In this review, recent examples featuring C-H functionalization in the synthesis of complex natural products are discussed. A focus is given to the way in which C-H functionalization can influence ...the logical process of retrosynthesis, and the review is organized by the type and method of C-H functionalization.
In this review, recent examples featuring C-H functionalization in the synthesis of complex natural products are discussed.
Shusterman's Somaesthetics is a wide-ranging collection of penetrating essays by twelve scholars examining in rich detail the many dimensions of philosopher Richard Shusterman's pragmatism and ...somaesthetics, complemented by his own chapter of responses to these scholars.
Causes for loss-to-follow-up, including early refusals of and stopping antiretroviral therapy (ART), in Malawi's Option B+ program are poorly understood. This study examines the main barriers and ...facilitators to uptake and adherence to ART under Option B+. In depth interviews were conducted with HIV-infected women who were pregnant or postpartum in Lilongwe, Malawi (N = 65). Study participants included women who refused ART initiation (N = 10), initiated ART and then stopped (N = 26), and those who initiated ART and remained on treatment (N = 29). The barriers to ART initiation were varied and included concerns about partner support, feeling healthy, and needing time to think. The main reasons for stopping ART included side effects and lack of partner support. A substantial number of women started ART after initially refusing or stopping ART. There were several facilitators for re-starting ART, including encouragement from community health workers, side effects subsiding, decline in health, change in partner, and fear of future sickness. Amongst those who remained on ART, desire to prevent transmission and improve health were the most influential facilitators. Reasons for refusing and stopping ART were varied. ART-related side effects and feeling healthy were common barriers to ART initiation and adherence. Providing consistent pre-ART counseling, early support for patients experiencing side effects, and targeted efforts to bring women who stop treatment back into care may improve long term health outcomes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Arrhythmogenic cardiomyopathy is a genetic disorder characterized by the risk of life-threatening arrhythmias, myocardial dysfunction and fibrofatty replacement of myocardial tissue. Mutations in ...genes that encode components of desmosomes, the adhesive junctions that connect cardiomyocytes, are the predominant cause of arrhythmogenic cardiomyopathy and can be identified in about half of patients with the condition. However, the molecular mechanisms leading to myocardial destruction, remodelling and arrhythmic predisposition remain poorly understood. Through the development of animal, induced pluripotent stem cell and other models of disease, advances in our understanding of the pathogenic mechanisms of arrhythmogenic cardiomyopathy over the past decade have brought several signalling pathways into focus. These pathways include canonical and non-canonical WNT signalling, the Hippo-Yes-associated protein (YAP) pathway and transforming growth factor-β signalling. These studies have begun to identify potential therapeutic targets whose modulation has shown promise in preclinical models. In this Review, we summarize and discuss the reported molecular mechanisms underlying the pathogenesis of arrhythmogenic cardiomyopathy.
Do all animals sleep? Sleep has been observed in many vertebrates, and there is a growing body of evidence for sleep-like states in arthropods and nematodes 1–5. Here we show that sleep is also ...present in Cnidaria 6–8, an earlier-branching metazoan lineage. Cnidaria and Ctenophora are the first metazoan phyla to evolve tissue-level organization and differentiated cell types, such as neurons and muscle 9–15. In Cnidaria, neurons are organized into a non-centralized radially symmetric nerve net 11, 13, 15–17 that nevertheless shares fundamental properties with the vertebrate nervous system: action potentials, synaptic transmission, neuropeptides, and neurotransmitters 15–20. It was reported that cnidarian soft corals 21 and box jellyfish 22, 23 exhibit periods of quiescence, a pre-requisite for sleep-like states, prompting us to ask whether sleep is present in Cnidaria. Within Cnidaria, the upside-down jellyfish Cassiopea spp. displays a quantifiable pulsing behavior, allowing us to perform long-term behavioral tracking. Monitoring of Cassiopea pulsing activity for consecutive days and nights revealed behavioral quiescence at night that is rapidly reversible, as well as a delayed response to stimulation in the quiescent state. When deprived of nighttime quiescence, Cassiopea exhibited decreased activity and reduced responsiveness to a sensory stimulus during the subsequent day, consistent with homeostatic regulation of the quiescent state. Together, these results indicate that Cassiopea has a sleep-like state, supporting the hypothesis that sleep arose early in the metazoan lineage, prior to the emergence of a centralized nervous system.
•Cassiopea jellyfish exhibit reversible behavioral quiescence during the night•Cassiopea show reduced responsiveness to stimuli during their quiescent state•The nighttime quiescence is regulated by both homeostatic and circadian systems•Pharmacological studies show evidence of molecular conservation of sleep regulation
Understanding the phylogenetic roots of behaviors sheds light on the evolutionary forces that shape them. Sleep has been observed in worms, flies, zebrafish, and mice. Nath et al. discover that jellyfish have a sleep-like state. This shifts the known root of sleep in the phylogenetic tree prior to the emergence of a centralized nervous system.
BACKGROUND:Catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited cardiac arrhythmia characterized by adrenergically triggered arrhythmias, is inadequately treated by current ...standard of care. Ca/calmodulin-dependent protein kinase II (CaMKII), an adrenergically activated kinase that contributes to arrhythmogenesis in heart disease models, is a candidate therapeutic target in CPVT. However, translation of CaMKII inhibition has been limited by the need for selective CaMKII inhibition in cardiomyocytes. Here, we tested the hypothesis that CaMKII inhibition with a cardiomyocyte-targeted gene therapy strategy would suppress arrhythmia in CPVT mouse models.
METHODS:We developed AAV9-GFP-AIP, an adeno-associated viral vector in which a potent CaMKII inhibitory peptide, autocamtide-2–related inhibitory peptide AIP, is fused to green fluorescent protein (GFP) and expressed from a cardiomyocyte selective promoter. The vector was delivered systemically. Arrhythmia burden was evaluated with invasive electrophysiology testing in adult mice. AIP was also tested on induced pluripotent stem cells derived from patients with CPVT with different disease-causing mutations to determine the effectiveness of our proposed therapy on human induced pluripotent stem cell–derived cardiomyocytes and different pathogenic genotypes.
RESULTS:AAV9-GFP-AIP was robustly expressed in the heart without significant expression in extracardiac tissues, including the brain. Administration of AAV9-GFP-AIP to neonatal mice with a known CPVT mutation (RYR2) effectively suppressed ventricular arrhythmias induced by either β-adrenergic stimulation or programmed ventricular pacing, without significant proarrhythmic effect. Intravascular delivery of AAV9-GFP-AIP to adolescent mice transduced ≈50% of cardiomyocytes and was effective in suppressing arrhythmia in CPVT mice. Induced pluripotent stem cell–derived cardiomyocytes derived from 2 different patients with CPVT with different pathogenic mutations demonstrated increased frequency of abnormal calcium release events, which was suppressed by a cell-permeable form of AIP.
CONCLUSIONS:This proof-of-concept study showed that AAV-mediated delivery of a CaMKII peptide inhibitor to the heart was effective in suppressing arrhythmias in a murine model of CPVT. CaMKII inhibition also reversed the arrhythmia phenotype in human CPVT induced pluripotent stem cell–derived cardiomyocyte models with different pathogenic mutations.
Abstract Objective We reviewed data on the epidemiology of epilepsy in the United States and estimated the prevalence and incidence of drug-resistant temporal lobe epilepsy (TLE) due to hippocampal ...sclerosis (HS) based on extrapolation from the available data drawn from the literature. Methods We searched the electronic database PubMed on December 14, 2016 using the following search terms in the title: “epilepsy” OR “temporal lobe” OR “hippocampal sclerosis” AND “epidemiology” OR “prevalence” OR “incidence”. Relevant original studies were included. We also reviewed several previous systematic reviews, meta-analyses, and their references. Results We concluded that the estimated current U.S. prevalence of drug-resistant HS-TLE is 0.51 – 0.66 cases per 1,000 people, and the estimated U.S. incidence is 3.1 – 3.4 cases per 100,000 people per year. Based on a U.S. population of 324 million, we estimate that as many as 143,000 - 191,000 U.S. patients still suffer from drug-resistant HS-TLE and are in need of surgery or other therapeutic options. Conclusions Although full scale epidemiological studies on drug resistant HS-TLE are needed, several observational studies allow adequate estimates of the range for the incidence and prevalence of this condition. Given the morbidity and mortality associated with poorly controlled seizures, this relatively large and growing patient population is a matter of concern. Considering the variety of treatment options that are available or in the pipeline to treat drug resistant epilepsy, future efforts should focus on advocating for early referral of patients with drug-resistant HS-TLE for more comprehensive epilepsy management.
A curated Web-based user-friendly sequence typing tool based on antimicrobial resistance determinants in
was developed and is publicly accessible (https://ngstar.canada.ca). The
Sequence Typing for ...Antimicrobial Resistance (NG-STAR) molecular typing scheme uses the DNA sequences of 7 genes (
,
,
,
,
,
, and 23S rRNA) associated with resistance to β-lactam antimicrobials, macrolides, or fluoroquinolones. NG-STAR uses the entire
sequence, combining the historical nomenclature for
types I to XXXVIII with novel nucleotide sequence designations; the full
sequence and a portion of its promoter region; portions of
,
,
, and
; and 23S rRNA sequences. NG-STAR grouped 768 isolates into 139 sequence types (STs) (
= 660) consisting of 29 clonal complexes (CCs) having a maximum of a single-locus variation, and 76 NG-STAR STs (
= 109) were identified as unrelated singletons. NG-STAR had a high Simpson's diversity index value of 96.5% (95% confidence interval CI = 0.959 to 0.969). The most common STs were NG-STAR ST-90 (
= 100; 13.0%), ST-42 and ST-91 (
= 45; 5.9%), ST-64 (
= 44; 5.72%), and ST-139 (
= 42; 5.5%). Decreased susceptibility to azithromycin was associated with NG-STAR ST-58, ST-61, ST-64, ST-79, ST-91, and ST-139 (
= 156; 92.3%); decreased susceptibility to cephalosporins was associated with NG-STAR ST-90, ST-91, and ST-97 (
= 162; 94.2%); and ciprofloxacin resistance was associated with NG-STAR ST-26, ST-90, ST-91, ST-97, ST-150, and ST-158 (
= 196; 98.0%). All isolates of NG-STAR ST-42, ST-43, ST-63, ST-81, and ST-160 (
= 106) were susceptible to all four antimicrobials. The standardization of nomenclature associated with antimicrobial resistance determinants through an internationally available database will facilitate the monitoring of the global dissemination of antimicrobial-resistant
strains.
As the number of HIV-infected women initiating lifelong antiretroviral therapy (ART) during pregnancy increases globally, concerns have emerged regarding low levels of retention in HIV services and ...suboptimal adherence to ART during the postpartum period. We examined the impact of integrating postpartum ART for HIV+ mothers alongside infant follow-up within maternal and child health (MCH) services in Cape Town, South Africa.
We conducted a randomised trial among HIV+ postpartum women aged ≥18 years who initiated ART during pregnancy in the local antenatal care clinic and were breastfeeding when screened before 6 weeks postpartum. We compared an integrated postnatal service among mothers and their infants (the MCH-ART intervention) to the local standard of care (control)-immediate postnatal referral of HIV+ women on ART to general adult ART services and their infants to separate routine infant follow-up. Evaluation data were collected through medical records and trial measurement visits scheduled and located separately from healthcare services involved in either arm. The primary trial outcome was a composite endpoint of women's retention in ART care and viral suppression (VS) (viral load < 50 copies/ml) at 12 months postpartum; secondary outcomes included duration of any and exclusive breastfeeding, mother-to-child HIV transmission, and infant mortality. Between 5 June 2013 and 10 December 2014, a total of 471 mother-infant pairs were enrolled and randomised (mean age, 28.6 years; 18% nulliparous; 57% newly diagnosed with HIV in pregnancy; median duration of ART use at randomisation, 18 weeks). Among 411 women (87%) with primary endpoint data available, 77% of women (n = 155) randomised to the MCH-ART intervention achieved the primary composite outcome of retention in ART services with VS at 12 months postpartum, compared to 56% of women (n = 117) randomised to the control arm (absolute risk difference, 0.21; 95% CI: 0.12-0.30; p < 0.001). The findings for improved retention in care and VS among women in the MCH-ART intervention arm were consistent across subgroups of participants according to demographic and clinical characteristics. The median durations of any breastfeeding and exclusive breastfeeding were longer in women randomised to the intervention versus control arm (6.9 versus 3.0 months, p = 0.006, and 3.0 versus 1.4 months, p < 0.001, respectively). For the infants, overall HIV-free survival through 12 months of age was 97%: mother-to-child HIV transmission was 1.2% overall (n = 4 and n = 1 transmissions in the intervention and control arms, respectively), and infant mortality was 1.9% (n = 6 and n = 3 deaths in the intervention and control arms, respectively), and these outcomes were similar by trial arm. Interpretation of these findings should be qualified by the location of this study in a single urban area as well as the self-reported nature of breastfeeding outcomes.
In this study, we found that integrating ART services into the MCH platform during the postnatal period was a simple and effective intervention, and this should be considered for improving maternal and child outcomes in the context of HIV.
ClinicalTrials.gov NCT01933477.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
In 2009, the Nomenclature Committee on Cell Death (NCCD) proposed a set of recommendations for the definition of distinct cell death morphologies and for the appropriate use of cell death-related ...terminology, including 'apoptosis', 'necrosis' and 'mitotic catastrophe'. In view of the substantial progress in the biochemical and genetic exploration of cell death, time has come to switch from morphological to molecular definitions of cell death modalities. Here we propose a functional classification of cell death subroutines that applies to both in vitro and in vivo settings and includes extrinsic apoptosis, caspase-dependent or -independent intrinsic apoptosis, regulated necrosis, autophagic cell death and mitotic catastrophe. Moreover, we discuss the utility of expressions indicating additional cell death modalities. On the basis of the new, revised NCCD classification, cell death subroutines are defined by a series of precise, measurable biochemical features.
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