PURPOSE OF REVIEWTo review the roles of enteric adenovirus types 40 and 41 and nonenteric adenoviruses in the global burden of pediatric diarrhea.
RECENT FINDINGSLarge studies using highly sensitive, ...type-specific molecular diagnostics have demonstrated a substantial and previously under-estimated burden of pediatric diarrheal disease because of enteric infections with adenovirus types 40/41. However, the true epidemiology of adenovirus 40/41 remains incompletely understood. Similarly, additional adenovirus types may also be implicated as agents of community-acquired pediatric gastroenteritis but current data are too limited to elucidate their epidemiological role(s), if any.
SUMMARYEfforts at global diarrhea control in low-income and middle-income countries will require combating pediatric gastroenteritis because of enteric adenovirus infections. Future research in these settings using type-specific molecular diagnostics or strain genotyping to fully characterize the epidemiology of adenovirus 40/41 infections, identify non-40/41 adenoviruses significantly associated with gastroenteritis, and develop vaccines effective at preventing adenovirus diarrhea is warranted.
Laparoscopic distal pancreatectomy (LDP) reduces postoperative morbidity, hospital stay, and recovery as compared with open distal pancreatectomy. Technical limitations of laparoscopic surgery may ...limit patient eligibility and require conversion to open or hand-assisted surgery to maintain patient safety. We hypothesized that robot-assisted distal pancreatectomy (RADP) was superior to LDP as a result of improved surgical manipulation and visualization, potentially expanding the indications for minimally invasive pancreatectomy.
We performed a retrospective analysis of all minimally invasive distal pancreatectomies at University of Pittsburgh Medical Center between January 2004 and February 2011. We compared the perioperative outcomes, 90-day morbidity and mortality of our first 30 RADPs to 94 consecutive historical control LDPs.
Patients undergoing RADP and LDP demonstrated equivalent age, sex, race, American Society of Anesthesiologists' score, and tumor size. Postoperative length of hospital stay and rates of pancreatic fistula, blood transfusion, and readmission were not statistically different. Patients in the RADP group did not require conversion to open surgery unlike the LDP group (16%, P < 0.05) and had reduced risk of excessive blood loss. There were more pancreatic ductal adenocarcinomas approached robotically (43%) than laparoscopically (15%) (P < 0.05). Oncological outcomes in these cases were superior for the robotic-assisted group with higher rates of margin negative resection and improved lymph node yield for both benign and malignant lesions (P < 0.0001).
RADPs were equivalent to LDPs in nearly all measures of outcome and safety but significantly reduced the risk of conversion to open resection, despite a statistically greater probability of malignancy in the robotic cohort. We concluded that robotic assistance may broaden indications for minimally invasive pancreatectomy.
Human embryonic stem cells (hESCs) share an identical genome with lineage-committed cells, yet possess the remarkable properties of self-renewal and pluripotency. The diverse cellular properties in ...different cells have been attributed to their distinct epigenomes, but how much epigenomes differ remains unclear. Here, we report that epigenomic landscapes in hESCs and lineage-committed cells are drastically different. By comparing the chromatin-modification profiles and DNA methylomes in hESCs and primary fibroblasts, we find that nearly one-third of the genome differs in chromatin structure. Most changes arise from dramatic redistributions of repressive H3K9me3 and H3K27me3 marks, which form blocks that significantly expand in fibroblasts. A large number of potential regulatory sequences also exhibit a high degree of dynamics in chromatin modifications and DNA methylation. Additionally, we observe novel, context-dependent relationships between DNA methylation and chromatin modifications. Our results provide new insights into epigenetic mechanisms underlying properties of pluripotency and cell fate commitment.
► 11 histone modifications mapped in human embryonic stem cells and fibroblasts ► Dramatic redistributions of repressive H3K9me3 and H3K27me3 marks ► Context-dependent relationship between DNA methylation and chromatin modifications ► Multiple distinct modes of repression of genes important for pluripotency
A direct Pd‐catalyzed CH functionalization of benzoquinone (BQ) can be controlled to give either mono‐ or disubstituted BQ, including the installation of two different groups in a one‐pot procedure. ...BQ can now be directly functionalized with aryl, heteroaryl, cycloalkyl, and cycloalkene groups and, moreover, the reaction is conducted in environmentally benign water or acetone as solvents.
Direct CH functionalization of benzoquinone in water or acetone is now possible with Pd catalysis. The reaction can be controlled to afford either the mono‐ or the disubstituted product, and the difunctionalization includes the installation of two different groups in a one‐pot procedure. 2,6‐DCBQ=2,6‐dichloro‐1,4‐benzoquinone, EDG=electron‐donating group, EWG=electron‐withdrawing group.
Cas9/gRNA-mediated gene-drive systems have advanced development of genetic technologies for controlling vector-borne pathogen transmission. These technologies include population suppression ...approaches, genetic analogs of insecticidal techniques that reduce the number of insect vectors, and population modification (replacement/alteration) approaches, which interfere with competence to transmit pathogens. Here, we develop a recoded gene-drive rescue system for population modification of the malaria vector, Anopheles stephensi, that relieves the load in females caused by integration of the drive into the kynurenine hydroxylase gene by rescuing its function. Non-functional resistant alleles are eliminated via a dominantly-acting maternal effect combined with slower-acting standard negative selection, and rare functional resistant alleles do not prevent drive invasion. Small cage trials show that single releases of gene-drive males robustly result in efficient population modification with ≥95% of mosquitoes carrying the drive within 5-11 generations over a range of initial release ratios.
Epigenetic mechanisms have been proposed to play crucial roles in mammalian development, but their precise functions are only partially understood. To investigate epigenetic regulation of embryonic ...development, we differentiated human embryonic stem cells into mesendoderm, neural progenitor cells, trophoblast-like cells, and mesenchymal stem cells and systematically characterized DNA methylation, chromatin modifications, and the transcriptome in each lineage. We found that promoters that are active in early developmental stages tend to be CG rich and mainly engage H3K27me3 upon silencing in nonexpressing lineages. By contrast, promoters for genes expressed preferentially at later stages are often CG poor and primarily employ DNA methylation upon repression. Interestingly, the early developmental regulatory genes are often located in large genomic domains that are generally devoid of DNA methylation in most lineages, which we termed DNA methylation valleys (DMVs). Our results suggest that distinct epigenetic mechanisms regulate early and late stages of ES cell differentiation.
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•Epigenome was mapped in depth for hESCs and four hESC-derived cell types•Lineage-restricted genes and regulatory sequences were identified in these cell types•Distinct mechanisms regulate lineage-restricted genes at early and late stages•Developmental genes tend to reside in large genomic domains devoid of DNA methylation
DNA methylation, histone modifications, and the transcriptome have been mapped in human ES cells and four lineages. The results suggest that early and late stages of ES cell differentiation are regulated by distinct epigenetic mechanisms.
Pluripotent stem cell-derived cardiomyocyte grafts can remuscularize substantial amounts of infarcted myocardium and beat in synchrony with the heart, but in some settings cause ventricular ...arrhythmias. It is unknown whether human cardiomyocytes can restore cardiac function in a physiologically relevant large animal model. Here we show that transplantation of ∼750 million cryopreserved human embryonic stem cell-derived cardiomyocytes (hESC-CMs) enhances cardiac function in macaque monkeys with large myocardial infarctions. One month after hESC-CM transplantation, global left ventricular ejection fraction improved 10.6 ± 0.9% vs. 2.5 ± 0.8% in controls, and by 3 months there was an additional 12.4% improvement in treated vs. a 3.5% decline in controls. Grafts averaged 11.6% of infarct size, formed electromechanical junctions with the host heart, and by 3 months contained ∼99% ventricular myocytes. A subset of animals experienced graft-associated ventricular arrhythmias, shown by electrical mapping to originate from a point-source acting as an ectopic pacemaker. Our data demonstrate that remuscularization of the infarcted macaque heart with human myocardium provides durable improvement in left ventricular function.
IMPORTANCE: Catheter ablation is effective in restoring sinus rhythm in atrial fibrillation (AF), but its effects on long-term mortality and stroke risk are uncertain. OBJECTIVE: To determine whether ...catheter ablation is more effective than conventional medical therapy for improving outcomes in AF. DESIGN, SETTING, AND PARTICIPANTS: The Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation trial is an investigator-initiated, open-label, multicenter, randomized trial involving 126 centers in 10 countries. A total of 2204 symptomatic patients with AF aged 65 years and older or younger than 65 years with 1 or more risk factors for stroke were enrolled from November 2009 to April 2016, with follow-up through December 31, 2017. INTERVENTIONS: The catheter ablation group (n = 1108) underwent pulmonary vein isolation, with additional ablative procedures at the discretion of site investigators. The drug therapy group (n = 1096) received standard rhythm and/or rate control drugs guided by contemporaneous guidelines. MAIN OUTCOMES AND MEASURES: The primary end point was a composite of death, disabling stroke, serious bleeding, or cardiac arrest. Among 13 prespecified secondary end points, 3 are included in this report: all-cause mortality; total mortality or cardiovascular hospitalization; and AF recurrence. RESULTS: Of the 2204 patients randomized (median age, 68 years; 37.2% female; 42.9% had paroxysmal AF and 57.1% had persistent AF), 89.3% completed the trial. Of the patients assigned to catheter ablation, 1006 (90.8%) underwent the procedure. Of the patients assigned to drug therapy, 301 (27.5%) ultimately received catheter ablation. In the intention-to-treat analysis, over a median follow-up of 48.5 months, the primary end point occurred in 8.0% (n = 89) of patients in the ablation group vs 9.2% (n = 101) of patients in the drug therapy group (hazard ratio HR, 0.86 95% CI, 0.65-1.15; P = .30). Among the secondary end points, outcomes in the ablation group vs the drug therapy group, respectively, were 5.2% vs 6.1% for all-cause mortality (HR, 0.85 95% CI, 0.60-1.21; P = .38), 51.7% vs 58.1% for death or cardiovascular hospitalization (HR, 0.83 95% CI, 0.74-0.93; P = .001), and 49.9% vs 69.5% for AF recurrence (HR, 0.52 95% CI, 0.45-0.60; P < .001). CONCLUSIONS AND RELEVANCE: Among patients with AF, the strategy of catheter ablation, compared with medical therapy, did not significantly reduce the primary composite end point of death, disabling stroke, serious bleeding, or cardiac arrest. However, the estimated treatment effect of catheter ablation was affected by lower-than-expected event rates and treatment crossovers, which should be considered in interpreting the results of the trial. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00911508
Many of the cognitive deficits of normal ageing (forgetfulness, distractibility, inflexibility and impaired executive functions) involve prefrontal cortex (PFC) dysfunction. The PFC guides behaviour ...and thought using working memory, which are essential functions in the information age. Many PFC neurons hold information in working memory through excitatory networks that can maintain persistent neuronal firing in the absence of external stimulation. This fragile process is highly dependent on the neurochemical environment. For example, elevated cyclic-AMP signalling reduces persistent firing by opening HCN and KCNQ potassium channels. It is not known if molecular changes associated with normal ageing alter the physiological properties of PFC neurons during working memory, as there have been no in vivo recordings, to our knowledge, from PFC neurons of aged monkeys. Here we characterize the first recordings of this kind, revealing a marked loss of PFC persistent firing with advancing age that can be rescued by restoring an optimal neurochemical environment. Recordings showed an age-related decline in the firing rate of DELAY neurons, whereas the firing of CUE neurons remained unchanged with age. The memory-related firing of aged DELAY neurons was partially restored to more youthful levels by inhibiting cAMP signalling, or by blocking HCN or KCNQ channels. These findings reveal the cellular basis of age-related cognitive decline in dorsolateral PFC, and demonstrate that physiological integrity can be rescued by addressing the molecular needs of PFC circuits.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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