early 1 (IE1) was reached at 24 h in the cornea and 48 h in the iris and ciliary body. MCMV localized in aqueous humor outflow facilities and the iris from 24 h to 28 d p.i. and was detected by in situ hybridization, though it did not transcribe after 7 d p.i. TM and iris pigment epithelial cells harboring viral inclusion bodies and autophagosomes were present at 28 d p.i. These findings shed light on how and where innate and adaptive immunity reacted after MCMV was found and transcribed in a highly ordered cascade, as well as pathogenetic changes in TM as a result of virus and uveitis behaviors.

Design, synthesis and biological evaluation of novel 9-methyl-9H-purine and thieno[3, 2-d]pyrimidine derivatives as potent mTOR inhibitors.

The mammalian target of rapamycin (mTOR) has been proved to be an effective target for cancer therapy. Two kinds of mTOR inhibitors, the rapalogs and mTOR kinase inhibitors (TORKi), have been developed and clinically validated in several types of malignancies. Compared with rapalogs, TORKi can exert better antitumor activity by inhibiting both mTORC1 and mTORC2, but the clinical development of current TORKi candidates has been relative slow, more TORKi with novel scaffold need to be developed to expand the current pipelines. In this study, a series of 9-methyl-9H-purine and thieno[3, 2-d]pyrimidine derivatives were designed, synthesized and biological evaluation. Most of these compounds exhibited good mTOR kinase inhibitory activity and selectivity over PI3Kα. Subsequent antiproliferative assay allowed us to identify the lead compound 15i, which display nanomolar to low micromolar IC50s against six human cancer cell lines. 15i could induce cell cycle arrest of MCF-7, PC-3 and A549 cells at the G0/G1 phase and suppress the migration and invasion of these cancer cells by suppressing the phosphorylation of AKT and P70S6 kinase. It could also regulate autophagy-related proteins to induce autophagy. Therefore, 15i would be a starting point for the development of new TORKi as anticancer drug.

Iris abnormalities may influence the efficacy and filtration strategies of Posner-Schlossman syndrome: a retrospective study involving trabeculectomy, ExPRESS and Ahmed valve implants.

PURPOSE: To evaluate and compare the one-year efficacy and influencing factors of different filtration surgeries on Posner-Schlossman syndrome (PSS) patients. METHODS: A retrospective study enrolling 91 PSS patients who underwent filtering surgeries and were followed for at least one year. Unilateral PSS was diagnosed as recurrent attacks of mild, unilateral, non-granulomatous anterior uveitis, elevated intraocular pressure (IOP), keratic precipitates (KPs) on the corneal endothelium, open angle, no posterior synechia, and no inflammatory lesions in the posterior segment; the IOP and anterior segment returned to normal between attacks. Medical histories and thorough ocular examination results were collected. Trabeculectomy and ExPRESS were chosen as the first line and AGV was considered for those under high risk of fibrosis. Follow-up data, mainly IOP, best-corrected visual acuity (BCVA), and anterior segment manifestations at the 1st week, 6th month, and 12th month were generated and analyzed. Iris abnormalities were determined by depigmentation or atrophic changes on the anterior segment photograph. Complete surgical success was defined as 5 mmHg < IOP ≤ 21 mmHg without IOP-lowering drug or needle revision; qualified surgical success was defined as 5 mmHg < IOP ≤ 21 mmHg with IOP-lowering drugs or needle revisions. Survival analysis was performed to obtain the success rates. RESULTS: At the 12th month, the complete surgical success rate of trabeculectomy (N = 54), ExPRESS (N = 23), and AGV group (N = 14) was 58.97% (95%CI 46.91-77.09%), 84.21% (95%CI 68.33-100.87%), and 100%; the qualified success rate was 71.79% (95%CI 62.46-88.34%), 89.47% (95%CI 77.07-103.33%), and 100%, respectively. Patients undergoing trabeculectomy experienced the largest decline of BCVA (from 0.58±0.46 to 1.01±0.51, P < .05); the trabeculectomy group endured the highest IOP (20.84±9.92 mmHg) compared to ExPRESS (14.51±2.86 mmHg, P < .05) and AGV group (13.17±3.32 mmHg, P < .05). At the 12th month, in the ExPRESS group, patients with iris abnormalities had higher IOP than the normal ones (15.65±2.05 mmHg, 12.93±3.17 mmHg, P < .05). ExPRESS helped patients with iris abnormalities maintain lower IOP than trabeculectomy (15.65±2.05 mmHg, 22.52±10.67 mmHg, P < .05). Three patients developed hypotony at the 3rd month (1 in ExPRESS and 2 in trabeculectomy group). CONCLUSION: AGV and ExPRESS performed better than trabeculectomy in PSS patients in terms of IOP and success rate. Iris abnormalities might influence the postoperative IOP and this may be valuable in guiding filtration strategies. TRIAL REGISTRATION: Chinese Clinical Trial Registry (No. ChiCTR1800017532, date: 2018/08/02).

Association between the second- and fourth-digit ratio and oral squamous cell carcinoma.

OBJECTIVES: Using an established proxy measure of intra-utero testosterone and estrogen levels-the ratio of second- and fourth-digit lengths-we estimated its association with the oral cancer risk among a population from Southern India. MATERIAL AND METHODS: In a hospital-based case-control study, incident oral cancer cases (N = 350) and non-cancer controls (N = 371), frequency-matched by age and sex, were recruited from two major referral hospitals in Kerala, India. Structured interviews collected information on several domains of exposure via detailed life course questionnaires. Digit lengths were measured using a ruler in a standardized manner. Unconditional logistic regression was performed to estimate the odds ratios and 95% confidence intervals. RESULTS: Second- and fourth-digit ratio lower than 1, which indicates relatively higher intra-utero level of testosterone and lower intra-utero level of estrogen, was associated with higher oral cancer risk (OR = 1.60, 95% CI: 1.02-2.52), after accounting for several confounders. CONCLUSION: Our findings suggest that intra-utero hormonal levels measured by second- and fourth-digit ratio are associated with oral cancer risk. Further studies in different population should confirm these results.

Graphene-Based Nanoelectromechanical Periodic Array with Tunable Frequency.

Phononic crystals (PnCs) have attracted much attention due to their great potential for dissipation engineering and propagation manipulation of phonons. Notably, the excellent electrical and mechanical properties of graphene make it a promising material for nanoelectromechanical resonators. Transferring a graphene flake to a prepatterned periodic mechanical structure enables the realization of a PnC with on-chip scale. Here, we demonstrate a nanoelectromechanical periodic array by anchoring a graphene membrane to a 9 × 9 array of standing nanopillars. The device exhibits a quasi-continuous frequency spectrum with resonance modes distributed from ∼120 MHz to ∼980 MHz. Moreover, the resonant frequencies of these modes can be electrically tuned by varying the voltage applied to the gate electrode sitting underneath. Simulations suggest that the observed band-like spectrum provides an experimental evidence for PnC formation. Our architecture has large fabrication flexibility, offering a promising platform for investigations on PnCs with electrical accessibility and tunability.

Tunable parametric amplification of a graphene nanomechanical resonator in the nonlinear regime.

Parametric amplification is widely used in nanoelectro-mechanical systems to enhance the transduced mechanical signals. Although parametric amplification has been studied in different mechanical resonator systems, the nonlinear dynamics involved receives less attention. Taking advantage of the excellent electrical and mechanical properties of graphene, we demonstrate electrical tunable parametric amplification using a doubly clamped graphene nanomechanical resonator. By applying external microwave pumping with twice the resonant frequency, we investigate parametric amplification in the nonlinear regime. We experimentally show that the extracted coefficient of the nonlinear Duffing force α and the nonlinear damping coefficient η vary as a function of external pumping power, indicating the influence of higher-order nonlinearity beyond the Duffing (∼x 3) and van der Pol (∼[Formula: see text]) types in our device. Even when the higher-order nonlinearity is involved, parametric amplification still can be achieved in the nonlinear regime. The parametric gain increases and shows a tendency of saturation with increasing external pumping power. Further, the parametric gain can be electrically tuned by the gate voltage with a maximum gain of 10.2 dB achieved at the gate voltage of 19 V. Our results will benefit studies on nonlinear dynamics, especially nonlinear damping in graphene nanomechanical resonators that has been debated in the community over past decade.

A Stepwise Evaluation of Hepatitis B Virus-Related Acute-on-Chronic Liver Failure to Optimize the Indication for Urgent Liver Transplantation.

BACKGROUND: Hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF) is a dynamic but reversible disease. AIM: We aimed to clarify whether the change in Chinese Group on the Study of Severe Hepatitis B-ACLF (COSSH-ACLF) grade in HBV-ACLF patients can be used to predict prognosis, and to explore the appropriate conditions for performing urgent liver transplantation. METHODS: We assessed the COSSH-ACLF grades of HBV-ACLF patients at different time points from June 2013 to May 2019 at Huashan Hospital in Shanghai, China, and analyzed the relationship between the change in grade and patient prognosis. RESULTS: A total of 207 HBV-ACLF patients were enrolled, of which 79 underwent urgent liver transplantation. Their COSSH-ACLF grades were calculated at diagnosis, 3-7 days after diagnosis, and on the final day. Most of the final ACLF grades were consistent with their corresponding grades at days 3-7 after diagnosis (62.5%), while only 44.5% were in accordance with the initial grades at diagnosis. In patients who had a poor prognosis (initial ACLF-3 and ACLF-2 or -3 at days 3-7), the 28-day survival rate was 93.3% in those who underwent transplantation and 6.8% in those who did not (P < 0.0001). However, in patients who had a good prognosis (ACLF-0 or ACLF-1 at days 3-7), the 28-day survival rate was 100% in transplanted patients and 91.5% in non-transplanted patients (P = 0.236). CONCLUSIONS: Reevaluation of the COSSH-ACLF grade 3-7 days after diagnosis could potentially show an indication for urgent liver transplantation.

[Absence of BAX differentially affects astrocyte density in the mouse cortex and hippocampus].

Astrocytes are a heterogenous group of macroglia present in all regions of the brain and play critical roles in many aspects of brain development, function and disease. Previous studies suggest that the B-cell lymphoma-2 associated X protein (BAX)-dependent apoptosis plays essential roles in regulating neuronal number and achieving optimal excitation/inhibition ratio. The aim of the present paper was to study whether BAX regulates astrocyte distribution in a region-specific manner. Immunofluorescence staining of SOX9 was used to analyze and compare astrocyte density in primary somatosensory cortex, motor cortex, retrosplenial cortex and hippocampus in heterozygous and homozygous BAX knockout mice at age of six weeks when cortical development has finished and glia development has reached a relatively steady state. The results showed that astrocyte density varied significantly among different cortical subdivisions and between cortex and hippocampus. In contrast to the significant increase in GABAergic interneurons, the overall and region-specific astrocyte density remained unchanged in the cortex when BAX was absent. Interestingly, a significant reduction of astrocyte density was observed in the hippocampus of BAX knockout mice. These data suggest that BAX differentially regulates neurons and astrocytes in cortex as well as astrocytes in different brain regions during development. This study provided important information about the regional heterogeneity of astrocyte distribution and the potential contribution of BAX gene during development.

Oscillating-rotating electric toothbrushes may have a better effect on gingivitis and plaque control than sonic and manual toothbrushes in adults.

ARTICLE TITLE AND BIBLIOGRAPHIC INFORMATION: Grender J, Adam R, Zou Y. The effects of oscillating-rotating electric toothbrushes on plaque and gingival health: A meta-analysis. Am J Dent. 2020 Feb;33(1):3-11. PMID: 32,056,408. SOURCE OF FUNDING: Industry (Procter & Gamble Company). TYPE OF STUDY/DESIGN: Systematic review with meta-analysis of data.

CD137 agonist induces gastric cancer cell apoptosis by enhancing the functions of CD8+ T cells via NF-κB signaling.

BACKGROUND: CD137 is a target for tumor immunotherapy. However, the role of CD137 in gastric cancer (GC), especially in inducing GC cell apoptosis, has not been studied. METHODS: Foxp3+ and CD8+ T cells in GCs were investigated using immunohistochemistry (IHC). CD137 expression in GCs was detected using flow cytometry, IHC and immunofluorescence (IF). Peripheral blood mononuclear cells (PBMCs) and CD8+ T cells isolated from peripheral blood were stimulated with a CD137 agonist in vitro. CD8+ T cell proliferation and p65 expression was examined using flow cytometry. P65 nuclear translocation was analyzed using IF. IL-10, TGF-ß, IFN-γ, perforin and granzyme B were detected using real-time quantitative PCR (real-time PCR). PBMCs and primary GC cells were cocultured and stimulated with a CD137 agonist in vitro. Apoptosis of primary GC cells was detected using flow cytometry. RESULTS: Our data demonstrated that GC tumors showed characteristics of an immunosuppressive microenvironment. CD137 was predominantly expressed in CD8+ T cells in GCs and had a positive correlation with tumor cell differentiation. The CD137 agonist promoted CD8+ T cell proliferation and increased the secretion of IFN-γ, perforin and granzyme B, which induced primary GC cell apoptosis. Mechanistically, this study found that the CD137 agonist induced NF-κB nuclear translocation in CD8+ T cells. CONCLUSION: Our results demonstrated that a CD137 agonist induced primary GC cell apoptosis by enhancing CD8+ T cells via activation of NF-κB signaling.

Multimode drug inducible CRISPR/Cas9 devices for transcriptional activation and genome editing.

Precise investigation and manipulation of dynamic biological processes often requires molecular modulation in a controlled inducible manner. The clustered, regularly interspaced, short palindromic repeats (CRISPR)/CRISPR associated protein 9 (Cas9) has emerged as a versatile tool for targeted gene editing and transcriptional programming. Here, we designed and vigorously optimized a series of Hybrid drug Inducible CRISPR/Cas9 Technologies (HIT) for transcriptional activation by grafting a mutated human estrogen receptor (ERT2) to multiple CRISPR/Cas9 systems, which renders them 4-hydroxytamoxifen (4-OHT) inducible for the access of genome. Further, extra functionality of simultaneous genome editing was achieved with one device we named HIT2. Optimized terminal devices herein delivered advantageous performances in comparison with several existing designs. They exerted selective, titratable, rapid and reversible response to drug induction. In addition, these designs were successfully adapted to an orthogonal Cas9. HIT systems developed in this study can be applied for controlled modulation of potentially any genomic loci in multiple modes.

Infection within 2 weeks before liver transplantation closely related to prognosis of posttransplant infection: A single-center retrospective observational study in China.

BACKGROUND: Infections still represent the main factors influencing morbidity and mortality following liver transplantation. This study aimed to evaluate the incidence and risk factors for infection and survival after liver transplantation. METHODS: We retrospectively examined medical records in 210 liver recipients who underwent liver transplantation between April 2015 and October 2017 in our hospital. Clinical manifestations and results of pathogen detection test were used to define infection. We analyzed the prevalence, risk factors and prognosis of patients with infection. RESULTS: The median follow-up was 214 days; the incidence of infection after liver transplantation was 46.7% (n = 98) which included pneumonia (43.4%), biliary tract infection (21.9%), peritonitis (21.4%) and bloodstream infection (7.6%). Among the pathogens in pneumonia, the most frequently isolated was Acinetobacter baumanii (23.5%) and Klebsiella pneumoniae (21.2%). Model for end-stage liver disease (MELD) score (OR = 1.083, 95% CI: 1.045-1.123; P < 0.001), biliary complication (OR = 4.725, 95% CI: 1.119-19.947; P = 0.035) and duration of drainage tube (OR = 1.040, 95% CI: 1.007-1.074; P = 0.017) were independent risk factors for posttransplant infection. All-cause mortality was 11.0% (n = 23). The prognostic factors for postoperative infection in liver recipients were prior-transplant infection, especially pneumonia within 2 weeks before transplantation. Kaplan-Meier curves of survival showed that recipients within 2 weeks prior infection had a significantly lower cumulative survival rate compared with those without infection (65.2% vs. 90.0%; hazard ratio: 4.480; P < 0.001). CONCLUSIONS: Infection, especially pneumonia within 2 weeks before transplantation, complication with impaired renal function and MELD score after 7 days of transplantation was an independent prognostic factor for postoperative infection in liver transplant recipients.

Case report: lactic acidosis and rhabdomyolysis during telbivudine and tenofovir treatment for chronic hepatitis B.

BACKGROUND: Current treatment options for chronic hepatitis B (CHB) are pegylated interferon alpha and nucleoside analogues (NAs). NAs have relatively fewer side effects than interferon alpha, and generally well tolerated. Previously 12.9% of patients on telbivudine treatment were reported to develop severe elevation of serum creatine phosphokinase (CPK) levels, but related clinical disease, like lactic acidosis (LA) and rhabdomyolysis (RM) were rare. The pathophysiology may be mitochondrial toxicity, for the NAs inhibit not only hepatitis B virus (HBV) polymerase, but also the host mitochondrial DNA polymerase γ. As mitochondria are the main sites of oxidative phosphorylation, there will be an increase of pyruvate reduction to lactic acid and insufficient adenosine triphosphate. The accumulation of lactic acid causes LA, while lack of energy leads to cell dysfunction and mitochondria-associated disease, including RM. All five NAs, except tenofovir, have been reported causing LA and RM. Here we report the first case of CHB patients developing fatal LA and RM during telbivudine and tenofovir treatment. CASE PRESENTATION: The patient is a 51-year-old man who was hospitalized in November 2015. He had taken telbivudine regularly because of CHB. Later, tenofovir was added to antiviral treatment because of HBV resistance. Then he had myalgia, chest tightness and anorexia. The blood lactate was 12.7 mmol/L. The arterial blood gas analysis showed pH 7.25, base excess 21.1 mmol/L. CPK was 991 U/L, myoglobin was 1745 ng/ml and creatine was 83 µmol/L. Abdomen magnetic resonance revealed cirrhosis. Muscle biopsy revealed myogenic lesion with abnormality of mitochondria and fat metabolism. The patient was diagnosed with Hepatitis B envelope Antigen positive CHB, cirrhosis, LA and RM characterized by myalgia and elevated myoglobin. He was given tenofovir alone as antiviral treatment instead. After hemodialysis and 4 weeks` treatment of corticosteroids, his symptoms recovered, and blood lactate gradually returned to a normal range. CONCLUSIONS: This case shows that tenofovir may trigger muscle damage and fatal RM in combination with telbivudine treatment in CHB patients. Thus, patients receiving tenofovir and telbivudine should be closely monitored for muscular abnormalities, blood lactate level and other mitochondrial toxicity associated side effects.

The Krüppel-associated box repressor domain induces reversible and irreversible regulation of endogenous mouse genes by mediating different chromatin states.

The Krüppel-associated box (KRAB) domain is a transcription repression module from the largest family of transcriptional regulators encoded by higher vertebrates. We developed a drug-controllable regulation system based on an artificial KRAB-containing repressor (tTS) that targets the endogenous Hprt gene to explore the regulatory mechanism and molecular basis of KRAB-containing regulators within the context of an endogenous gene in vivo. We show that KRAB can mediate irreversible and reversible regulation of endogenous genes in mouse that is dependent on embryonic developmental stage. KRAB-induced stable DNA methylation within the KRAB binding region during the early embryonic stage, resulting in irreversible gene repression. In later stages, KRAB mainly induced de-acetylation and methylation of histone, resulting in reversible gene repression. Thus, we have characterized the KRAB-mediated regulation system within the context of an endogenous gene and multiple spatiotemporal ranges, thereby providing a basis for identifying the function of KRAB-containing regulators and aiding development of novel KRAB-based gene regulation tools in vivo.

Class IIa histone deacetylases and myocyte enhancer factor 2 proteins regulate the mesenchymal-to-epithelial transition of somatic cell reprogramming.

Class IIa histone deacetylases (HDACs) and myocyte enhancer factor 2 (MEF2) proteins compose a signaling module that orchestrates lineage specification during embryogenesis. We show here that this module also regulates the generation of mouse induced pluripotent stem cells by defined transcription factors. Class IIa HDACs and MEF2 proteins rise steadily during fibroblast reprogramming to induced pluripotent stem cells. MEF2 proteins tend to block the process by inducing the expression of Tgfß cytokines, which impairs the necessary phase of mesenchymal-to-epithelial transition (MET). Conversely, class IIa HDACs endeavor to suppress the activity of MEF2 proteins, thus enhancing the MET and colony formation efficiency. Our work highlights an unexpected role for a developmental axis in somatic cell reprogramming and provides new insight into how the MET is regulated in this context.