Exposure to Secreted Bacterial Factors Promotes HIV-1 Replication in CD4+ T Cells.

Microbial translocation is associated with systemic immune activation in HIV-1 disease. Circulating T cells can encounter microbial products in the bloodstream and lymph nodes, where viral replication takes place. The mechanisms by which bacteria contribute to HIV-associated pathogenesis are not completely deciphered. Here, we examined how bacteria may impact T cell function and viral replication. We established cocultures between a panel of live bacteria and uninfected or HIV-1-infected activated peripheral blood CD4-positive (CD4+) T cells. We show that some bacteria, such as Escherichia coli and Acinetobacter baumannii, sustain lymphocyte activation and enhance HIV-1 replication. Bacteria secrete soluble factors that upregulate CD25 and ICAM-1 cell surface levels and activate NF-κB nuclear translocation. Our data also demonstrate that CD25 polarizes at the virological synapse, suggesting a previously unappreciated role of CD25 during viral replication. These findings highlight how interactions between bacterial factors and T cells may promote T cell activation and HIV-1 replication. IMPORTANCE People living with HIV suffer from chronic immune activation despite effective antiretroviral therapy. Early after infection, HIV-1 actively replicates in the gut, causing the breakage of the intestinal epithelial barrier and microbial translocation. Microbial translocation and chronic immune activation have been proven linked; however, gaps in our knowledge on how bacteria contribute to the development of HIV-related diseases remain. Whether T cells in the peripheral blood react to bacterial products and how this affects viral replication are unknown. We show that some bacteria enriched in people living with HIV activate T cells and favor HIV-1's spread. Bacteria release soluble factors that cause the overexpression of cellular molecules related to their activation state. T cells overexpressing these molecules also replicate HIV-1 more efficiently. These results help us learn more about how HIV-1, T cells, and bacteria interact with each other, as well as the mechanisms behind chronic immune activation.

Type I interferon response and vascular alteration in chilblain-like lesions during the COVID-19 outbreak.

BACKGROUND: The outbreak of chilblain-like lesions (CLL) during the COVID-19 pandemic has been reported extensively, potentially related to SARS-CoV-2 infection, yet its underlying pathophysiology is unclear. OBJECTIVES: To study skin and blood endothelial and immune system activation in CLL in comparison with healthy controls and seasonal chilblains (SC), defined as cold-induced sporadic chilblains occurring during 2015 and 2019 with exclusion of chilblain lupus. METHODS: This observational study was conducted during 9-16 April 2020 at Saint-Louis Hospital, Paris, France. All patients referred with CLL seen during this period of the COVID-19 pandemic were included in this study. We excluded patients with a history of chilblains or chilblain lupus. Fifty patients were included. RESULTS: Histological patterns were similar and transcriptomic signatures overlapped in both the CLL and SC groups, with type I interferon polarization and a cytotoxic-natural killer gene signature. CLL were characterized by higher IgA tissue deposition and more significant transcriptomic activation of complement and angiogenesis factors compared with SC. We observed in CLL a systemic immune response associated with IgA antineutrophil cytoplasmic antibodies in 73% of patients, and elevated type I interferon blood signature in comparison with healthy controls. Finally, using blood biomarkers related to endothelial dysfunction and activation, and to angiogenesis or endothelial progenitor cell mobilization, we confirmed endothelial dysfunction in CLL. CONCLUSIONS: Our findings support an activation loop in the skin in CLL associated with endothelial alteration and immune infiltration of cytotoxic and type I IFN-polarized cells leading to clinical manifestations.

The ratio of morning cortisol to CRP prospectively predicts first-onset depression in at-risk adolescents.

RATIONALE: Early-onset adolescent depression is related to poor prognosis and a range of psychiatric and medical comorbidities later in life, making the identification of a priori risk factors for depression highly important. Increasingly, dysregulated levels of immune and neuroendocrine markers, such as C-reactive protein (CRP) and cortisol, have been demonstrated as both precursors to and consequences of depression. However, longitudinal research with adolescent populations is limited and demonstrates mixed immuno-endocrine-depression links. OBJECTIVE: This study explored the putative bidirectional relationship between salivary measures of cortisol (Cort) and CRP, including the novel Cort:CRP ratio and depression. METHODS: Participants from the randomized control trial 'Sleep and Education: learning New Skills Early' (SENSE) Study were 122 adolescents at risk for depression (73 females) aged 12-16 years (M = 12.71 years, SD = 1.01 years) assessed at baseline (T1), post-intervention (T2), and a two-year follow-up (T3). RESULTS: Logistic regression results demonstrated that adolescents with higher T1 Cort:CRPmorn ratio levels were two-fold more likely to develop a first-onset depressive disorder from T2 to T3 as compared to adolescents with lower Cort:CRPmorn ratio levels, ß = 0.73, t (36) = 2.15, p = .04, OR = 2.08. This effect was not moderated by treatment condition (ß = -1.38, t (13) = -1.33, p = .20) and did not change when controlling for known risk factors for depression, including sex, age, body-mass index, socio-economic status, T1 anxiety disorder, nor T1 sleep disturbance, anxiety, or depressive symptoms (ß = 0.91, t (31) = 2.14, p = .04). CONCLUSION: Results highlight potential immuno-endocrine dysregulation as an underlying risk factor for adolescent first-onset depression, and may inform the development of targeted, preventative biobehavioral treatment strategies for youth depression.

Salivary C-reactive protein among at-risk adolescents: A methods investigation of out of range immunoassay data.

Inflammatory markers including C-Reactive Protein (CRP) are increasingly used within research and clinical settings. Yet, varying methodologies for cleaning immunoassay data with out of range (OOR) samples may alter characteristic levels of CRP, thereby obscuring interpretation and reliability. This study investigated the influence of eight immunoassay OOR data treatment techniques on salivary CRP (sCRP) samples from at-risk adolescents. Participants from the 'Sleep and Education: learning New Skills Early' (SENSE) Study were 86 adolescents at-risk for depression (50 female), aged 14.29 years (SD = 1.04). ANOVA results showed no statistically significant differences in average morning (F(7, 590) = 1.24, p = .28) and evening (F(7, 599)=1.29, p = .25) values produced by each OOR data cleaning technique. However, varying techniques produced differences in the magnitude of Pearson's correlations between consecutive saliva samples (r's between 0.27-0.78), and influenced the significance of a sCRP diurnal pattern; two techniques produced statistically higher morning than evening sCRP levels (t(85) = 2.70, p = .01 and t(85) = 2.67, p = .01), whereas six techniques failed to find statistical differences between morning and evening sCRP levels (p's >.05). Varying techniques also produced statistically divergent associations between sCRP and age and depressive symptoms. Results from this study provide evidence for the temporal stability of sCRP among adolescents, show winsorization as an effective OOR data management technique, and highlight the influence of methodological decisions in cleaning salivary biomarker data and the need for consistency within the field.

Near-concentric Fabry-Pérot cavity for continuous-wave laser control of electron waves.

Manipulating free-space electron wave functions with laser fields can bring about new electron-optical elements for transmission electron microscopy (TEM). In particular, a Zernike phase plate would enable high-contrast TEM imaging of soft matter, leading to new opportunities in structural biology and materials science. A Zernike phase plate can be implemented using a tight, intense continuous laser focus that shifts the phase of the electron wave by the ponderomotive potential. Here, we use a near-concentric cavity to focus 7.5 kW of continuous-wave circulating laser power at 1064 nm into a 7 µm mode waist, achieving a record continuous laser intensity of 40 GW/cm2. Such parameters are sufficient to impart a phase shift of 1 rad to a 10 keV electron beam, or 0.16 rad to a 300 keV beam. Our numerical simulations confirm that the standing-wave phase shift profile imprinted on the electron wave by the intra-cavity field can serve as a nearly ideal Zernike phase plate.

Study protocol: families and childhood transitions study (FACTS) - a longitudinal investigation of the role of the family environment in brain development and risk for mental health disorders in community based children.

BACKGROUND: Extant research has demonstrated that parenting behaviour can be a significant contributor to the development of brain structure and mental health during adolescence. Nonetheless, there is limited research examining these relationships during late childhood, and particularly in the critical period of brain development occurring between 8 and 10 years of age. The effects of the family environment on the brain during late childhood may have significant implications for later functioning, and particularly mental health. The Families and Childhood Transitions Study (FACTS) is a multidisciplinary longitudinal cohort study of brain development and mental health, with two waves of data collection currently funded, occurring 18-months apart, when child participants are aged approximately 8- and 10-years old. METHODS/DESIGN: Participants are 163 children (M age [SD] = 8.44 [0.34] years, 76 males) and their mothers (M age [SD] = 40.34 [5.43] years). Of the 163 families who consented to participate, 156 completed a video-recorded and observer-coded dyadic interaction task and 153 completed a child magnetic resonance imaging brain scan at baseline. Families were recruited from lower socioeconomic status (SES) areas to maximise rates of social disadvantage and variation in parenting behaviours. All experimental measures and tasks completed at baseline are repeated at an 18-month follow-up, excluding the observer coded family interaction tasks. The baseline assessment was completed in October 2015, and the 18-month follow up will be completed May 2017. DISCUSSION: This study, by examining the neurobiological and mental health consequences of variations in parenting, has the potential to significantly advance our understanding of child development and risk processes. Recruitment of lower SES families will also allow assessment of resilience factors given the poorer outcomes often associated with this population.

Broadly neutralizing antibodies suppress post-transcytosis HIV-1 infectivity.

Broadly neutralizing antibodies (bNAbs) offer promising opportunities for preventing HIV-1 infection in humans. Immunoprophylaxis with potent bNAbs efficiently protects non-human primates from mucosal transmission even after repeated challenges. However, the precise mechanisms of bNAb-mediated viral inhibition in mucosal tissues are currently unknown. Here, we show that immunoglobulin (Ig)G and IgA bNAbs do not interfere with the endocytic transport of HIV-1 across epithelial cells, a process referred to as transcytosis. Instead, both viruses and antibodies are translocated to the basal pole of epithelial cells, possibly in the form of an immune complex. Importantly, as opposed to free virions, viral particles bound by bNAbs are no longer infectious after transepithelial transit. Post-transcytosis neutralization activity of bNAbs displays comparable inhibitory concentrations as those measured in classical neutralization assays. Thus, bNAbs do not block the transport of incoming HIV-1 viruses across the mucosal epithelium but rather neutralize the transcytosed virions, highlighting their efficient prophylactic and protective activity in vivo.

Dispositional mindfulness is predicted by structural development of the insula during late adolescence.

Adolescence is a critical period of development, in which the increasing social and cognitive demands of independence need to be met by enhanced self-regulatory abilities. The cultivation of mindfulness has been associated with improved self-regulation in adult populations, and it is theorized that one neurodevelopmental mechanism that supports this capacity is the development of the prefrontal cortex. The current study examined the neurodevelopmental mechanisms associated with dispositional mindfulness in adolescence. Using a longitudinal within-persons design, 82 participants underwent structural magnetic resonance imaging (MRI) assessments at approximately ages 16 and 19, and also completed self-reported measurements of mindfulness at age 19. It was hypothesized that adolescents who demonstrated greater thinning of frontal cortical regions between the age of 16 and 19 would exhibit higher dispositional mindfulness levels at age 19. Results indicated that, contrary to predictions, adolescents with higher levels of mindfulness demonstrated less thinning in the left anterior insula. By contrast, higher IQ was associated with greater thinning of the right caudal middle frontal and right superior frontal regions. The involvement of insula development in mindfulness is consistent with a direct role for this structure in managing self-regulation, and in doing so concords with recent models of self-referential interoceptive awareness.

Functional brain-imaging correlates of negative affectivity and the onset of first-episode depression.

BACKGROUND: The amygdala and subgenual anterior cingulate cortex (sACC) are key brain regions for the generation of negative affect. In this longitudinal fMRI study of adolescents we investigated how amygdala-sACC connectivity was correlated with negative affectivity (NA) both cross-sectionally and longitudinally, and examined its relationship to the onset of first-episode depression. METHOD: Fifty-six adolescents who were part of a larger longitudinal study of adolescent development were included. They had no history of mental illness at the time of their baseline scan (mean age 16.5 years) and had a follow-up scan 2 years later (mean age 18.8 years). We used resting-state functional-connectivity MRI to investigate whether cross-sectional and change measures of amygdala-sACC connectivity were (i) correlated with NA and its change over time, and (ii) related to the onset of first-episode depression. RESULTS: The magnitude of amygdala connectivity with sACC showed significant positive correlation with NA at both time-points. Further analysis confirmed that change in amygdala-sACC connectivity between assessments was correlated with change in NA. Eight participants developed a first episode of depression between the baseline and follow-up assessments: they showed increased amygdala-sACC connectivity at follow-up. CONCLUSIONS: Amygdala-sACC connectivity is associated with NA in adolescence, with change in connectivity between these regions showing positive correlation with change in NA. Our observation that the onset of depression was associated with an increase in connectivity between the regions provides support for the neurobiological 'scar' hypothesis of depression.

Cooperative Lamb shift in a mesoscopic atomic array.

According to quantum electrodynamics, the exchange of virtual photons in a system of identical quantum emitters causes a shift of its energy levels. Such shifts, known as cooperative Lamb shifts, have been studied mostly in the near-field regime. However, the resonant electromagnetic interaction persists also at large distances, providing coherent coupling between distant atoms. Here, we report a direct spectroscopic observation of the cooperative Lamb shift of an optical electric-dipole transition in an array of Sr(+) ions suspended in a Paul trap at inter-ion separations much larger than the resonance wavelength. By controlling the precise positions of the ions, we studied the far-field resonant coupling in chains of up to eight ions, extending to a length of 40 µm. This method provides a novel tool for experimental exploration of cooperative emission phenomena in extended mesoscopic atomic arrays.

Trends and changes in Clostridium difficile diagnostic policies and their impact on the proportion of positive samples: a national survey.

In June 2012, Israeli guidelines for laboratories were published defining the recommended methods for diagnosis of Clostridium difficile infection (CDI). We conducted this survey to examine the effects of the new recommendations on the proportions of rejected and positive samples by the different methods. A survey was mailed to the directors of all general hospital (GH) and health maintenance organization (HMO) clinical microbiology laboratories. The report was divided into two periods, before and after implementation of the guidelines. Surveys were completed by 13/28 GH laboratories and 5/6 HMO laboratories. All 18 of these laboratories used C. difficile toxin (CDT) enzyme immunoassay alone during the first period of the survey. In the second period, nine laboratories (Group A) used CDT-PCR: two of them used this method exclusively while the other seven used it to resolve most (>90%) of the discrepant results (glutamate dehydrogenase antigen (GDH) +/CDT-]. The other nine laboratories (Group B) used combined GDH/CDT assay, using CDT PCR in only a minority (<20%) of GDH+/CDT- cases. The overall proportion of rejected samples increased from 9.5% in the first period to 13.9% in the second (p<0.001). Between the first and second periods the proportion of positive samples increased from 9.0% to 11.6% in group A laboratories (p<0.001), but decreased from 12.9% to 9.7% in group B laboratories (p<0.001). Implementation of the guidelines has resulted in a significant increase in the proportion of rejected samples and in the proportion testing positive, suggesting more appropriate test utilization and improved sensitivity in the laboratory diagnosis of CDI.

Vectorial phase retrieval for linear characterization of attosecond pulses.

The waveforms of attosecond pulses produced by high-harmonic generation carry information on the electronic structure and dynamics in atomic and molecular systems. Current methods for the temporal characterization of such pulses have limited sensitivity and impose significant experimental complexity. We propose a new linear and all-optical method inspired by widely used multidimensional phase retrieval algorithms. Our new scheme is based on the spectral measurement of two attosecond sources and their interference. As an example, we focus on the case of spectral polarization measurements of attosecond pulses, relying on their most fundamental property-being well confined in time. We demonstrate this method numerically by reconstructing the temporal profiles of attosecond pulses generated from aligned CO(2) molecules.

Suicide attempt in first-episode psychosis: a 7.4 year follow-up study.

BACKGROUND: Individuals with first-episode psychosis demonstrate high rates of suicide attempt (SA). AIMS: 1) To examine the prevalence of, and risk factors for, SA in a first-episode psychosis (FEP) cohort over a 7.4 year follow-up period. 2) To investigate differences between single versus multiple suicide attempters. METHODS: This study reports baseline and follow-up data from a naturalistic, prospective follow-up of 413 FEP patients treated at a specialist early psychosis centre. Assessments were conducted at treatment entry, initial symptom remission or stabilization, and long term follow-up. Binary logistic regression models were used to assess unadjusted and adjusted associations between early illness and sociodemographic characteristics and two outcome measures: any SA during follow-up; and multiple SAs. RESULTS: Follow-up data were available for 282 participants. Sixty-one (21.6%) made a suicide attempt over the follow-up period, including 12 successful suicides. The following baseline risk factors increased the risk of any SA: history of self-harm (OR=4.27; p<0.001), suicidal tendencies (OR=2.30; p=0.022), being depressed for >50% of the initial psychotic episode (OR=2.49; p=0.045), and hopelessness (OR=2.03; p=0.030). History of problem alcohol use increased the risk of multiple SAs (OR=4.43; 95% CI (1.05-18.7); p=0.043). DISCUSSION: The prevalence of suicide attempt in this study exceeds reports from short-term FEP studies but is comparable to longer term follow-up studies, indicating that risk remains elevated for at least 7 years following commencement of treatment. The key predictor of future suicide attempt was previous self-harm, indicating that interventions for self-harm are required.

Detection and imaging of non-contractile inclusions and sarcomeric anomalies in skeletal muscle by second harmonic generation combined with two-photon excited fluorescence.

The large size of the multinucleated muscle fibers of skeletal muscle makes their examination for structural and pathological defects a challenge. Sections and single fibers are accessible to antibodies and other markers but imaging of such samples does not provide a three-dimensional view of the muscle. Regrettably, bundles of fibers cannot be stained or imaged easily. Two-photon microscopy techniques overcome these obstacles. Second harmonic generation (SHG) by myosin filaments and two-photon excited fluorescence (2PEF) of mitochondrial and lysosomal components provides detailed structural information on unstained tissue. Furthermore, the infrared exciting light can penetrate several layers of muscle fibers and the minimal processing is particularly valuable for fragile biopsies. Here we demonstrate the usefulness of SHG, combined with 2PEF, to reveal enlarged lysosomes and accumulations of non-contractile material in muscles from the mouse model for the lysosomal storage disorder Pompe disease (PD), and in biopsies from adult and infant PD patients. SHG and 2PEF also detect sarcomeric defects that may presage the loss of myofibrils in atrophying muscle and signify loss of elasticity. The combination of SHG and 2PEF should be useful in the analysis and diagnosis of a wide range of skeletal muscle pathologies.

Prevalence and correlates of comorbidity 8 years after a first psychotic episode.

OBJECTIVE: While rates and correlates of comorbidity have been investigated in the early course of psychosis, little is known about comorbidity in the medium-to-longer term or its relationship with outcome. METHOD: A total of 182 first-episode psychosis (FEP) patients who met DSM-IV criteria for a current psychotic disorder 8 years after index presentation were grouped according to concurrent comorbidity [no concurrent axis I disorder; concurrent substance use disorder (SUD); other concurrent axis I disorder; concurrent SUD and other axis I disorder]. Outcomes were compared between groups controlling for relevant covariates. RESULTS: As much as 39% met criteria for one or more concurrent axis 1 diagnoses. Comorbidity was associated with greater severity of general psychopathology, but not with measures of functioning, treatment or negative symptoms. CONCLUSION: Specific combinations of comorbid disorders may influence patterns of psychotic symptomatology. Routine examination of axis I disorders is warranted in the ongoing management of psychosis.