Anti-JCV serology during natalizumab treatment: Review and meta-analysis of 17 independent patient cohorts analyzing anti-John Cunningham polyoma virus sero-conversion rates under natalizumab treatment and differences between technical and biological sero-converters.

BACKGROUND: Anti-John Cunningham virus (JCV) serology has been studied with varying results concerning longitudinal changes. OBJECTIVES AND METHODS: Results from 17 published natalizumab-treated multiple sclerosis (MS) patient cohorts were analyzed with common parameters and subsequently verified in two large independent cohorts with 722 and 499 patients from Germany and the United States. RESULTS: Published studies and the verification showed (1) a mean of 10.80% sero-negative patients presented with sero-status change to positivity per year; (2) patients, who sero-convert to index values <0.9, convert from near the threshold and have a high probability of reverting with time; (3) patients, who convert to index values >0.9, start with low index values; (4) while JCV sero-positive patients with low index values sometimes revert to sero-negativity, patients with high index values almost never revert; and (5) the conversion rate of natalizumab-treated patients is three to four times higher than the biological conversion by age. CONCLUSION: JCV sero-conversion was comparable using standardized parameters and indicates influence of natalizumab on JCV immune control. Converters to low index values are probably consistently infected with JCV with varying low levels of activity, in line with their low risk to develop progressive multifocal leukoencephalopathy (PML). Patients with high index values rarely revert back to sero-negativity.

Baseline EEG abnormalities in mild traumatic brain injury from the BIMA study.

The Brain Injury and Mechanisms of Action of HBO2 for Persistent Post-Concussive Symptoms after Mild Traumatic Brain Injury (BIMA), sponsored by the Department of Defense, is a randomized, double-blind, sham-controlled trial of hyperbaric oxygen (HBO2) in service members with persistent post-concussive symptoms following mild TBI, undergoing comprehensive assessments. The clinical EEG was assessed by neurologists for slow wave activity, ictal/interictal epileptiform abnormalities, and background periodic discharges. There is scant literature about EEG findings in this population, so we report baseline clinical EEG results and explore associations with other evaluations, including demographics, medication, neurological assessments, and clinical MRI outcomes. Seventy-one participants were enrolled: median age 32 years, 99% male, 49% comorbid PTSD, 28% with mTBI in the previous year, 32% blast injuries only, and 73% multiple injuries. All participants reported medication use (mean medications = 8, SD = 5). Slowing was present in 39%: generalized 37%, localized 8%, both 6%. No other abnormalities were identified. Slowing was not significantly associated with demographics, medication or neurological evaluation. Participants without EEG abnormalities paradoxically had significantly higher number of white matter hyperintensities as identified on MRI (p = 0.003). EEG slowing is present in more than one-third of participants in this study without evidence of associations with demographics, medications or neurological findings. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01611194; https://clinicaltrials.gov/show/NCT01611194.

Selectivity in the Use of Gi/o Proteins Is Determined by the DRF Motif in CXCR6 and Is Cell-Type Specific.

CXCR6, the receptor for CXCL16, is expressed on multiple cell types and can be a coreceptor for human immunodeficiency virus 1. Except for CXCR6, all human chemokine receptors contain the D(3.49)R(3.50)Y(3.51) sequence, and all but two contain A(3.53) at the cytoplasmic terminus of the third transmembrane helix (H3C), a region within class A G protein-coupled receptors that contacts G proteins. In CXCR6, H3C contains D(3.49)R(3.50)F(3.51)I(3.52)V(3.53) at positions 126-130. We investigated the importance and interdependence of the canonical D126 and the noncanonical F128 and V130 in CXCR6 by mutating D126 to Y, F128 to Y, and V130 to A singly and in combination. For comparison, we mutated the analogous positions D142, Y144, and A146 to Y, F, and V, respectively, in CCR6, a related receptor containing the canonical sequences. Mutants were analyzed in both human embryonic kidney 293T and Jurkat E6-1 cells. Our data show that for CXCR6 and/or CCR6, mutations in H3C can affect both receptor signaling and chemokine binding; noncanonical H3C sequences are functionally linked, with dual changes mitigating the effects of single mutations; mutations in H3C that compromise receptor activity show selective defects in the use of individual Gi/o proteins; and the effects of mutations in H3C on receptor function and selectivity in Gi/o protein use can be cell-type specific. Our findings indicate that the ability of CXCR6 to make promiscuous use of the available Gi/o proteins is exquisitely dependent on sequences within the H3C and suggest that the native sequence allows for preservation of this function across different cellular environments.

Poachers turned gamekeepers in T cells.

The efficacy of therapeutic T cells is enhanced by incorporating mutations associated with autoimmunity or lymphoma.

Palmitoylation promotes pores.

Palmitoylation of intact or cleaved gasdermin D causes plasma membrane pore formation.

Taking down tumors takes atypical integrins.

An unexpected integrin pairing enhances T cell receptor signaling and cytotoxicity in antitumor T cells.

Systemic inflammation from the brain.

The actions of glucagon-like peptide 1 receptor agonists in the CNS reduce systemic inflammation.

Nanobody pharmacology.

Antibody fragments can act as pharmacological tools to modulate the functions of G protein-coupled receptors.

Association between serum multi-protein biomarker profile and real-world disability in multiple sclerosis.

Few studies examined blood biomarkers informative of patient-reported outcome (PRO) of disability in people with multiple sclerosis (MS). We examined the associations between serum multi-protein biomarker profiles and patient-reported MS disability. In this cross-sectional study (2017-2020), adults with diagnosis of MS (or precursors) from two independent clinic-based cohorts were divided into a training and test set. For predictors, we examined seven clinical factors (age at sample collection, sex, race/ethnicity, disease subtype, disease duration, disease-modifying therapy [DMT], and time interval between sample collection and closest PRO assessment) and 19 serum protein biomarkers potentially associated with MS disease activity endpoints identified from prior studies. We trained machine learning (ML) models (Least Absolute Shrinkage and Selection Operator regression [LASSO], Random Forest, Extreme Gradient Boosting, Support Vector Machines, stacking ensemble learning, and stacking classification) for predicting Patient Determined Disease Steps (PDDS) score as the primary endpoint and reported model performance using the held-out test set. The study included 431 participants (mean age 49 years, 81% women, 94% non-Hispanic White). For binary PDDS score, combined feature input of routine clinical factors and the 19 proteins consistently outperformed base models (comprising clinical features alone or clinical features plus one single protein at a time) in predicting severe (PDDS ≥ 4) versus mild/moderate (PDDS < 4) disability across multiple machine learning approaches, with LASSO achieving the best area under the curve (AUCPDDS = 0.91) and other metrics. For ordinal PDDS score, LASSO model comprising combined clinical factors and 19 proteins as feature input (R2PDDS = 0.31) again outperformed base models. The two best-performing LASSO models (i.e., binary and ordinal PDDS score) shared six clinical features (age, sex, race/ethnicity, disease subtype, disease duration, DMT efficacy) and nine proteins (cluster of differentiation 6, CUB-domain-containing protein 1, contactin-2, interleukin-12 subunit-beta, neurofilament light chain [NfL], protogenin, serpin family A member 9, tumor necrosis factor superfamily member 13B, versican). By comparison, LASSO models with clinical features plus one single protein at a time as feature input did not select either NfL or glial fibrillary acidic protein (GFAP) as a final feature. Forcing either NfL or GFAP as a single protein feature into models did not improve performance beyond clinical features alone. Stacking classification model using five functional pathways to represent multiple proteins as meta-features implicated those involved in neuroaxonal integrity as significant contributors to predictive performance. Thus, serum multi-protein biomarker profiles improve the prediction of real-world MS disability status beyond clinical profile alone or clinical profile plus single protein biomarker, reaching clinically actionable performance.

In Science Journals.

Highlights from the Science family of journals.

In Science Journals.

Highlights from the Science family of journals.

In Science Journals.

Highlights from the Science family of journals.

In Science Journals.

Highlights from the Science family of journals.

In Science Journals.

Highlights from the Science family of journals.

A prospective trial of hyperbaric oxygen for chronic sequelae after brain injury (HYBOBI).

OBJECTIVE: Some practitioners advocate hyperbaric oxygen (HBO2) for sequelae following brain injury. This study assessed recruitment, tolerance and safety in preparation for a randomized clinical trial. DESIGN: Prospective, open-label feasibility study. SETTING: Hyperbaric medicine department of a tertiary academic hospital. PARTICIPANTS: Participatory adult outpatients with problems from stroke (n=22), anoxia (13) or trauma (28) that occurred at least 12 months before enrollment, without contraindications to HBO2. Sixty-three participants enrolled in the study (21 females,42 males). Age was 45 +/- 16 years (18-76) and time from injury was 6.9 +/- 7.1 years (1.0-29.3). Fifty-three completed the study intervention, and 55 completed the assessment battery. METHODS: PARTICIPANTS underwent 60 daily HBO2 sessions (1.5 atm abs, 100% oxygen, 60 minutes). Assessments were conducted at baseline, after the HBO2 course, and six months later. MAIN OUTCOME MEASUREMENTS: The prime outcome was feasibility. To estimate the immediate and long-term effects of HBO2, we assessed neuropsychological measures, questionnaires, neurologic exam and physical functioning measures. Some participants also had pre- and post-HBO2 speech evaluation (n=27) and neuroimaging (n=17). RESULTS: The study met our a priori definition for feasibility for recruitment, but 44% required additional time to complete the 60 sessions (up to 105 days). HBO2-related adverse events were rare and not serious. Although many participants reported improvement in symptoms (51% memory, 51% attention/concentration, 48% balance/coordination, 45% endurance, 20% sleep) post-HBO2, and 93% reported that they would participate in the study again, no standardized testing showed clinically important improvement. In the small subset of those undergoing neuroimaging, apparent improvement was observed in auditory functional MRI (8/13), MR spectroscopy (9/17) and brain perfusionby CT angiography (5/9). CONCLUSIONS: Conducting an HBO2 clinical trial in this population was feasible. Although many participants reported improvement, the lack of concurrent controls limits the strength of inferences from this trial, especially considering lack of change in standardized testing. The clinical relevance of neuroimaging changes is unknown. The findings of this study may indicate a need for caution when considering the broad application of HBO2 more than one year after brain injury due to stroke, severe TBI and anoxia, until there is more compelling evidence from carefully designed sham-controlled, blinded clinical trials.

Dopamine suppresses ILC2s.

Dopamine reduces the allergen-induced responses of group 2 innate lymphoid cells to alleviate airway inflammation in mice.

Bias comes in layers.

GINIP promotes Gßγ signaling while inhibiting Gαi signaling to fine-tune GPCR-mediated neuromodulation.

Bypassing ACE2.

SARS-CoV-2 binds to a lysosomal transmembrane protein to enter cells independently of ACE2.

Stressing the gut-brain axis.

Stress-induced changes in gut microbiota cause γδ T cell migration to the meninges, where they affect behavior in mice.

Arrestins lie in wait.

Preassociation of ß-arrestins with the plasma membrane facilitates their interactions with GPCRs.