An oligotrophic deep-subsurface community dependent on syntrophy is dominated by sulfur-driven autotrophic denitrifiers

Subsurface lithoautotrophic microbial ecosystems (SLiMEs) under oligotrophic conditions are typically supported by H₂. Methanogens and sulfate reducers, and the respective energy processes, are thought to be the dominant players and have been the research foci. Recent investigations showed that, in some deep, fluid-filled fractures in the Witwatersrand Basin, South Africa, methanogens contribute <5% of the total DNA and appear to produce sufficient CH₄ to support the rest of the diverse community. This paradoxical situation reflects our lack of knowledge about the in situ metabolic diversity and the overall ecological trophic structure of SLiMEs. Here, we show the active metabolic processes and interactions in one of these communities by combining metatranscriptomic assemblies, metaproteomic and stable isotopic data, and thermodynamic modeling. Dominating the active community are four autotrophic β-proteobacterial genera that are capable of oxidizing sulfur by denitrification, a process that was previously unnoticed in the deep subsurface. They co-occur with sulfate reducers, anaerobic methane oxidizers, and methanogens, which each comprise <5% of the total community. Syntrophic interactions between these microbial groups remove thermodynamic bottlenecks and enable diverse metabolic reactions to occur under the oligotrophic conditions that dominate in the subsurface. The dominance of sulfur oxidizers is explained by the availability of electron donors and acceptors to these microorganisms and the ability of sulfur-oxidizing denitrifiers to gain energy through concomitant S and H₂ oxidation. We demonstrate that SLiMEs support taxonomically and metabolically diverse microorganisms, which, through developing syntrophic partnerships, overcome thermodynamic barriers imposed by the environmental conditions in the deep subsurface

Gemini Imaging of Mid-IR Emission from the Nuclear Region of Centaurus A

We present high spatial resolution mid-IR images of the nuclear region of NGC 5128 (Centaurus A). Images were obtained at 8.8 micron, N-band (10.4 micron), and 18.3 micron using the mid-IR imager/spectrometer T-ReCS on Gemini South. These images show a bright unresolved core surrounded by low-level extended emission. We place an upper limit to the size of the unresolved nucleus of 3.2 pc (0.19") at 8.8 micron and 3.5 pc (0.21") at 18.3 micron at the level of the FWHM. The most likely source of nuclear mid-IR emission is from a dusty torus and possibly dusty narrow line region with some contribution from synchrotron emission associated with the jet as well as relatively minor starburst activity. Clumpy tori models are presented which predict the mid-IR size of this torus to be no larger than 0.05" (0.85pc). Surrounding the nucleus is extensive low-level mid-IR emission. Previously observed by ISO and Spitzer, this paper presents to date the highest spatial resolution mid-IR images of this extended near nuclear structure. Much of the emission is coincident with Pa-alpha sources seen by HST implying emission from star forming areas, however evidence for jet induced star formation, synchrotron emission from the jet, a nuclear bar/ring, and an extended dusty narrow emission line region is also discussed.Comment: 22 pages, 6 figures, accepted by Ap

Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.Objective: To identify the genetic variants associated with juvenile ALS.Design, Setting, and Participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism.Main Outcomes and Measures: De novo variants present only in the index case and not in unaffected family members.Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway.Conclusions and Relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.</p

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to &lt;90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], &gt;300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of &lt;15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P&lt;0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P&lt;0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Understanding the medical marriage: Physicians and their partners share strategies for success

Physicians and their spouses experience challenges to their relationships, some of which are shared with the general population and others of which are unique to the field of medicine. Trainees and junior faculty members remain curious about how they will balance their careers alongside marriage and family obligations. This study explores the challenges and strengths of dual- and single-physician relationships. METHOD: In 2009, using appreciative inquiry as a theoretical framework, the authors conducted in-depth qualitative interviews with 25 individuals: 12 women and 13 men; 10 from dual-physician and 15 from single-physician relationships. A phenomenological analytic approach was used to arrive at the final themes. RESULTS: Four themes emerged during the interviews: We rely on mutual support in our relationships, We recognize the important roles of each family member, We have shared values, and We acknowledge the benefit of being a physician to our relationships. CONCLUSIONS: These findings illustrate that physicians identify strategies to navigate the difficult aspects of their lives. Learn ing from others\u27 best practices can assist in managing personal relationships and work-life balance. These data can also be useful when counseling physicians on successful relationship strategies. As systems are developed that improve wellness and focus on role models for work-life balance, it will be important for this topic to be integrated into formal curricula across the continuum of medical education

Faculty reflections on the implementation of socio-cultural eportfolio assessment tool

Electronic portfolios (eportfolios) are increasingly used to assess student development. The degree to which faculty in North American medical schools are confident in their ability to evaluate such materials and their perceptions of the utility of eportfolios are unclear. Thirteen medical educators developed skills necessary to critically assess students\u27 reflective essays. Qualitative methods were used to explore faculty experiences with a socio-cultural eportfolio. Despite selfperceptions of being novice users, faculty were willing to engage with the eportfolio and assume an unfamiliar role in guiding medical students\u27 personal reflections. Additionally, we uncovered unique faculty expectations regarding the quality of students\u27 essays and their thoughts about the utility of an eportfolio as an assessment tool. Our findings indicate that given adequate time and training, faculty will use an eportfolio. They believe it is an effective method for both longitudinal assessment of student learning and achieving curricular objectives. Our findings also illustrate the numerous unintended ethical challenges faculty encounter as they engage in student assessment. © 2011 Taylor & Francis

A successful faculty development program for implementing a sociocultural eportfolio assessment tool

Portfolios are emerging as a tool for documenting learning progression and assessing competency. ePortfolios are appealing as a portable and fluid means of documenting both learning and relevant experiences in a large number of students. Competence and learning can be especially difficult to document in important aspects of education and training, such as patient-centeredness, the cultural context of disease, and social determinants of health that do not lend themselves to fact-based assessment methods. Successful implementation of a method such as an ePortfolio requires explicit faculty development, as many faculty members have limited expertise with modern educational assessment technology. As part of the authors\u27 introduction of a Sociocultural ePortfolio Assessment Tool in the undergraduate medical curriculum, three faculty development workshops were held to expand faculty skills in using this technology. In addition to gaining comfort using a new Web-based technology, faculty members also needed to develop skills with providing mentored feedback and stimulating student reflection. Workshops were modeled after other successful programs reported in the literature and allowed faculty to develop a structured format for evaluating student content. Faculty members were given multiple opportunities to practice their newly developed skills providing mentored reflections using an ePortfolio. The workshop evaluations were positive, suggesting that faculty participation in the workshops were a necessary component for them to develop sufficient assessment skills for providing mentored reflection. Faculty members who participated in this program - whether or not they had content expertise in sociocultural medicine - valued the hands-on faculty development program