A switch element in the autophagy E2 Atg3 mediates allosteric regulation across the lipidation cascade

Autophagy depends on the E2 enzyme, Atg3, functioning in a conserved E1-E2-E3 trienzyme cascade that catalyzes lipidation of Atg8-family ubiquitin-like proteins (UBLs). Molecular mechanisms underlying Atg8 lipidation remain poorly understood despite association of Atg3, the E1 Atg7, and the composite E3 Atg12-Atg5-Atg16 with pathologies including cancers, infections and neurodegeneration. Here, studying yeast enzymes, we report that an Atg3 element we term E123IR (E1, E2, and E3-interacting region) is an allosteric switch. NMR, biochemical, crystallographic and genetic data collectively indicate that in the absence of the enzymatic cascade, the Atg3(E123IR) makes intramolecular interactions restraining Atg3's catalytic loop, while E1 and E3 enzymes directly remove this brace to conformationally activate Atg3 and elicit Atg8 lipidation in vitro and in vivo. We propose that Atg3's E123IR protects the E2 similar to UBL thioester bond from wayward reactivity toward errant nucleophiles, while Atg8 lipidation cascade enzymes induce E2 active site remodeling through an unprecedented mechanism to drive autophagy

Vulnerability and Post-Stroke Experiences of Working-Age Survivors During Recovery

Survivors who experience stroke of mild to moderate severity are typically discharged home quickly, with only minimal referral for rehabilitation follow-up or support to meet specific needs in recovery. Particular vulnerabilities of younger, higher functioning stroke survivors have received some recognition in international literature in recent years. This article reports on findings of a small Australian qualitative study focusing on recovery and return to work experiences of young higher functioning female stroke survivors, in particular exploring experiences of post-stroke vulnerability from participants’ own perspectives. Our research adds depth and nuance to this developing area of interest and research. Our findings include survivors’ reflections on the consequences of delayed diagnosis, the impacts of empowering and disempowering interactions with health care professionals, a general lack of access to psychosocial rehabilitation, and frustrations of financial hardship. Implications for health professionals, service systems, and income support provision are discussed, along with directions for future research

The Mismatch Between Life Insurance Holdings and Financial Vulnerabilities: Evidence from the Survey of Consumer Finances

Using the 1995 Survey of Consumer Finances and an elaborate life-cycle model, we quantify the potential financial impact of each individual's death on his or her survivors, and we measure the degree to which life insurance moderates these consequences. Life insurance is essentially uncorrelated with financial vulnerability at every stage of the life cycle. As a result, the impact of insurance among at-risk households is modest, and substantial uninsured vulnerabilities are widespread, particularly among younger couples. Roughly two-thirds of poverty among surviving women and more than one-third of poverty among surviving men results from a failure to insure survivors against an undiminished living standard. We also identify a systematic gender bias: for any given level of financial vulnerability, couples provide significantly more protection for wives than for husbands.

Explaining Political Violence Against Civilians in Northern Ireland: A Contention-Oriented Approach

In contrast to prevalent theories of terrorism, this study develops a contention-oriented approach where levels and forms of political violence against civilians depend upon: (1) the strategies of combatants; (2) the means of contention; (3) the locations of allies and opponents; (4) the collective identities of combatants; and (5) the dynamics of contention, including whether or not representatives of paramilitary organizations are included in formal peace processes. Quantitative analyses of a multi-source database of civilian deaths taking place in Northern Ireland between 1966 and 2006 offer preliminary support for this approach. The study underscores the insights provided by theories and methods used in the fields of social movements research and peace and conflict studies

New resource for the Indian beche-de-mer industry and its management

Although sea cucumber processing was introduced to India more than one thousand years back, the processing was restricted only to a few species. Hornell (1917) in his classic paper on the Indian Beche-de-mer industry, its history and recent revival mentioned only Holothuria scabra, H. spinijera and Bohadschia mQrmorata as important species for processing_ These three species alone were processed till 1989 in the Gulf of Mannar and Palk Bay

Controlled release nanoparticulate matter delivery system

A controlled release nanoparticulate matter delivery system includes a plurality of thermoresponsive modules containing a respective nanoparticulate matter. Each thermoresponsive module is selectively operable in at least one of a heating mode that releases the nanoparticulate matter and a cooling mode that inhibits release of the nanoparticulate matter. A control module is in electrical communication with the plurality of thermoresponsive modules. The control module is configured to determine a temperature of each thermoresponsive module and to select the at least one heating mode and cooling mode based on the temperature. The heating and cooling mode may be selected in response to a desired dosing profile and/or a biometric condition.Board of Regents, University of Texas Syste

Clinical impact of splicing in neurodevelopmental disorders.

Clinical exome sequencing is frequently used to identify gene-disrupting variants in individuals with neurodevelopmental disorders. While splice-disrupting variants are known to contribute to these disorders, clinical interpretation of cryptic splice variants outside of the canonical splice site has been challenging. Here, we discuss papers that improve such detection

Geographic and Age-Based Variations in Medicare Reimbursement Among ASSH Members.

Background: The purpose of this study was to investigate how American Society for Surgery of the Hand (ASSH) members\u27 Medicare reimbursement depends on their geographical location and number of years in practice. Methods: Demographic data for surgeons who were active members of the ASSH in 2012 were obtained using information publicly available through the US Centers for Medicare and Medicaid Services (CMS). Hand-surgeons-per-capita and average reimbursement per surgeon were calculated for each state. Regression analysis was performed to determine a relationship between (1) each state\u27s average reimbursement versus the number of ASSH members in that state, (2) average reimbursement versus number of hand surgeons per capita, and (3) total reimbursement from Medicare versus number of years in practice. Analysis of variance (ANOVA) was used to detect a difference in reimbursement based on categorical range of years as an ASSH member. Results: A total of 1667 ASSH members satisfied inclusion in this study. Although there was significant variation among states\u27 average reimbursement, reimbursement was not significantly correlated with the state\u27s hand surgeons per capita or total number of hand surgeons in that given state. Correlation between years as an ASSH member and average reimbursement was significant but non-linear; the highest reimbursements were seen in surgeons who had been ASSH members from 8 to 20 years. Conclusions: Peak reimbursement from Medicare for ASSH members appears to be related to the time of surgeons\u27 peak operative volume, rather than any age-based bias for or against treating Medicare beneficiaries. In addition, though geographic variation in reimbursement does exist, this does not appear to correlate with density or availability of hand surgeons