Variable resistance to zinc intoxication among Streptococcus agalactiae reveals a novel IS1381 insertion element within the zinc efflux transporter gene czcD

Streptococcus agalactiae, also known as group B Streptococcus, is an important human and animal pathogen. Zinc (Zn) is an essential trace element for normal bacterial physiology but intoxicates bacteria at high concentrations. Molecular systems for Zn detoxification exist in S. agalactiae, however the degree to which Zn detoxification may vary among different S. agalactiae isolates is not clear. We measured resistance to Zn intoxication in a diverse collection of clinical isolates of S. agalactiae by comparing the growth of the bacteria in defined conditions of Zn stress. We found significant differences in the ability of different S. agalactiae isolates to resist Zn intoxication; some strains such as S. agalactiae 18RS21 were able to survive and grow at 3.8-fold higher levels of Zn stress compared to other reference strains such as BM110 (6.4mM vs 1.68mM Zn as inhibitory, respectively). We performed in silico analysis of the available genomes of the S. agalactiae isolates used in this study to examine the sequence of czcD, which encodes an efflux protein for Zn that supports resistance in S. agalactiae. Interestingly, this revealed the presence of a mobile insertion sequence (IS) element, termed IS1381, in the 5′ region of czcD in S. agalactiae strain 834, which was hyper-resistant to Zn intoxication. Interrogating a wider collection of S. agalactiae genomes revealed identical placement of IS1381 in czcD in other isolates from the clonal-complex-19 (CC19) 19 lineage. Collectively, these results show a resistance spectrum among S. agalactiae isolates enables survival in varying degrees of Zn stress, and this phenotypic variability has implications for understanding bacterial survival in metal stress

Stellar Astrophysics and Exoplanet Science with the Maunakea Spectroscopic Explorer (MSE)

The Maunakea Spectroscopic Explorer (MSE) is a planned 11.25-m aperture facility with a 1.5 square degree field of view that will be fully dedicated to multi-object spectroscopy. A rebirth of the 3.6m Canada-France-Hawaii Telescope on Maunakea, MSE will use 4332 fibers operating at three different resolving powers (R ~ 2500, 6000, 40000) across a wavelength range of 0.36-1.8mum, with dynamical fiber positioning that allows fibers to match the exposure times of individual objects. MSE will enable spectroscopic surveys with unprecedented scale and sensitivity by collecting millions of spectra per year down to limiting magnitudes of g ~ 20-24 mag, with a nominal velocity precision of ~100 m/s in high-resolution mode. This white paper describes science cases for stellar astrophysics and exoplanet science using MSE, including the discovery and atmospheric characterization of exoplanets and substellar objects, stellar physics with star clusters, asteroseismology of solar-like oscillators and opacity-driven pulsators, studies of stellar rotation, activity, and multiplicity, as well as the chemical characterization of AGB and extremely metal-poor stars.Comment: 31 pages, 11 figures; To appear as a chapter for the Detailed Science Case of the Maunakea Spectroscopic Explore

Antimony-Doped Tin(II) Sulfide Thin Films

Thin-film solar cells made from earth-abundant, inexpensive, and nontoxic materials are needed to replace the current technologies whose widespread use is limited by their use of scarce, costly, and toxic elements. Tin monosulfide (SnS) is a promising candidate for making absorber layers in scalable, inexpensive, and nontoxic solar cells. SnS has always been observed to be a p-type semiconductor. Doping SnS to form an n-type semiconductor would permit the construction of solar cells with p-n homojunctions. This paper reports doping SnS films with antimony, a potential n-type dopant. Small amounts of antimony (1%) were found to greatly increase the electrical resistance of the SnS. The resulting intrinsic SnS(Sb) films could be used for the insulating layer in a p-i-n design for solar cells. Higher concentrations (5%) of antimony did not convert the SnS(Sb) to low-resistivity n-type conductivity, but instead the films retain such a high resistance that the conductivity type could not be determined. Extended X-ray absorption fine structure analysis reveals that the highly doped films contain precipitates of a secondary phase that has chemical bonds characteristic of metallic antimony, rather than the antimony–sulfur bonds found in films with lower concentrations of antimony.United States. Dept. of Energy. Sunshot Initiative (Contract DE-EE0005329)National Science Foundation (U.S.) (Grant CBET-1032955

Multiple order-up-to policy for mitigating bullwhip effect in supply chain network

This paper proposes a multiple order-up-to policy based inventory replenishment scheme to mitigate the bullwhip effect in a multi-stage supply chain scenario, where various transportation modes are available between the supply chain (SC) participants. The proposed policy is similar to the fixed order-up-to policy approach where replenishment decision “how much to order” is made periodically on the basis of the predecided order-up-to inventory level. In the proposed policy, optimal multiple order-up-to levels are assigned to each SC participants, which provides decision making reference point for deciding the transportation related order quantity. Subsequently, a mathematical model is established to define optimal multiple order-up-to levels for each SC participants that aims to maximize overall profit from the SC network. In parallel, the model ensures the control over supply chain pipeline inventory, high satisfaction of customer demand and enables timely utilization of available transportation modes. Findings from the various numerical datasets including stochastic customer demand and lead times validate that—the proposed optimal multiple order-up-to policy based inventory replenishment scheme can be a viable alternative for mitigating the bullwhip effect and well-coordinated SC. Moreover, determining the multiple order-up-to levels is a NP hard combinatorial optimization problem. It is found that the implementation of new emerging optimization algorithm named bacterial foraging algorithm (BFA) has presented superior optimization performances. The robustness and applicability of the BFA algorithm are further validated statistically by employing the percentage heuristic gap and two-way ANOVA analysis

SPAG5 as a prognostic biomarker and chemotherapy sensitivity predictor in breast cancer: a retrospective, integrated genomic, transcriptomic, and protein analysis

Background: Although the use of proliferation markers/profiles has been recommended when choosing the appropriate systemic-treatment for breast cancer (BC), the best molecular-marker/test that should be used needs to be identified. Methods: To identify factors that drive proliferation and its associated features in BC an artificial neural network (ANN) based integrative data-mining methodology was applied to three cohorts [(Nottingham-discovery (ND), Uppsala and METABRIC (Molecular Taxonomy of Breast Cancer International Consortium)]. The most prominent genes in the resulting interactome-map were then identified. Given that SPAG5 was associated with many features of proliferation, featured prominently in the interactome-map and has a fundamental role in mitotic-progression,, we hypothesized that it could be a better indicator of proliferation activity. (BC). Subsequently to test if it could provide a more accurate guide for the delivery of systemic therapies in BC, we investigated the clinico-pathological utility of SPAG5: gene copy number aberrations (CNAs); mRNA and protein expression, in over 10,000 BCs. Integrated analysis of SPAG5-gene CNAs, transcript and protein expression was conducted in the ND cohort (n=171) and validated in the METABRIC cohort (n=1980). In addition, the associations of SPAG5 CNAs, transcript and/or protein with BC specific survival (BCSS), disease free survival (DFS) and/or distant relapse free survival (DRFS) were analysed in multiple cohorts including Uppsala (n=249), METABRIC, three-untreated lymph node (LN) negative cohorts (n=684), a combined multicentre clinical data set (n=5439), Nottingham historical early-stage-primary BC (Nottingham-HES-BC; n=1650), Nottingham oestrogen receptor (ER) negative BC (n=697), Nottingham anthracycline-Neoadjuvant-chemotherapy (Nottingham-AC-Neo-ACT; n=200), and MD Anderson Cancer Centre Taxane/anthracycline (MDACC-T/AC-Neo-ACT; n=508) cohorts. The association of SPAG5 transcript and protein expression with pathological response rate (pCR) were also tested in [MDACC-T/AC-Neo-ACT (n=508) and the phase II trial NCT00455533; n=253)] and [Nottingham-AC-Neo-ACT (n=200)] cohorts; respectively. Findings: SPAG5 gene gain/amplification at the Ch17q11·2 locus was found in 10.4% of BC (206/1980 (; METABRIC) and was reported in 19·4% of PAM50-HER2 (46/237) and 17·8% of PAM50-LumB (87/488). SPAG5-CNA gain/amplification and high SPAG5-transcript and SPAG5-protein were associated with increased risk of death from BC [Uppsala; (HR (CI 95%): 1·50 (1·18-1·92); p=0·00010, METABRIC; (HR (CI 95%): 1·68 (1·40-2·01) p<0·0001), and Nottingham-HSE-BC; (HR (CI 95%): 1·68 (1·32-2·12), p<0·0001); respectively]. Multivariable Cox regression models, including other validated-prognostic factors, (Uppsala: age, size, LN-stage, genomic grade index (GGI), ER, TP53 mutation and MKi67; METABRIC: age, size, LN-stage, histologic-grade, ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), hormone-therapy, chemotherapy, interaction term of SPAG5 and both chemotherapyy and hormonotherapy; Desmedt-untreated LN- cohort: ER, Nottingham prognostic index (NPI), 76-gene prognostic signature (Veridex) and Adjuvant-Online (AOL); Nottingham-HES-BC: menopausal status, size, LN- stage, histologic-grade, ER, PR, HER2, ki67, hormone-therapy, chemotherapy, interaction term of SPAG5 and both chemotherapy[y and hormonotherapy), showed that high SPAG5-transcript and high SPAG5-protein were associated with shorter BCSS [Uppsala: (HR (CI 95%): 1·62 (1·03-2·53) p=0·036); METABRIC: (HR (CI 95%): 1·27 (1·02-1·58) p=0·034); Desmedt-untreated LN- cohort: (HR (CI 95%): 2·34 (1·24-4·42) p=0·0090), and Nottingham-HES-BC (HR (CI 95%): 1·73 (1·23-2·46) p=0·0020); respectively]. In ER-negative-BC with high SPAG5-protein, administration of anthracycline-adjuvant-chemotherapy had reduced the risk of death by 60% compared to chemotherapy-naive (HR (95% CI): 0·37 (0·20-0·60); p=0·0010). A multivariable Cox regression analysis, which included other validated prognostic factors for chemotherapy (e.g., menopausal status, size, lymph node stage, histologic grade, ER, PR, HER2, Bcl2, chemotherapy, interaction term of SPAG5 and both chemotherapy[y), revealed that SPAG5-transcript+ was independently associated with decreased risk of DRFS after receiving Taxane/anthracycline-Neo-ACT [MDACC-T/AC-Neo-ACT: (HR (CI 95%): 0·68 (0·48-0·97); p=0·0070)]. In multivariable logistic regression analysis, both SPAG5-transcript+ and SPAG5-protein+ and were independent predictors for higher pCR after combination-cytotoxic chemotherapy [MDACC-T/AC-Neo-ACT: (OR (95% CI) 1·71 (1·07-2·74); p=0·024), and Nottingham-AC-Neo-AC: (OR (95% CI): 8·75 (2·42-31); p=0·0010); respectively]. Interpretation: SPAG5 is a novel amplified gene on Ch17q11.2 in PAM50-LumB and PAM-HER2 BC, and its transcript and protein products are independent prognostic and predictive biomarkers, with potential clinical utility as a biomarker for combination cytotoxic chemotherapy sensitivity, especially in ER- BC

A Genotype-First Approach for the Molecular and Clinical Characterization of Uncommon De Novo Microdeletion of 20q13.33

Background: Subtelomeric deletions of the long arm of chromosome 20 are rare, with only 11 described in the literature. Clinical features of individuals with these microdeletions include severe limb malformations, skeletal abnormalities, growth retardation, developmental and speech delay, mental retardation, seizures and mild, non-specific dysmorphic features. Methodology/Principal Findings: We characterized microdeletions at 20q13.33 in six individuals referred for genetic evaluation of developmental delay, mental retardation, and/or congenital anomalies. A comparison to previously reported cases of 20q13.33 microdeletion shows phenotypic overlap, with clinical features that include mental retardation, developmental delay, speech and language deficits, seizures, and behavior problems such as autistic spectrum disorder. There does not appear to be a clinically recognizable constellation of dysmorphic features among individuals with subtelomeric 20q microdeletions. Conclusions/Significance: Based on genotype-phenotype correlation among individuals in this and previous studies, we discuss several possible candidate genes for specific clinical features, including ARFGAP1, CHRNA4 and KCNQ2 and neurodevelopmental deficits. Deletion of this region may play an important role in cognitive development

Urinary Exosomal microRNA-451-5p Is a Potential Early Biomarker of Diabetic Nephropathy in Rats

Non-invasive renal signatures can help in serial monitoring of diabetic patients. We tested whether urinary exosomal (UE) microRNA (miR) analysis could non-invasively predict renal pathology in diabetic rats during the course of diabetes. Diabetes mellitus (DM) was induced in male Wistar rats by a single intraperitoneal injection of streptozotocin (STZ, 50 mg/kg body weight). Non-diabetic control (CTRL) rats were injected with vehicle. Insulin (INS) treatment (5U/d, s.c.) was provided to 50% of the DM rats. Urine samples were collected at weeks 3, 6, and 9 following injections and UE prepared. An increase in miR-451-5p and miR-16, observed by pilot small RNA sequencing of UE RNA, was confirmed by quantitative real-time polymerase chain reaction (qPCR) and selected for further study. Subsets of rats were euthanized after 3, 6, and 9 weeks of diabetes for renal pathology analysis, including determination of the tubulointerstitial fibrotic index (TFI) and glomerulosclerotic index (GI) scores. qPCR showed a substantial rise in miR-451-5p in UE from DM rats during thecourse of diabetes, with a significant rise (median fold change >1000) between 3 and 6 weeks. Moreover, UE miR-451-5p at 6 weeks predicted urine albumin at 9 weeks (r = 0.76). A delayed but significant rise was also observed for miR-16. In contrast, mean urine albumin only increased 21% between 3 and 6 weeks (non-significant rise), and renal TFI and GI were unchanged till 9 weeks. Renal expression of miR-451-5p and miR-16 (at 10 weeks) did not correlate with urine levels, and moreover, was negatively associated with indices of renal pathology (r�-0.70, p = 0.005 for TFI and r�-0.6, p�0.02 for GI). Overall, a relative elevation in renal miR-451-5p and miR-16 in diabetes appeared protective against diabetes- induced kidney fibrosis; while UE miR-451-5p may hold prognostic value as an earlyand sensitive non-invasive indicator of renal diseas

CoNIC Challenge: Pushing the Frontiers of Nuclear Detection, Segmentation, Classification and Counting

Nuclear detection, segmentation and morphometric profiling are essential in helping us further understand the relationship between histology and patient outcome. To drive innovation in this area, we setup a community-wide challenge using the largest available dataset of its kind to assess nuclear segmentation and cellular composition. Our challenge, named CoNIC, stimulated the development of reproducible algorithms for cellular recognition with real-time result inspection on public leaderboards. We conducted an extensive post-challenge analysis based on the top-performing models using 1,658 whole-slide images of colon tissue. With around 700 million detected nuclei per model, associated features were used for dysplasia grading and survival analysis, where we demonstrated that the challenge's improvement over the previous state-of-the-art led to significant boosts in downstream performance. Our findings also suggest that eosinophils and neutrophils play an important role in the tumour microevironment. We release challenge models and WSI-level results to foster the development of further methods for biomarker discovery

PANC Study (Pancreatitis: A National Cohort Study): national cohort study examining the first 30 days from presentation of acute pancreatitis in the UK

Abstract Background Acute pancreatitis is a common, yet complex, emergency surgical presentation. Multiple guidelines exist and management can vary significantly. The aim of this first UK, multicentre, prospective cohort study was to assess the variation in management of acute pancreatitis to guide resource planning and optimize treatment. Methods All patients aged greater than or equal to 18 years presenting with acute pancreatitis, as per the Atlanta criteria, from March to April 2021 were eligible for inclusion and followed up for 30 days. Anonymized data were uploaded to a secure electronic database in line with local governance approvals. Results A total of 113 hospitals contributed data on 2580 patients, with an equal sex distribution and a mean age of 57 years. The aetiology was gallstones in 50.6 per cent, with idiopathic the next most common (22.4 per cent). In addition to the 7.6 per cent with a diagnosis of chronic pancreatitis, 20.1 per cent of patients had a previous episode of acute pancreatitis. One in 20 patients were classed as having severe pancreatitis, as per the Atlanta criteria. The overall mortality rate was 2.3 per cent at 30 days, but rose to one in three in the severe group. Predictors of death included male sex, increased age, and frailty; previous acute pancreatitis and gallstones as aetiologies were protective. Smoking status and body mass index did not affect death. Conclusion Most patients presenting with acute pancreatitis have a mild, self-limiting disease. Rates of patients with idiopathic pancreatitis are high. Recurrent attacks of pancreatitis are common, but are likely to have reduced risk of death on subsequent admissions. </jats:sec