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101.
Macaques infected with a CCR5-tropic simian/human immunodeficiency virus (SHIV) develop broadly reactive anti-HIV neutralizing antibodies
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Kraft Z Derby NR McCaffrey RA Niec R Blay WM Haigwood NL Moysi E Saunders CJ Wrin T Petropoulos CJ McElrath MJ Stamatatos L 《Journal of virology》2007,81(12):6402-6411
The development of anti-human immunodeficiency virus (anti-HIV) neutralizing antibodies and the evolution of the viral envelope glycoprotein were monitored in rhesus macaques infected with a CCR5-tropic simian/human immunodeficiency virus (SHIV), SHIVSF162P4. Homologous neutralizing antibodies developed within the first month of infection in the majority of animals, and their titers were independent of the extent and duration of viral replication during chronic infection. The appearance of homologous neutralizing antibody responses was preceded by the appearance of amino acid changes in specific variable and conserved regions of gp120. Amino acid changes first appeared in the V1, V2, C2, and V3 regions and subsequently in the C3, V4, and V5 regions. Heterologous neutralizing antibody responses developed over time only in animals with sustained plasma viremia. Within 2 years postinfection the breadth of these responses was as broad as that observed in certain patients infected with HIV type 1 (HIV-1) for over a decade. Despite the development of broad anti-HIV-1 neutralizing antibody responses, viral replication persisted in these animals due to viral escape. Our studies indicate that cross-reactive neutralizing antibodies are elicited in a subset of SHIVSF162P4 infected macaques and that their development requires continuous viral replication for extended periods of time. More importantly, their late appearance does not prevent progression to disease. The availability of an animal model where cross-reactive anti-HIV neutralizing antibodies are developed may facilitate the identification of virologic and immunologic factors conducive to the development of such antibodies. 相似文献
102.
Many models of eyeblink conditioning assume that there is a simple linear relationship between the firing patterns of neurons in the interpositus nucleus and the time course of the conditioned response (CR). However, the complexities of muscle behaviour and plant dynamics call this assumption into question. We investigated the issue by implementing the most detailed model available of the rabbit nictitating membrane response (Bartha and Thompson in Biol Cybern 68:135-143, 1992a and in Biol Cybern 68:145-154, 1992b), in which each motor unit of the retractor bulbi muscle is represented by a Hill-type model, driven by a non-linear activation mechanism designed to reproduce the isometric force measurements of Lennerstrand (J Physiol 236:43-55, 1974). Globe retraction and NM extension are modelled as linked second order systems. We derived versions of the model that used a consistent set of SI units, were based on a physically realisable version of calcium kinetics, and used simulated muscle cross-bridges to produce force. All versions showed similar non-linear responses to two basic control strategies. (1) Rate-coding with no recruitment gave a sigmoidal relation between control signal and amplitude of CR, reflecting the measured relation between isometric muscle force and stimulation frequency. (2) Recruitment of similar strength motor units with no rate coding gave a sublinear relation between control signal and amplitude of CR, reflecting the increase in muscle stiffness produced by recruitment. However, the system response could be linearised by either a suitable combination of rate-coding and recruitment, or by simple recruitment of motor units in order of (exponentially) increasing strength. These plausible control strategies, either alone or in combination, would in effect present the cerebellum with the simplified virtual plant that is assumed in many models of eyeblink conditioning. Future work is therefore needed to determine the extent to which motor neuron firing is in fact linearly related to the nictitating membrane response. 相似文献
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Toshi A. Furukawa Kiyomi Shinohara Ethan Sahker Eirini Karyotaki Clara Miguel Marketa Ciharova Claudi L.H. Bockting Josefien
J.F. Breedvelt Aran Tajika Hissei Imai Edoardo G. Ostinelli Masatsugu Sakata Rie Toyomoto Sanae Kishimoto Masami Ito Yuki Furukawa Andrea Cipriani Steven D. Hollon Pim Cuijpers 《World psychiatry》2021,20(3):387
Major depression is often a relapsing disorder. It is therefore important to start its treatment with therapies that maximize the chance of not only getting the patients well but also keeping them well. We examined the associations between initial treatments and sustained response by conducting a network meta‐analysis of randomized controlled trials (RCTs) in which adult patients with major depression were randomized to acute treatment with a psychotherapy (PSY), a protocolized antidepressant pharmacotherapy (PHA), their combination (COM), standard treatment in primary or secondary care (STD), or pill placebo, and were then followed up through a maintenance phase. By design, acute phase treatment could be continued into the maintenance phase, switched to another treatment or followed by discretionary treatment. We included 81 RCTs, with 13,722 participants. Sustained response was defined as responding to the acute treatment and subsequently having no depressive relapse through the maintenance phase (mean duration: 42.2±16.2 weeks, range 24‐104 weeks). We extracted the data reported at the time point closest to 12 months. COM resulted in more sustained response than PHA, both when these treatments were continued into the maintenance phase (OR=2.52, 95% CI: 1.66‐3.85) and when they were followed by discretionary treatment (OR=1.80, 95% CI: 1.21‐2.67). The same applied to COM in comparison with STD (OR=2.90, 95% CI: 1.68‐5.01 when COM was continued into the maintenance phase; OR=1.97, 95% CI: 1.51‐2.58 when COM was followed by discretionary treatment). PSY also kept the patients well more often than PHA, both when these treatments were continued into the maintenance phase (OR=1.53, 95% CI: 1.00‐2.35) and when they were followed by discretionary treatment (OR=1.66, 95% CI: 1.13‐2.44). The same applied to PSY compared with STD (OR=1.76, 95% CI: 0.97‐3.21 when PSY was continued into the maintenance phase; OR=1.83, 95% CI: 1.20‐2.78 when PSY was followed by discretionary treatment). Given the average sustained response rate of 29% on STD, the advantages of PSY or COM over PHA or STD translated into risk differences ranging from 12 to 16 percentage points. We conclude that PSY and COM have more enduring effects than PHA. Clinical guidelines on the initial treatment choice for depression may need to be updated accordingly. 相似文献
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Franc Llorens Katrin Thüne Waqas Tahir Eirini Kanata Daniela Diaz-Lucena Konstantinos Xanthopoulos Eleni Kovatsi Catharina Pleschka Paula Garcia-Esparcia Matthias Schmitz Duru Ozbay Susana Correia Ângela Correia Ira Milosevic Olivier Andréoletti Natalia Fernández-Borges Ina M. Vorberg Markus Glatzel Theodoros Sklaviadis Juan Maria Torres Susanne Krasemann Raquel Sánchez-Valle Isidro Ferrer Inga Zerr 《Molecular neurodegeneration》2017,12(1):83
Background
YKL-40 (also known as Chitinase 3-like 1) is a glycoprotein produced by inflammatory, cancer and stem cells. Its physiological role is not completely understood but YKL-40 is elevated in the brain and cerebrospinal fluid (CSF) in several neurological and neurodegenerative diseases associated with inflammatory processes. Yet the precise characterization of YKL-40 in dementia cases is missing.Methods
In the present study, we comparatively analysed YKL-40 levels in the brain and CSF samples from neurodegenerative dementias of different aetiologies characterized by the presence of cortical pathology and disease-specific neuroinflammatory signatures.Results
YKL-40 was normally expressed in fibrillar astrocytes in the white matter. Additionally YKL-40 was highly and widely expressed in reactive protoplasmic cortical and perivascular astrocytes, and fibrillar astrocytes in sporadic Creutzfeldt-Jakob disease (sCJD). Elevated YKL-40 levels were also detected in Alzheimer’s disease (AD) but not in dementia with Lewy bodies (DLB). In AD, YKL-40-positive astrocytes were commonly found in clusters, often around β-amyloid plaques, and surrounding vessels with β-amyloid angiopathy; they were also distributed randomly in the cerebral cortex and white matter. YKL-40 overexpression appeared as a pre-clinical event as demonstrated in experimental models of prion diseases and AD pathology.CSF YKL-40 levels were measured in a cohort of 288 individuals, including neurological controls (NC) and patients diagnosed with different types of dementia. Compared to NC, increased YKL-40 levels were detected in sCJD (p < 0.001, AUC = 0.92) and AD (p < 0.001, AUC = 0.77) but not in vascular dementia (VaD) (p > 0.05, AUC = 0.71) or in DLB/Parkinson’s disease dementia (PDD) (p > 0.05, AUC = 0.70). Further, two independent patient cohorts were used to validate the increased CSF YKL-40 levels in sCJD. Additionally, increased YKL-40 levels were found in genetic prion diseases associated with the PRNP-D178N (Fatal Familial Insomnia) and PRNP-E200K mutations.Conclusions
Our results unequivocally demonstrate that in neurodegenerative dementias, YKL-40 is a disease-specific marker of neuroinflammation showing its highest levels in prion diseases. Therefore, YKL-40 quantification might have a potential for application in the evaluation of therapeutic intervention in dementias with a neuroinflammatory component.107.
Sridharan Raghavan Jie Huang Catherine Tcheandjieu Jennifer E. Huffman Elizabeth Litkowski Chang Liu Yuk-Lam A. Ho Haley Hunter-Zinck Hongyu Zhao Eirini Marouli Kari E. North the VA Million Veteran Program Ethan Lange Leslie A. Lange Benjamin F. Voight J. Michael Gaziano Saiju Pyarajan Elizabeth R. Hauser Philip S. Tsao Peter W. F. Wilson Kyong-Mi Chang Kelly Cho Christopher J. ODonnell Yan V. Sun Themistocles L. Assimes 《PLoS genetics》2022,18(6)
BackgroundHeight has been associated with many clinical traits but whether such associations are causal versus secondary to confounding remains unclear in many cases. To systematically examine this question, we performed a Mendelian Randomization-Phenome-wide association study (MR-PheWAS) using clinical and genetic data from a national healthcare system biobank.Methods and findingsAnalyses were performed using data from the US Veterans Affairs (VA) Million Veteran Program in non-Hispanic White (EA, n = 222,300) and non-Hispanic Black (AA, n = 58,151) adults in the US. We estimated height genetic risk based on 3290 height-associated variants from a recent European-ancestry genome-wide meta-analysis. We compared associations of measured and genetically-predicted height with phenome-wide traits derived from the VA electronic health record, adjusting for age, sex, and genetic principal components. We found 345 clinical traits associated with measured height in EA and an additional 17 in AA. Of these, 127 were associated with genetically-predicted height at phenome-wide significance in EA and 2 in AA. These associations were largely independent from body mass index. We confirmed several previously described MR associations between height and cardiovascular disease traits such as hypertension, hyperlipidemia, coronary heart disease (CHD), and atrial fibrillation, and further uncovered MR associations with venous circulatory disorders and peripheral neuropathy in the presence and absence of diabetes. As a number of traits associated with genetically-predicted height frequently co-occur with CHD, we evaluated effect modification by CHD status of genetically-predicted height associations with risk factors for and complications of CHD. We found modification of effects of MR associations by CHD status for atrial fibrillation/flutter but not for hypertension, hyperlipidemia, or venous circulatory disorders.ConclusionsWe conclude that height may be an unrecognized but biologically plausible risk factor for several common conditions in adults. However, more studies are needed to reliably exclude horizontal pleiotropy as a driving force behind at least some of the MR associations observed in this study. 相似文献
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Robert M. Paris Constantinos Petrovas Sara Ferrando-Martinez Eirini Moysi Kristin L. Boswell Eva Archer Takuya Yamamoto David Ambrozak Joseph P. Casazza Richard Haubrich Mark Connors Julie Ake Jerome H. Kim Richard A. Koup 《PloS one》2015,10(12)
The role of PD-1 expression on CD4 T cells during HIV infection is not well
understood. Here, we describe the differential expression of PD-1 in
CD127high CD4 T cells within the early/intermediate differentiated (EI)
(CD27highCD45RAlow) T cell population among uninfected and
HIV-infected subjects, with higher expression associated with decreased viral
replication (HIV-1 viral load). A significant loss of circulating
PD-1highCTLA-4low CD4 T cells was found specifically in the
CD127highCD27highCD45RAlow compartment, while
initiation of antiretroviral treatment, particularly in subjects with advanced
disease, reversed these dynamics. Increased HIV-1 Gag DNA was also found in
PD-1high compared to PD-1low ED CD4 T cells. In line with an
increased susceptibility to HIV infection, PD-1 expression in this CD4 T cell subset
was associated with increased activation and expression of the HIV co-receptor, CCR5.
Rather than exhaustion, this population produced more IFN-g, MIP1-a, IL-4, IL-10, and
IL-17a compared to PD-1low EI CD4 T cells. In line with our previous
findings, PD-1high EI CD4 T cells were also characterized by a high
expression of CCR7, CXCR5 and CCR6, a phenotype associated with increased in
vitro B cell help. Our data show that expression of PD-1 on
early-differentiated CD4 T cells may represent a population that is highly
functional, more susceptible to HIV infection and selectively lost in chronic HIV
infection. 相似文献
110.
Morad Zahid Mateo Vélez-Fort Eirini Papagiakoumou Cathie Ventalon María Cecilia Angulo Valentina Emiliani 《PloS one》2010,5(2)