Natural variants of human SARM1 cause both intrinsic and dominant loss-of-function influencing axon survival.

SARM1 is a central executioner of programmed axon death, and this role requires intrinsic NAD(P)ase or related enzyme activity. A complete absence of SARM1 robustly blocks axon degeneration in mice, but even a partial depletion confers meaningful protection. Since axon loss contributes substantially to the onset and progression of multiple neurodegenerative disorders, lower inherent SARM1 activity is expected to reduce disease susceptibility in some situations. We, therefore, investigated whether there are naturally occurring SARM1 alleles within the human population that encode SARM1 variants with loss-of-function. Out of the 18 natural SARM1 coding variants we selected as candidates, we found that 10 display loss-of-function in three complimentary assays: they fail to robustly deplete NAD in transfected HEK 293T cells; they lack constitutive and NMN-induced NADase activity; and they fail to promote axon degeneration in primary neuronal cultures. Two of these variants are also able to block axon degeneration in primary culture neurons in the presence of endogenous, wild-type SARM1, indicative of dominant loss-of-function. These results demonstrate that SARM1 loss-of-function variants occur naturally in the human population, and we propose that carriers of these alleles will have different degrees of reduced susceptibility to various neurological conditions.

Case-based learning and multiple choice questioning methods favored by students.

BACKGROUND: Investigating and understanding how students learn on their own is essential to effective teaching, but studies are rarely conducted in this context. A major aim within medical education is to foster procedural knowledge. It is known that case-based questioning exercises drive the learning process, but the way students deal with these exercises is explored little. METHODS: This study examined how medical students deal with case-based questioning by evaluating 426 case-related questions created by 79 fourth-year medical students. The subjects covered by the questions, the level of the questions (equivalent to United States Medical Licensing Examination Steps 1 and 2), and the proportion of positively and negatively formulated questions were examined, as well as the number of right and wrong answer choices, in correlation to the formulation of the question. RESULTS: The evaluated case-based questions' level matched the United States Medical Licensing Examination Step 1 level. The students were more confident with items aiming on diagnosis, did not reject negatively formulated questions and tended to prefer handling with right content, while keeping wrong content to a minimum. CONCLUSION: These results should be taken into consideration for the formulation of case-based questioning exercises in the future and encourage the development of bedside teaching in order to foster the acquisition of associative and procedural knowledge, especially clinical reasoning and therapy-oriented thinking.