The role of Lamin B1 in the organization of the nuclear envelope and myelin regulation in development and disease

The nuclear lamina is a structural meshwork composed of intermediate filament proteins known as lamins that maintains nuclear shape and function. Perturbations of lamins lead to diseases, collectively known as laminopathies, which affect a wide variety of organ systems. One such laminopathy is autosomal dominant leukodystrophy (ADLD), a severe and fatal adult-onset demyelinating laminopathy caused by overexpression of LMNB1, one of the lamin proteins that make up the nuclear lamina. My studies aim to elucidate the role of lamin B1 in the organization of the nuclear envelope, its role in myelin regulation during oligodendrocyte maturation, and to understand how the genomic rearrangements involving LMNB1 cause ADLD. Our results suggest a novel concentric organization model of the nuclear lamina, with lamin B1 facing the inner nuclear membrane while lamins A and C together face the nucleoplasm. Lamin B1’s outward-facing localization maintains nuclear shape by restraining the lamin A/C meshwork from protruding outward. To study lamin B1’s function in mature oligodendrocytes, conditional Lmnb1 knockout mice were used to study behavioral and molecular changes in the central nervous system. Knockout mice did not exhibit any overt behavioral phenotypes or myelination defects, but a careful analysis revealed alterations in the number of myelinating oligodendrocyte populations. We conclude that while mature oligodendrocytes do not require lamin B1 for their proper function, it might be important for the regulation of oligodendrocyte cell number. Array CGH studies revealed that deletions upstream of LMNB1 can also lead to ADLD, while large duplications involving LMNB1 and a significant upstream region do not. Real-time PCR analysis demonstrate much higher LMNB1 expression in white matter than in grey matter and fibroblasts. We propose that an oligodendrocyte-specific silencer element lies upstream of LMNB1, explaining ADLD’s central nervous system exclusivity despite a constitutional LMNB1 duplication. As demyelination and white matter injuries are common in disorders affecting a wide age range – from preterm neonates to young adults and the elderly – researching pathways involved in myelination and ways to reverse it could have a significant impact to public health

An Exploratory Study to Understand Factors Associated with Health-related Quality of Life Among Uninsured/Underinsured Patients as Identified by Clinic Providers and Staff

Since the release of Healthy People 2020, there has been extensive research understanding factors associated with health-related quality of life (HRQoL) among specific populations. Despite this growing body of research, little has been conducted to understand the factors associated with HRQoL among uninsured/underinsured Americans. The purposes of the present study were to assess clinic staff to determine: (1) whether there is a need to examine HRQoL among uninsured/underinsured individuals, (2) whether there is a need for tailored HRQoL-promoting interventions among uninsured/underinsured individuals, and (3) the factors associated with HRQoL among uninsured/underinsured individuals. A survey was sent to an association of 41 clinics that provides free medical services to uninsured/underinsured individuals. The majority of participants indicated that uninsured/underinsured individuals experience unique factors associated with HRQoL and that there was a need to implement tailored HRQoL-improving interventions among uninsured/underinsured individuals. The results also present the personal/contextual factors associated with HRQoL of uninsured/underinsured individuals

A hub and spoke nuclear lamina architecture in trypanosomes

The nuclear lamina supports many functions, including maintaining nuclear structure and gene expression control, and correct spatio-temporal assembly is vital to meet these activities. Recently, multiple lamina systems have been described that, despite independent evolutionary origins, share analogous functions. In trypanosomatids the two known lamina proteins, NUP-1 and NUP-2, have molecular masses of 450 and 170 kDa, respectively, which demands a distinct architecture from the ∼60 kDa lamin-based system of metazoa and other lineages. To uncover organizational principles for the trypanosome lamina we generated NUP-1 deletion mutants to identify domains and their arrangements responsible for oligomerization. We found that both the N- and C-termini act as interaction hubs, and that perturbation of these interactions impacts additional components of the lamina and nuclear envelope. Furthermore, the assembly of NUP-1 terminal domains suggests intrinsic organizational capacity. Remarkably, there is little impact on silencing of telomeric variant surface glycoprotein genes. We suggest that both terminal domains of NUP-1 have roles in assembling the trypanosome lamina and propose a novel architecture based on a hub-and-spoke configuration

An atypical form of AOA2 with myoclonus associated with mutations in SETX and AFG3L2

Background: Hereditary ataxias are a heterogeneous group of neurodegenerative disorders, where exome sequencing may become an important diagnostic tool to solve clinically or genetically complex cases. Methods: We describe an Italian family in which three sisters were affected by ataxia with postural/intentional myoclonus and involuntary movements at onset, which persisted during the disease. Oculomotor apraxia was absent. Clinical and genetic data did not allow us to exclude autosomal dominant or recessive inheritance and suggest a disease gene. Results: Exome sequencing identified a homozygous c.6292C>T (p.Arg2098*) mutation in SETX and a heterozygous c.346G>A (p.Gly116Arg) mutation in AFG3L2 shared by all three affected individuals. A fourth sister (II.7) had subclinical myoclonic jerks at proximal upper limbs and perioral district, confirmed by electrophysiology, and carried the p.Gly116Arg change. Three siblings were healthy. Conclusions: Exome sequencing is a powerful tool in identifying disease genes. We identified an atypical form of Ataxia with Oculoapraxia type 2 (AOA2) with myoclonus at onset associated with the c.6292C>T (p.Arg2098*) homozygous mutation. Because the same genotype was described in six cases from a Tunisian family with a typical AOA2 without myoclonus, we speculate this latter feature is associated with a second mutated gene, namely AFG3L2 (p.Gly116Arg variant)

The Associations between Depression, Acculturation, and Cardiovascular Health among African Immigrants in the United States

Cardiovascular disease (CVD) is the leading cause of death both globally and in the United States (U.S.). Racial health disparities in cardiovascular health (CVH) persist with non-Hispanic Black adults having a higher burden of CVD morbidity and mortality compared to other racial groups. African immigrants represent an increasingly growing sub-population of the overall U.S. non-Hispanic Black adult population, however little is known about how specific psychological and social factors (i.e., depression and acculturation) influence the CVH of U.S. African immigrants. We sought to examine the association between severity of depression symptomology and CVH among African immigrants, and whether acculturation moderated the relationship between severity of depression symptoms and CVH. Study participants were those in the African Immigrant Health Study conducted in the Baltimore-Washington D.C. area. Severity of depression symptoms were assessed using the Patient Health Questionnaire-8 (PHQ-8). CVH was assessed using the American Heart Association Life’s Simple 7 metrics and categorized as poor, intermediate, and ideal CVH. Acculturation measured as length of stay and acculturation strategy was examined as a moderator variable. Multivariable logistic regression was used to examine the association between depression and CVH and the moderating effect of acculturation adjusting for known confounders. In total 317 African immigrants participated in the study. The mean (±SD) age of study participants was 46.9 (±11.1) and a majority (60%) identified as female. Overall, 8.8% of study participants endorsed moderate-to-severe symptoms of depression. African immigrants endorsing moderate-to-severe levels of depression were less likely to have ideal CVH compared to those with minimal-to-mild symptoms of depression (Adjusted Odds Ratio [AOR]: 0.42, 95% CI: 0.17–0.99). Acculturation measured either as length of stay or acculturation strategy did not moderate the relationship between depression and CVH among study participants. Study participants exhibited elevated levels of symptoms of depression. Greater severity of depression symptoms was associated with worse CVH. Efforts to treat and prevent CVD among African immigrants should also include a focus on addressing symptoms of depression within this population

Effectiveness of medication abortion with misoprostol alone in the SAFE study: a prospective observational cohort study

Introduction: Misoprostol alone regimens for abortion may be more effective than previously thought; real-world effectiveness data on misoprostol alone regimens can provide critical evidence. The aim of this study was to estimate the effectiveness of medication abortion using misoprostol alone among a sample of participants self-managing their abortion with support from safe abortion hotlines and accompaniment groups. Methods: The SAFE study was a prospective observational cohort study of callers to safe abortion hotlines and accompaniment groups in Argentina, Nigeria, and Southeast Asia; participants were recruited prior to starting their medication abortion and completed a baseline and two follow-up surveys. Recruitment started July 31, 2019 and concluded October 1, 2020. Callers 13 years or older with no contraindications to medication abortion who contacted above groups for support in a new self-managed abortion process were eligible to participate. The primary outcome was method effectiveness, classified as having a complete abortion without need for surgical intervention by last follow-up. Secondary outcomes included method safety, measured by self-report of experiencing warning signs (heavy bleeding, pain, fever, discharge) and medical treatment (blood transfusion, intravenous fluids, overnight hospital stay) indicative of a potential complication. Additional outcomes included length of bleeding and cramping, time to expulsion, and experience of side effects. Results: Of the 1352 enrolled participants, 637 (591 [92.8%] from Nigeria, 384 [60.2%] aged 20 - 29, 522 [82.0%] pregnancy durations below 9 weeks) used misoprostol alone regimens for abortion and are included in this analysis. At last follow-up, 625 participants (98.1%, 95% CI: 96.7 to 98.9) had a complete abortion without surgical intervention. Potential adverse events were reported by 6 participants (0.9%, 0.4% to 2.1%). Most participants experienced bleeding for less than one week (median: 4 days, IQR: 3 to 6 days), and expelled their pregnancy within 24 hours of starting their abortion process (median: 12 hours, IQR: 9 to 15 hours). Common side effects included nausea (52.6%), fever (36.4%), and diarrhea (28.4%). Conclusions: Misoprostol alone is a highly effective method of pregnancy termination; future research should explore strategies to maximize effectiveness in clinical and non-clinical settings

The Cardiometabolic Health of African Immigrants in High-Income Countries: A Systematic Review

In recent decades, the number of African immigrants in high-income countries (HICs) has increased significantly. However, the cardiometabolic health of this population remains poorly examined. Thus, we conducted a systematic review to examine the prevalence of cardiometabolic risk factors among sub-Saharan African immigrants residing in HICs. Studies were identified through searches in electronic databases including PubMed, Embase, CINAHL, Cochrane, Scopus, and Web of Science up to July 2021. Data on the prevalence of cardiometabolic risk factors were extracted and synthesized in a narrative format, and a meta-analysis of pooled proportions was also conducted. Of 8655 unique records, 35 articles that reported data on the specific African countries of origin of African immigrants were included in the review. We observed heterogeneity in the burden of cardiometabolic risk factors by African country of origin and HIC. The most prevalent risk factors were hypertension (27%, range: 6–55%), overweight/obesity (59%, range: 13–91%), and dyslipidemia (29%, range: 11–77.2%). The pooled prevalence of diabetes was 11% (range: 5–17%), and 7% (range: 0.7–14.8%) for smoking. Few studies examined kidney disease, hyperlipidemia, and diagnosed cardiometabolic disease. Policy changes and effective interventions are needed to improve the cardiometabolic health of African immigrants, improve care access and utilization, and advance health equity