Evidence is emerging that interdaily meal pattern variability potentially affects response such as thermic effect of food (TEF), macronutrient metabolism, and appetite.
To investigate the effect of ...irregular meal pattern on TEF, glucose, insulin, lipid profile, and appetite regulation in women who are overweight or with obesity and confirmed insulin resistance.
In a randomized crossover trial, 9 women mean ± SD BMI (in kg/m2): 33.3 ± 3.1 with confirmed insulin resistance consumed a regular (14 d; 6 meals/d) and an irregular (14 d; 3–9 meals/d) meal pattern separated by a 14-d washout interval. Identical foods were provided during the interventions, and at the start and end of each meal pattern, participants attended the laboratory after an overnight fast. Energy expenditure, glucose, insulin, lipids, adiponectin, leptin, glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and ghrelin were measured at baseline and for 3 h after consumption of a test drink, after which an ad libitum test meal was offered. Subjective appetite ratings were recorded before and after the test drink, after the ad libitum meal, and during the intervention. Continuous interstitial glucose monitoring was undertaken for 7 consecutive days during each intervention.
TEF (over 3 h) was significantly lower postirregular intervention compared with postregular (97.7 ± 19.2 kJ*3 h in postregular visit and 76.7 ± 35.2 kJ*3 h in postirregular visit, paired t test, P = 0.048). Differences in HOMA-IR between the 2 interventions (3.3 ± 1.7 and 3.6 ± 1.6 in postregular and postirregular meal pattern, respectively) were not significant. Net incremental AUC for GLP-1 concentrations (over 3 h) for the postregular meal pattern were higher (864.9 ± 456.1 pmol/L*3 h) than the postirregular meal pattern (487.6 ± 271.7 pmol/L*3 h, paired t test, P = 0.005).
Following a 14-d period of an irregular meal pattern, TEF was significantly less than following a regular meal pattern, potentially compromising weight management if sustained long term. This study was registered at www.clinicaltrials.gov as NCT02582606.
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Complement activation by antibodies bound to pathogens, tumors, and self antigens is a critical feature of natural immune defense, a number of disease processes, and immunotherapies. How antibodies ...activate the complement cascade, however, is poorly understood. We found that specific noncovalent interactions between Fc segments of immunoglobulin G (IgG) antibodies resulted in the formation of ordered antibody hexamers after antigen binding on cells. These hexamers recruited and activated C1, the first component of complement, thereby triggering the complement cascade. The interactions between neighboring Fc segments could be manipulated to block, reconstitute, and enhance complement activation and killing of target cells, using all four human IgG subclasses. We offer a general model for understanding antibody-mediated complement activation and the design of antibody therapeutics with enhanced efficacy.
The capsid revolution Taylor, Ian A; Fassati, Ariberto
Journal of molecular cell biology,
04/2024, Letnik:
15, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Abstract Lenacapavir, targeting the human immunodeficiency virus type-1 (HIV-1) capsid, is the first-in-class antiretroviral drug recently approved for clinical use. The development of Lenacapavir is ...attributed to the remarkable progress in our understanding of the capsid protein made during the last few years. Considered little more than a component of the virus shell to be shed early during infection, the capsid has been found to be a key player in the HIV-1 life cycle by interacting with multiple host factors, entering the nucleus, and directing integration. Here, we describe the key advances that led to this ‘capsid revolution’.
SAMHD1, an analogue of the murine interferon (IFN)-γ-induced gene Mg11 (ref. 1), has recently been identified as a human immunodeficiency virus-1 (HIV-1) restriction factor that blocks early-stage ...virus replication in dendritic and other myeloid cells and is the target of the lentiviral protein Vpx, which can relieve HIV-1 restriction. SAMHD1 is also associated with Aicardi-Goutières syndrome (AGS), an inflammatory encephalopathy characterized by chronic cerebrospinal fluid lymphocytosis and elevated levels of the antiviral cytokine IFN-α. The pathology associated with AGS resembles congenital viral infection, such as transplacentally acquired HIV. Here we show that human SAMHD1 is a potent dGTP-stimulated triphosphohydrolase that converts deoxynucleoside triphosphates to the constituent deoxynucleoside and inorganic triphosphate. The crystal structure of the catalytic core of SAMHD1 reveals that the protein is dimeric and indicates a molecular basis for dGTP stimulation of catalytic activity against dNTPs. We propose that SAMHD1, which is highly expressed in dendritic cells, restricts HIV-1 replication by hydrolysing the majority of cellular dNTPs, thus inhibiting reverse transcription and viral complementary DNA (cDNA) synthesis.
Exosomal miRNA transfer is a mechanism for cell-cell communication that is important in the immune response, in the functioning of the nervous system and in cancer. Syncrip/hnRNPQ is a highly ...conserved RNA-binding protein that mediates the exosomal partition of a set of miRNAs. Here, we report that Syncrip's amino-terminal domain, which was previously thought to mediate protein-protein interactions, is a cryptic, conserved and sequence-specific RNA-binding domain, designated NURR (N-terminal unit for RNA recognition). The NURR domain mediates the specific recognition of a short hEXO sequence defining Syncrip exosomal miRNA targets, and is coupled by a non-canonical structural element to Syncrip's RRM domains to achieve high-affinity miRNA binding. As a consequence, Syncrip-mediated selection of the target miRNAs implies both recognition of the hEXO sequence by the NURR domain and binding of the RRM domains 5' to this sequence. This structural arrangement enables Syncrip-mediated selection of miRNAs with different seed sequences.
Exacerbations of asthma cause a substantial global illness burden. Adults with uncontrolled persistent asthma despite maintenance treatment require additional therapy. Since macrolide antibiotics can ...be used to treat persistent asthma, we aimed to assess the efficacy and safety of oral azithromycin as add-on therapy in patients with uncontrolled persistent asthma on medium-to-high dose inhaled corticosteroids plus a long-acting bronchodilator.
We did a randomised, double-blind, placebo controlled parallel group trial to determine whether oral azithromycin decreases the frequency of asthma exacerbations in adults (≥18 years) with symptomatic asthma despite current use of inhaled corticosteroid and long-acting bronchodilator, and who had no hearing impairment or abnormal prolongation of the corrected QT interval. Patients were randomly assigned (1:1) to receive azithromycin 500 mg or placebo three times per week for 48 weeks. Patients were centrally allocated using concealed random allocation from a computer-generated random numbers table with permuted blocks of 4 or 6 and stratification for centre and past smoking. Primary efficacy endpoints were the rate of total (severe and moderate) asthma exacerbations over 48 weeks and asthma quality of life. Data were analysed on an intention-to-treat basis. The trial is registered at the Australian and New Zealand Clinical Trials Registry (ANZCTR), number 12609000197235.
Between June 12, 2009, and Jan 31, 2015, 420 patients were randomly assigned (213 in the azithromycin group and 207 in the placebo group). Azithromycin reduced asthma exacerbations (1·07 per patient-year 95% CI 0·85–1·29) compared with placebo (1·86 per patient-year 1·54–2·18; incidence rate ratio IRR 0·59 95% CI 0·47–0·74; p<0·0001). The proportion of patients experiencing at least one asthma exacerbation was reduced by azithromycin treatment (127 61% patients in the placebo group vs 94 44% patients in the azithromycin group, p<0·0001). Azithromycin significantly improved asthma-related quality of life (adjusted mean difference, 0·36 95% CI 0·21–0·52; p=0·001). Diarrhoea was more common in azithromycin-treated patients (72 34% vs 39 19%; p=0·001).
Adults with persistent symptomatic asthma experience fewer asthma exacerbations and improved quality of life when treated with oral azithromycin for 48 weeks. Azithromycin might be a useful add-on therapy in persistent asthma.
National Health and Medical Research Council of Australia, John Hunter Hospital Charitable Trust.
Older adults are disproportionately vulnerable to fraud, and federal agencies have speculated that excessive trust explains their greater vulnerability. Two studies, one behavioral and one using ...neuroimaging methodology, identified age differences in trust and their neural underpinnings. Older and younger adults rated faces high in trust cues similarly, but older adults perceived faces with cues to untrustworthiness to be significantly more trustworthy and approachable than younger adults. This age-related pattern was mirrored in neural activation to cues of trustworthiness. Whereas younger adults showed greater anterior insula activation to untrustworthy versus trustworthy faces, older adults showed muted activation of the anterior insula to untrustworthy faces. The insula has been shown to support interoceptive awareness that forms the basis of "gut feelings," which represent expected risk and predict risk-avoidant behavior. Thus, a diminished "gut" response to cues of untrustworthiness may partially underlie older adults' vulnerability to fraud.
The effects of breakfast consumption on energy intake and the responses to foods consumed later in the day remain unclear. Twelve men of healthy body weight who reported regularly consuming breakfast ...(mean ± SD age 23.4 ± 7.3 y; BMI 23.5 ± 1.7 kg/m²) completed 2 trials using a randomized crossover design. Participants were provided with a 1050-kJ liquid preload 150 min after consuming a standardized breakfast (B) (10% daily energy requirement and 14, 14, and 72% energy from protein, fat, and carbohydrate, respectively), or no breakfast (NB). Blood glucose and serum insulin responses to the preload (area under the curve) were higher in the NB condition (P < 0.05). Plasma FFA responses to the preload were higher in the NB condition (P < 0.01). Plasma glucagon-like peptide 1 (P < 0.01) and plasma peptide Y (P < 0.05) responses were higher after the preload in the B condition. Desire to eat, fullness, and hunger ratings collected immediately prior to consuming the preload were all different from the fasting values in the NB condition (P < 0.05). Thus, immediately prior to consuming the preload, the fullness rating was lower and hunger and desire to eat ratings were higher in the NB condition (P < 0.05). Energy intake at the lunchtime test meal was approximately 17% lower in the B condition (P < 0.01). In conclusion, missing breakfast causes metabolic and hormonal differences in the responses to foods consumed later in the morning as well as differences in subjective appetite and a compensatory increase in energy intake.
Why save endangered species without clear aesthetic, economic, or ecosystemic value? This book takes on this challenging question through an account of the intrinsic goods of species. Ian A. Smith ...argues that a species' intrinsic value stems from its ability to flourish-its organisms continuing to reproduce successfully and it avoiding extinction-which helps to demonstrate a further claim, that humans ought to preserve species that we have endangered. He shows our need to exercise humility in our relations with endangered species through the preservation of their intrinsic goods, which in turn rectifies our degradation of their importance. Unique in its appeal to virtue ethics and to species concepts, The Intrinsic Value of Endangered Species is an important resource for scholars working in environmental ethics and the philosophy of biology.
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