AIM:To determine the dose-related effects of a novel probiotic combination,I.31,on irritable bowel syndrome(IBS)-related quality of life(IBS-QoL).METHODS:A ...multicenter,randomized,double-blind,placebo-controlled intervention clinical trial with three parallel arms was designed.A total of 84 patients(53female,31 male;age range 20-70 years)with IBS and diarrhea according to Rome-Ⅲcriteria were randomly allocated to receive one capsule a day for 6 wk containing:(1)I.31 high dose(n=28);(2)I.31 low dose(n=27);and(3)placebo(n=29).At baseline,and 3and 6 wk of treatment,patients filled the IBSQoL,Visceral Sensitivity Index(VSI),and global symptom relief questionnaires.RESULTS:During treatment,IBS-QoL increased in all groups,but this increment was significantly larger in patients treated with I.31 than in those receiving placebo(P=0.008).After 6 wk of treatment,IBS-QoL increased by 18±3 and 22±4 points in the high and the low dose groups,respectively(P=0.041 and P=0.023vs placebo),but only 9±3 in the placebo group.Gutspecific anxiety,as measured with VSI,also showed a significantly greater improvement after 6 wk of treatment in patients treated with probiotics(by 10±2 and14±2 points,high and low dose respectively,P<0.05for both vs 7±1 score increment in placebo).Symptom relief showed no significant changes between groups.No adverse drug reactions were reported following the consumption of probiotic or placebo capsules.CONCLUSION:A new combination of three different probiotic bacteria was superior to placebo in improving IBS-related quality of life in patients with IBS and diarrhea.
While genetic variation is of crucial importance for organisms to be able to adapt to their ever-changing environments over generations, cognitive processes can serve the same purpose by acting at ...shorter time scales. Cognition, and its resulting behaviour, allows animals to display flexible, fast and reversible responses that, without implying a genetic change, are crucial for adaptation and survival. In the research field on sexual conflict, where studies focus on male and female mating strategies that increase the individual's reproductive fitness while forcing a cost on the partner, the role that cognition may play in how such strategies can be optimised has been widely overlooked. However, a careful analysis of behavioural studies shows that animals can develop and change their responses depending on what they perceive as well as on what they can predict from their experience, which can be of prime importance for optimising their reproductive fitness. As will be reviewed here, largely psychological processes, such as perception, memory, learning and decision-making, can not only modulate sexual conflict, but can also have a big impact on the reproductive success of a given individual. This review highlights the need for a more integrative view of sexual conflict where cognitive processes are also considered as a fundamental part of an animal's adaptive mating response.
Antibodies triggering Fc‐mediated NK cell activity may contribute to protection against disease caused by SARS‐CoV‐2 infection in humans. However, how these Fc‐mediated humoral responses compare ...between individuals displaying hybrid immunity (Vac‐ex) and those fully vaccinated with no history of SARS‐CoV‐2 infection (Vac‐n) and whether they correlate with neutralizing antibody (NtAb) responses remains largely undetermined. In this retrospective study serum samples from 50 individuals (median age, 44.5 years; range, 11–85; 25 males), 25 Vac‐ex and 25 Vac‐n were studied. A flow‐cytometry‐based antibody‐mediated NK‐cell activation assay was used to quantitate effector NK‐cells stimulated to express LAMP1 (lysosomal associated membrane protein 1), MIP1 (Macrophage inflammatory protein 1), and interferon‐γ (IFNγ); NK cells isolated from two donors (D1 and D2) were used. NtAb levels targeting the Spike protein of Wuhan‐Hu‐1 and Omicron BA.1 SARS‐CoV‐2 variants were quantitated using a SARS‐CoV‐2 S pseudotyped neutralization assay. Regardless of the SARS‐CoV‐2 variant S antigen used in the NK‐cell activation assay, the frequency of NK cells stimulated to express LAMP‐1, MIP1β, and IFNγ was higher in Vac‐ex compared with Vac‐n (p values ranging from 0.07 to 0.006) for D1; this was only seen for BA.1 when NK cells from D2 were employed. The frequency of functional NK cells activated by antibody binding to either Wuhan‐Hu‐1 or Omicron BA.1 S protein was not significantly different for both VAC‐ex and VAC‐n. In contrast, NtAb titers against BA.1 were around 10‐fold lower than that against Wuhan‐Hu‐1. Vac‐ex displayed higher NtAb titers against both (sub)variants than Vac‐n. NK‐cell responses correlated poorly with NtAb titers (ρ ≤ 0.30). The data demonstrate higher cross‐reactivity across variants of concern for antibodies triggering Fc‐mediated NK cell than for NtAb. Moreover, Vac‐Ex seemed to display more robust functional antibody responses as compared with Vac‐n.
Maytansinoids are a successful class of natural and semisynthetic tubulin binders, known for their potent cytotoxic activity. Their wider application as cytotoxins and chemical probes to study ...tubulin dynamics has been held back by the complexity of natural product chemistry. Here we report the synthesis of long‐chain derivatives and maytansinoid conjugates. We confirmed that bulky substituents do not impact their high activity or the scaffold's binding mode. These encouraging results open new avenues for the design of new maytansine‐based probes.
The design and synthesis as well as biochemical and structural characterization of long‐chain maytansinoids and maytansinoid conjugates is reported. The results show the prospects of maytansinoids as probes to study microtubule dynamics and lead towards the design of new maytansine‐based derivatives.
Invited for the cover of this issue are the groups of Professors Passarella and Pieraccini at the University of Milan, in collaboration with some of the members of TubInTrain consortium. The image ...depicts work with the elements of nature, in particular the destabilising effect of maytansinol (the constellation) on microtubules (the trees). Read the full text of the article at 10.1002/chem.202203431.
The role of HCV on the HIV reservoir is controversial since the reduction on HIV-DNA levels after HCV eradication with IFNα/RBV treatment seems to be the result of drugs instead of HCV clearance. We ...assessed whether HCV eradication can decrease HIV-DNA content in HIV/HCV-coinfected patients treated with direct-acting antivirals, DAAs (IFNα/RBV-free regimens). Cell-associated HIV-DNA was measured by ddPCR in 25 HIV-monoinfected and 25 HIV/HCV-coinfected patients. There were no differences in HIV-DNA levels between groups neither at baseline nor at 12 weeks after DAAs treatment completion. Our results indicate that HCV does not appear to influence the HIV reservoir size and suggest the lack of an anti-HIV action for DAAs.
Summary
The controlled in situ delivery of biologics (e.g. enzymes, cytokines, antibodies) by engineered bacteria of our microbiome will allow the sustainable production of these complex and ...expensive drugs locally in the human body, overcoming many of the technical and economical barriers currently associated with the global use of these potent medicines. We provide examples showing how engineered bacteria can be effective treatments against multiple pathologies, including autoimmune and inflammatory diseases, metabolic disorders, diabetes, obesity, infectious diseases and cancer, hence contributing to achieve the Global Sustainable Goal 3: ensure healthy lives and promote well‐being for all at all ages.
The controlled in situ delivery of biologics (e.g. enzymes, cytokines, antibodies) by engineered bacteria of our microbiome will allow the sustainable production of these complex and expensive drugs locally in the human body, overcoming many of the technical and economical barriers currently associated with the global use of these potent medicines.
Studies investigating the cumulative incidence of and immune status against SARS‐CoV‐2 infection provide valuable information for shaping public health decision‐making. A cross‐sectional study on 935 ...participants, conducted in the Valencian Community (VC), measuring anti‐SARS‐CoV‐2‐receptor binding domain‐RBD‐total antibodies and anti‐Nucleocapsid (N)‐IgGs via electrochemiluminescence assays. Quantitation of neutralizing antibodies (NtAb) against ancestral and Omicron BA.1 and BA.2 variants and enumeration of SARS‐CoV‐2‐S specific‐IFNγ‐producing CD4+ and CD8+ T cells was performed in 100 and 137 participants, respectively. The weighted cumulative incidence was 51.9% (95% confidence interval CI: 48.7–55.1) and was inversely related to age. Anti‐RBD total antibodies were detected in 97% of participants; vaccinated and SARS‐CoV‐2‐experienced (VAC‐ex; n = 442) presented higher levels (p < 0.001) than vaccinated/naïve (VAC‐n; n = 472) and nonvaccinated/experienced (UNVAC‐ex; n = 63) subjects. Antibody levels correlated inversely with time elapsed since last vaccine dose in VAC‐n (Rho, −0.52; p < 0.001) but not in VAC‐ex (rho −0.02; p = 0.57). Heterologous booster shots resulted in increased anti‐RBD antibody levels compared with homologous schedules in VAC‐n, but not in VAC‐ex. NtAbs against Omicron BA.1 were detected in 94%, 75%, and 50% of VAC‐ex, VAC‐n and UNVAC‐ex groups, respectively. For Omicron BA.2, the figures were 97%, 84%, and 40%, respectively. SARS‐CoV‐2‐S‐reactive IFN‐γ T cells were detected in 73%, 75%, and 64% of VAC‐ex, VAC‐n and UNVAC‐ex, respectively. Median frequencies for both T‐cell subsets were comparable across groups. In summary, by April 2022, around half of the VC population had been infected with SARS‐CoV‐2 and, due to extensive vaccination, displayed hybrid immunity.
T-cell exhaustion has been involved in the pathogenesis of HIV infection. We have longitudinally analyzed PD1 and Tim3 surrogate markers of T-cells exhaustion, in parallel with other markers of HIV ...progression, and its potential association with CD4 changes in treated and untreated infection.
96 HIV patients, 49 of them followed in the absence of cART (cART-naïve group) and 47 after initiation of cART (cART group) were included and followed for a median of 43 IQR: 31-60 months. PD1 and Tim3 expression, CD8 T-cells activation, recent thymic emigrants, activation/apoptosis and turnover of CD4 cells were assessed at baseline and during follow up. Univariate and multivariate associations with CD4 evolution were explored.
Parameters significantly associated with CD4 depletion in cART-naïve group were: baseline level (p = 0.02) and variation (p = 0.002) of PD1 and Tim3 co-expression on CD8, and variation of CD95 expression on CD4 (p = 0.007). Parameters significantly associated with CD4 restoration in cART group were: baseline level of CD38+HLADR- subset of CD8 (p = 0.01), variation of PD1 expression on CD8 (p = 0.036), variation of Tim3 expression on CD4 (p = 0.039) and variation of CD95 expression on CD4 (p = 0.035).
Our results suggest that PD1 and Tim3 markers of exhaustion have a pivotal role in CD4 dynamics in HIV patients and its down-regulation would be a desirable effect of immunotherapies aimed to restore CD4 T-cell pool during progression of HIV infection.
The longevity-promoting NAD⁺–dependent class III histone deacetylase Sirtuin 1 (SIRT1) is involved in stem cell function by controlling cell fate decision and/or by regulating the p53-dependent ...expression of NANOG. We show that SIRT1 is down-regulated precisely during human embryonic stem cell differentiation at both mRNA and protein levels and that the decrease in Sirt1 mRNA is mediated by a molecular pathway that involves the RNA-binding protein HuR and the arginine methyltransferase coactivator-associated arginine methyltransferase 1 (CARM1). SIRT1 down-regulation leads to reactivation of key developmental genes such as the neuroretinal morphogenesis effectors DLL4, TBX3, and PAX6, which are epigenetically repressed by this histone deacetylase in pluripotent human embryonic stem cells. Our results indicate that SIRT1 is regulated during stem cell differentiation in the context of a yet-unknown epigenetic pathway that controls specific developmental genes in embryonic stem cells.
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