MRI Is a DNA Damage Response Adaptor during Classical Non-homologous End Joining.

The modulator of retrovirus infection (MRI or CYREN) is a 30-kDa protein with a conserved N-terminal Ku-binding motif (KBM) and a C-terminal XLF-like motif (XLM). We show that MRI is intrinsically disordered and interacts with many DNA damage response (DDR) proteins, including the kinases ataxia telangiectasia mutated (ATM) and DNA-PKcs and the classical non-homologous end joining (cNHEJ) factors Ku70, Ku80, XRCC4, XLF, PAXX, and XRCC4. MRI forms large multimeric complexes that depend on its N and C termini and localizes to DNA double-strand breaks (DSBs), where it promotes the retention of DDR factors. Mice deficient in MRI and XLF exhibit embryonic lethality at a stage similar to those deficient in the core cNHEJ factors XRCC4 or DNA ligase IV. Moreover, MRI is required for cNHEJ-mediated DSB repair in XLF-deficient lymphocytes. We propose that MRI is an adaptor that, through multivalent interactions, increases the avidity of DDR factors to DSB-associated chromatin to promote cNHEJ.

Implementation of a Structured Surgery Mentorship Program and Success in the Surgical Residency Match.

INTRODUCTION: General Surgery residency programs remain competitive, with over a quarter of US MD seniors failing to match into a categorical program each year. While previous literature has shown the role of mentorship in attracting medical students to surgery, there is a dearth of information demonstrating the role of mentorship in successfully matching those students to surgery programs. METHODS: We implemented a structured mentorship program for medical students interested in applying to general surgery or integrated plastics, vascular, or cardiothoracic residencies over the course of one year, consisting of seven standardized meetings and events spanning the students' MS3 and MS4 years. Following Match Day, we sent students a five-point Likert scale survey to assess the perceived utility of each event and solicited self-reported application information. RESULTS: Of the 22 students at a single institution who attended the structured mentorship program and applied to general surgery residency, 100% matched into a categorical program, significantly higher than the 73% national match rate of US MD seniors into general surgery (P < 0.01). There were no significant differences between the two cohorts in terms of United States Medical Licensing Examination board scores, Alpha Omega Alpha Honor Society status, or median number of publications, research experiences, work experiences, or volunteer experiences. Nineteen of the 22 students responded to the survey, yielding an 86% response rate. Ninety percent of the students attended at least six out of the seven events. Six out of the seven events had median helpfulness scores (out of five) that were significantly higher than a "neutral" baseline (P < 0.05). CONCLUSIONS: A structured mentorship program may play a useful role in successfully matching general surgery applicants to residencies and would be a simple and low-cost program to implement at other medical schools.

The Variable Insertional Anatomy of the Abductor Pollicis Longus: Functional Relevance and Relationship to Adjacent Thumb Extensors.

BACKGROUND: The abductor pollicis longus (APL) is classically described as inserting on the base of the first metacarpal. This study analyzed APL insertional anatomy and quantified the size of various elements of the extensor side of the thumb to determine associations with size and function. METHODS: Twenty-four formalin-preserved upper limbs were dissected. The insertional anatomy of the APL, extensor pollicis brevis, and extensor pollicis longus were characterized, and the capacity of APL tendon slips to perform palmar abduction of the first digit was quantified based on slip size and insertion. RESULTS: The mean number of APL tendon slips observed was 2.3. Abductor pollicis longus insertion sites included the base of the first metacarpal, trapezium, abductor pollicis brevis, and opponens pollicis. Only 4 specimens had a solitary metacarpal slip, while 83% of specimens had insertions onto at least 1 thenar muscle. A total of 62.5% of APL tendons exhibited some form of branching that we categorized into "Y" and "Z" patterns. In assessing palmar abduction capacity, we found that APL tendon slips inserting into the base of the first metacarpal were larger in cross-sectional area than nonmetacarpal slips and reproduced complete palmar abduction of the digit in the absence of nonmetacarpal slips. The abduction capacity of APL tendon slips was not correlated to the cross-sectional area. CONCLUSIONS: There is significant variability in APL tendon slips, branching patterns, and insertional anatomy. These findings provide further understanding of the function of the APL and its surgical implications.

Joseph Murray: Pioneering Plastic Surgeon and Father of the First Organ Transplant.

Dr. Joseph Murray was a plastic surgeon who is best known for performing the first successful human organ transplant. After graduating from Harvard Medical School and completing a surgical internship at Peter Bent Brigham Hospital, Murray enlisted in the US Army Medical Corp and spent 5 years at Valley Forge General Hospital treating World War II soldiers injured in combat. He treated hundreds of burn victims with skin grafts and took an interest in the variable process of graft rejection based on both the patient's relation to the graft donor and the patient's level of immunocompetency. His work at Valley Forge set the stage for his research investigating the feasibility of kidney transplantation and immunosuppression. He went on to perform the first successful kidney transplant between identical twins in 1954, between fraternal twins in 1959, and between an unrelated donor and recipient in 1962. For his efforts, he was awarded the 1990 Nobel Prize in Medicine.

Rab46 integrates Ca2+ and histamine signaling to regulate selective cargo release from Weibel-Palade bodies.

Endothelial cells selectively release cargo stored in Weibel-Palade bodies (WPBs) to regulate vascular function, but the underlying mechanisms are poorly understood. Here we show that histamine evokes the release of the proinflammatory ligand, P-selectin, while diverting WPBs carrying non-inflammatory cargo away from the plasma membrane to the microtubule organizing center. This differential trafficking is dependent on Rab46 (CRACR2A), a newly identified Ca2+-sensing GTPase, which localizes to a subset of P-selectin-negative WPBs. After acute stimulation of the H1 receptor, GTP-bound Rab46 evokes dynein-dependent retrograde transport of a subset of WPBs along microtubules. Upon continued histamine stimulation, Rab46 senses localized elevations of intracellular calcium and evokes dispersal of microtubule organizing center-clustered WPBs. These data demonstrate for the first time that a Rab GTPase, Rab46, integrates G protein and Ca2+ signals to couple on-demand histamine signals to selective WPB trafficking.