A Comparison of Plastic Surgery Authorship Trends Under Single Versus Double-Blinded Review.

INTRODUCTION: Research is key to academic advancement in plastic surgery. However, access to publication opportunities may be inequitable as seen in other fields. We compared authorship trends of plastic surgery manuscripts that underwent single-blinded review (SBR) versus double-blinded review (DBR) to identify potential disparities in publication opportunities. METHODS: Publications from two plastic surgery journals using SBR and two using DBR from September 2019 to September 2021 were evaluated. Name and institution of the article's first and senior author and journal's editor-in-chief (EIC) were recorded. Chi-squared and Fisher's exact analyses were used to compare author characteristics between SBR and DBR articles. RESULTS: Of 2500 manuscripts, 65.7% underwent SBR and 34.3% underwent DBR. SBR articles had higher percentages of women as first authors (31.9% versus 24.3%, P < 0.001) but lower percentages of first (50.7% versus 71.2%, P < 0.001) and senior (49.6% versus 70.3%, P < 0.001) authors from international institutions. First (26.0% versus 12.9%, P < 0.001) and senior (27.9% versus 18.0%, P = 0.007) authors of SBR articles tended to have more plastic surgery National Institutes of Health funding. Journals using SBR tended to have higher rates of authorship by EICs or authors sharing institutions with the EIC (P ≤ 0.005). CONCLUSIONS: While associated with greater female first authorship suggesting potential efforts toward gender equity in academia, SBR of plastic surgery articles tends to favor authors from institutions with higher National Institutes of Health funding and disadvantage authors from international or lower-resourced programs. Careful consideration of current peer-review proceedings may make publication opportunities more equitable.

The Medical Student Race to Research: Who Presents More at National Plastic Surgery Conferences?

BACKGROUND: presentations increase research output and facilitate networking for medical students applying to plastic surgery. We aim to determine predictors of increased medical student presentation at national plastic surgery conferences, identifying disparities in access to research opportunities. METHODS: Abstracts presented at the 2 most recent meetings of the American Society of Plastic Surgeons, American Association of Plastic Surgeons, and Plastic Surgery Research Council were extracted from online archives. Presenters without MDs or other professional credentials were classified as medical students. Presenter gender, medical school ranking, plastic surgery division/department, National Institutes of Health funding, number of total and first-author publications, H-index, and research fellowship completion status were recorded. Students with 3 or more (>75th percentile) presentations were compared with those with less by χ2 tests. Univariate and multivariable regressions identified factors associated with 3 or more presentations. RESULTS: Of 1576 abstracts, 549 (34.8%) were presented by 314 students. The gender distribution was 46.5% male and 53.5% female. Most were from the Northeast (36.9%), 35% came from top 20 medical schools, and 85% attended schools with home plastic surgery programs. While 61.8% presented once, 14.6% presented 3 or more times. Those who previously presented, completed research fellowships or had more publications or higher H-indices were likely to present more ( P ≤ 0.007). On multivariable-adjusted analysis, completing research fellowships (odds ratio [OR], 2.34-2.52; P = 0.028-0.045), affiliation with institutions having higher National Institutes of Health funding (OR, 3.47-3.73; P = 0.004-0.006), or having more total number of publications (OR, 3.81; P = 0.018) or first-author publications (OR, 3.84; P = 0.008) was associated with 3 or more presentations. Presenter gender, geographic region, medical school ranking, home program status, and H-indices were not significant predictors on multivariable analysis. CONCLUSIONS: There are several potential inequities in access to research opportunities for medical students, disadvantaging those with less well-funded plastic surgery programs and existing research experience. Improving the equitability of these opportunities is crucial for limiting bias in trainee recruitment and diversifying representation in the field.

The Slow Progression of Diabetic Retinopathy Is Associated with Transient Protection of Retinal Vessels from Death.

The purpose of this study was to investigate the reason that diabetic retinopathy (DR) is delayed from the onset of diabetes (DM) in diabetic mice. To this end, we tested the hypothesis that the deleterious effects of DM are initially tolerated because endogenous antioxidative defense is elevated and thereby confers resistance to oxidative stress-induced death. We found that this was indeed the case in both type 1 DM (T1D) and type 2 DM (T2D) mouse models. The retinal expression of antioxidant defense genes was increased soon after the onset of DM. In addition, ischemia/oxidative stress caused less death in the retinal vasculature of DM versus non-DM mice. Further investigation with T1D mice revealed that protection was transient; it waned as the duration of DM was prolonged. Finally, a loss of protection was associated with the manifestation of both neural and vascular abnormalities that are diagnostic of DR in mice. These observations demonstrate that DM can transiently activate protection from oxidative stress, which is a plausible explanation for the delay in the development of DR from the onset of DM.

Are Opioids Out? Assessing Prescription Patterns in Plastic Surgery Using Medicare Part D Beneficiary Data.

INTRODUCTION: Since 1999, nearly 841,000 individuals have died from overdoses, 29% involving prescription opioids. Use of opioids for postoperative pain lacks evidence-based guidelines, and despite studies showing the efficacy of nonopioid agents in reducing postoperative morbidity, opioids are still routinely prescribed. However, multiple states are adopting prescription drug monitoring programs and prescription drug laws. The authors sought to investigate recent opioid prescription patterns among plastic surgeons. METHODS: This cross-sectional study used "Medicare Provider Utilization and Payment Data: Part D Prescriber" provided by the Centers for Medicare & Medicaid Services from 2016 to 2018. Entries were filtered to include plastic surgeons. Demographic variables included surgeon sex, geographic region and state, board certification status, and length of experience. The surgeon's practice was designated as academic, private, or both. Outcomes included total opioid claims, opioid prescriber rate, and days per claim. Kruskal-Wallis tests were used for statistical comparison (α = .05). RESULTS: From 2016 to 2018, plastic surgeons wrote 289,525 opioid prescriptions for 1,729,523 days (6.0 days per prescription), totaling $3,346,979.39. In 2018, 62.2% of plastic surgeons prescribed 0 to 10 opioids, 36.5% prescribed 11 to 50 opioids, and 1.3% prescribed more than 50. Furthermore, 99.5% of plastic surgeons prescribing opioids are practicing in metropolitan areas (rural-urban commuting area codes 1-3). Plastic surgeons who were male or were board certified had significantly lower opioid prescriber rates (P < 0.001). There were no significant variations in outcomes by length of surgeon experience. Geographic region was significantly associated with opioid prescription rates and days per claim, with Southern plastic surgeons having lower rates (P < 0.001) and those Northeastern ones prescribing shorter courses (P = 0.004). The number of opioid claims, days per claim, and opioid prescriber rates were all significantly lower in 2018 than in 2017 and 2016 (P < 0.001). CONCLUSIONS: Prescriptions written by plastic surgeons may have contributed to the opioid epidemic, but 2018 data suggest opioids are becoming less routine in postoperative pain control. Further studies are warranted to assess factors related to reduced and shorter opioid prescriptions by plastic surgeons in the South and Northeast, respectively. Such insight, if adopted into law and implemented into clinical practice, may help reduce the burden of the opioid epidemic.

Acquisition of IDH2 mutations in relapsed/refractory AML is associated with worse patient outcomes.

OBJECTIVES: The presence of targeted therapy, Enasidenib, for IDH2-mutated AML underscores the importance of understanding the clonal dynamics of IDH2 mutations, which has not been elucidated. In the largest study of IDH2 clonal dynamics, we detail the IDH2-evolutionary patterns and their clinical significance. METHODS: We analyzed ~6000 patients with NGS results to identify 120 AML patients with IDH2 mutations and longitudinal NGS testing. IDH2 mutation status was recorded at diagnosis, remission, relapse, and persistent disease. RESULTS: One hundred and five patients were IDH2-positive at the initial diagnosis, and 15 acquired the mutation later. Of those 15 patients, 7 patients gained the mutation during persistent disease, 6 during relapse, and 2 at remission. Twenty-one patients (18%) who were IDH2-positive in a prior test remained IDH2-positive in remission. Twenty-four patients with IDH2-positive AML were IDH2-positive at relapse. IDH2-positive at diagnosis had better survival than IDH2 mutation acquired later in disease (P = .024). Patients who were IDH2-negative in remission had significantly improved survival (P = .002). Also, loss-of-IDH2 mutation with persistent disease had better OS (P = .035). CONCLUSIONS: There are 70% that clear IDH2 in disease remission. 12% gain IDH2 mutation later, usually in the setting of refractory/relapsed AML. These patients fared worse. Longitudinal IDH2 testing may be helpful in prognostic stratification.

Recurrent reactive infectious mucocutaneous eruption (RIME) in two adolescents triggered by several distinct pathogens including SARS-CoV-2 and influenza A.

Reactive infectious mucocutaneous eruption (RIME) was proposed as new terminology to encompass postinfectious mucocutaneous eruptions. The term includes all postinfectious mucocutaneous eruptions such as the widely reported Mycoplasma pneumoniae-induced rash and mucositis (MIRM). Very few reports in the literature regarding recurrent RIME are found. We present two adolescent cases of recurrent RIME that involve SARS-CoV-2 and influenza A where the latter is a newly reported infectious trigger; in both patients, the initial episode was likely triggered by Mycoplasma pneumoniae (MP) infection.

Erythroid variant evolving from chronic myeloid leukemia resistant to multiple tyrosine kinase inhibitors: a rare case report.

BACKGROUND: Chronic myeloid leukemia (CML) is characterized by the presence of BCR::ABL1 fusion gene resulting from a reciprocal translocation, t(9;22)(q34;q11.2), leading to prominent granulocytic proliferation. The majority of patients initially present in chronic phase (CP), which may progress to advanced CML with predominantly granulocytic phenotypes in the absence of proper treatment or response to tyrosine kinase inhibitors (TKIs). We present an exceptionally rare case in which an erythroid variant emerged from a CML patient resistant to multiple TKIs. This variant is characterized by the detection of t(9;22) BCR::ABL1 fusion in erythroid precursors at various maturation stages and the absence of granulocytic progenitor hyperplasia typically seen in classical CML. CASE PRESENTATION: A 33-year-old female with CP-CML had received multiple TKI therapies since her initial diagnosis in 2015. Due to intolerable side effects and inconsistent adherence, she exhibited an inadequate response and developed new-onset pancytopenia. Bone marrow (BM) biopsy specimen revealed a hypercellular marrow with significant erythroid hyperplasia (90% of marrow cellularity) and a reversed myeloid-to-erythroid (M: E) ratio of 1:10. Both erythroid and myeloid cells displayed progressive maturation without dysplasia or excess blasts. Chromosomal analysis identified t(9;22) (q34;q11.2) in 19 out of 20 metaphase cells. BCR::ABL1 fusion transcript (p210 isoform) was confirmed by real-time quantitative polymerase chain reaction (RT-qPCR) and next-generation sequencing (NGS). Notably, no additional pathogenic cytogenetic abnormalities or ABL1 kinase domain mutations were detected. Here, we report the first published case of an erythroid variant emerging in a CML patient resistant to multiple TKIs-a distinct entity from the erythroid blast crisis evolving from CML. CONCLUSION: The erythroid variant of CML is distinguished by the presence of t(9;22) (q34;q11.2) BCR::ABL1 in predominant erythroid precursors at different stages of maturation. In a myeloid neoplasm showing predominant erythroid hyperplasia without typical CML features, it is vital to correlate morphology and t(9;22) BCR::ABL1 cytogenetic testing for accurate diagnosis, and to prevent confusion with PEL transformation in CML.

EBV-Positive Pleomorphic Variant Transformation of CD5-Negative Mantle Cell Lymphoma: A Rare Case Report and Literature Review.

Mantle cell lymphoma (MCL) is a mature B-cell lymphoma associated with cyclin D family rearrangements and typically expresses CD5 and cyclin D1. Epstein-Barr virus- (EBV-) positive MCL is rare, and the role of EBV infection and its transformation in MCL remains unclear. We present a case of CD5-negative classic MCL that progressed to an EBV + pleomorphic MCL six years after the initial diagnosis. Molecular studies confirmed the same clonal origin. To the best of our knowledge, the EBV-positive transformation of CD5-negative MCL into a pleomorphic variant has rarely been reported, and its recognition is important for the diagnosis and the management of patients with MCL.

A PRISMA-IPD systematic review and meta-analysis: does age and follow-up improve active range of motion of the wrist and forearm following pediatric upper extremity cerebral palsy surgery?

Purpose: Surgical treatments such as tendon transfers and muscle lengthening play a significant role in cerebral palsy management,but timing of upper extremity cerebral palsy surgery remains controversial. This study systematically reviews the current literature and investigates the correlation between age at surgery and follow-up time with surgical outcomes in pediatric upper extremity cerebral palsy patients. Methods: A comprehensive search of PubMed, Cochrane, Web of Science, and CINAHL databases was performed from inception to July 2020 and articles were screened using PRISMA guidelines to include full-text, English papers. Data analysis was performed using itemized data points for age at surgery, follow-up length, and surgery outcomes, reported as changes in active forearm and wrist motion. A 3D linear model was performed, to analyze the relationship between age, follow-up length, and surgery outcomes. Results: A total of 3,855 papers were identified using the search terms and a total of 8 studies with itemized patient data (n=126) were included in the study. The studies overall possessed moderate bias according to the ROBINS-I scale. Regression analysis showed that age is a significant predictor of change (|t| > 2) in active forearm supination (Estimate = -2.3465, Std. Error = 1.0938, t-value= -2.145) and wrist flexion (Estimate = -2.8474, Std. Error = 1.0771, t-value = -2.643) post-intervention, with older individuals showing lesser improvements. The duration of follow-up is a significant predictor of improvement in forearm supination (Estimate = 0.3664, Std. Error = 0.1797, t-value = 2.039) and wrist extension (Estimate = 0.7747, Std. Error = 0.2750, t-value = 2.817). In contrast, forearm pronation (Estimate = -0.23756, Std. Error = 0.09648, t-value = -2.462) and wrist flexion (Estimate = -0.4243, Std. Error=0.1859, t-value = -2.282) have a significant negative association with follow-up time. Conclusion: These results suggest that there is significant correlation between the age and follow up after surgery with range of motion gains. Most notably, increased age at surgery had a significant negative correlation with select active range of motion postoperative outcomes. Future research should focus on identifying other factors that could affect results of surgical treatment in upper extremity.

Dendritic spinule-mediated structural synaptic plasticity: Implications for development, aging, and psychiatric disease.

Dendritic spines are highly dynamic and changes in their density, size, and shape underlie structural synaptic plasticity in cognition and memory. Fine membranous protrusions of spines, termed dendritic spinules, can contact neighboring neurons or glial cells and are positively regulated by neuronal activity. Spinules are thinner than filopodia, variable in length, and often emerge from large mushroom spines. Due to their nanoscale, spinules have frequently been overlooked in diffraction-limited microscopy datasets. Until recently, our knowledge of spinules has been interpreted largely from single snapshots in time captured by electron microscopy. We summarize herein the current knowledge about the molecular mechanisms of spinule formation. Additionally, we discuss possible spinule functions in structural synaptic plasticity in the context of development, adulthood, aging, and psychiatric disorders. The literature collectively implicates spinules as a mode of structural synaptic plasticity and suggests the existence of morphologically and functionally distinct spinule subsets. A recent time-lapse, enhanced resolution imaging study demonstrated that the majority of spinules are small, short-lived, and dynamic, potentially exploring their environment or mediating retrograde signaling and membrane remodeling via trans-endocytosis. A subset of activity-enhanced, elongated, long-lived spinules is associated with complex PSDs, and preferentially contacts adjacent axonal boutons not presynaptic to the spine head. Hence, long-lived spinules can form secondary synapses with the potential to alter synaptic connectivity. Published studies further suggest that decreased spinules are associated with impaired synaptic plasticity and intellectual disability, while increased spinules are linked to hyperexcitability and neurodegenerative diseases. In summary, the literature indicates that spinules mediate structural synaptic plasticity and perturbations in spinules can contribute to synaptic dysfunction and psychiatric disease. Additional studies would be beneficial to further delineate the molecular mechanisms of spinule formation and determine the exact role of spinules in development, adulthood, aging, and psychiatric disorders.

Characterization of genital injuries secondary to foreign bodies from 2011 to 2020.

PURPOSE: To identify demographic trends of foreign object genital injuries presenting to emergency departments from 2011 to 2020. MATERIALS AND METHODS: The National Electronic Injury Surveillance System database reports consumer product-related injuries in United States ED visits. The database was queried to identify 375 cases of genital injuries from 2011 to 2020. Inclusion criteria consisted of cases reporting injuries involving the urethra, penis, or scrotum. Data was reported and analyzed using linear regression. RESULTS: Based on 375 cases, an estimated 13,170 (95% confidence interval, 10,817-15,522) patients in the US suffered genital injuries due to foreign bodies between 2011 and 2020. These injuries involved the penis (65.9%), urethra (30.7%) and scrotum (3.5%). Of all patients, 11.8% required hospital admission after treatment of which injuries to the urethra were most common (44.0%). Most of these patients were ages 19 to 64 (66.1%). Consumer products most implicated included rings (50.7%), zippers (17.1%), and pens and pencils (10.3%). Injuries due to zippers and swimming apparel occurred significantly more frequently in patients ages 0-18 (p<0.05). Injuries due to kitchen gadgets occurred significantly more in patients ages ≥65 (p<0.05). Pens, pencils, and massage devices were items that routinely resulted in urethral injuries, often requiring hospitalization. Linear regression showed genital injuries related to foreign objects significantly increased from 2011 to 2020 (p<0.001). CONCLUSIONS: Due to the nature of injury caused to genitalia by intentional and unintentional exposure to foreign bodies, educating individuals on this topic in sexual education classes is necessary for preventing future injuries.

Expanding diagnostic criteria: Multiorgan T-Cell/myeloid mixed phenotype acute leukemia with t(v;11q23) KMT2A-rearrangement successfully treated by allogeneic stem cell transplant.

Mixed phenotype acute leukemia (MPAL) consists of a leukemia of two different lineages (myeloid, T, and/or B) co-occurring in the same tissue. KMT2A-rearrangement is rare and usually seen in B/myeloid MPAL. We report a unique case of T/myeloid MPAL with a t(v;11q23) KMT2A-rearrangement, with acute myeloid leukemia (AML) in the bone marrow but concurrent T-cell acute lymphoblastic leukemia (T-ALL) in lymph node and skin. Genomic interrogation suggests an undifferentiated stem cells with KMT2A rearrangement as the founder mutation that acquired additional lineage-specific mutations resulting in AML in the marrow and T-ALL in other sites.

Current Trends of Research Productivity among Students Matching at Top Ophthalmology Programs.

Importance San Francisco Match publishes no data on the research output of matched applicants to an ophthalmology residency. Objective The aim of this study was to examine the temporal trends in publication volume by medical students who successfully matched into a top ophthalmology residency. Methods This retrospective case series compared all residents in the top 30 ophthalmology residency programs from the class of 2022 and 2017. Publication volume from before September 15th of the residents' fourth year of medical school was recorded using PubMed and Google Scholar. We recorded total number of publications (any authorship), first/second author publications, and ophthalmology-specific publications. Using Welch's t -test, publication volumes were statistically compared against all others. Results One-hundred sixty-one residents from the class of 2022 and 145 residents from the class of 2017 were included. Total publications per matched applicant (mean ± standard deviation) were 3.04 ± 0.35 for the class of 2022 and 1.67 ± 0.23 for the class of 2017. Mean publications in ophthalmology journals were 1.07 ± 0.20 (2022) and 0.58 ± 0.13 (2017); mean first author publications were 1.00 ± 0.13 (2022) and 0.64 ± 0.11 (2017) and mean second author publications were 0.70 ± 0.10 (2022) and 0.37 ± 0.06 (2017). Research productivity in all four metrics (total, ophthalmology journals, first author, and second author publications) was significantly higher for the class of 2022 than the class of 2017 ( p = 0.001; p = 0.03; p = 0.03; p = 0.02, respectively) supporting the trend of increasing research output among students. Applicants with PhD degrees had statistically more total and first author publications in 2017 ( p = 0.01; p = 0.045), but only more first author publications in 2022 ( p = 0.01). International applicants produced significantly more total publications in 2022 ( p < 0.001). Conclusions Overall, after a 5-year period, the authors found matched applicants had significantly increased publications compared with those at the beginning of the period. We also identified several applicant factors that may have variable effects on research publication. This analysis emphasizes the growing importance of research in the match process and can help future applicants navigate the ophthalmology match.

Characterization of Pediatric Genital Injuries Due to Consumer Products From 2011 to 2020.

OBJECTIVE: To describe demographic trends of consumer product-related injuries in the pediatric cohort from 2011 - 2020. METHODS: The National Electronic Injury Surveillance System (NEISS) database surveying emergency department visits was retrospectively searched for all pediatric genitourinary injuries from 2011 to 2020. Data on demographics, diagnosis, products, disposition, and anatomy injured were collected on patients between the ages of 0-19 years. Statistical analysis was performed using linear regression. RESULTS: There were 12,953 reported pediatric cases involving injuries of the genital region from 2011 to 2020 with a national estimate of 324,636 (95% CI 241,527 - 407,746) pediatric genital injuries, comprising 0.76% of total pediatric injuries in the past decade. Of these patients, female (54.2%), white (39.7%) individuals sustained the most injuries, and items most commonly responsible included bicycles (9.4%), playground equipment (6.9%), toilets (4.6%), beds (4.5%), bathtubs and showers (4.4%), soaps (4.4%), chairs (4.1%), and razors and shavers (2.3%). Urethral injuries were due to chemical injuries from soaps (22%), furniture (17%), playground injuries (17%), insertion of foreign bodies into the urethra (13%), bicycles (10%), and swimming related injuries (4%). Genital injuries in children 0-5 years old were primarily caused by furniture (47.8%), while injuries in the 6-10, 11-15, and 16-19 age groups were attributed to sports and recreation (41.2%, 24.6%, 12.2% respectively). There was no significant change in the annual number of pediatric genital injuries from 2011 to 2020 (R2 = 0.38, P = 0.057). CONCLUSION: Identifying factors involved in pediatric genital trauma can allow for increased legislation, surveillance, and prevention of such injuries in targeted age groups.

Therapeutic Strategies for Restoring Perturbed Corneal Epithelial Homeostasis in Limbal Stem Cell Deficiency: Current Trends and Future Directions.

Limbal stem cells constitute an important cell population required for regeneration of the corneal epithelium. If insults to limbal stem cells or their niche are sufficiently severe, a disease known as limbal stem cell deficiency occurs. In the absence of functioning limbal stem cells, vision-compromising conjunctivalization of the corneal epithelium occurs, leading to opacification, inflammation, neovascularization, and chronic scarring. Limbal stem cell transplantation is the standard treatment for unilateral cases of limbal stem cell deficiency, but bilateral cases require allogeneic transplantation. Herein we review the current therapeutic utilization of limbal stem cells. We also describe several limbal stem cell markers that impact their phenotype and function and discuss the possibility of modulating limbal stem cells and other sources of stem cells to facilitate the development of novel therapeutic interventions. We finally consider several hurdles for widespread adoption of these proposed methodologies and discuss how they can be overcome to realize vision-restoring interventions.

Post-transplant relapse of therapy-related MDS as gastric myeloid sarcoma: Case report and review of literature.

INTRODUCTION: Myelodysplastic syndrome (MDS) are hematologic neoplasms characterized by morphologic dysplasia and ineffective hematopoiesis in the bone marrow. The only potentially curative therapy is stem cell transplant. However, relapse remains a major challenge and is seen in about 25-40% of cases. Myeloid sarcoma presenting as relapse post allogeneic transplant for myeloid neoplasms is rare. We report the sentinel case of a patient with MDS who relapsed as gastric myeloid sarcoma 1 ½ years after allogeneic stem cell transplant. CASE PRESENTATION: Sixty-nine-year-old male who was diagnosed with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) in 2006 and transitional cell bladder carcinoma in 2008. In 2011, he developed therapy-related myeloid neoplasm t(7;22) and no excess blasts. He was treated with Vidaza followed by a MUD hematopoietic stem cell transplant on 8/24/2012. In 2013 the patient developed anorexia and gastric biopsies showed severe gastritis. Repeat gastric biopsy on 02/05/2014 showed an extensive mononuclear infiltrate which could easily be confused with lymphocytes but staining showed myeloid sarcoma. Marrow was negative. The patient remained refractory to therapy and expired 08/10/2016. CONCLUSION: In summary, we report the first case of GI relapse of MDS as a myeloid sarcoma post-transplant. We seek to alert our audience of this potentially serious diagnostic pitfall, particularly one that can be relatively easily resolved on the basis of immunohistochemical profiling.

Rapid 3D Enhanced Resolution Microscopy Reveals Diversity in Dendritic Spinule Dynamics, Regulation, and Function.

Dendritic spinules are thin protrusions, formed by neuronal spines, not adequately resolved by diffraction-limited light microscopy, which has limited our understanding of their behavior. Here we performed rapid structured illumination microscopy and enhanced resolution confocal microscopy to study spatiotemporal spinule dynamics in cortical pyramidal neurons. Spinules recurred at the same locations on mushroom spine heads. Most were short-lived, dynamic, exploratory, and originated near simple PSDs, whereas a subset was long-lived, elongated, and associated with complex PSDs. These subtypes were differentially regulated by Ca2+ transients. Furthermore, the postsynaptic Rac1-GEF kalirin-7 regulated spinule formation, elongation, and recurrence. Long-lived spinules often contained PSD fragments, contacted distal presynaptic terminals, and formed secondary synapses. NMDAR activation increased spinule number, length, and contact with distal presynaptic elements. Spinule subsets, dynamics, and recurrence were validated in cortical neurons of acute brain slices. Thus, we identified unique properties, regulatory mechanisms, and functions of spinule subtypes, supporting roles in neuronal connectivity.

Dissecting the in vivo leukemogenic potency of BCLxl.

Overexpression of anti-apoptotic members of the BCL2 family has been found in all types of cancer. A member of the family, BCLxl (B-cell lymphoma extra-large), is known to be associated with the progression of leukemogenesis. In the present study, we focused on understanding the domains of BCLxl responsible for in vivo oncogenic potency. To this end, we utilized engineered BCLxl proteins with alternative transmembrane domains (TM) or chimeric BCLxl proteins containing domains from a less potent BCL2-like protein, BCLb. As expected, mice receiving MYC-only expressing bone marrow develop leukemia by 100 days, whereas co-expression of MYC with wild-type BCLxl led to aggressive myeloid leukemia with an average latency of ~25 days. Interestingly, mice injected with bone marrow co-expressing MYC and BCLxl targeted specifically to either mitochondria or ER also succumbed to leukemia with an average latency of ~25 days. Further, our study was extended to examine the role of the BH4 domain in driving potent leukemogenesis. Mice injected with bone marrow co-expressing MYC and BCLb succumb to leukemia in an average of ~55 days, but interestingly a BCLxl protein containing only the loop region of BCLb drove MYC-induced leukemogenesis with the same latency as wild-type BCLxl. These data suggest that the localization of exogenous BCLxl to either mitochondria or ER is not a steadfast dictator of in vivo oncogenic potency. Further, our findings suggest that the loop domain of BCLb and BCLxl is not responsible for dictating the in vivo leukemogeneic potency. This study provides further mechanistic details into the biochemical functions of BCLxl.