Measures of microbial growth, used as indicators of cellular stress, are sometimes quantified at a single time-point. In reality, these measurements are compound representations of length of lag, ...exponential growth-rate, and other factors. Here, we investigate whether length of lag phase can act as a proxy for stress, using a number of model systems (Aspergillus penicillioides; Bacillus subtilis; Escherichia coli; Eurotium amstelodami, E. echinulatum, E. halophilicum, and E. repens; Mrakia frigida; Saccharomyces cerevisiae; Xerochrysium xerophilum; Xeromyces bisporus) exposed to mechanistically distinct types of cellular stress including low water activity, other solute-induced stresses, and dehydration-rehydration cycles. Lag phase was neither proportional to germination rate for X. bisporus (FRR3443) in glycerol-supplemented media (r
= 0.012), nor to exponential growth-rates for other microbes. In some cases, growth-rates varied greatly with stressor concentration even when lag remained constant. By contrast, there were strong correlations for B. subtilis in media supplemented with polyethylene-glycol 6000 or 600 (r
= 0.925 and 0.961), and for other microbial species. We also analysed data from independent studies of food-spoilage fungi under glycerol stress (Aspergillus aculeatinus and A. sclerotiicarbonarius); mesophilic/psychrotolerant bacteria under diverse, solute-induced stresses (Brochothrix thermosphacta, Enterococcus faecalis, Pseudomonas fluorescens, Salmonella typhimurium, Staphylococcus aureus); and fungal enzymes under acid-stress (Terfezia claveryi lipoxygenase and Agaricus bisporus tyrosinase). These datasets also exhibited diversity, with some strong- and moderate correlations between length of lag and exponential growth-rates; and sometimes none. In conclusion, lag phase is not a reliable measure of stress because length of lag and growth-rate inhibition are sometimes highly correlated, and sometimes not at all.
The hypotheses of this systematic review were the following: 1) Prevalence of post-traumatic stress disorder (PTSD) will differ between various types of chronic pain (CP), and 2) there will be ...consistent evidence that CP is associated with PTSD.
Of 477 studies, 40 fulfilled the inclusion/exclusion criteria of this review and were grouped according to the type of CP. The reported prevalence of PTSD for each grouping was determined by aggregating all the patients in all the studies in that group. Additionally all patients in all groupings were combined. Percentage of studies that had found an association between CP and PTSD was determined. The consistency of the evidence represented by the percentage of studies finding an association was rated according to the Agency for Health Care Policy and Research guidelines.
Grouping PTSD prevalence differed ranging from a low of 0.69% for chronic low back pain to a high of 50.1% in veterans. Prevalence in the general population with CP was 9.8%. Of 19 studies, 16 had found an association between CP and PTSD (84.2%) generating an A consistency rating (consistent multiple studies). Three of the groupings had an A or B (generally consistent) rating. The veterans grouping received a C (finding inconsistent) rating.
The results of this systematic review confirmed the hypotheses of this review.
Summary Background Doxorubicin chemotherapy is associated with cardiomyopathy. Dexrazoxane reduces cardiac damage during treatment with doxorubicin in children with acute lymphoblastic leukaemia ...(ALL). We aimed to establish the long-term effect of dexrazoxane on the subclinical state of cardiac health in survivors of childhood high-risk ALL 5 years after completion of doxorubicin treatment. Methods Between January, 1996, and September, 2000, children with high-risk ALL were enrolled from nine centres in the USA, Canada, and Puerto Rico. Patients were assigned by block randomisation to receive ten doses of 30 mg/m2 doxorubicin alone or the same dose of doxorubicin preceded by 300 mg/m2 dexrazoxane. Treatment assignment was obtained through a telephone call to a centralised registrar to conceal allocation. Investigators were masked to treatment assignment but treating physicians and patients were not; however, investigators, physicians, and patients were masked to study serum cardiac troponin-T concentrations and echocardiographic measurements. The primary endpoints were late left ventricular structure and function abnormalities as assessed by echocardiography; analyses were done including all patients with data available after treatment completion. This trial has been completed and is registered with ClinicalTrials.gov , number NCT00165087. Findings 100 children were assigned to doxorubicin (66 analysed) and 105 to doxorubicin plus dexrazoxane (68 analysed). 5 years after the completion of doxorubicin chemotherapy, mean left ventricular fractional shortening and end-systolic dimension Z scores were significantly worse than normal for children who received doxorubicin alone (left ventricular fractional shortening: −0·82, 95% CI −1·31 to −0·33; end-systolic dimension: 0·57, 0·21–0·93) but not for those who also received dexrazoxane (−0·41, −0·88 to 0·06; 0·15, −0·20 to 0·51). The protective effect of dexrazoxane, relative to doxorubicin alone, on left ventricular wall thickness (difference between groups: 0·47, 0·46–0·48) and thickness-to-dimension ratio (0·66, 0·64–0·68) were the only statistically significant characteristics at 5 years. Subgroup analysis showed dexrazoxane protection (p=0·04) for left ventricular fractional shortening at 5 years in girls (1·17, 0·24–2·11), but not in boys (−0·10, −0·87 to 0·68). Similarly, subgroup analysis showed dexrazoxane protection (p=0·046) for the left ventricular thickness-to-dimension ratio at 5 years in girls (1·15, 0·44–1·85), but not in boys (0·19, −0·42 to 0·81). With a median follow-up for recurrence and death of 8·7 years (range 1·3–12·1), event-free survival was 77% (95% CI 67–84) for children in the doxorubicin-alone group, and 76% (67–84) for children in the doxorubicin plus dexrazoxane group (p=0·99). Interpretation Dexrazoxane provides long-term cardioprotection without compromising oncological efficacy in doxorubicin-treated children with high-risk ALL. Dexrazoxane exerts greater long-term cardioprotective effects in girls than in boys. Funding US National Institutes of Health, Children's Cardiomyopathy Foundation, University of Miami Women's Cancer Association, Lance Armstrong Foundation, Roche Diagnostics, Pfizer, and Novartis.
Hypertrophic cardiomyopathy (HCM) is often caused by pathogenic variants in sarcomeric genes and characterized by left ventricular (LV) hypertrophy, myocardial fibrosis and increased risk of heart ...failure and arrhythmias. There are no existing therapies to modify disease progression. In this study, we conducted a multi-center, double-blind, placebo-controlled phase 2 clinical trial to assess the safety and efficacy of the angiotensin II receptor blocker valsartan in attenuating disease evolution in early HCM. In total, 178 participants with early-stage sarcomeric HCM were randomized (1:1) to receive valsartan (320 mg daily in adults; 80-160 mg daily in children) or placebo for 2 years ( NCT01912534 ). Standardized changes from baseline to year 2 in LV wall thickness, mass and volumes; left atrial volume; tissue Doppler diastolic and systolic velocities; and serum levels of high-sensitivity troponin T and N-terminal pro-B-type natriuretic protein were integrated into a single composite z-score as the primary outcome. Valsartan (n = 88) improved cardiac structure and function compared to placebo (n = 90), as reflected by an increase in the composite z-score (between-group difference +0.231, 95% confidence interval (+0.098, +0.364); P = 0.001), which met the primary endpoint of the study. Treatment was well-tolerated. These results indicate a key opportunity to attenuate disease progression in early-stage sarcomeric HCM with an accessible and safe medication.
Weakly electric fish encode perturbations in a self-generated electric field to sense their environment. Localizing objects using this electric sense requires that distance be decoded from a ...two-dimensional \emph{electric image} of the field perturbations on their skin. Many studies of object localization by weakly electric fish, and by electric sensing in a generic context, have focused on extracting location information from different features of the electric image. Some of these studies have also considered the additional information gained from sampling the electric image at different times, and from different viewpoints. Here, we take a different perspective and instead consider the information available at a single point in space (i.e. a single sensor or receptor) at a single point in time (i.e. constant field). By combining the information from multiple receptors, we show that an object's distance can be unambiguously encoded by as few as four receptors at specific locations on a sensing surface in a manner that is relatively robust to environmental noise. This provides a lower bound on the information (i.e. receptor array size) required to decode the three-dimensional location of an object using an electric sense.
We present a strategy for the analysis of the yeast phosphoproteome that uses endo-Lys C as the proteolytic enzyme, immobilized metal affinity chromatography for phosphopeptide enrichment, a 90-min ...nanoflow-HPLC/electrospray-ionization MS/MS experiment for phosphopeptide fractionation and detection, gas phase ion/ion chemistry, electron transfer dissociation for peptide fragmentation, and the Open Mass Spectrometry Search Algorithm for phosphoprotein identification and assignment of phosphorylation sites. From a 30-μg (≈600 pmol) sample of total yeast protein, we identify 1,252 phosphorylation sites on 629 proteins. Identified phosphoproteins have expression levels that range from <50 to 1,200,000 copies per cell and are encoded by genes involved in a wide variety of cellular processes. We identify a consensus site that likely represents a motif for one or more uncharacterized kinases and show that yeast kinases, themselves, contain a disproportionately large number of phosphorylation sites. Detection of a pHis containing peptide from the yeast protein, Cdc10, suggests an unexpected role for histidine phosphorylation in septin biology. From diverse functional genomics data, we show that phosphoproteins have a higher number of interactions than an average protein and interact with each other more than with a random protein. They are also likely to be conserved across large evolutionary distances.
A high-fat diet has been associated with an increased risk of ulcerative colitis (UC). We studied the effects of a low-fat, high-fiber diet (LFD) vs an improved standard American diet (iSAD, included ...higher quantities of fruits, vegetables, and fiber than a typical SAD). We collected data on quality of life, markers of inflammation, and fecal markers of intestinal dysbiosis in patients with UC.
We analyzed data from a parallel-group, cross-over study of 17 patients with UC in remission or with mild disease (with a flare within the past 18 mo), from February 25, 2015, through September 11, 2018. Participants were assigned randomly to 2 groups and received a LFD (10% of calories from fat) or an iSAD (35%–40% of calories from fat) for the first 4-week period, followed by a 2-week washout period, and then switched to the other diet for 4 weeks. All diets were catered and delivered to patients’ homes, and each participant served as her or his own control. Serum and stool samples were collected at baseline and week 4 of each diet and analyzed for markers of inflammation. We performed 16s ribosomal RNA sequencing and untargeted and targeted metabolomic analyses on stool samples. The primary outcome was quality of life, which was measured by the short inflammatory bowel disease (IBD) questionnaire at baseline and week 4 of the diets. Secondary outcomes included changes in the Short-Form 36 health survey, partial Mayo score, markers of inflammation, microbiome and metabolome analysis, and adherence to the diet.
Participants’ baseline diets were unhealthier than either study diet. All patients remained in remission throughout the study period. Compared with baseline, the iSAD and LFD each increased quality of life, based on the short IBD questionnaire and Short-Form 36 health survey scores (baseline short IBD questionnaire score, 4.98; iSAD, 5.55; LFD, 5.77; baseline vs iSAD, P = .02; baseline vs LFD, P = .001). Serum amyloid A decreased significantly from 7.99 mg/L at baseline to 4.50 mg/L after LFD (P = .02), but did not decrease significantly compared with iSAD (7.20 mg/L; iSAD vs LFD, P = .07). The serum level of C-reactive protein decreased numerically from 3.23 mg/L at baseline to 2.51 mg/L after LFD (P = .07). The relative abundance of Actinobacteria in fecal samples decreased from 13.69% at baseline to 7.82% after LFD (P = .017), whereas the relative abundance of Bacteroidetes increased from 14.6% at baseline to 24.02% on LFD (P = .015). The relative abundance of Faecalibacterium prausnitzii was higher after 4 weeks on the LFD (7.20%) compared with iSAD (5.37%; P = .04). Fecal levels of acetate (an anti-inflammatory metabolite) increased from a relative abundance of 40.37 at baseline to 42.52 on the iSAD and 53.98 on the LFD (baseline vs LFD, P = .05; iSAD vs LFD, P = .09). The fecal level of tryptophan decreased from a relative abundance of 1.33 at baseline to 1.08 on the iSAD (P = .43), but increased to a relative abundance of 2.27 on the LFD (baseline vs LFD, P = .04; iSAD vs LFD, P = .08); fecal levels of lauric acid decreased after LFD (baseline, 203.4; iSAD, 381.4; LFD, 29.91; baseline vs LFD, P = .04; iSAD vs LFD, P = .02).
In a cross-over study of patients with UC in remission, we found that a catered LFD or iSAD were each well tolerated and increased quality of life. However, the LFD decreased markers of inflammation and reduced intestinal dysbiosis in fecal samples. Dietary interventions therefore might benefit patients with UC in remission. ClinicalTrials.gov no: NCT04147598.
In 2013, the American Psychiatric Association (APA) published the 5th edition of its Diagnostic and Statistical Manual of Mental Disorders (DSM‐5). In 2019, the World Health Assembly approved the ...11th revision of the International Classification of Diseases (ICD‐11). It has often been suggested that the field would benefit from a single, unified classification of mental disorders, although the priorities and constituencies of the two sponsoring organizations are quite different. During the development of the ICD‐11 and DSM‐5, the World Health Organization (WHO) and the APA made efforts toward harmonizing the two systems, including the appointment of an ICD‐DSM Harmonization Group. This paper evaluates the success of these harmonization efforts and provides a guide for practitioners, researchers and policy makers describing the differences between the two systems at both the organizational and the disorder level. The organization of the two classifications of mental disorders is substantially similar. There are nineteen ICD‐11 disorder categories that do not appear in DSM‐5, and seven DSM‐5 disorder categories that do not appear in the ICD‐11. We compared the Essential Features section of the ICD‐11 Clinical Descriptions and Diagnostic Guidelines (CDDG) with the DSM‐5 criteria sets for 103 diagnostic entities that appear in both systems. We rated 20 disorders (19.4%) as having major differences, 42 disorders (40.8%) as having minor definitional differences, 10 disorders (9.7%) as having minor differences due to greater degree of specification in DSM‐5, and 31 disorders (30.1%) as essentially identical. Detailed descriptions of the major differences and some of the most important minor differences, with their rationale and related evidence, are provided. The ICD and DSM are now closer than at any time since the ICD‐8 and DSM‐II. Differences are largely based on the differing priorities and uses of the two diagnostic systems and on differing interpretations of the evidence. Substantively divergent approaches allow for empirical comparisons of validity and utility and can contribute to advances in the field.
A high-throughput screen (HTS) of the MLPCN library using a homogenous fluorescence polarization assay identified a small molecule as a first-in-class direct inhibitor of Keap1–Nrf2 protein–protein ...interaction. The HTS hit has three chiral centers; a combination of flash and chiral chromatographic separation demonstrated that Keap1-binding activity resides predominantly in one stereoisomer (SRS)-5 designated as ML334 (LH601A), which is at least 100× more potent than the other stereoisomers. The stereochemistry of the four cis isomers was assigned using X-ray crystallography and confirmed using stereospecific synthesis. (SRS)-5 is functionally active in both an ARE gene reporter assay and an Nrf2 nuclear translocation assay. The stereospecific nature of binding between (SRS)-5 and Keap1 as well as the preliminary but tractable structure–activity relationships support its use as a lead for our ongoing optimization
•We propose a novel algorithm for distance estimation in electric sensing.•Distance is determined from electric image width at two different sensor thresholds.•Distance is determined from electric ...image width at two different field strengths.•Distance estimation algorithm is robust to discretized sensor location.
Electric sensing involves measuring the voltage changes in an actively generated electric field, enabling an environment to be characterized by its electrical properties. It has been applied in a variety of contexts, from geophysics to biomedical imaging. Some species of fish also use an active electric sense to explore their environment in the dark. One of the primary challenges in such electric sensing involves mapping an environment in three-dimensions using voltage measurements that are limited to a two-dimensional sensor array (i.e. a two-dimensional electric image). In some special cases, the distance of simple objects from the sensor array can be estimated by combining properties of the electric image. Here, we describe a novel algorithm for distance estimation based on a single property of the electric image. Our algorithm can be implemented in two simple ways, involving either different electric field strengths or different sensor thresholds, and is robust to changes in object properties and noise.
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