•We identify vinylsulfones as lead candidate inhibitors of Ebola virus and SARS-CoV.•K11777 inhibited Ebola virus and SARS-CoV entry in the sub-nanomolar range.•Potent inhibition correlated with the ...presence of a basic piperazine ring at P3.•Serine protease inhibitor and K11777 blocked coronavirus entry into caco-2 cells.•Camostat protected 6 out of ten mice from lethal infection with SARS-CoV.
In order to gain entry into cells, diverse viruses, including Ebola virus, SARS-coronavirus and the emerging MERS-coronavirus, depend on activation of their envelope glycoproteins by host cell proteases. The respective enzymes are thus excellent targets for antiviral intervention. In cell culture, activation of Ebola virus, as well as SARS- and MERS-coronavirus can be accomplished by the endosomal cysteine proteases, cathepsin L (CTSL) and cathepsin B (CTSB). In addition, SARS- and MERS-coronavirus can use serine proteases localized at the cell surface, for their activation. However, it is currently unclear which protease(s) facilitate viral spread in the infected host. We report here that the cysteine protease inhibitor K11777, ((2S)-N-(1E,3S)-1-(benzenesulfonyl)-5-phenylpent-1-en-3-yl-2-{(E)-4-methylpiperazine-1-carbonylamino}-3-phenylpropanamide) and closely-related vinylsulfones act as broad-spectrum antivirals by targeting cathepsin-mediated cell entry. K11777 is already in advanced stages of development for a number of parasitic diseases, such as Chagas disease, and has proven to be safe and effective in a range of animal models. K11777 inhibition of SARS-CoV and Ebola virus entry was observed in the sub-nanomolar range. In order to assess whether cysteine or serine proteases promote viral spread in the host, we compared the antiviral activity of an optimized K11777-derivative with that of camostat, an inhibitor of TMPRSS2 and related serine proteases. Employing a pathogenic animal model of SARS-CoV infection, we demonstrated that viral spread and pathogenesis of SARS-CoV is driven by serine rather than cysteine proteases and can be effectively prevented by camostat. Camostat has been clinically used to treat chronic pancreatitis, and thus represents an exciting potential therapeutic for respiratory coronavirus infections. Our results indicate that camostat, or similar serine protease inhibitors, might be an effective option for treatment of SARS and potentially MERS, while vinyl sulfone-based inhibitors are excellent lead candidates for Ebola virus therapeutics.
An urgent global quest for effective therapies to prevent and treat coronavirus disease 2019 (COVID-19) is ongoing. We previously described REGN-COV2, a cocktail of two potent neutralizing antibodies ...(REGN10987 and REGN10933) that targets nonoverlapping epitopes on the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. In this report, we evaluate the in vivo efficacy of this antibody cocktail in both rhesus macaques, which may model mild disease, and golden hamsters, which may model more severe disease. We demonstrate that REGN-COV-2 can greatly reduce virus load in the lower and upper airways and decrease virus-induced pathological sequelae when administered prophylactically or therapeutically in rhesus macaques. Similarly, administration in hamsters limits weight loss and decreases lung titers and evidence of pneumonia in the lungs. Our results provide evidence of the therapeutic potential of this antibody cocktail.
A major public health concern associated with schizophrenia and psychotic disorders is the long-term disability that involves impaired cognition, lack of social support, and an inability to function ...independently in the community. A critical goal of early detection and intervention studies in psychosis is therefore to understand the factors leading to this often profound impairment.
To develop a predictive model of functional (social and role) outcome in a clinical high-risk sample for psychosis.
Prospective, naturalistic, longitudinal 3- to 5-year follow-up study.
The Recognition and Prevention Program in New York, a research clinic located in the Zucker Hillside Hospital in New York.
One hundred one treatment-seeking patients at clinical high risk for psychosis. Ninety-two (91%) were followed up prospectively for a mean (SD) of 3 (1.6) years.
Neurocognitive and clinical assessment.
The primary outcome variables were social and role functioning at the last follow-up visit.
Poor social outcome was predicted by reduced processing speed (odds ratio OR, 1.38; 95% CI, 1.050-1.823; P = .02), impaired social functioning at baseline (OR, 1.85; 95% CI, 1.258-2.732; P = .002), and total disorganized symptoms (OR, 5.06; 95% CI, 1.548-16.527; P = .007). Reduced performance on tests for verbal memory (OR, 1.74; 95% CI, 1.169-2.594; P = .006), role functioning at baseline (OR, 1.34; 95% CI, 1.053-1.711; P = .02), and motor disturbances (OR, 1.77; 95% CI, 1.060-2.969; P = .03) predicted role outcome. The areas under the curve for the social and role prediction models were 0.824 (95% CI, 0.736-0.913; P < .001) and 0.77 (95% CI, 0.68-0.87; P < .001), respectively, demonstrating a high discriminative ability. In addition, poor functional outcomes were not entirely dependent on the development of psychosis, because 40.3% and 45.5% of nonconverters at clinical high risk had poor social and role outcomes, respectively.
Results from this study support the increasing emphasis on functional decline as a critically important outcome that parallels conversion to psychosis and suggest that both psychosis and long-term functional disability are equally important targets for prevention. Reduced neurocognitive performance, functional impairments, and nonpositive attenuated symptoms at baseline were associated with an increased risk of poor functional outcomes in our sample. Poor functional outcomes were not entirely dependent on positive symptoms and the development of psychosis, further highlighting the need for intervention at this early stage of development for those who do and do not convert to a full-blown psychotic disorder.
Monoclonal antibodies against SARS-CoV-2 are a clinically validated therapeutic option against COVID-19. Because rapidly emerging virus mutants are becoming the next major concern in the fight ...against the global pandemic, it is imperative that these therapeutic treatments provide coverage against circulating variants and do not contribute to development of treatment-induced emergent resistance. To this end, we investigated the sequence diversity of the spike protein and monitored emergence of virus variants in SARS-COV-2 isolates found in COVID-19 patients treated with the two-antibody combination REGEN-COV, as well as in preclinical in vitro studies using single, dual, or triple antibody combinations, and in hamster in vivo studies using REGEN-COV or single monoclonal antibody treatments. Our study demonstrates that the combination of non-competing antibodies in REGEN-COV provides protection against all current SARS-CoV-2 variants of concern/interest and also protects against emergence of new variants and their potential seeding into the population in a clinical setting.
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•REGEN-COV retains neutralization potency against current variants of concern/interest•In vitro escape studies can predict emergence of viral variants in animals and humans•3 noncompeting mAb in combination reduce variant risk compared to a combination of 2•Treatment with REGEN-COV in humans does not lead to emergence of viral variants
Treatment with monoclonal antibody combinations limits generation of SARS-CoV-2 escape variants in humans and model animals and protects against current variants of concern.
Impaired social, role, and neurocognitive functioning are preillness characteristics of people who later develop psychosis. In people with schizophrenia, neurocognition and negative symptoms are ...associated with functional impairment. We examined the relative contributions of neurocognition and symptoms to social and role functioning over time in clinically high-risk (CHR) individuals and determined if negative symptoms mediated the influence of cognition on functioning.
Social, role, and neurocognitive functioning and positive, negative, and disorganized symptoms were assessed in 167 individuals at CHR for psychosis in the North American Prodrome Longitudinal Study Phase 1 (NAPLS-1), of whom 96 were reassessed at 12 months.
Regression analyses indicated that negative symptoms accounted for unique variance in social and role functioning at baseline and follow-up. Composite neurocognition accounted for unique, but modest, variance in social and role functioning at baseline and in role functioning at follow-up. Negative symptoms mediated the relationship between composite neurocognition and social and role functioning across time points. In exploratory analyses, individual tests (IQ estimate, Digit Symbol/Coding, verbal memory) selectively accounted for social and role functioning at baseline and follow-up after accounting for symptoms. When negative symptom items with content overlapping with social and role functioning measures were removed, the relationship between neurocognition and social and role functioning was strengthened.
The modest overlap among neurocognition, negative symptoms, and social and role functioning indicates that these domains make substantially separate contributions to CHR individuals.
Risk for psychosis is currently defined primarily on the basis of attenuated positive symptoms (APS), with no inclusion of the functional deficits characteristic of schizophrenia. Impaired social and ...role functioning have been of interest for reflecting poor outcome but far less is known about the developmental impact of these deficits as vulnerability or risk factors.
Age-appropriate social and role functioning were prospectively assessed in 100 individuals at clinical high risk (CHR) for psychosis included in the 8-site North American Prodromal Longitudinal Study database. A nested case-control design was used to compare changes in social and role functioning in 26 individuals converting to psychosis shortly after baseline assessment and 24 converting over a year later. Individuals in each converter subgroup were directly matched to a non-converter at the same site, controlling for time to conversion, age, gender, and severity of baseline symptoms.
At baseline, CHR subjects who later became psychotic were significantly more likely to be impaired socially than matched non-converters. Onset of psychosis did not further disrupt social difficulties. Role functioning showed some of the same trends, but the overall pattern was not as consistent as for the social domain. Controlling for neurocognition did not change the pattern of group differences.
Early impaired social functioning appears to be a risk factor for psychosis and, added to APS, could potentially contribute to accurate identification of CHR individuals and provide a new direction for early intervention to reduce long-term disability.
Fetal brain vulnerability to SARS-CoV-2 infection McMahon, Courtney L.; Castro, Joshua; Silvas, Jesus ...
Brain, behavior, and immunity,
August 2023, 2023-08-00, 20230801, Letnik:
112
Journal Article
Recenzirano
Odprti dostop
•SARS-CoV-2 transmission to the fetal brain occurs at later stages of gestation in a human ACE2-KI mouse model.•SARS-CoV-2 targets blood vessel-comprising endothelial cells, neurons, glia, and ...choroid plexus cells in the fetal brain.•.Following in utero infection, developmental and neurological consequences are seen in neonatal mice.•COVID-19 infection in pregnant hACE2-KI mice replicates infection severity and effects seen in pregnant women.
Whether or not SARS-CoV-2 can cross from mother to fetus during a prenatal infection has been controversial; however, recent evidence such as viral RNA detection in umbilical cord blood and amniotic fluid, as well as the discovery of additional entry receptors in fetal tissues suggests a potential for viral transmission to and infection of the fetus. Furthermore, neonates exposed to maternal COVID-19 during later development have displayed neurodevelopmental and motor skill deficiencies, suggesting the potential for consequential neurological infection or inflammation in utero. Thus, we investigated transmission potential of SARS-CoV-2 and the consequences of infection on the developing brain using human ACE2 knock-in mice. In this model, we found that viral transmission to the fetal tissues, including the brain, occurred at later developmental stages, and that infection primarily targeted male fetuses. In the brain, SARS-CoV-2 infection largely occurred within the vasculature, but also within other cells such as neurons, glia, and choroid plexus cells; however, viral replication and increased cell death were not observed in fetal tissues. Interestingly, early gross developmental differences were observed between infected and mock-infected offspring, and high levels of gliosis were seen in the infected brains 7 days post initial infection despite viral clearance at this time point. In the pregnant mice, we also observed more severe COVID-19 infections, with greater weight loss and viral dissemination to the brain, compared to non-pregnant mice. Surprisingly, we did not observe an increase in maternal inflammation or the antiviral IFN response in these infected mice, despite showing clinical signs of disease. Overall, these findings have concerning implications regarding neurodevelopment and pregnancy complications of the mother following prenatal COVID-19 exposure.
As part of the second phase of the North American Prodrome Longitudinal Study (NAPLS-2), Cannon and colleagues report, concurrently with the present article, on a risk calculator for the ...individualized prediction of a psychotic disorder in a 2-year period. The present study represents an external validation of the NAPLS-2 psychosis risk calculator using an independent sample of patients at clinical high risk for psychosis collected as part of the Early Detection, Intervention, and Prevention of Psychosis Program (EDIPPP).
Of the total EDIPPP sample of 210 subjects rated as being at clinical high risk based on the Structured Interview for Prodromal Syndromes, 176 had at least one follow-up assessment and were included in the construction of a new prediction model with six predictor variables in the NAPLS-2 psychosis risk calculator (unusual thoughts and suspiciousness, symbol coding test performance, verbal learning test performance, decline in social functioning, baseline age, and family history). Discrimination performance was assessed with the area under the receiver operating characteristic curve (AUC). The NAPLS-2 risk calculator was then used to generate a psychosis risk estimate for each case in the external validation sample.
The external validation model showed good discrimination, with an AUC of 0.790 (95% CI=0.644-0.937). In addition, the personalized risk generated by the risk calculator provided a solid estimation of the actual conversion outcome in the validation sample.
Two independent samples of clinical high-risk patients converge to validate the NAPLS-2 psychosis risk calculator. This prediction calculator represents a meaningful step toward early intervention and the personalized treatment of psychotic disorders.
Objectives
The aim of the present study was to systematically evaluate the prodrome to mania in youth.
Methods
New‐onset/worsening symptoms/signs of ≥ moderate severity preceding first mania were ...systematically assessed in 52 youth (16.2 ± 2.8 years) with a research diagnosis of bipolar I disorder (BD‐I). Youth and/or caregivers underwent semi‐structured interviews, using the Bipolar Prodrome Symptom Scale–Retrospective.
Results
The mania prodrome was reported to start gradually in most youth (88.5%), with either slow (59.6%) or rapid (28.8%) deterioration, while a rapid‐onset‐and‐deterioration prodrome was rare (11.5%). The manic prodrome, conservatively defined as requiring ≥ 3 symptoms, lasted 10.3 ± 14.4 months 95% confidence interval (CI): 6.3–14.4, being present for ≥ 4 months in 65.4% of subjects. Among prodromal symptoms reported in ≥ 50% of youth, three were subthreshold manic in nature (irritability: 61.5%, racing thoughts: 59.6%, increased energy/activity: 50.0%), two were nonspecific (decreased school/work functioning: 65.4%, mood swings/lability: 57.7%), and one each was depressive (depressed mood: 53.8%) or subthreshold manic/depressive (inattention: 51.9%). A decreasing number of youth had ≥ 1 (84.6%), ≥ 2 (48.1%), or ≥ 3 (26.9%) ‘specific’ subthreshold mania symptoms (i.e., elation, grandiosity, decreased need for sleep, racing thoughts, or hypersexuality), lasting 9.5 ± 14.9 months (95% CI: 5.0–14.0), 3.5 ± 3.5 months (95% CI: 2.0–4.9), and 3.0 ± 3.2 months (95% CI: 1.0–5.0) for ≥ 1, ≥ 2, or ≥ 3 specific symptoms, respectively.
Conclusions
In youth with BD‐I, a relatively long, predominantly slow‐onset mania prodrome appears to be common, including subthreshold manic and depressive psychopathology symptoms. This suggests that early clinical identification and intervention may be feasible in bipolar disorder. Identifying biological markers associated with clinical symptoms of impending mania may help to increase chances for early detection and prevention before full mania.
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