Clonotypic IgH Response against Systemic Viral infection in Pronephros and Spleen of a Teleost Fish.

Upon infection, B lymphocytes develop clonal responses. In teleost fish, which lack lymph nodes, the kinetics and location of B cell responses remain poorly characterized. Fish pronephros is the site of B cell differentiation and the main niche for persistence of plasma cells. In this study, we undertook the analysis of the rainbow trout IgHµ repertoire in this critical tissue for humoral adaptive immunity after primary immunization and boost with a rhabdovirus, the viral hemorrhagic septicemia virus (VHSV). We used a barcoded 5' RACE-cDNA sequencing approach to characterize modifications of the IgHµ repertoire, including VH usage in expressed V(D)J rearrangements, clonal diversity, and clonotype sharing between individual fish and treatments. In the pronephros, our approach quantified the clonotype frequency across the whole IgH repertoire (i.e., with all VH), measuring the frequency of Ag-responding clonotypes. Viral infection led to extensive modifications of the pronephros B cell repertoire, implicating several VH subgroups after primary infection. In contrast, only modest changes in repertoire persisted 5 mo later, including VHSV-specific public expansions. The IgM public response implicating IgHV1-18 and JH5, previously described in spleen, was confirmed in pronephros in all infected fish, strongly correlated to the response. However, the distribution of top clonotypes showed that pronephros and spleen B cells constitute distinct compartments with different IgH repertoires. Unexpectedly, after boost, the frequency of anti-VHSV clonotypes decreased both in pronephros and spleen, raising questions about B cell circulation. A better monitoring of B cell response kinetics in lymphoid tissues will be an essential step to understand B memory and plasmocyte formation mechanisms in fish.

Reduced IGF-1 signaling delays age-associated proteotoxicity in mice.

The insulin/insulin growth factor (IGF) signaling (IIS) pathway is a key regulator of aging of worms, flies, mice, and likely humans. Delayed aging by IIS reduction protects the nematode C. elegans from toxicity associated with the aggregation of the Alzheimer's disease-linked human peptide, Abeta. We reduced IGF signaling in Alzheimer's model mice and discovered that these animals are protected from Alzheimer's-like disease symptoms, including reduced behavioral impairment, neuroinflammation, and neuronal loss. This protection is correlated with the hyperaggregation of Abeta leading to tightly packed, ordered plaques, suggesting that one aspect of the protection conferred by reduced IGF signaling is the sequestration of soluble Abeta oligomers into dense aggregates of lower toxicity. These findings indicate that the IGF signaling-regulated mechanism that protects from Abeta toxicity is conserved from worms to mammals and point to the modulation of this signaling pathway as a promising strategy for the development of Alzheimer's disease therapy.

Detection and assessment of risk factors associated with Newcastle disease virus infection in birds in backyard poultry in Laichau province of Vietnam.

Newcastle disease (ND) is a highly pathogenic and contagious viral infectious disease of poultry that causes a very serious problem for poultry production and economic loss worldwide. ND has been an epizootic disease in Vietnam. Information about the risk factors that are associated with virus transmission in backyard chickens in Vietnam is limited. To provide more epidemiological information about ND in Vietnam, this study was performed to estimate NDV prevalence and identify the risk factors for ND virus (NDV) infection in birds at the backyard flock level. Choanal swabs were taken from 400 randomly selected birds from 100 apparently healthy flocks from May to July 2020. Based on RT-PCR analysis, 43 of 400 swab samples (10.75%; 95% CI 8-14.17) and 21 of 100 flocks (21%; 95% CI 14.17-29.98) were positive for the fusion (F) gene of NDV. The management practice risks were: backyard flocks contacting wild birds (OR = 3.89; P = 0.030), mixed flocks with different types and species of birds (OR = 5.46; P = 0.004), and infrequency of cleaning and disinfecting poultry houses (OR (odds ratio) = 4.43; P = 0.034). The second and third risks (above) showed a positive interaction on the risk of NDV infection in birds (OR = 39.38; P = 0.001), and the first risk showed a negative interaction. Further studies on NDV surveillance in domestic waterfowl, longitudinal studies, a well-optimized RT-qPCR assay, and genetic characterization are needed. The development of handbooks, flyers, or lessons for educating poultry keepers are also needed.RESEARCH HIGHLIGHT RT-PCR was used to detect the F gene of NDV in choanal swabs.Risk factors associated with NDV-positive samples were determined.The evidence for NDV circulation in backyard healthy birds was observed.Contact with wild birds, mixed flocks, and poor hygiene were major risk factors.

Effects of Roasting Conditions on Antibacterial Properties of Vietnamese Turmeric (Curcuma longa) Rhizomes.

Processing with heat treatment has been reported to alter several therapeutic effects of turmeric. In Vietnamese traditional medicine, turmeric has been long used for bacterial infections, and roasting techniques are sometimes applied with this material. However, there have been no studies investigating the effects of these thermal processes on the plant's antibacterial properties. Our study was therefore performed to examine the changes that roasting produced on this material. Slices of dried turmeric were further subjected to light-roasting (80 °C in 20 min) or dark-roasting (160 °C in 20 min) processes. Broth dilution and agar-well diffusion methods were applied to examine and compare the effects of ethanol extracts obtained from non-roasted, light-roasted and dark-roasted samples, on a set of 6 gram-positive and gram-negative bacteria. In both investigations, dark-roasted turmeric was significantly less antibacterial than non-roasted and light-roasted materials, as evident by the higher values of minimum inhibitory concentrations and the smaller diameters of induced inhibitory zones. In addition, dark-roasting was also found to clearly reduce curcumin contents, total polyphenol values and antioxidant activities of the extracts. These results suggest that non-roasting or light-roasting might be more suitable for the processing of turmeric materials that are aimed to be applied for bacterial infections.

Anti-neuroinflammatory effects of alkaloid-enriched extract from Huperzia serrata on lipopolysaccharide-stimulated BV-2 microglial cells.

CONTEXT: Alkaloid-enriched extract of Huperzia serrata (Thunb.) Trevis (Lycopodiaceae) (HsAE) can potentially be used to manage neuronal disorders. OBJECTIVE: This study determines the anti-neuroinflammatory effects of HsAE on lipopolysaccharide (LPS)-stimulated BV-2 microglial cells and the underlying mechanisms. MATERIALS AND METHODS: BV-2 cells were pre- or post-treated with different concentrations of HsAE (25-150 µg/mL) for 30 min before or after LPS induction. Cell viability was assessed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay and no cytotoxicity was found. Nitric oxide (NO) concentration was determined using Griess reagent. The levels of prostaglandin E2 (PGE2), tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 were determined using enzyme-linked immunosorbent assay. The levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 and the phosphorylation of mitogen-activated protein kinase (MAPK) were analyzed using western blotting. RESULTS: HsAE reduced LPS-induced NO production with half-maximal inhibitory concentration values of 99.79 and 92.40 µg/mL at pre- and post-treatment, respectively. Pre-treatment with HsAE at concentrations of 50, 100, and 150 µg/mL completely inhibited the secretion of PGE2, TNF-α, IL-6, and IL-1ß compared to post-treatment with HsAE. This suggests that prophylactic treatment is better than post-inflammation treatment. HsAE decreased the expression levels of iNOS and COX-2 and attenuated the secretion of pro-inflammatory factors by downregulating the phosphorylation of p38 and extracellular signal-regulated protein kinase in the MAPK signaling pathway. DISCUSSION AND CONCLUSIONS: HsAE exerts anti-neuroinflammatory effects on LPS-stimulated BV-2 cells, suggesting that it may be a potential candidate for the treatment of neuroinflammation in neurodegenerative diseases.

Low-dose interleukin-2 therapy in active systemic lupus erythematosus (LUPIL-2): a multicentre, double-blind, randomised and placebo-controlled phase II trial.

OBJECTIVES: A regulatory T cell (Treg) insufficiency due to shortage of interleukin-2 (IL-2) is central to the pathophysiology of systemic lupus erythematosus (SLE). We performed a multicentre, double-blinded, randomised, placebo-controlled phase II proof-of-concept trial to evaluate the efficacy of low-dose IL-2 therapy in patients with SLE having moderate-to-severe disease activity while receiving standard treatment. METHODS: We randomly assigned 100 patients in a 1:1 ratio to receive either 1.5 million IU/day of subcutaneous IL-2 (ILT-101) or placebo for 5 days followed by weekly injections for 12 weeks. Clinical efficacy was assessed at week 12 in a predefined hierarchical analysis of (1) the SLE responder index-4 (SRI-4) response as a primary end point, and of (2) relative and (3) absolute changes in the Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index scores as key secondary end points. RESULTS: The primary end point was not met in the intention-to-treat population (ILT-101: 68%, placebo: 58%; p=0.3439), due to a 100% SRI-4 response rate in the placebo group from the two sites from Bulgaria. A post hoc per-protocol analysis on a prespecified population that excluded patients from these two sites (n=53) showed a statistically significant difference for the SRI-4 response rate (ILT-101: 83.3%; placebo: 51.7%; p=0.0168), and for the two key secondary end points, accompanied by differences in several secondary exploratory end points. ILT-101 was well tolerated and there was no generation of antidrug antibodies. CONCLUSIONS: The post hoc hierarchical analysis of the primary and key secondary end points in a per-protocol population, complemented by the exploratory analyses of multiple other secondary end points, support that low-dose IL-2 is beneficial in active SLE. TRIAL REGISTRATION NUMBER: NCT02955615.

Anti-hypertensive effects of Callisia fragrans extract on Reno-vascular hypertensive rats.

OBJECTIVES: This study aims to investigate the anti-hypertensive effects of aqueous extract of Callisia fragrans and their underlying mechanism using a two-kidney one-clip (2K1C) model of reno-vascular hypertension in rats. METHODS: The reno-vascular hypertensive rats were treated with C. fragrans leaf extract (100 and 500 mg/kg; p.o.) and a reference drug, captopril (20 mg/kg; p.o.), for 4 weeks. The blood pressure and heart rate were recorded using a tail-cuff. The heart weight, left ventricular wall thickness, and serum creatinine and urea levels were measured. A spectrophotometric assay was used to analyze the angiotensin-converting enzyme (ACE) inhibition activity of the extract and the reference drug. The total volume and the concentration of sodium, potassium, and chloride in urine samples were evaluated. RESULTS: C. fragrans extract significantly reduced both systolic and diastolic blood pressures in the reno-vascular hypertensive rats. No significant difference in the heart rate was observed between each animal group. C. fragrans extract reduced the 2K1C-induced increase in the heart and body weight ratio and the left ventricular wall thickness. Moreover, the extract also attenuated the increase in serum urea induced by the 2K1C treatment. C. fragrans extract inhibited ACE activity in vitro with an IC50 of 20.97 ± 3.94 µg/ml. The urine output and urinary electrolyte excretion significantly increased in C. fragrans extract-treated rats. CONCLUSIONS: These findings demonstrated that C. fragrans extract can mitigate hypertension and alleviate ventricular hypertrophy and renal dysfunction in reno-vascular hypertensive rats, at least in part via ACE activity inhibition and diuretic property.

Cortactin Interacts with Hepatitis C Virus Core and NS5A Proteins: Implications for Virion Assembly.

Hepatitis C virus (HCV) exploits cellular proteins to facilitate viral propagation. To identify the cellular factors involved in the HCV life cycle, we previously performed protein microarray assays using either HCV nonstructural 5A (NS5A) protein or core protein as a probe. Interestingly, cellular cortactin strongly interacted with both NS5A and core. Cortactin is an actin-binding protein critically involved in tumor progression by regulating the migration and invasion of cancerous cells. Protein interaction between cortactin and NS5A or core was confirmed by coimmunoprecipitation and immunofluorescence assays. We showed that cortactin interacted with NS5A and core via the N-terminal acidic domain of cortactin. Cortactin expression levels were not altered by HCV infection. Small interfering RNA (siRNA)-mediated knockdown of cortactin dramatically decreased HCV protein expression and infectivity levels, whereas overexpression of cortactin increased viral propagation. Ectopic expression of the siRNA-resistant cortactin recovered the viral infectivity, suggesting that cortactin was specifically required for HCV propagation. We further showed that cortactin was involved in the assembly step without affecting viral entry, HCV internal ribosome entry site (IRES)-mediated translation, and the replication steps of the HCV life cycle. Of note, silencing of cortactin markedly reduced both NS5A and core protein levels on the lipid droplets (LDs), and this effect was reversed by the overexpression of cortactin. Importantly, NS5A and core promoted cell migration by activating the phosphorylation of cortactin at tyrosine residues 421 and 466. Taken together, these data suggest that cortactin is not only involved in HCV assembly but also plays an important role in the cell migration.IMPORTANCE Cortactin is a cytoskeletal protein that regulates cell migration in response to a number of extracellular stimuli. The functional involvement of cortactin in the virus life cycle is not yet fully understood. The most significant finding is that cortactin strongly interacted with both hepatitis C virus (HCV) core and NS5A. Cortactin is involved in HCV assembly by tethering core and NS5A on the lipid droplets (LDs) with no effect on LD biogenesis. It was noteworthy that HCV NS5A and core activated cortactin by phosphorylation at tyrosines 421 and 466 to regulate cell migration. Collectively, our study shows that cortactin is a novel host factor involved in viral production and HCV-associated pathogenesis.

Genome-wide analysis of SARS-CoV-2 strains circulating in Vietnam: Understanding the nature of the epidemic and role of the D614G mutation.

Genome-wide analysis of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) strains is essential to better understand infectivity and virulence and to track coronavirus disease 2019 (COVID-19) cases and outbreaks. We performed whole-genome sequencing of 27 SARS-CoV-2 strains isolated between January 2020 and April 2020. A total of 54 mutations in different genomic regions was found. The D614G mutation, first detected in March 2020, was identified in 18 strains and was more likely associated with a lower cycle threshold (<25) in real-time reverse-transcription polymerase chain reaction diagnostic tests than the original D614 (prevalence ratio = 2.75; 95% confidence interval, 1.19-6.38). The integration of sequencing and epidemiological data suggests that SARS-CoV-2 transmission in both quarantine areas and in the community in Vietnam occur at the beginning of the epidemic although the country implemented strict quarantine quite early, with strict contact tracing, and testing. These findings provide insights into the nature of the epidemic, as well as shape strategies for COVID-19 prevention and control in Vietnam.

Ilex kudingcha C.J. Tseng Mitigates Phenotypic Characteristics of Human Autism Spectrum Disorders in a Drosophila Melanogaster Rugose Mutant.

Autism spectrum disorders (ASD) have heterogeneous etiologies involving dysfunction of central nervous systems, for which no effective pan-specific treatments are available. Ilex kudingcha (IK) C.J. Tseng is a nootropic botanical used in Asia for neuroprotection and improvement of cognition. This study establishes that a chemically characterized extract from IK (IKE) mitigates behavioral traits in the Drosophila melanogaster rugose mutant, whose traits resemble human ASD, and examines possible mechanisms. IKE treatment significantly ameliorated deficits in social interaction, short-term memory, and locomotor activity in Drosophila rugose, and significantly increased synaptic bouton number of size more than 2 µm2 in the neuromuscular junctions (NMJs) of Drosophila rugose. To clarify mechanism(s) of IKE action, methylphenidate (MPH), a dopamine transporter inhibitor, was included as a reference drug in the behavioral assays: MPH significantly improved social interaction and short-term memory deficit in Drosophila rugose; administration of the dopamine D1 receptor antagonist SCH23390 and dopamine D2 receptor antagonist sulpiride reversed the ameliorative effects of both MPH and IKE on the social interaction deficits of Drosophila rugose. To extend analysis of IKE treatment to the vertebrate central nervous system, ASD-associated gene expression in mouse hippocampus was studied by RNA-seq: IKE treatment altered the expression of genes coding phosphoinositide 3-kinases/protein kinase B (PI3K-Akt), proteins in glutamatergic, dopaminergic, serotonergic, and GABAergic synapses, cAMP response element-binding protein (CREB), and RNA transporter proteins. These results provide a foundation for further analysis of IKE as a candidate for treatment of some forms of ASD.

The SALT-Readout ASIC for Silicon Strip Sensors of Upstream Tracker in the Upgraded LHCb Experiment.

SALT, a new dedicated readout Application Specific Integrated Circuit (ASIC) for the Upstream Tracker, a new silicon detector in the Large Hadron Collider beauty (LHCb) experiment, has been designed and developed. It is a 128-channel chip using an innovative architecture comprising a low-power analogue front-end with fast pulse shaping and a 40 MSps 6-bit Analog-to-Digital Converter (ADC) in each channel, followed by a Digital Signal Processing (DSP) block performing pedestal and Mean Common Mode (MCM) subtraction and zero suppression. The prototypes of SALT were fabricated and tested, confirming the full chip functionality and fulfilling the specifications. A signal-to-noise ratio of about 20 is achieved for a silicon sensor with a 12 pF input capacitance. In this paper, the SALT architecture and measurements of the chip performance are presented.

Hepatitis C Virus Downregulates Ubiquitin-Conjugating Enzyme E2S Expression To Prevent Proteasomal Degradation of NS5A, Leading to Host Cells More Sensitive to DNA Damage.

Hepatitis C virus (HCV) infection may cause chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. HCV exploits cellular machineries to establish persistent infection. We demonstrate here that ubiquitin-conjugating enzyme E2S (UBE2S), a member of the ubiquitin-conjugating enzyme family (E2s), was downregulated by endoplasmic reticulum stress caused by HCV in Huh7 cells. UBE2S interacted with domain I of HCV NS5A and degraded NS5A protein through the Lys11-linked proteasome-dependent pathway. Overexpression of UBE2S suppressed viral propagation, while depletion of UBE2S expression increased viral infectivity. Enzymatically inactive UBE2S C95A mutant exerted no antiviral activity, suggesting that ubiquitin-conjugating enzymatic activity was required for the suppressive role of UBE2S. Chromatin ubiquitination plays a crucial role in the DNA damage response. We showed that the levels of UBE2S and Lys11 chains bound to the chromatin were markedly decreased in the context of HCV replication, rendering HCV-infected cells more sensitive to DNA damage. These data suggest that HCV counteracts antiviral activity of UBE2S to optimize viral propagation and may contribute to HCV-induced liver pathogenesis.IMPORTANCE Protein homeostasis is essential to normal cell function. HCV infection disturbs the protein homeostasis in the host cells. Therefore, host cells exert an anti-HCV activity in order to maintain normal cellular metabolism. We showed that UBE2S interacted with HCV NS5A and degraded NS5A protein through the Lys11-linked proteasome-dependent pathway. However, HCV has evolved to overcome host antiviral activity. We demonstrated that the UBE2S expression level was suppressed in HCV-infected cells. Since UBE2S is an ubiquitin-conjugating enzyme and this enzyme activity is involved in DNA damage repair, HCV-infected cells are more sensitive to DNA damage, and thus UBE2S may contribute to viral oncogenesis.

Clinical features, isolation, and complete genome sequence of severe acute respiratory syndrome coronavirus 2 from the first two patients in Vietnam.

In January 2020, we identified two severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients in a familial cluster with one person coming from Wuhan, China. The complete genome sequences of two SARS-CoV-2 strains isolated from these patients were identical and 99.98% similar to strains isolated in Wuhan. This is genetically suggestive of human-to-human transmission of SARS-CoV-2 and indicates Wuhan as the most plausible origin of the early outbreak in Vietnam. The younger patient had a mild upper respiratory illness and a brief viral shedding, whereas the elderly with multi-morbidity had pneumonia, prolonged viral shedding, and residual lung damage. The evidence of nonsynonymous substitutions in the ORF1ab region of the viral sequence warrants further studies.

New multimodal stationary phases prepared by Ugi multicomponent approach.

Eight different stationary phases based on two aminopropyl silicas of different brands suitable for multimodal chromatography applications have been prepared by a four-component Ugi reaction. The intention was to synthesize stationary phases significantly differing in their properties hereby demonstrating flexibility of the Ugi synthetic protocol. Diverse functional groups including a nonpolar long aliphatic chain, phenyl moiety, cholic acid scaffold, phenylboronic and monosaccharide units, charged betaine, and arginine moieties were immobilized on a silica surface. The novel sorbents were extensively characterized by elemental analysis, Raman spectroscopy, and chromatography. Considering the anchored chemical structures covalently bonded to the silica surface, reversed-phase, hydrophilic, and ion-exchange separation modes were expected. The chromatographic evaluation was performed directed to map the potential of the individual columns specifically in the mentioned chromatographic modes. The Ugi synthetic protocol has proven to be a simple, feasible, and versatile tool for the synthesis of sorbents of variable properties. The newly prepared stationary phases differed considerably in hydrophobicity and ion-exchange ability. A significant influence of the supporting aminopropyl silica on the final chromatographic behavior was observed. Finally, one practical example confirming applicability of the newly prepared sorbents was demonstrated in separation of cytarabine.

Correction: Ueoka, I., et al. Autism Spectrum Disorder-Related Syndromes: Modeling with Drosophila and Rodents. Int. J. Mol. Sci. 2019, 20, 4071.

The author wishes to make the following correction to this paper [...].

Bacopa monnieri (L.) Wettst. Extract Improves Memory Performance via Promotion of Neurogenesis in the Hippocampal Dentate Gyrus of Adolescent Mice.

Bacopa monnieri L. Wettst. (BM) is a botanical component of Ayurvedic medicines and of dietary supplements used worldwide for cognitive health and function. We previously reported that administration of BM alcoholic extract (BME) prevents trimethyltin (TMT)-induced cognitive deficits and hippocampal cell damage and promotes TMT-induced hippocampal neurogenesis. In this study, we demonstrate that administration of BME improves spatial working memory in adolescent (5-week- old) healthy mice but not adult (8-week-old) mice. Moreover, improved spatial working memory was retained even at 4 weeks after terminating 1-week treatment of adolescent mice. One-week BME treatment of adolescent mice significantly enhanced hippocampal BrdU incorporation and expression of genes involved in neurogenesis determined by RNAseq analysis. Cell death, as detected by histochemistry, appeared not to be significant. A significant increase in neurogenesis was observed in the dentate gyrus region 4 weeks after terminating 1-week treatment of adolescent mice with BME. Bacopaside I, an active component of BME, promoted the proliferation of neural progenitor cells in vitro in a concentration-dependent manner via the facilitation of the Akt and ERK1/2 signaling. These results suggest that BME enhances spatial working memory in healthy adolescent mice by promoting hippocampal neurogenesis and that the effects of BME are due, in significant amounts, to bacopaside I.

The regenerating family member 3 ß instigates IL-17A-mediated neutrophil recruitment downstream of NOD1/2 signalling for controlling colonisation resistance independently of microbiota community structure.

OBJECTIVE: Loss of the Crohn's disease predisposing NOD2 gene results in an intestinal microenvironment conducive for colonisation by attaching-and-effacing enteropathogens. However, it remains elusive whether it relies on the intracellular recruitment of the serine-threonine kinase RIPK2 by NOD2, a step that is required for its activation of the transcription factor NF-κB. DESIGN: Colonisation resistance was evaluated in wild type and mutant mice, as well as in ex-germ-free (ex-GF) mice which were colonised either with faeces from Ripk2-deficient mice or with bacteria with similar preferences for carbohydrates to those acquired by the pathogen. The severity of the mucosal pathology was quantified at several time points postinfection by using a previously established scoring. The community resilience in response to infection was evaluated by 16S ribosomal RNA gene sequence analysis. The control of pathogen virulence was evaluated by monitoring the secretion of Citrobacter-specific antibody response in the faeces. RESULTS: Primary infection was similarly outcompeted in ex-GF Ripk2-deficient and control mice, demonstrating that the susceptibility to infection resulting from RIPK2 deficiency cannot be solely attributed to specific microbiota community structures. In contrast, delayed clearance of Citrobacter rodentium and exacerbated histopathology were preceded by a weakened propensity of intestinal macrophages to afford innate lymphoid cell activation. This tissue protection unexpectedly required the regenerating family member 3ß by instigating interleukin (IL) 17A-mediated neutrophil recruitment to the intestine and subsequent phosphorylation of signal transducer and activator of transcription 3. CONCLUSIONS: These results unveil a previously unrecognised mechanism that efficiently protects from colonisation by diarrhoeagenic bacteria early in infection.

Immunological and clinical effects of low-dose interleukin-2 across 11 autoimmune diseases in a single, open clinical trial.

OBJECTIVE: Regulatory T cells (Tregs) prevent autoimmunity and control inflammation. Consequently, any autoimmune or inflammatory disease reveals a Treg insufficiency. As low-dose interleukin-2 (ld-IL2) expands and activates Tregs, it has a broad therapeutic potential. AIM: We aimed to assess this potential and select diseases for further clinical development by cross-investigating the effects of ld-IL2 in a single clinical trial treating patients with 1 of 11 autoimmune diseases. METHODS: We performed a prospective, open-label, phase I-IIa study in 46 patients with a mild to moderate form of either rheumatoid arthritis, ankylosing spondylitis, systemic lupus erythematosus, psoriasis, Behcet's disease, granulomatosis with polyangiitis, Takayasu's disease, Crohn's disease, ulcerative colitis, autoimmune hepatitis and sclerosing cholangitis. They all received ld-IL2 (1 million IU/day) for 5 days, followed by fortnightly injections for 6 months. Patients were evaluated by deep immunomonitoring and clinical evaluation. RESULTS: ld-IL2 was well tolerated whatever the disease and the concomitant treatments. Thorough supervised and unsupervised immunomonitoring demonstrated specific Treg expansion and activation in all patients, without effector T cell activation. Indication of potential clinical efficacy was observed. CONCLUSION: The dose of IL-2 and treatment scheme used selectively activate and expand Tregs and are safe across different diseases and concomitant treatments. This and preliminary indications of clinical efficacy should licence the launch of phase II efficacy trial of ld-IL2 in various autoimmune and inflammatory diseases. TRIAL REGISTRATION NUMBER: NCT01988506.

Bacopa monnieri (L.) Ameliorates Cognitive Deficits Caused in a Trimethyltin-Induced Neurotoxicity Model Mice.

We previously demonstrated that Bacopa monnier (L.) WETTST. extract (BME) ameliorated cognitive dysfunction in animal models of dementia by enhancing synaptic plasticity-related signaling in the hippocampus and protecting cholinergic neurons in the medial septum. To further clarify the pharmacological features and availability of BME as a novel anti-dementia agent, we investigated whether BME affects neuronal repair using a mouse model of trimethyltin (TMT)-induced neuronal loss/self-repair in the hippocampus. Mice pretreated with TMT (2.8 mg/kg, intraperitoneally (i.p.)) on day 0 were given BME (50 mg/kg, per os (p.o.)) once daily for 15-30 d. Cognitive performance of the animals was elucidated twice by the object location test and modified Y maze test on days 17-20 (Phase I) and days 32-35 (Phase II) or by the passive avoidance test on Phase II. TMT impaired hippocampus-dependent spatial working memory and amygdala-dependent fear-motivated memory. The administration of BME significantly prevented TMT-induced cognitive deficits. The protective effects of BME on the spatial memory deficits were confirmed by Nissl staining of hippocampal tissues and propidium iodide staining of organotypic hippocampal slice cultures. Immunohistochemical studies conducted on days 17 and 32 revealed that thirty days of treatment with BME increased the number of 5-bromo-2'-deoxyuridine (BrdU)-immunopositive cells in the dentate gyrus region of TMT-treated mice, whereas fifteen days of treatment with BME had no effect. These results suggest that BME ameliorates TMT-induced cognition dysfunction mainly via protecting the hippocampal neurons from TMT-induced hippocampal lesions and partly via promoting neuroregeneration in the dentate gyrus regions.

Autism Spectrum Disorder-Related Syndromes: Modeling with Drosophila and Rodents.

Whole exome analyses have identified a number of genes associated with autism spectrum disorder (ASD) and ASD-related syndromes. These genes encode key regulators of synaptogenesis, synaptic plasticity, cytoskeleton dynamics, protein synthesis and degradation, chromatin remodeling, transcription, and lipid homeostasis. Furthermore, in silico studies suggest complex regulatory networks among these genes. Drosophila is a useful genetic model system for studies of ASD and ASD-related syndromes to clarify the in vivo roles of ASD-associated genes and the complex gene regulatory networks operating in the pathogenesis of ASD and ASD-related syndromes. In this review, we discuss what we have learned from studies with vertebrate models, mostly mouse models. We then highlight studies with Drosophila models. We also discuss future developments in the related field.