Fever is a universal response to infection, and opportunistic pathogens such as Candida albicans have evolved complex circuitry to sense and respond to heat. Here we harness RNA-seq and ChIP-seq to ...discover that the heat shock transcription factor, Hsf1, binds distinct motifs in nucleosome-depleted promoter regions to regulate heat shock genes and genes involved in virulence in C. albicans. Consequently, heat shock increases C. albicans host cell adhesion, damage and virulence. Hsf1 activation depends upon the molecular chaperone Hsp90 under basal and heat shock conditions, but the effects are opposite and in part controlled at the level of Hsf1 expression and DNA binding. Finally, we demonstrate that Hsp90 regulates global transcription programs by modulating nucleosome levels at promoters of stress-responsive genes. Thus, we describe a mechanism by which C. albicans responds to temperature via Hsf1 and Hsp90 to orchestrate gene expression and chromatin architecture, thereby enabling thermal adaptation and virulence.
The capacity to coordinate environmental sensing with initiation of cellular responses underpins microbial survival and is crucial for virulence and stress responses in microbial pathogens. Here we ...define circuitry that enables the fungal pathogen Candida albicans to couple cell cycle dynamics with responses to cell wall stress induced by echinocandins, a front-line class of antifungal drugs. We discover that the C. albicans transcription factor Cas5 is crucial for proper cell cycle dynamics and responses to echinocandins, which inhibit β-1,3-glucan synthesis. Cas5 has distinct transcriptional targets under basal and stress conditions, is activated by the phosphatase Glc7, and can regulate the expression of target genes in concert with the transcriptional regulators Swi4 and Swi6. Thus, we illuminate a mechanism of transcriptional control that couples cell wall integrity with cell cycle regulation, and uncover circuitry governing antifungal drug resistance.Cas5 is a transcriptional regulator of responses to cell wall stress in the fungal pathogen Candida albicans. Here, Xie et al. show that Cas5 also modulates cell cycle dynamics and responses to antifungal drugs.
Unfractionated heparin (UFH), the standard anticoagulant for cardiopulmonary bypass (CPB) surgery, carries a risk of post-operative bleeding and is potentially harmful in patients with ...heparin-induced thrombocytopenia-associated antibodies. To improve the activity of an alternative anticoagulant, the RNA aptamer 11F7t, we solved X-ray crystal structures of the aptamer bound to factor Xa (FXa). The finding that 11F7t did not bind the catalytic site suggested that it could complement small-molecule FXa inhibitors. We demonstrate that combinations of 11F7t and catalytic-site FXa inhibitors enhance anticoagulation in purified reaction mixtures and plasma. Aptamer-drug combinations prevented clot formation as effectively as UFH in human blood circulated in an extracorporeal oxygenator circuit that mimicked CPB, while avoiding side effects of UFH. An antidote could promptly neutralize the anticoagulant effects of both FXa inhibitors. Our results suggest that drugs and aptamers with shared targets can be combined to exert more specific and potent effects than either agent alone.
Background Sub-Saharan Africa (SSA) has a disproportionate burden of both infectious and chronic diseases compared with other world regions. Current disease estimates for SSA are based on sparse ...data, but projections indicate increases in non-communicable diseases (NCDs) caused by demographic and epidemiologic transitions. We review the literature on NCDs in SSA and summarize data from the World Health Organization and International Agency for Research on Cancer on the prevalence and incidence of cardiovascular diseases, diabetes mellitus Type 2, cancer and their risk factors.
Methods We searched the PubMed database for studies on each condition, and included those that were community based, conducted in any SSA country and reported on disease or risk factor prevalence, incidence or mortality.
Results We found few community-based studies and some countries (such as South Africa) were over-represented. The prevalence of NCDs and risk factors varied considerably between countries, urban/rural location and other sub-populations. The prevalence of stroke ranged from 0.07 to 0.3%, diabetes mellitus from 0 to 16%, hypertension from 6 to 48%, obesity from 0.4 to 43% and current smoking from 0.4 to 71%. Hypertension prevalence was consistently similar among men and women, whereas women were more frequently obese and men were more frequently current smokers.
Conclusions The prevalence of NCDs and their risk factors is high in some SSA settings. With the lack of vital statistics systems, epidemiologic studies with a variety of designs (cross-sectional, longitudinal and interventional) capable of in-depth analyses of risk factors could provide a better understanding of NCDs in SSA, and inform health-care policy to mitigate the oncoming NCD epidemic.
Hypertension, the leading single cause of morbidity and mortality worldwide, is a growing public health problem in sub-Saharan Africa (SSA). Few studies have estimated and compared the burden of ...hypertension across different SSA populations. We conducted a cross-sectional analysis of blood pressure data collected through a cohort study in four SSA countries, to estimate the prevalence of pre-hypertension, the prevalence of hypertension, and to identify the factors associated with hypertension.
Participants were from five different population groups defined by occupation and degree of urbanization, including rural and peri-urban residents in Uganda, school teachers in South Africa and Tanzania, and nurses in Nigeria. We used a standardized questionnaire to collect data on demographic and behavioral characteristics, injuries, and history of diagnoses of chronic diseases and mental health. We also made physical measurements (weight, height and blood pressure), as well as biochemical measurements; which followed standardized protocols across the country sites. Modified Poison regression modelling was used to estimate prevalence ratios (PR) as measures of association between potential risk factors and hypertension.
The overall age-standardized prevalence of hypertension among the 1216 participants was 25.9%. Prevalence was highest among nurses with an age-standardized prevalence (ASP) of 25.8%, followed by school teachers (ASP = 23.2%), peri-urban residents (ASP = 20.5%) and lowest among rural residents (ASP = 8.7%). Only 50.0% of participants with hypertension were aware of their raised blood pressure. The overall age-standardized prevalence of pre-hypertension was 21.0%. Factors found to be associated with hypertension were: population group, older age, higher body mass index, higher fasting plasma glucose level, lower level of education, and tobacco use.
The prevalence of hypertension and pre-hypertension are high, and differ by population group defined by occupation and degree of urbanization. Only half of the populations with hypertension are aware of their hypertension, indicating a high burden of undiagnosed and un-controlled high blood pressure in these populations.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Overweight and obesity are on the rise in developing countries including sub-Saharan Africa. We undertook a four-country survey to show the collective burden of these health conditions as they occur ...currently in sub-Saharan Africa and to determine the differences between urban and rural populations and other socio-economic factors.
Participants were nurses in two hospitals in Nigeria (200), school teachers in South Africa (489) and Tanzania (229), and village residents in one peri-urban (297) and one rural location in Uganda (200) who completed a standardised questionnaire. Their height and weight were measured and body mass index calculated. Factor analysis procedure (Principal component) was used to generate a wealth index. Univariate and multivariate analyses with binary logistic regression models were conducted to examine the associations between potential correlates and the prevalence of overweight and obesity with 95 % confidence intervals.
The prevalence of overweight and obese (combined) was 46 %, 48 %, 68 %, 75 % and 85 % in rural Uganda, peri-urban Uganda, Nigeria, Tanzania and South Africa (SA), respectively. Rural Uganda, Peri- urban Uganda, Nigeria, Tanzania and SA had obesity prevalence of 10 %, 14 %, 31 %, 40 % and 54 %, respectively (p < 0.001). Overall, prevalence of overweight was 374 (31 %) and obesity, 414 (34 %). Female sex was a predictor of overweight and obesity (combined) in peri-urban Uganda AOR = 8.01; 95 % CI: 4.02, 15.96) and obesity in rural Uganda AOR = 11.22; 95%CI: 2.27, 55.40), peri-urban Uganda AOR = 27.80; 95 % CI: 7.13, 108.41) and SA AOR = 2.17; 95 % CI: 1.19, 4.00). Increasing age was a predictor of BMI > =25 kg/m
in Nigeria Age > =45 - AOR = 9.11; 95 % CI: 1.72, 48.16 and SA AOR = 6.22; 95 % CI: 2.75, 14.07, while marital status was predictor of BMI > =25 kg/m
only in peri-urban Uganda. Married - AOR = 4.49; 95 % CI: 1.74, 11.57. Those in Nigeria AOR = 2.56; 95 % CI: 1.45, 4.53, SA AOR = 4.97; 95 % CI: 3.18, 7.78, and Tanzania AOR = 2.68; 95 % CI: 1.60, 4.49 were more likely to have BMI > =25 kg/m
compared with the rural and peri-urban sites.
The high prevalence of overweight and obesity in these sub-Saharan African countries and the differentials in prevalence and risk factors further highlights the need for urgent focused intervention to stem this trend, especially among women, professionals and urban dwellers.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Fatalities stemming from hepatotoxicity associated with the clinical use of lapatinib (Tykerb), an oral dual tyrosine kinase inhibitor (ErbB-1 and ErbB-2) used in the treatment of metastatic breast ...cancer, have been reported. We investigated the inhibition of CYP3A4 by lapatinib as a possible cause of its idiosyncratic toxicity. Inhibition of CYP3A4 was time-, concentration-, and NADPH-dependent, with k(inact) = 0.0202 min(-1) and K(i) = 1.709 μM. The partition ratio was approximately 50.9. Addition of GSH did not affect the rate of inactivation. Testosterone protected CYP3A4 from inactivation by lapatinib. The characteristic Soret peak associated with a metabolite-intermediate complex was not observed for lapatinib during spectral difference scanning. However, reduced carbon monoxide (CO)-difference spectroscopy did reveal a 43% loss of the spectrally detectable CYP3A4-CO complex in the presence of lapatinib. Incubation of either lapatinib or its dealkylated metabolite with human liver microsomes in the presence of GSH resulted in the formation of a reactive metabolite (RM)-GSH adduct derived from the O-dealkylated metabolite of lapatinib. In addition, coincubation of lapatinib with ketoconazole inhibited the formation of the RM-GSH adduct. In conclusion, we demonstrated for the first time that lapatinib is a mechanism-based inactivator of CYP3A4, most likely via the formation and further oxidation of its O-dealkylated metabolite to a quinoneimine that covalently modifies the CYP3A4 apoprotein and/or heme moiety.
Background
Elucidating the molecular pathogenesis underlying East Texas bleeding disorder (ET) led to the discovery of alternatively spliced F5 transcripts harboring large deletions within exon 13. ...These alternatively spliced transcripts produce a shortened form of coagulation factor V (FV) in which a large portion of its B‐domain is deleted. These FV isoforms bind tissue factor pathway inhibitor alpha (TFPIα) with high affinity, prolonging its circulatory half‐life and enhancing its anticoagulant effects. While two missense pathogenic variants highlighted this alternative splicing event, similar internally deleted FV proteins are found in healthy controls.
Objective
We identified a novel heterozygous 832 base pair deletion within F5 exon 13, termed F5‐Atlanta (F5‐ATL), in a patient with severe bleeding. Our objective is to investigate the effect of this deletion on F5 and FV expression.
Methods & Results
Assessment of patient plasma revealed markedly elevated levels of total and free TFPI and a FV isoform similar in size to the FV‐short described in ET. Sequencing analyses of cDNA revealed the presence of a transcript alternatively spliced using the ET splice sites, thereby removing the F5‐ATL deletion. This alternative splicing pattern was recapitulated by heterologous expression in mammalian cells.
Conclusions
These findings support a mechanistic model consisting of cis‐acting regulatory sequences encoded within F5 exon 13 that control alternative splicing at the ET splice sites and thereby regulate circulating FV‐short and TFPIα levels.
Information on the clinicopathologic characteristics of invasive carcinomas arising from mucinous cystic neoplasms (MCNs) is limited, because in many early studies they were lumped and analyzed ...together with noninvasive MCNs. Even more importantly, many of the largest prior studies did not require ovarian-type stroma (OTS) for diagnosis. We analyzed 178 MCNs, all strictly defined by the presence of OTS, 98% of which occurred in perimenopausal women (mean age, 47 y) and arose in the distal pancreas. Twenty-nine (16%) patients had associated invasive carcinoma, and all were female with a mean age of 53. Invasion was far more common in tumors with grossly visible intracystic papillary nodule formation ≥1.0 cm (79.3% vs. 8.7%, P=0.000) as well as in larger tumors (mean cyst size9.4 vs. 5.4 cm, P=0.006); only 4/29 (14%) invasive carcinomas occurred in tumors that were <5 cm; however, none were <3 cm. Increased serum CA19-9 level (>37 U/L) was also more common in the invasive tumors (64% vs. 23%, P=0.011). Most invasive carcinomas (79%) were of tubular type, and the remainder (5 cases) were mostly undifferentiated carcinoma (2, with osteoclast-like giant cells), except for 1 with papillary features. Interestingly, there were no colloid carcinomas; 2 patients had nodal metastasis at the time of diagnosis, and both died of disease at 10 and 35 months, respectively. While noninvasive MCNs had an excellent prognosis (100% at 5 y), tumors with invasion often had an aggressive clinical course with 3- and 5-year survival rates of 44% and 26%, respectively (P=0.000). The pT2 (>2 cm) invasive tumors had a worse prognosis than pT1 (≤2 cm) tumors (P=0.000), albeit 3 patients with T1a (<0.5 cm) disease also died of disease. In conclusion, invasive carcinomas are seen in 16% of MCNs and are mostly of tubular (pancreatobiliary) type; colloid carcinoma is not seen in MCNs. Serum CA19-9 is often higher in invasive carcinomas, and invasion is typically seen in OTS-depleted areas with lower progesterone receptor expression. Invasion is not seen in small tumors (<3 cm) and those lacking intracystic papillary (mural) nodules of ≥1 cm, thus making the current branch-duct intraductal papillary mucinous neoplasm management protocols also applicable to MCNs.
Michelle Holmes and colleagues argue that there is an urgent need for longitudinal cohorts based in sub-Saharan Africa to address the growing burden of noncommunicable diseases in the region.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
PDF
