The Crystal Structure of the Extracellular 11-heme Cytochrome UndA Reveals a Conserved 10-heme Motif and Defined Binding Site for Soluble Iron Chelates

Members of the genus Shewanella translocate deca- or undeca-heme cytochromes to the external cell surface thus enabling respiration using extracellular minerals and polynuclear Fe(III) chelates. The high resolution structure of the first undeca-heme outer membrane cytochrome, UndA, reveals a crossed heme chain with four potential electron ingress/egress sites arranged within four domains. Sequence and structural alignment of UndA and the deca-heme MtrF reveals the extra heme of UndA is inserted between MtrF hemes 6 and 7. The remaining UndA hemes can be superposed over the heme chain of the decaheme MtrF, suggesting that a ten heme core is conserved between outer membrane cytochromes. The UndA structure has also been crystallographically resolved in complex with substrates, an Fe(III)-nitrilotriacetate dimer or an Fe(III)-citrate trimer. The structural resolution of these UndA-Fe(III)-chelate complexes provides a rationale for previous kinetic measurements on UndA and other outer membrane cytochromes

Comprehensive Analysis of Copy Number Variation of Genes at Chromosome 1 and 10 Loci Associated with Late Age Related Macular Degeneration

Copy Number Variants (CNVs) are now recognized as playing a significant role in complex disease etiology. Age-related macular degeneration (AMD) is the most common cause of irreversible vision loss in the western world. While a number of genes and environmental factors have been associated with both risk and protection in AMD, the role of CNVs has remained largely unexplored. We analyzed the two major AMD risk-associated regions on chromosome 1q32 and 10q26 for CNVs using Multiplex Ligation-dependant Probe Amplification. The analysis targeted nine genes in these two key regions, including the Complement Factor H (CFH) gene, the 5 CFH-related (CFHR) genes representing a known copy number “hotspot”, the F13B gene as well as the ARMS2 and HTRA1 genes in 387 cases of late AMD and 327 controls. No copy number variation was detected at the ARMS2 and HTRA1 genes in the chromosome 10 region, nor for the CFH and F13B genes at the chromosome 1 region. However, significant association was identified for the CFHR3-1 deletion in AMD cases (p = 2.38×10−12) OR = 0.31, CI-0.95 (0.23–0.44), for both neovascular disease (nAMD) (p = 8.3×10−9) OR = 0.36 CI-0.95 (0.25–0.52) and geographic atrophy (GA) (p = 1.5×10−6) OR = 0.36 CI-0.95 (0.25–0.52) compared to controls. In addition, a significant association with deletion of CFHR1-4 was identified only in patients who presented with bilateral GA (p = 0.02) (OR = 7.6 CI-0.95 1.38–41.8). This is the first report of a phenotype specific association of a CNV for a major subtype of AMD and potentially allows for pre-diagnostic identification of individuals most likely to proceed to this end stage of disease

Faculty-Wide Peer-Support Program During the COVID-19 Pandemic: Design and Preliminary Results

Background: Physicians experience higher rates of burnout relative to the general population. Concerns of confidentiality, stigma, and professional identities as health care providers act as barriers to seeking and receiving appropriate support. In the context of the COVID-19 pandemic, factors that contribute to burnout and barriers to seeking support have been amplified, elevating the overall risks of mental distress and burnout for physicians. Objective: This paper aimed to describe the rapid development and implementation of a peer support program within a health care organization located in London, Ontario, Canada. Methods: A peer support program leveraging existing infrastructures within the health care organization was developed and launched in April 2020. The “Peers for Peers” program drew from the work of Shapiro and Galowitz in identifying key components within hospital settings that contributed to burnout. The program design was derived from a combination of the peer support frameworks from the Airline Pilot Assistance Program and the Canadian Patient Safety Institute. Results: Data gathered over 2 waves of peer leadership training and program evaluations highlighted a diversity of topics covered through the peer support program. Further, enrollment continued to increase in size and scope over the 2 waves of program deployments into 2023. Conclusions: Findings suggest that the peer support program is acceptable to physicians and can be easily and feasibly implemented within a health care organization. The structured program development and implementation can be adopted by other organizations in support of emerging needs and challenge

Potent and Broad Inhibition of HIV-1 by a Peptide from the gp41 Heptad Repeat-2 Domain Conjugated to the CXCR4 Amino Terminus.

HIV-1 entry can be inhibited by soluble peptides from the gp41 heptad repeat-2 (HR2) domain that interfere with formation of the 6-helix bundle during fusion. Inhibition has also been seen when these peptides are conjugated to anchoring molecules and over-expressed on the cell surface. We hypothesized that potent anti-HIV activity could be achieved if a 34 amino acid peptide from HR2 (C34) were brought to the site of virus-cell interactions by conjugation to the amino termini of HIV-1 coreceptors CCR5 or CXCR4. C34-conjugated coreceptors were expressed on the surface of T cell lines and primary CD4 T cells, retained the ability to mediate chemotaxis in response to cognate chemokines, and were highly resistant to HIV-1 utilization for entry. Notably, C34-conjugated CCR5 and CXCR4 each exhibited potent and broad inhibition of HIV-1 isolates from diverse clades irrespective of tropism (i.e., each could inhibit R5, X4 and dual-tropic isolates). This inhibition was highly specific and dependent on positioning of the peptide, as HIV-1 infection was poorly inhibited when C34 was conjugated to the amino terminus of CD4. C34-conjugated coreceptors could also inhibit HIV-1 isolates that were resistant to the soluble HR2 peptide inhibitor, enfuvirtide. When introduced into primary cells, CD4 T cells expressing C34-conjugated coreceptors exhibited physiologic responses to T cell activation while inhibiting diverse HIV-1 isolates, and cells containing C34-conjugated CXCR4 expanded during HIV-1 infection in vitro and in a humanized mouse model. Notably, the C34-conjugated peptide exerted greater HIV-1 inhibition when conjugated to CXCR4 than to CCR5. Thus, antiviral effects of HR2 peptides can be specifically directed to the site of viral entry where they provide potent and broad inhibition of HIV-1. This approach to engineer HIV-1 resistance in functional CD4 T cells may provide a novel cell-based therapeutic for controlling HIV infection in humans

Should a Sentinel Node Biopsy Be Performed in Patients with High-Risk Breast Cancer?

A negative sentinel lymph node (SLN) biopsy spares many breast cancer patients the complications associated with lymph node irradiation or additional surgery. However, patients at high risk for nodal involvement based on clinical characteristics may remain at unacceptably high risk of axillary disease even after a negative SLN biopsy result. A Bayesian nomogram was designed to combine the probability of axillary disease prior to nodal biopsy with customized test characteristics for an SLN biopsy and provides the probability of axillary disease despite a negative SLN biopsy. Users may individualize the sensitivity of an SLN biopsy based on factors known to modify the sensitivity of the procedure. This tool may be useful in identifying patients who should have expanded upfront exploration of the axilla or comprehensive axillary irradiation

Bariatric Endocrinology: Principles of Medical Practice

Obesity, is a chronic, biological, preventable, and treatable disease. The accumulation of fat mass causes physical changes (adiposity), metabolic and hormonal changes due to adipose tissue dysfunction (adiposopathy), and psychological changes. Bariatric endocrinology was conceived from the need to address the neuro-endocrinological derangements that are associated with adiposopathy, and from the need to broaden the scope of the management of its complications. In addition to the well-established metabolic complications of overweight and obesity, adiposopathy leads to hyperinsulinemia, hyperleptinemia, hypoadiponectinemia, dysregulation of gut peptides including GLP-1 and ghrelin, the development of an inflammatory milieu, and the strong risk of vascular disease. Therapy for adiposopathy hinges on effectively lowering the ratio of orexigenic to anorexigenic signals reaching the the hypothalamus and other relevant brain regions, favoring a lower caloric intake. Adiposopathy, overweight and obesity should be treated indefinitely with the specific aims to reduce fat mass for the adiposity complications, and to normalize adipose tissue function for the adiposopathic complications. This paper defines the principles of medical practice in bariatric endocrinology—the treatment of overweight and obesity as means to treat adiposopathy and its accompanying metabolic and hormonal derangements

Objectively measured physical activity of USA adults by sex, age, and racial/ethnic groups: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>Accelerometers were incorporated in the 2003–2004 National Health and Nutritional Examination Survey (NHANES) study cycle for objective assessment of physical activity. This is the first time that objective physical activity data are available on a nationally representative sample of U.S. residents. The use of accelerometers allows researchers to measure total physical activity, including light intensity and unstructured activities, which may be a better predictor of health outcomes than structured activity alone. The aim of this study was to examine objectively determined physical activity levels by sex, age and racial/ethnic groups in a national sample of U.S. adults.</p> <p>Methods</p> <p>Data were obtained from the 2003–2004 NHANES, a cross-sectional study of a complex, multistage probability sample of the U.S. population. Physical activity was assessed with the Actigraph AM-7164 accelerometer for seven days following an examination. 2,688 U.S. adults with valid accelerometer data (i.e. at least four days with at least 10 hours of wear-time) were included in the analysis. Mean daily total physical activity counts, as well as counts accumulated in minutes of light, and moderate-vigorous intensity physical activity are presented by sex across age and racial/ethnic groups. Generalized linear modeling using the log link function was performed to compare physical activity in sex and racial/ethnic groups adjusting for age.</p> <p>Results</p> <p>Physical activity decreases with age for both men and women across all racial/ethnic groups with men being more active than women, with the exception of Hispanic women. Hispanic women are more active at middle age (40–59 years) compared to younger or older age and not significantly less active than men in middle or older age groups (i.e. age 40–59 or age 60 and older). Hispanic men accumulate more total and light intensity physical activity counts than their white and black counterparts for all age groups.</p> <p>Conclusion</p> <p>Physical activity levels measured objectively by accelerometer demonstrated that Hispanic men are, in general, more active than their white and black counterparts. This appears to be in contrast to self-reported physical activity previously reported in the literature and identifies the need to use objective measures in situations where the contribution of light intensity and/or unstructured physical activity cannot be assumed homogenous across the populations of interest.</p

Multiallelic copy number variation in the complement component 4A (C4A) gene is associated with late-stage age-related macular degeneration (AMD)

Peer reviewedPublisher PD

X chromosomal abnormalities in basal-like human breast cancer

SummarySporadic basal-like cancers (BLC) are a distinct class of human breast cancers that are phenotypically similar to BRCA1-associated cancers. Like BRCA1-deficient tumors, most BLC lack markers of a normal inactive X chromosome (Xi). Duplication of the active X chromosome and loss of Xi characterized almost half of BLC cases tested. Others contained biparental but nonheterochromatinized X chromosomes or gains of X chromosomal DNA. These abnormalities did not lead to a global increase in X chromosome transcription but were associated with overexpression of a small subset of X chromosomal genes. Other, equally aneuploid, but non-BLC rarely displayed these X chromosome abnormalities. These results suggest that X chromosome abnormalities contribute to the pathogenesis of BLC, both inherited and sporadic

Risk factors in adolescent suicides

Samoubojstvo je treći vodeći uzrok smrti među adolescentima. Brojni su uzroci koji dovode do povećanja suicidalnog rizika. Dominiraju mentalne bolesti jer je 90 % onih koji su počinili samoubojstvo imalo psihijatrijsku dijagnozu. Odnosi unutar obitelji te odnosi s okolinom također imaju važnu ulogu. Nepripadanje dominantnoj kulturi može povećati suicidalni rizik, pogotovo u onim sredinama koje su zatvorene i netolerantne. Kao najčešći motivi za samoubojstvo mladih spominju se: školski neuspjeh, pad razreda, isključenje iz škole, socijalna nestabilnost, nesigurnost, patološka ljubomora, konflikti s roditeljima i profesorima. Upravo razumijevanje rizičnih čimbenika koji mogu dovesti do samoubojstva ključno je u prevenciji ovakvog ponašanja.Suicide is the third leading cause of death among adolescents. Many causes canincrease suicidal risk. 90 % of those who committed suicide had psychiatric diagnosis. Relationships within the family and with the social surroundings also play an important role. Not being a part of the dominant culture may increase suicidal risk, especially in those societies which are closed and intolerant. The most common motives for youth suicide are school failure, drop in grades, expulsion from school, social instability, insecurity, pathological jealousy, conflict with parents and teachers. Understanding risk factors which can lead to suicide is crucial in preventing this behavior