Nevin Manimala

Nat Commun. 2022 Jul 2;13(1):3832. doi: 10.1038/s41467-022-31653-1.

ABSTRACT

Plant alkaloids constitute an important class of bioactive chemicals with applications in medicine and agriculture. However, the knowledge gap of the diversity and biosynthesis of phytoalkaloids prevents systematic advances in biotechnology for engineered production of these high-value compounds. In particular, the identification of cytochrome P450s driving the structural diversity of phytoalkaloids has remained challenging. Here, we use a combination of reverse genetics with discovery metabolomics and multivariate statistical analysis followed by in planta transient assays to investigate alkaloid diversity and functionally characterize two candidate cytochrome P450s genes from Atropa belladonna without a priori knowledge of their functions or information regarding the identities of key pathway intermediates. This approach uncovered a largely unexplored root localized alkaloid sub-network that relies on pseudotropine as precursor. The two cytochrome P450s catalyze N-demethylation and ring-hydroxylation reactions within the early steps in the biosynthesis of diverse N-demethylated modified tropane alkaloids.

PMID:35780230 | DOI:10.1038/s41467-022-31653-1

Ann Surg Oncol. 2022 Jul 2. doi: 10.1245/s10434-022-12035-9. Online ahead of print.

ABSTRACT

BACKGROUND: Secondary lymphedema is a debilitating morbidity. This study investigated the outcomes of vascularized lymph node transfer (VLNT) in elderly patients with secondary upper extremity lymphedema.

METHODS: Between 2008 and 2018, elderly (≥65 years) patients with secondary upper extremity lymphedema who underwent VLNT were retrospectively reviewed. Cheng’s Lymphedema Grading, Taiwan Lymphoscintigraphy Staging, and indocyanine green lymphography were used to select the procedures. Outcome measurements included complications, circumferential difference, episodes of cellulitis, and the Lymphedema-Specific Quality of Life questionnaire (LYMQoL).

RESULTS: Eleven patients with a mean age of 70.2 ± 5.3 years (range 65-80 years) who underwent VLNT survived and no major complications were encountered. At a mean follow-up of 6.5 ± 3.6 years (range 2-13 years), the mean limb circumferential difference was significantly improved from 25.6 ± 11.5% to 8.3 ± 4.2% (p = 0.016), and the mean episode of cellulitis was statistically reduced from 2.4 ± 1.3 to 0.4 ± 0.9 times/year (p = 0.007). At a follow-up of 24 months, four domains of Function (from 30.6 ± 2.8 to 14.5 ± 2.5), Appearance (from 18.2 ± 1.9 to 8.5 ± 2.1), Symptoms (from 30.4 ± 5.9 to 10.9 ± 1.0) and Mood (from 29.2 ± 4.4 to 10.7 ± 1.0), as well as overall LYMQoL score (from 3.9 ± 1.1 to 7.4 ± 0.5), showed statistical improvement (all p < 0.05).

CONCLUSIONS: VLNT for secondary upper extremity lymphedema in elderly patients significantly decreased the limb circumferential difference and frequency of cellulitis and improved quality of life without using compression garments postoperatively.

PMID:35780215 | DOI:10.1245/s10434-022-12035-9

Nat Commun. 2022 Jul 2;13(1):3817. doi: 10.1038/s41467-022-31236-0.

ABSTRACT

Long diagnostic wait times hinder international efforts to address antibiotic resistance in M. tuberculosis. Pathogen whole genome sequencing, coupled with statistical and machine learning models, offers a promising solution. However, generalizability and clinical adoption have been limited by a lack of interpretability, especially in deep learning methods. Here, we present two deep convolutional neural networks that predict antibiotic resistance phenotypes of M. tuberculosis isolates: a multi-drug CNN (MD-CNN), that predicts resistance to 13 antibiotics based on 18 genomic loci, with AUCs 82.6-99.5% and higher sensitivity than state-of-the-art methods; and a set of 13 single-drug CNNs (SD-CNN) with AUCs 80.1-97.1% and higher specificity than the previous state-of-the-art. Using saliency methods to evaluate the contribution of input sequence features to the SD-CNN predictions, we identify 18 sites in the genome not previously associated with resistance. The CNN models permit functional variant discovery, biologically meaningful interpretation, and clinical applicability.

PMID:35780211 | DOI:10.1038/s41467-022-31236-0

Sci Rep. 2022 Jul 2;12(1):11219. doi: 10.1038/s41598-022-15549-0.

ABSTRACT

Systemic lupus erythematosus (SLE) is the prototype of an autoimmune disease. Belimumab, a monoclonal antibody targets BAFF, is the only biologic approved for SLE and active lupus nephritis. BAFF is a cytokine with a key-regulatory role in the B cell homeostasis, which acts by binding to three receptors: BAFF-R, TACI and BCMA. TACI and BCMA also bind APRIL. Many studies reported elevated soluble BAFF and APRIL levels in the sera of SLE patients, but other questions about the role of this system in the disease remain open. The study aimed to investigate the utility of the cytokine levels in serum and urine as biomarkers, the role of non-functional isoforms, and the association of gene variants with the disease. This case-control study includes a cohort (women, 18-60 years old) of 100 patients (48% with nephritis) and 100 healthy controls. We used ELISA assays to measure the cytokine concentrations in serum (sBAFF and sAPRIL) and urine (uBAFF and uAPRIL); TaqMan Gene Expression Assays to quantify the relative mRNA expression of ΔBAFF, βAPRIL, and εAPRIL, and next-generation sequencing to genotype the cytokine (TNFSF13 and TNFSF13B) and receptor (TNFRSF13B, TNFRSF17 and TNFRSF13C) genes. The statistical tests used were: Kruskal-Wallis (qualitative variables), the Spearman Rho coefficient (correlations), the Chi-square and SKAT (association of common and rare genetic variants, respectively). As expected, sBAFF and sAPRIL levels were higher in patients than in controls (p ≤ 0.001) but found differences between patient subgroups. sBAFF and sAPRIL significantly correlated only in patients with nephritis (r_s = 0.67, p ≤ 0.001) and βAPRIL levels were lower in patients with nephritis (p = 0.04), and ΔBAFF levels were lower in patients with dsDNA antibodies (p = 0.04). Rare variants of TNFSF13 and TNFRSF13B and TNFSF13 p.Gly67Arg and TNFRSF13B p.Val220Ala were associated with SLE. Our study supports differences among SLE patient subgroups with diverse clinical features in the BAFF/APRIL pathway. In addition, it suggests the involvement of genetic variants in the susceptibility to the disease.

PMID:35780200 | DOI:10.1038/s41598-022-15549-0

Sci Rep. 2022 Jul 2;12(1):11212. doi: 10.1038/s41598-022-15062-4.

ABSTRACT

Systemic sclerosis (SSc) is characterized by the presence of SSc-specific or SSc-associated antibodies (SSc-Abs): anti-topoisomerase I (ATA), anti-centromere (ACA), anti-RNA polymerase III (ARA), anti-U3RNP (U3RNP), anti-U1RNP (U1RNP), anti-PmScl (PmScl), anti-Ku (Ku) and anti-Th/To (Th/To), each being associated with specific clinical features and prognosis. The detection of more than one SSc-Abs in SSc patients is rare and only few data about these patients’ clinical phenotype is available. The aim of our study was to evaluate the frequency and the disease’s features associated with the presence of > 1 SSc-Abs positivity in a large cohort of SSc patients. The autoantibody profiles of 2799 SSc patients from February 2001 to June 2017 were retrospectively reviewed. Patients with > 1 SSc-Abs were identified. Clinical features were collected and compared to a large historical cohort of SSc patients with single SSc-Ab positivity. SSc patients were excluded if previously treated with rituximab, intravenous immunoglobulins or stem cell transplantation. Non-parametric tests were used for statistical analysis. Nearly 5% of SSc patients from our cohort had ≥ 2 autoantibody positivity, and 2.3% (n = 72) had ≥ 2 SSc-Abs positivity. Th e most common combination was U1RNP and ATA (35%). These patients were younger than patients with single autoantibody positivity and showed more commonly a diffuse cutaneous SSc form. They also had higher rates of overlap features compared to ATA patients. Other combinations included U1RNP and ACA (13%), ATA and ACA (7%) and U1RNP and PmScl (5%). In our study we observed that, while infrequently, SSc patients can present with a combination of two SSc-Abs and that the double positivity can influence their clinical phenotype compared to patients with single SSc-Ab positivity. The importance of re-testing SSc-Abs in patients with changing clinical phenotypes was also highlighted, as this may confer a differing risk stratification.

PMID:35780179 | DOI:10.1038/s41598-022-15062-4

Nat Commun. 2022 Jul 2;13(1):3816. doi: 10.1038/s41467-022-31572-1.

ABSTRACT

Although urban greening is universally recognized as an essential part of sustainable and climate-responsive cities, a growing literature on green gentrification argues that new green infrastructure, and greenspace in particular, can contribute to gentrification, thus creating social and racial inequalities in access to the benefits of greenspace and further environmental and climate injustice. In response to limited quantitative evidence documenting the temporal relationship between new greenspaces and gentrification across entire cities, let alone across various international contexts, we employ a spatially weighted Bayesian model to test the green gentrification hypothesis across 28 cities in 9 countries in North America and Europe. Here we show a strong positive and relevant relationship for at least one decade between greening in the 1990s-2000s and gentrification that occurred between 2000-2016 in 17 of the 28 cities. Our results also determine whether greening plays a “lead”, “integrated”, or “subsidiary” role in explaining gentrification.

PMID:35780176 | DOI:10.1038/s41467-022-31572-1

Sci Rep. 2022 Jul 2;12(1):11220. doi: 10.1038/s41598-022-15413-1.

ABSTRACT

Human adenovirus (HAdV) types F40/41 have long been recognized as major viral agents of acute gastroenteritis (AGE) in children. Despite this, studies on HAdV molecular epidemiology are sparse, and their real impact is likely under-estimated. Thus, our goal was to investigate HAdV incidence, enteric and non-enteric types circulation, co-detections with rotavirus and norovirus and DNA shedding in stool samples from inpatients and outpatients from eleven Brazilian states. During the three-year study, 1012 AGE stool samples were analysed by TaqMan-based qPCR, to detect and quantify HAdV. Positive samples were genotyped by partial sequencing of the hexon gene followed by phylogenetic analysis. Co-detections were accessed by screening for rotavirus and norovirus. Overall, we detected HAdV in 24.5% of single-detected samples (n = 248), with a prevalence of type F41 (35.8%). We observed a higher incidence in children between 6 to 24 months, without marked seasonality. Additionally, we observed a statistically higher median viral load among single-detections between enteric and non-enteric types and a significantly lower HAdV viral load compared to rotavirus and norovirus in co-detections (p < 0.0001). Our study contributes to the knowledge of HAdV epidemiology and reinforces the need for the inclusion of enteric types F40/41 in molecular surveillance programs.

PMID:35780169 | DOI:10.1038/s41598-022-15413-1

BMC Vet Res. 2022 Jul 2;18(1):256. doi: 10.1186/s12917-022-03343-z.

ABSTRACT

BACKGROUND: Dogs with degenerative mitral valve disease are commonly presented to small animal clinicians. Diagnosis, clinical staging, and therapeutic design are based on a combination of clinical examination, radiography, and echocardiography. To support diagnosis and clinical monitoring, a multi-marker-based approach would be conceivable. The aim of this study was to investigate the suitability of Galectin-3 and interleukin-1 receptor-like 1 protein (ST2) in dogs with degenerative mitral valve disease in accordance with N-terminal-prohormone-B-type natriuretic peptide (NT-proBNP) and cardiac troponin I (cTnI). For this purpose, serum concentrations of Galectin-3 and ST2 of 64 dogs with different stages of mitral valve disease and 21 dogs without cardiac disease were analyzed at the first examination and six months later. Echocardiography, blood cell count and clinical chemistry were performed and established biomarkers NT-proBNP and cTnI were measured additionally. Differences in the biomarker concentrations between all groups at both timepoints and the change in biomarker concentrations from first to second evaluation was investigated. Furthermore, correlations of each biomarker, between biomarkers and echocardiographic measurements, were calculated. Finally, the receiver-operating characteristic curve and the area under the curve analysis were performed to differentiate between disease stages and controls.

RESULTS: Serum concentrations of Galectin-3 and ST2 were not statistically different between canine patients in the respective stages of mitral valve disease or in comparison to dogs in the control group at any timepoint. A significant increase in ST2 concentrations from the baseline to the follow-up examination was observed in dogs classified as stage B1 and the control group. The concentrations of NT-proBNP and cTnI in stage C dogs were significantly increased in comparison to the other groups.

CONCLUSIONS: In this study, no relation between Galectin-3 and ST2 levels to the presence or stage of mitral valve disease could be detected. Nevertheless, considering the increase in ST2 concentrations from the first to second measurement, its value on monitoring disease progress could be feasible. In agreement with previous studies, NT-proBNP and cTnI have once more proven their utility in assessing disease severity. The approach of examining new cardiac biomarkers in dogs is still worth pursuing.

PMID:35780161 | DOI:10.1186/s12917-022-03343-z

BMC Med Educ. 2022 Jul 2;22(1):519. doi: 10.1186/s12909-022-03576-4.

ABSTRACT

BACKGROUND: Comfort of patients with medical students is important and promotes appropriate clinical reasoning and skills development in the students. There is however limited data in this field in Uganda. In this study, we examined the attitudes and comfort of patients attending care at the medical and obstetrics/gynecology specialties in teaching hospitals of three public universities in Uganda.

METHODS: We conducted a cross sectional study among patients attending care at teaching hospitals for three public universities; Makerere University (Mak), Mbarara University of Science and Technology (MUST), and Gulu University (GU). Logistic regression was used to determine the magnitude of associations between independent and dependent variables. Two-sided p < 0.05 was considered statistically significant.

RESULTS: Eight hundred fifty-five patients participated in the study. Majority were aged 18 – 39 years (54%, n = 460), female (81%, n = 696) and married (67%, n = 567). Seventy percent (n = 599) of participants could recognize and differentiate medical students from qualified physicians, and had ever interacted with medical students (65%, n = 554) during earlier consultations. Regarding attitudes of patients towards presence of medical students during their consultations, most participants (96%; n = 818) considered involvement of medical students in patients’ care as essential ingredient of training of future doctors. Most participants prefer that medical students are trained in the tertiary public hospitals (80%; n = 683) where they attend care. Participants who were single/never married were 68% less likely to recognize and differentiate medical students (aOR = 0.32, 95%CI: 0.22 – 0.53) from other members of the healthcare team as compared with married participants. Participants with university education had 55% lower odds of being comfortable with presence of medical students during consultation compared to those with primary education (aOR = 0.45, 95%CI: 0.21 – 0.94). Participants from MUST teaching hospital had twofold higher odds of being comfortable with presence of medical students compared to participants from Mak teaching hospitals (aOR = 2.01; 95%CI: 1.20 – 3.39).

CONCLUSION: Patients are generally comfortable with medical students’ involvement in their care; they prefer to seek care in hospitals where medical students are trained so that the students may contribute to their care. Medical students need to introduce themselves appropriately so that all patients can know them as doctors in training; this will promote patients’ autonomy and informed decisions.

PMID:35780159 | DOI:10.1186/s12909-022-03576-4

BMC Med Inform Decis Mak. 2022 Jul 3;22(1):175. doi: 10.1186/s12911-022-01907-5.

ABSTRACT

BACKGROUND: Insightful feedback generation for daily home-based stroke rehabilitation is currently unavailable due to the inefficiency of exercise inspection done by therapists. We aim to produce a compact anomaly representation that allows a therapist to pay attention to only a few specific sections in a long exercise session record and boost their efficiency in feedback generation.

METHODS: This study proposes a data-driven technique to model a repetitive exercise using unsupervised phase learning on an artificial neural network and statistical learning on principal component analysis (PCA). After a model is built on a set of normal healthy movements, the model can be used to extract a sequence of anomaly scores from a movement of the same prescription.

RESULTS: The method not only works on a standard marker-based motion capture system but also performs well on a more compact and affordable motion capture system based-on Kinect V2 and wrist-worn inertial measurement units that can be used at home. An evaluation of four different exercises shows its potential in separating anomalous movements from normal ones with an average area under the curve (AUC) of 0.9872 even on the compact motion capture system.

CONCLUSIONS: The proposed processing technique has the potential to help clinicians in providing high-quality feedback for telerehabilitation in a more scalable way.

PMID:35780122 | DOI:10.1186/s12911-022-01907-5