The cerebrospinal fluid immune cell landscape in animal models of multiple sclerosis

The fluid compartment surrounding the central nervous system (CNS) is a unique source of immune cells capable of reflecting the pathophysiology of neurologic diseases. While human clinical and experimental studies often employ cerebrospinal fluid (CSF) analysis, assessment of CSF in animal models of disease are wholly uncommon, particularly in examining the cellular component. Barriers to routine assessment of CSF in animal models of multiple sclerosis (MS) include limited sample volume, blood contamination, and lack of feasible longitudinal approaches. The few studies characterizing CSF immune cells in animal models of MS are largely outdated, but recent work employing transcriptomics have been used to explore new concepts in CNS inflammation and MS. Absence of extensive CSF data from rodent and other systems has curbed the overall impact of experimental models of MS. Future approaches, including examination of CSF myeloid subsets, single cell transcriptomics incorporating antigen receptor sequencing, and use of diverse animal models, may serve to overcome current limitations and provide critical insights into the pathogenesis of, and therapeutic developments for, MS

Asymmetric additions to dienes catalysed by a dithiophosphoric acid.

Chiral Brønsted acids (proton donors) have been shown to facilitate a broad range of asymmetric chemical transformations under catalytic conditions without requiring additional toxic or expensive metals. Although the catalysts developed thus far are remarkably effective at activating polarized functional groups, it is not clear whether organic Brønsted acids can be used to catalyse highly enantioselective transformations of unactivated carbon-carbon multiple bonds. This deficiency persists despite the fact that racemic acid-catalysed Markovnikov additions to alkenes are well known chemical transformations. Here we show that chiral dithiophosphoric acids can catalyse the intramolecular hydroamination and hydroarylation of dienes and allenes to generate heterocyclic products in exceptional yield and enantiomeric excess. We present a mechanistic hypothesis that involves the addition of the acid catalyst to the diene, followed by nucleophilic displacement of the resulting dithiophosphate intermediate; we also report mass spectroscopic and deuterium labelling studies in support of the proposed mechanism. The catalysts and concepts revealed in this study should prove applicable to other asymmetric functionalizations of unsaturated systems

The cerebrospinal fluid immune cell landscape in animal models of multiple sclerosis

The fluid compartment surrounding the central nervous system (CNS) is a unique source of immune cells capable of reflecting the pathophysiology of neurologic diseases. While human clinical and experimental studies often employ cerebrospinal fluid (CSF) analysis, assessment of CSF in animal models of disease are wholly uncommon, particularly in examining the cellular component. Barriers to routine assessment of CSF in animal models of multiple sclerosis (MS) include limited sample volume, blood contamination, and lack of feasible longitudinal approaches. The few studies characterizing CSF immune cells in animal models of MS are largely outdated, but recent work employing transcriptomics have been used to explore new concepts in CNS inflammation and MS. Absence of extensive CSF data from rodent and other systems has curbed the overall impact of experimental models of MS. Future approaches, including examination of CSF myeloid subsets, single cell transcriptomics incorporating antigen receptor sequencing, and use of diverse animal models, may serve to overcome current limitations and provide critical insights into the pathogenesis of, and therapeutic developments for, MS

B cells are capable of independently eliciting rapid reactivation of encephalitogenic CD4 T cells in a murine model of multiple sclerosis

<div><p>Recent success with B cell depletion therapies has revitalized efforts to understand the pathogenic role of B cells in Multiple Sclerosis (MS). Using the adoptive transfer system of experimental autoimmune encephalomyelitis (EAE), a murine model of MS, we have previously shown that mice in which B cells are the only MHCII-expressing antigen presenting cell (APC) are susceptible to EAE. However, a reproducible delay in the day of onset of disease driven by exclusive B cell antigen presentation suggests that B cells require optimal conditions to function as APCs in EAE. In this study, we utilize an <i>in vivo</i> genetic system to conditionally and temporally regulate expression of MHCII to test the hypothesis that B cell APCs mediate attenuated and delayed neuroinflammatory T cell responses during EAE. Remarkably, induction of MHCII on B cells following the transfer of encephalitogenic CD4 T cells induced a rapid and robust form of EAE, while no change in the time to disease onset occurred for recipient mice in which MHCII is induced on a normal complement of APC subsets. Changes in CD4 T cell activation over time did not account for more rapid onset of EAE symptoms in this new B cell-mediated EAE model. Our system represents a novel model to study how the timing of pathogenic cognate interactions between lymphocytes facilitates the development of autoimmune attacks within the CNS.</p></div

Demographics and baseline disease characteristics of Black and Hispanic patients with multiple sclerosis in the open-label, single-arm, multicenter, phase IV CHIMES trial

BACKGROUND: Black/African American patients with multiple sclerosis (BpwMS) and Hispanic/Latino patients with multiple sclerosis (HpwMS), who historically have been underrepresented in multiple sclerosis (MS) clinical trials, exhibit greater disease severity and more rapid disease progression than White patients with MS (WpwMS). The lack of diversity and inclusion in clinical trials, which may be due to barriers at the system, patient and study levels, impacts the ability to effectively assess risks, benefits and treatment responses in a generalized patient population. METHODS: CHIMES (Characterization of Ocrelizumab in Minorities With Multiple Sclerosis), an open-label, single-arm, multicenter, phase IV study of self-identified BpwMS and HpwMS aged 18-65 years with relapsing MS and an Expanded Disability Status Score (EDSS) of ≤5.5, was developed in collaboration with patients with MS, national advocacy groups and clinical researchers. Patients were enrolled at study centers across the US, including Puerto Rico, and 1 site in Kenya. RESULTS: A total of 182 patients enrolled in CHIMES: 113 (62.1%) were BpwMS, and 69 (37.9%) were HpwMS; the mean (SD) baseline EDSS score was 2.4 (1.4), and 62.6% of patients were treatment naive. Using the pooled non-BpwMS/HpwMS group in the OPERA ocrelizumab trials as a reference population, patients enrolled in CHIMES were younger, had a higher mean body mass and had a greater T2 lesion volume but similar T2 lesion number on MRI. CONCLUSION: BpwMS and HpwMS have been consistently underrepresented in clinical trials, limiting the understanding of disease biology and response to treatment in this population. Data from the CHIMES study revealed differences in demographics and some baseline disease characteristics and disease burden between BpwMS and HpwMS vs WpwMS. These differences could have an impact when assessing clinical outcomes in BpwMS and HpwMS. GOV IDENTIFIER: NCT04377555

The role of B cells in primary progressive multiple sclerosis

The success of ocrelizumab in reducing confirmed disability accumulation in primary progressive multiple sclerosis (PPMS) via CD20-targeted depletion implicates B cells as causal agents in the pathogenesis of PPMS. This review explores the possible mechanisms by which B cells contribute to disease progression in PPMS, specifically exploring cytokine production, antigen presentation, and antibody synthesis. B cells may contribute to disease progression in PPMS through cytokine production, specifically GM-CSF and IL-6, which can drive naïve T-cell differentiation into pro-inflammatory Th1/Th17 cells. B cell production of the cytokine LT-α may induce follicular dendritic cell production of CXCL13 and lead indirectly to T and B cell infiltration into the CNS. In contrast, production of IL-10 by B cells likely induces an anti-inflammatory effect that may play a role in reducing neuroinflammation in PPMS. Therefore, reduced production of IL-10 may contribute to disease worsening. B cells are also capable of potent antigen presentation and may induce pro-inflammatory T-cell differentiation via cognate interactions. B cells may also contribute to disease activity via antibody synthesis, although it\u27s unlikely the benefit of ocrelizumab in PPMS occurs via antibody decrement. Finally, various B cell subsets likely promulgate pro- or anti-inflammatory effects in MS

Spin Density wave instability in a ferromagnet

Ferromagnetic (FM) and incommensurate spin-density wave (ISDW) states are an unusual set of competing magnetic orders that are seldom observed in the same material without application of a polarizing magnetic field. We report, for the first time, the discovery of an ISDW state that is derived from a FM ground state through a Fermi surface (FS) instability in Fe$_3$Ga$_4$. This was achieved by combining neutron scattering experiments with first principles simulations. Neutron diffraction demonstrates that Fe$_3$Ga$_4$ is in an ISDW state at intermediate temperatures and that there is a conspicuous re-emergence of ferromagnetism above 360 K. First principles calculations show that the ISDW ordering wavevector is in excellent agreement with a prominent nesting condition in the spin-majority FS demonstrating the discovery of a novel instability for FM metals; ISDW formation due to Fermi surface nesting in a spin-polarized Fermi surface.Comment: 6 pages with 4 figures. Supplemental Materials Include

The relation between 13CO(2-1) line width in molecular clouds and bolometric luminosity of associated IRAS sources

We search for evidence of a relation between properties of young stellar objects (YSOs) and their parent molecular clouds to understand the initial conditions of high-mass star formation. A sample of 135 sources was selected from the Infrared Astronomical Satellite (IRAS) Point Source Catalog, on the basis of their red color to enhance the possibility of discovering young sources. Using the Kolner Observatorium fur SubMillimeter Astronomie (KOSMA) 3-m telescope, a single-point survey in 13CO(2-1) was carried out for the entire sample, and 14 sources were mapped further. Archival mid-infrared (MIR) data were compared with the 13CO emissions to identify evolutionary stages of the sources. A 13CO observed sample was assembled to investigate the correlation between 13CO line width of the clouds and the luminosity of the associated YSOs. We identified 98 sources suitable for star formation analyses for which relevant parameters were calculated. We detected 18 cores from 14 mapped sources, which were identified with eight pre-UC HII regions and one UC HII region, two high-mass cores earlier than pre-UC HII phase, four possible star forming clusters, and three sourceless cores. By compiling a large (360 sources) 13CO observed sample, a good correlation was found between the 13CO line width of the clouds and the bolometric luminosity of the associated YSOs, which can be fitted as a power law: lg(dV13/km/s)=-0.023+0.135lg(Lbol/Lsolar). Results show that luminous (>10^3Lsolar) YSOs tend to be associated with both more massive and more turbulent (dV13>2km/s) molecular cloud structures.Comment: Accepted by Astronomy and Astrophysics; this version: sent to publisher; 13 pages, 4 figures, 2 tables, 1 online appendi