Pomegranate (
Punica granatum) is an important source of polyphenols with assessed antioxidant properties. The aims of this study were: (i) the characterization of the monomeric phenolic variability ...on each isolated fruit component (endocarp, mesocarp, aril); (ii) the study on the effect of pomegranate fruit components on human thrombin amidolytic activity. Collectively, our data show that pomegranate components contain bioactive metabolites (mainly ellagic acid) and suggest a potential role for the pomegranate extract in the regulation of a number of physio-pathological processes involving thrombin (or thrombin-like proteinase).
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The objective of this investigation was to conduct a randomized controlled trial to evaluate whether KiActiv Heart alongside usual care (UC) promotes positive physical activity (PA) change versus UC ...alone.
Patients in cardiac rehabilitation (n = 130) undertook an 8-wk intervention with follow-up at wk 8. Both groups attended UC and wore a PA monitor during the intervention. The intervention group accessed the digital service and received weekly one-to-one remote mentor sessions. The primary outcome was change in PA to achieve the Association of Certified Physiotherapists in Cardiac Rehabilitation (ACPICR) recommendations. The secondary outcome was cardiorespiratory fitness (CRF) change, measured using incremental shuttle walk test (ISWT).
The probability of meeting ACPICR "Daily Activity" recommendation was statistically significantly greater in the intervention group versus control at wk 8 ( P < .05). No statistically significant differences between groups were found for mean ISWT change (intervention 89 ± 116 m; control 44 ± 124 m).
Participation in KiActiv Heart alongside UC was associated with statistically significant improvement in probability of meeting ACPICR recommendation and non-statistically significant but potentially clinically important increases in CRF versus UC alone. This builds on existing evidence for effectiveness.
BACKGROUND: Sperm DNA integrity is essential for the accurate transmission of genetic information. The clinical significance of this assessment lies in its association with not only natural ...conception rates, but also the success of assisted reproduction technology (ART). It has been reported that sperm chromatin structure assay (SCSA) identified thresholds for negative pregnancy outcome after ART when the DNA fragmentation index (DFI), previously known as COMPαt, was >30%. METHODS: In a prospective clinical study, we examined 34 male infertile patients, the husbands of women undergoing conventional IVF or ICSI. SCSA and ART were carried out on semen aliquots taken from the same ejaculate. Fertilization rate, embryo quality and pregnancy rates were correlated to SCSA parameters, DFI and highly DNA stainable (HDS) cells. RESULTS: No differences were seen in SCSA parameter values between patients initiating pregnancies and not doing so in either ICSI or conventional IVF. Pregnancies and normal delivery were obtained even with high levels of DFI. CONCLUSIONS: There is still controversy over whether analytical techniques currently in use are able to identify the level of damage to spermatozoa. Large‐scale studies should be conducted in different clinical settings to determine the effects of sperm DNA damage on the outcome of ART.
Acute myeloid leukemia (AML) remains difficult to treat and requires new therapeutic approaches. Potent inhibitors of the chromatin-associated protein MENIN have recently entered human clinical ...trials, opening new therapeutic opportunities for some genetic subtypes of this disease. Using genome-scale functional genetic screens, we identified IKAROS (encoded by IKZF1) as an essential transcription factor in KMT2A (MLL1)-rearranged (MLL-r) AML that maintains leukemogenic gene expression while also repressing pathways for tumor suppression, immune regulation and cellular differentiation. Furthermore, IKAROS displays an unexpected functional cooperativity and extensive chromatin co-occupancy with mixed lineage leukemia (MLL)1-MENIN and the regulator MEIS1 and an extensive hematopoietic transcriptional complex involving homeobox (HOX)A10, MEIS1 and IKAROS. This dependency could be therapeutically exploited by inducing IKAROS protein degradation with immunomodulatory imide drugs (IMiDs). Finally, we demonstrate that combined IKAROS degradation and MENIN inhibition effectively disrupts leukemogenic transcriptional networks, resulting in synergistic killing of leukemia cells and providing a paradigm for improved drug targeting of transcription and an opportunity for rapid clinical translation.
Abstract
Background
There is limited evidence to date about changes to sexual and reproductive health (SRH) during the initial wave of coronavirus disease 2019 (COVID-19). To address this gap, our ...team organized a multicountry, cross-sectional online survey as part of a global consortium.
Methods
Consortium research teams conducted online surveys in 30 countries. Sampling methods included convenience, online panels, and population-representative. Primary outcomes included sexual behaviors, partner violence, and SRH service use, and we compared 3 months prior to and during policy measures to mitigate COVID-19. We conducted meta-analyses for primary outcomes and graded the certainty of the evidence.
Results
Among 4546 respondents with casual partners, condom use stayed the same for 3374 (74.4%), and 640 (14.1%) reported a decline. Fewer respondents reported physical or sexual partner violence during COVID-19 measures (1063 of 15 144, 7.0%) compared to before COVID-19 measures (1469 of 15 887, 9.3%). COVID-19 measures impeded access to condoms (933 of 10 790, 8.7%), contraceptives (610 of 8175, 7.5%), and human immunodeficiency virus/sexually transmitted infection (HIV/STI) testing (750 of 1965, 30.7%). Pooled estimates from meta-analysis indicate that during COVID-19 measures, 32.3% (95% confidence interval CI, 23.9%–42.1%) of people needing HIV/STI testing had hindered access, 4.4% (95% CI, 3.4%–5.4%) experienced partner violence, and 5.8% (95% CI, 5.4%–8.2%) decreased casual partner condom use (moderate certainty of evidence for each outcome). Meta-analysis findings were robust in sensitivity analyses that examined country income level, sample size, and sampling strategy.
Conclusions
Open science methods are feasible to organize research studies as part of emergency responses. The initial COVID-19 wave impacted SRH behaviors and access to services across diverse global settings.
The I-SHARE-1 study in 30 countries assessed sexual and reproductive health outcomes among adults. During COVID-19 measures, 32.3% of people needing HIV/STI testing had hindered access, 4.4% experienced partner violence, and 5.8% decreased casual partner condom use.
Aims/hypothesis
Individualised variable-interval risk-based screening offers better targeting and improved cost-effectiveness in screening for diabetic retinopathy. We developed a generalisable risk ...calculation engine (RCE) to assign personalised intervals linked to local population characteristics, and explored differences in assignment compared with current practice.
Methods
Data from 5 years of photographic screening and primary care for people with diabetes, screen negative at the first of > 1 episode, were combined in a purpose-built near-real-time warehouse. Covariates were selected from a dataset created using mixed qualitative/quantitative methods. Markov modelling predicted progression to screen-positive (referable diabetic retinopathy) against the local cohort history. Retinopathy grade informed baseline risk and multiple imputation dealt with missing data. Acceptable intervals (6, 12, 24 months) and risk threshold (2.5%) were established with patients and professional end users.
Results
Data were from 11,806 people with diabetes (46,525 episodes, 388 screen-positive). Covariates with sufficient predictive value were: duration of known disease, HbA
1c
, age, systolic BP and total cholesterol. Corrected AUC (95% CIs) were: 6 months 0.88 (0.83, 0.93), 12 months 0.90 (0.87, 0.93) and 24 months 0.91 (0.87, 0.94). Sensitivities/specificities for a 2.5% risk were: 6 months 0.61, 0.93, 12 months 0.67, 0.90 and 24 months 0.82, 0.81. Implementing individualised RCE-based intervals would reduce the proportion of people becoming screen-positive before the allocated screening date by > 50% and the number of episodes by 30%.
Conclusions/interpretation
The Liverpool RCE shows sufficient performance for a local introduction into practice before wider implementation, subject to external validation. This approach offers potential enhancements of screening in improved local applicability, targeting and cost-effectiveness.
BACKGROUND: Persistent organochlorine pollutants (POP), such as polychlorinated biphenyls (PCB) and dichlorodiphenyldichloroethylene (p, p′-DDE), are widely found in the environment and considered ...potential endocrine-disrupting compounds (EDC). Their impact on male fertility is still unknown. METHODS: To explore the hypothesis that POP is associated with altered sperm chromatin integrity, a cross-sectional study involving 707 adult males (193 Inuits from Greenland, 178 Swedish fishermen, 141 men from Warsaw, Poland, and 195 men from Kharkiv, Ukraine) was carried out. Serum levels of 2,2′,4,4′,5,5′-hexachlorobiphenyl (CB-153), as a proxy of the total PCB burden, and of p,p′-DDE were determined. Sperm chromatin structure assay (SCSA) was used to assess sperm DNA/chromatin integrity. RESULTS: We found a strong and monotonically increasing DNA fragmentation index with increasing serum levels of CB-153 among European but not Inuit men, reaching a 60% higher average level in the highest exposure group. No significant associations were found between SCSA-derived parameters and p, p′-DDE serum concentrations. CONCLUSION: These results suggest that human dietary PCB exposure might have a negative impact on the sperm chromatin integrity of adult males but additional issues, including differences in the genetic background and lifestyle habits, still need to be elucidated.
Alzheimer's disease (AD) is a progressive neurodegeneration characterized by neuron death ending in memory and cognitive decline. A major concern in AD research is the identification of new ...therapeutics that could prevent or delay the onset of the disorder, with current treatments being effective only in reducing symptoms. In this perspective, the use of engineered probiotics as therapeutic tools for the delivery of molecules to eukaryotic cells is finding application in several disorders. This work introduces a new strategy for AD treatment based on the use of a
strain carrying one plasmid (pExu) that contains a eukaryotic expression cassette encoding the human p62 protein. 3xTg-AD mice orally administered with these bacteria for two months showed an increased expression of endogenous p62 in the brain, with a protein delivery mechanism involving both lymphatic vessels and neural terminations, and positive effects on the major AD hallmarks. Mice showed ameliorated memory, modulation of the ubiquitin-proteasome system and autophagy, reduced levels of amyloid peptides, and diminished neuronal oxidative and inflammatory processes. Globally, we demonstrate that these extremely safe, non-pathogenic and non-invasive bacteria used as delivery vehicles for the p62 protein represent an innovative and realistic therapeutic approach in AD.
The multicatalytic proteinase complex (MPC or proteasome) from bovine thymus was isolated and purified to homogeneity applying a protocol utilizing ion exchange and gel permeation chromatography as ...major purification tools. The purified complex shows molecular properties that are common for proteasomal molecules (high molecular mass, multisubunit organization, and multiple proteolytic activities) even though a peculiar subunit composition and the presence of specific regulatory mechanisms affecting the assembled proteolytic activities suggest a specialized function for this complex. Thymus proteasome is characterized by the presence of LMP2, LMP7, and LMP10 (MECL1) subunits, which replace the X, Y, and Z subunits. Since a similar complex was previously isolated in bovine spleen, it appears that the proteasomal population containing the LMP subunits is characteristic for organs involved in immune response. Both the thymus and spleen proteasomes are characterized by a marked efficiency in cleaving peptide bonds after branched-chain and aromatic amino acids, indicating that this proteasomal population is most likely involved in intracellular processing of class I antigenic peptides and is an example of an “in vivo” functioning immunoproteasome. However, in spite of several similarities, the complexes isolated from the two lymphoid organs do not show superimposable functional properties, which suggests the presence of organ-specific regulatory mechanisms affecting each of the proteolytic components assembled in the complex.
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