Charting a global research strategy for progressive MS-An international progressive MS Alliance proposal.

BACKGROUND: Progressive forms of multiple sclerosis (MS) affect more than 1 million individuals globally. Recent approvals of ocrelizumab for primary progressive MS and siponimod for active secondary progressive MS have opened the therapeutic door, though results from early trials of neuroprotective agents have been mixed. The recent introduction of the term 'active' secondary progressive MS into the therapeutic lexicon has introduced potential confusion to disease description and thereby clinical management. OBJECTIVE: This paper reviews recent progress, highlights continued knowledge and proposes, on behalf of the International Progressive MS Alliance, a global research strategy for progressive MS. METHODS: Literature searches of PubMed between 2015 and May, 2021 were conducted using the search terms "progressive multiple sclerosis", "primary progressive multiple sclerosis", "secondary progressive MS". Proposed strategies were developed through a series of in-person and virtual meetings of the International Progressive MS Alliance Scientific Steering Committee. RESULTS: Sustaining and accelerating progress will require greater understanding of underlying mechanisms, identification of potential therapeutic targets, biomarker discovery and validation, and conduct of clinical trials with improved trial design. Encouraging developments in symptomatic and rehabilitative interventions are starting to address ongoing challenges experienced by people with progressive MS. CONCLUSION: We need to manage these challenges and realise the opportunities in the context of a global research strategy, which will improve quality of life for people with progressive MS.

COVID-19 in the pregnant or postpartum MS patient: Symptoms and outcomes.

Women with multiple sclerosis (MS) are often of childbearing age. Thirty-six women with MS who were pregnant (n = 27) or within 6 weeks postpartum (n = 9) were reported in the North American COViMS registry and their COVID-19 outcomes were described. One pregnant and one postpartum woman were hospitalized. No deaths occurred. To compare COVID-19 clinical outcomes in pregnant and postpartum females with females who were not pregnant or postpartum, a 1:2 propensity score match was performed. While not powered to detect small differences, it was reassuring that no increased risks for those with MS who were pregnant/postpartum were revealed.

From the prodromal stage of multiple sclerosis to disease prevention.

A prodrome is an early set of signs or symptoms that indicate the onset of a disease before more typical symptoms develop. Prodromal stages are well recognized in some neurological and immune-mediated diseases such as Parkinson disease, schizophrenia, type 1 diabetes mellitus and rheumatoid arthritis. Emerging evidence indicates that a prodromal stage exists in multiple sclerosis (MS), raising the possibility of intervention at this stage to delay or prevent the development of classical MS. However, much remains unclear about the prodromal stage of MS and considerable research is needed to fully characterize the prodrome and develop standardized criteria to reliably identify individuals with prodromal MS who are at high risk of progressing to a diagnosis of MS. In this Roadmap, we draw on work in other diseases to propose a disease framework for MS that incorporates the prodromal stage, and set out key steps and considerations needed in future research to fully characterize the MS prodrome, identify early disease markers and develop standardized criteria that will enable reliable identification of individuals with prodromal MS, thereby facilitating trials of interventions to slow or stop progression beyond the prodrome.

COVID-19 in Patients With Neuromyelitis Optica Spectrum Disorders and Myelin Oligodendrocyte Glycoprotein Antibody Disease in North America: From the COViMS Registry.

BACKGROUND AND OBJECTIVE: To describe the impact of coronavirus disease 2019 (COVID-19) on people with neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD). METHODS: The COVID-19 Infections in Multiple Sclerosis (MS) and Related Diseases (COViMS) Registry collected data on North American patients with MS and related diseases with laboratory-positive or highly suspected SARS-CoV-2 infection. Deidentified data were entered into a web-based registry by health care providers. Data were analyzed using t-tests, Pearson χ2 tests, or Fisher exact tests for categorical variables. Univariate logistic regression models examined effects of risk factors and COVID-19 clinical severity. RESULTS: As of June 7, 2021, 77 patients with NMOSD and 20 patients with MOGAD were reported in the COViMS Registry. Most patients with NMOSD were laboratory positive for SARS-CoV-2 and taking rituximab at the time of COVID-19 diagnosis. Most patients with NMOSD were not hospitalized (64.9% [95% CI: 53.2%-75.5%]), whereas 15.6% (95% CI: 8.3%-25.6%) were hospitalized only, 9.1% (95% CI: 3.7%-17.8%) were admitted to the ICU and/or ventilated, and 10.4% (95% CI: 4.6%-19.5%) died. In patients with NMOSD, having a comorbidity was the sole factor identified for poorer COVID-19 outcome (OR = 6.0, 95% CI: 1.79-19.98). Most patients with MOGAD were laboratory positive for SARS-CoV-2, and almost half were taking rituximab. Among patients with MOGAD, 75.0% were not hospitalized, and no deaths were recorded; no factors were different between those not hospitalized and those hospitalized, admitted to the ICU, or ventilated. DISCUSSION: Among the reported patients with NMOSD, a high mortality rate was observed, and the presence of comorbid conditions was associated with worse COVID-19 outcome. There were no deaths reported in the patients with MOGAD, although these observations are limited due to small sample size.

Outcomes and Risk Factors Associated With SARS-CoV-2 Infection in a North American Registry of Patients With Multiple Sclerosis.

Importance: Emergence of SARS-CoV-2 causing COVID-19 prompted the need to gather information on clinical outcomes and risk factors associated with morbidity and mortality in patients with multiple sclerosis (MS) and concomitant SARS-CoV-2 infections. Objective: To examine outcomes and risk factors associated with COVID-19 clinical severity in a large, diverse cohort of North American patients with MS. Design, Setting, and Participants: This analysis used deidentified, cross-sectional data on patients with MS and SARS-CoV-2 infection reported by health care professionals in North American academic and community practices between April 1, 2020, and December 12, 2020, in the COVID-19 Infections in MS Registry. Health care professionals were asked to report patients after a minimum of 7 days from initial symptom onset and after sufficient time had passed to observe the COVID-19 disease course through resolution of acute illness or death. Data collection began April 1, 2020, and is ongoing. Exposures: Laboratory-positive SARS-CoV-2 infection or highly suspected COVID-19. Main Outcomes and Measures: Clinical outcome with 4 levels of increasing severity: not hospitalized, hospitalization only, admission to the intensive care unit and/or required ventilator support, and death. Results: Of 1626 patients, most had laboratory-positive SARS-CoV-2 infection (1345 [82.7%]), were female (1202 [74.0%]), and had relapsing-remitting MS (1255 [80.4%]). A total of 996 patients (61.5%) were non-Hispanic White, 337 (20.8%) were Black, and 190 (11.7%) were Hispanic/Latinx. The mean (SD) age was 47.7 (13.2) years, and 797 (49.5%) had 1 or more comorbidity. The overall mortality rate was 3.3% (95% CI, 2.5%-4.3%). Ambulatory disability and older age were each independently associated with increased odds of all clinical severity levels compared with those not hospitalized after adjusting for other risk factors (nonambulatory: hospitalization only, odds ratio [OR], 2.8 [95% CI, 1.6-4.8]; intensive care unit/required ventilator support, OR, 3.5 [95% CI, 1.6-7.8]; death, OR, 25.4 [95% CI, 9.3-69.1]; age [every 10 years]: hospitalization only, OR, 1.3 [95% CI, 1.1-1.6]; intensive care unit/required ventilator support, OR, 1.3 [95% CI, 0.99-1.7]; death, OR, 1.8 [95% CI, 1.2-2.6]). Conclusions and Relevance: In this registry-based cross-sectional study, increased disability was independently associated with worse clinical severity including death from COVID-19. Other risk factors for worse outcomes included older age, Black race, cardiovascular comorbidities, and recent treatment with corticosteroids. Knowledge of these risk factors may improve the treatment of patients with MS and COVID-19 by helping clinicians identify patients requiring more intense monitoring or COVID-19 treatment.

A screen for suppressors of gross chromosomal rearrangements identifies a conserved role for PLP in preventing DNA lesions.

Genome instability is a hallmark of cancer cells. One class of genome aberrations prevalent in tumor cells is termed gross chromosomal rearrangements (GCRs). GCRs comprise chromosome translocations, amplifications, inversions, deletion of whole chromosome arms, and interstitial deletions. Here, we report the results of a genome-wide screen in Saccharomyces cerevisiae aimed at identifying novel suppressors of GCR formation. The most potent novel GCR suppressor identified is BUD16, the gene coding for yeast pyridoxal kinase (Pdxk), a key enzyme in the metabolism of pyridoxal 5' phosphate (PLP), the biologically active form of vitamin B6. We show that Pdxk potently suppresses GCR events by curtailing the appearance of DNA lesions during the cell cycle. We also show that pharmacological inhibition of Pdxk in human cells leads to the production of DSBs and activation of the DNA damage checkpoint. Finally, our evidence suggests that PLP deficiency threatens genome integrity, most likely via its role in dTMP biosynthesis, as Pdxk-deficient cells accumulate uracil in their nuclear DNA and are sensitive to inhibition of ribonucleotide reductase. Since Pdxk links diet to genome stability, our work supports the hypothesis that dietary micronutrients reduce cancer risk by curtailing the accumulation of DNA damage and suggests that micronutrient depletion could be part of a defense mechanism against hyperproliferation.

Elg1 forms an alternative PCNA-interacting RFC complex required to maintain genome stability.

BACKGROUND: Genome instability is a hallmark of cancer and plays a critical role in generating the myriad of phenotypes selected for during tumor progression. However, the mechanisms that prevent genome rearrangements remain poorly understood. RESULTS: To elucidate the mechanisms that ensure genome stability, we screened a collection of candidate genes for suppressors of gross chromosomal rearrangements (GCRs) in budding yeast. One potent suppressor gene encodes Elg1, a conserved but uncharacterized homolog of the large RFC subunit Rfc1 and the alternative RFC subunits Ctf18/Chl12 and Rad24. Our results are consistent with the hypothesis that Elg1 forms a novel and distinct RFC-like complex in both yeast and human cells. We find that Elg1 is required for efficient S phase progression and telomere homeostasis in yeast. Elg1 interacts physically with the PCNA homolog Pol30 and the FEN-1 homolog Rad27. The physical and genetic interactions suggest a role for Elg1 in Okazaki fragment maturation. Furthermore, Elg1 acts in concert with the alternative Rfc1-like proteins Rad24 and Ctf18 to enable Rad53 checkpoint kinase activation in response to replication stress. CONCLUSIONS: Collectively, these results reveal that Elg1 forms a novel and conserved alternative RFC complex. Furthermore, we propose that genome instability arises at high frequency in elg1 mutants due to a defect in Okazaki fragment maturation.

The F-box protein Dia2 overcomes replication impedance to promote genome stability in Saccharomyces cerevisiae.

The maintenance of DNA replication fork stability under conditions of DNA damage and at natural replication pause sites is essential for genome stability. Here, we describe a novel role for the F-box protein Dia2 in promoting genome stability in the budding yeast Saccharomyces cerevisiae. Like most other F-box proteins, Dia2 forms a Skp1-Cdc53/Cullin-F-box (SCF) E3 ubiquitin-ligase complex. Systematic analysis of genetic interactions between dia2Delta and approximately 4400 viable gene deletion mutants revealed synthetic lethal/synthetic sick interactions with a broad spectrum of DNA replication, recombination, checkpoint, and chromatin-remodeling pathways. dia2Delta strains exhibit constitutive activation of the checkpoint kinase Rad53 and elevated counts of endogenous DNA repair foci and are unable to overcome MMS-induced replicative stress. Notably, dia2Delta strains display a high rate of gross chromosomal rearrangements (GCRs) that involve the rDNA locus and an increase in extrachromosomal rDNA circle (ERC) formation, consistent with an observed enrichment of Dia2 in the nucleolus. These results suggest that Dia2 is essential for stable passage of replication forks through regions of damaged DNA and natural fragile regions, particularly the replication fork barrier (RFB) of rDNA repeat loci. We propose that the SCFDia2 ubiquitin ligase serves to modify or degrade protein substrates that would otherwise impede the replication fork in problematic regions of the genome.

The ramC gene is required for morphogenesis in Streptomyces coelicolor and expressed in a cell type-specific manner under the direct control of RamR.

The bacterium Streptomyces coelicolor produces two cell types during the course of its life cycle: the aerial hyphae, which metamorphose into spores, and the substrate hyphae, which synthesize antibiotics. We show that the genes ramC and ramR are required for the production of the aerial hyphae but are dispensable for vegetative growth and antibiotic synthesis. We find that ramC is expressed in the substrate hyphae and shut off in the aerial hyphae by the time visible signs of sporulation-associated septation are evident. Production of RamC requires the developmental regulators bldD, cprA and ramR, but not bldM or bldN, and we show that the RamR protein interacts directly with DNA in the ramC promoter region suggesting that it is, at least in part, responsible for regulating ramC expression.