The Daily Fact Pile: Exploring Mutual Microlearning in Neurology Resident Education.

Problem: A significant proportion of learning during residency takes place through informal channels. Spontaneous collaboration among medical learners significantly contributes to this informal learning and is increasingly recognized as a component of the hidden curriculum in medical education. Yet historically, a disproportionate emphasis in medical education has been placed on didactic, structured, and faculty-initiated methods, leaving an important force in medical education understudied and underutilized. We hypothesize that there is significant educational potential in studying and deploying targeted tools to facilitate collaboration among medical learners. Intervention: At our institution, neurology residents implemented the "Daily Fact Pile" (DFP), a resident-led, email-based collaboration that served as a platform to share clinical pearls in an informal, digital way. Participation was voluntary and participants were encouraged to share facts that were new to them and thought to be clinically relevant. Motivated by the positive collective experience, we conducted a retrospective examination of this phenomenon. In this context, we developed the concept of "mutual microlearning" to characterize this efficient, multidirectional exchange of information. Context: Thirty-six residents in a single neurology residency program utilized the DFP at a large university hospital in the USA between 2018 and 2019. After 21 months of spontaneous and voluntary participation, we assessed the feasibility of the DFP, its impact on the education and morale of neurology residents, and compared its mutual microlearning approach to traditional lectures. This was done through a survey of the DFP participants with a response rate of 80.7%, and analysis of the statistics of participation and interaction with the DFP. Impact: Most participants felt that the DFP was beneficial to their education and thought they often or always learned something new from reading the DFP. The impact of the DFP extended beyond education by improving interest in neurology, morale, and sense of teamwork. The DFP was feasible during neurology residency and participation was high, though participants were more likely to read facts than share them. Lessons learned: Mutual microlearning represents an opportunity to augment residents' education, and well-designed mutual microlearning tools hold promise for complementing traditional teaching methods. We learned that efficiency, ease of use, and a supportive, non-judgmental environment are all essential to the success of such tools. Future research should delve deeper into the underlying mechanisms of mutual microlearning to establish its position within the theoretical frameworks of medical education.

Lin28a maintains a subset of adult muscle stem cells in an embryonic-like state.

During homeostasis and after injury, adult muscle stem cells (MuSCs) activate to mediate muscle regeneration. However, much remains unclear regarding the heterogeneous capacity of MuSCs for self-renewal and regeneration. Here, we show that Lin28a is expressed in embryonic limb bud muscle progenitors, and that a rare reserve subset of Lin28a+Pax7- skeletal MuSCs can respond to injury at adult stage by replenishing the Pax7+ MuSC pool to drive muscle regeneration. Compared with adult Pax7+ MuSCs, Lin28a+ MuSCs displayed enhanced myogenic potency in vitro and in vivo upon transplantation. The epigenome of adult Lin28a+ MuSCs showed resemblance to embryonic muscle progenitors. In addition, RNA-sequencing revealed that Lin28a+ MuSCs co-expressed higher levels of certain embryonic limb bud transcription factors, telomerase components and the p53 inhibitor Mdm4, and lower levels of myogenic differentiation markers compared to adult Pax7+ MuSCs, resulting in enhanced self-renewal and stress-response signatures. Functionally, conditional ablation and induction of Lin28a+ MuSCs in adult mice revealed that these cells are necessary and sufficient for efficient muscle regeneration. Together, our findings connect the embryonic factor Lin28a to adult stem cell self-renewal and juvenile regeneration.

Muscle Injuries Induce a Prostacyclin-PPARγ/PGC1a-FAO Spike That Boosts Regeneration.

It is well-known that muscle regeneration declines with aging, and aged muscles undergo degenerative atrophy or sarcopenia. While exercise and acute injury are both known to induce muscle regeneration, the molecular signals that help trigger muscle regeneration have remained unclear. Here, mass spectrometry imaging (MSI) is used to show that injured muscles induce a specific subset of prostanoids during regeneration, including PGG1, PGD2, and the prostacyclin PGI2. The spike in prostacyclin promotes skeletal muscle regeneration via myoblasts, and declines with aging. Mechanistically, the prostacyclin spike promotes a spike in PPARγ/PGC1a signaling, which induces a spike in fatty acid oxidation (FAO) to control myogenesis. LC-MS/MS and MSI further confirm that an early FAO spike is associated with normal regeneration, but muscle FAO became dysregulated during aging. Functional experiments demonstrate that the prostacyclin-PPARγ/PGC1a-FAO spike is necessary and sufficient to promote both young and aged muscle regeneration, and that prostacyclin can synergize with PPARγ/PGC1a-FAO signaling to restore aged muscles' regeneration and physical function. Given that the post-injury prostacyclin-PPARγ-FAO spike can be modulated pharmacologically and via post-exercise nutrition, this work has implications for how prostacyclin-PPARγ-FAO might be fine-tuned to promote regeneration and treat muscle diseases of aging.

Adult progenitor rejuvenation with embryonic factors.

During ageing, adult stem cells' regenerative properties decline, as they undergo replicative senescence and lose both their proliferative and differentiation capacities. In contrast, embryonic and foetal progenitors typically possess heightened proliferative capacities and manifest a more robust regenerative response upon injury and transplantation, despite undergoing many rounds of mitosis. How embryonic and foetal progenitors delay senescence and maintain their proliferative and differentiation capacities after numerous rounds of mitosis, remains unknown. It is also unclear if defined embryonic factors can rejuvenate adult progenitors to confer extended proliferative and differentiation capacities, without reprogramming their lineage-specific fates or inducing oncogenic transformation. Here, we report that a minimal combination of LIN28A, TERT, and sh-p53 (LTS), all of which are tightly regulated and play important roles during embryonic development, can delay senescence in adult muscle progenitors. LTS muscle progenitors showed an extended proliferative capacity, maintained a normal karyotype, underwent myogenesis normally, and did not manifest tumorigenesis nor aberrations in lineage differentiation, even in late passages. LTS treatment promoted self-renewal and rescued the pro-senescence phenotype of aged cachexia patients' muscle progenitors, and promoted their engraftment for skeletal muscle regeneration in vivo. When we examined the mechanistic basis for LIN28A's role in the LTS minimum combo, let-7 microRNA suppression could not fully explain how LIN28A promoted muscle progenitor self-renewal. Instead, LIN28A was promoting the translation of oxidative phosphorylation mRNAs in adult muscle progenitors to optimize mitochondrial reactive oxygen species (mtROS) and mitohormetic signalling. Optimized mtROS induced a variety of mitohormetic stress responses, including the hypoxic response for metabolic damage, the unfolded protein response for protein damage, and the p53 response for DNA damage. Perturbation of mtROS levels specifically abrogated the LIN28A-driven hypoxic response in Hypoxia Inducible Factor-1α (HIF1α) and glycolysis, and thus LTS progenitor self-renewal, without affecting normal or TS progenitors. Our findings connect embryonically regulated factors to mitohormesis and progenitor rejuvenation, with implications for ageing-related muscle degeneration.

Observations that suggest a contribution of altered dermal papilla mitochondrial function to androgenetic alopecia.

Androgenetic alopecia (AGA) is a prevalent hair loss condition in males that develops due to the influence of androgens and genetic predisposition. With the aim of elucidating genes involved in AGA pathogenesis, we modelled AGA with three-dimensional culture of keratinocyte-surrounded dermal papilla (DP) cells. We co-cultured immortalised balding and non-balding human DP cells (DPCs) derived from male AGA patients with epidermal keratinocyte (NHEK) using multi-interfacial polyelectrolyte complexation technique. We observed up-regulated mitochondria-related gene expression in balding compared with non-balding DP aggregates which indicated altered mitochondria metabolism. Further observation of significantly reduced electron transport chain complex activity (complexes I, IV and V), ATP levels and ability to uptake metabolites for ATP generation demonstrated compromised mitochondria function in balding DPC. Balding DP was also found to be under significantly higher oxidative stress than non-balding DP. Our experiments suggest that application of antioxidants lowers oxidative stress levels and improves metabolite uptake in balding DPC. We postulate that the observed up-regulation of mitochondria-related genes in balding DP aggregates resulted from an over-compensatory effort to rescue decreased mitochondrial function in balding DP through the attempted production of new functional mitochondria. In all, our three-dimensional co-culturing revealed mitochondrial dysfunction in balding DPC, suggesting a metabolic component in the aetiology of AGA.

Vasculitic neuropathy associated with IgG4-related kidney disease: A case report and literature review.

IgG4-related disease is an immune-mediated systemic inflammatory condition characterized by tissue infiltration of IgG4-positive plasma cells and elevated serum IgG4 concentrations. Peripheral neuropathy is an atypical manifestation of this disease. We describe an unusual case of vasculitic neuropathy in a patient with IgG4-related kidney disease. A 55-year-old woman presented with right leg weakness progressing to bilateral leg weakness, pain and numbness of the legs, and impaired gait. She was previously evaluated for weight loss and anemia with a CT scan of the abdomen due to concern for malignancy. Abnormal enhancement of the kidneys was seen, and laboratory work-up and kidney biopsy were consistent with IgG4-related disease. Myeloperoxidase-antineutrophil cytoplasmic antibodies were also positive. In combination with the patient's asymmetric leg weakness and painful neuropathy, this raised concern for vasculitis. Sural nerve biopsy confirmed vasculitic neuropathy. Recent studies have demonstrated an overlap in the clinical characteristics of IgG4-related disease and the anti-neutrophil cytoplasmic antibody-associated vasculitides, which are known to cause vasculitic neuropathy. Clinicians should recognize this association, and IgG4-related disease should be considered in the differential diagnosis in patients with peripheral neuropathy in the right clinical context.

Assessment of different strategies for scalable production and proliferation of human myoblasts.

OBJECTIVES: Myoblast transfer therapy (MTT) is a technique to replace muscle satellite cells with genetically repaired or healthy myoblasts, to treat muscular dystrophies. However, clinical trials with human myoblasts were ineffective, showing almost no benefit with MTT. One important obstacle is the rapid senescence of human myoblasts. The main purpose of our study was to compare the various methods for scalable generation of proliferative human myoblasts. METHODS: We compared the immortalization of primary myoblasts with hTERT, cyclin D1 and CDK4R24C , two chemically defined methods for deriving myoblasts from pluripotent human embryonic stem cells (hESCs), and introduction of viral MyoD into hESC-myoblasts. RESULTS: Our results show that, while all the strategies above are suboptimal at generating bona fide human myoblasts that can both proliferate and differentiate robustly, chemically defined hESC-monolayer-myoblasts show the most promise in differentiation potential. CONCLUSIONS: Further efforts to optimize the chemically defined differentiation of hESC-monolayer-myoblasts would be the most promising strategy for the scalable generation of human myoblasts, for applications in MTT and high-throughput drug screening.

Molecular Targets of Ascochlorin and Its Derivatives for Cancer Therapy.

Cancer is an extremely complex disease comprising of a multitude of characteristic hallmarks that continue to evolve with time. At the genomic level, random mutations leading to deregulation of diverse oncogenic signal transduction cascades and polymorphisms coupled with environmental as well as life style-related factors are major causative agent contributing to chemoresistance and the failure of conventional therapies as well as molecular targeted agents. Hence, there is an urgent need to identify novel alternative therapies based on alternative medicines to combat this dreaded disease. Ascochlorin (ASC), an isoprenoid antibiotic isolated initially from the fermented broth of Ascochyta viciae, and its synthetic derivatives have recently demonstrated substantial antineoplastic effects in a variety of tumor cell lines and mouse models. The major focus of this review article is to briefly analyze the chemopreventive as well as therapeutic properties of ASC and its derivatives and to identify the multiple molecular targets modulated by this novel class of anticancer agent.

Excessive fatty acid oxidation induces muscle atrophy in cancer cachexia.

Cachexia is a devastating muscle-wasting syndrome that occurs in patients who have chronic diseases. It is most commonly observed in individuals with advanced cancer, presenting in 80% of these patients, and it is one of the primary causes of morbidity and mortality associated with cancer. Additionally, although many people with cachexia show hypermetabolism, the causative role of metabolism in muscle atrophy has been unclear. To understand the molecular basis of cachexia-associated muscle atrophy, it is necessary to develop accurate models of the condition. By using transcriptomics and cytokine profiling of human muscle stem cell-based models and human cancer-induced cachexia models in mice, we found that cachectic cancer cells secreted many inflammatory factors that rapidly led to high levels of fatty acid metabolism and to the activation of a p38 stress-response signature in skeletal muscles, before manifestation of cachectic muscle atrophy occurred. Metabolomics profiling revealed that factors secreted by cachectic cancer cells rapidly induce excessive fatty acid oxidation in human myotubes, which leads to oxidative stress, p38 activation and impaired muscle growth. Pharmacological blockade of fatty acid oxidation not only rescued human myotubes, but also improved muscle mass and body weight in cancer cachexia models in vivo. Therefore, fatty acid-induced oxidative stress could be targeted to prevent cancer-induced cachexia.

Association of computerized texture features on MRI with early treatment response following laser ablation for neuropathic cancer pain: preliminary findings.

Laser interstitial thermal therapy (LITT) has recently emerged as a new treatment modality for cancer pain management that targets the cingulum (pain center in the brain) and has shown promise over radio frequency (RF)-based ablation, due to magnetic resonance image (MRI) guidance that allows for precise ablation. Since laser ablation for pain management is currently exploratory and is only performed at a few centers worldwide, its short- and long-term effects on the cingulum are currently unknown. Traditionally, treatment effects for neurological conditions are evaluated by monitoring changes in intensities and/or volume of the ablation zone on post-treatment Gadolinium-contrast T1-w (Gd-T1) MRI. However, LITT introduces subtle localized changes corresponding to tissues response to treatment, which may not be appreciable on visual inspection of volumetric or intensity changes. Additionally, different MRI protocols [Gd-T1, T2w, gradient echo sequence (GRE), fluid-attenuated inversion recovery (FLAIR)] are known to capture complementary diagnostic information regarding the patient's response to treatment; the utility of these MRI protocols has so far not been investigated to evaluate early and localized response to LITT treatment in the context of neuropathic cancer pain. In this work, we present the first attempt at (a) examining early treatment-related changes on a per-voxel basis via quantitative comparison of computer-extracted texture descriptors across pre- and post-LITT multiparametric (MP-MRI) (Gd-T1, T2w, GRE, FLAIR), subtle microarchitectural texture changes that may not be appreciable on original MR intensities or volumetric differences, and (b) investigating the efficacy of different MRI protocols in accurately capturing immediate post-treatment changes reflected (1) within and (2) outside the ablation zone. A retrospective cohort of four patient studies comprising pre- and immediate (24 h) post-LITT 3 Tesla Gd-T1, T2w, GRE, and FLAIR acquisitions was considered. Our quantitative approach first involved intensity standardization to allow for grayscale MR intensities acquired pre- and post-LITT to have a fixed tissue-specific meaning within the same imaging protocol, the same body region, and within the same patient. An affine registration was then performed on individual post-LITT MRI protocols to a reference MRI protocol pre-LITT. A total of 78 computerized texture features (co-occurrence matrix homogeneity, neighboring gray-level dependence matrix, Gabor) are then extracted from pre- and post-LITT MP-MRI on a per-voxel basis. Quantitative, voxelwise comparison of the changes in MRI texture features between pre- and post-LITT MRI indicate that (a) Gabor texture features at specific orientations were highly sensitive as well as specific in predicting subtle microarchitectural changes within and around the ablation zone pre- and post-LITT, (b) FLAIR was identified as the most sensitive MRI protocol in identifying early treatment changes yielding a normalized percentage change of 360% within the ablation zone relative to its pre-LITT value, and (c) GRE was identified as the most sensitive MRI protocol in quantifying changes outside the ablation zone post-LITT. Our preliminary results thus indicate potential for noninvasive computerized MP-MRI features over volumetric features in determining localized microarchitectural early focal treatment changes post-LITT for neuropathic cancer pain treatment.