Miracle-dz/UniFAR-FTUs huggingface dataset:
Effect of statins on β‐amyloid metabolism in humans: potential importance for the development of senile plaques in Alzheimer's disease

According to the amyloid cascade hypothesis, both familial and sporadic Alzheimer's disease (AD) is caused by the toxic effect of over‐production and/or aggregation of β‐amyloid (Aβ). Recent cell and animal studies have linked the production of Aβ to high levels of cholesterol and the use of statins, compounds inhibiting the de novo synthesis of cholesterol. Epidemiological studies have also supported such linkage by showing a reduced prevalence of AD for subjects taking statins. A limited number of clinical studies have been published trying to elucidate the effect of statin treatment on amyloid precursor protein (APP) processing and metabolism of brain cholesterol in AD in humans and this review focuses on the current state of these clinical studies. The results are contradictory, but the overall interpretation suggests that statin treatment probably does not have a direct impact through lowering of cholesterol on the APP processing and Aβ production in humans. To confirm this, further clinical studies needs to be performed with extended treatment periods and where several parameters (lipid profile, lipoproteins, sterols, biomarkers related to AD and APP metabolites) are analyzed, both in the cerebrospinal fluid and plasma. The pleiotropic effects of statins should be investigated further. One approach is presented in this review.
An update on genetic variants of the NKX2‐5

NKX2‐5 is a homeodomain transcription factor that plays a crucial role in heart development. It is the first gene where a single genetic variant (GV) was found to be associated with congenital heart diseases in humans. In this study, we carried out a comprehensive survey of NKX2‐5 GVs to build a unified, curated, and updated compilation of all available GVs. We retrieved a total of 1,380 unique GVs. From these, 970 had information on their frequency in the general population and 143 have been linked to pathogenic phenotypes in humans. In vitro effect was ascertained for 38 GVs. The homeodomain had the biggest cluster of pathogenic variants in the protein: 49 GVs in 60 residues, 23 in its third α‐helix, where 11 missense variants may affect protein–DNA interaction or the hydrophobic core. We also pinpointed the likely location of pathogenic GVs in four linear motifs. These analyses allowed us to assign a putative explanation for the effect of 90 GVs. This study pointed to reliable pathogenicity for GVs in helix 3 of the homeodomain and may broaden the scope of functional and structural studies that can be done to better understand the effect of GVs in NKX2‐5 function.
Blood pressure variability at midlife is associated with all-cause, coronary heart disease and stroke long term mortality.

OBJECTIVE Elevated blood pressure (BP) is associated with cardiovascular mortality. BP variability (BPV) is also associated with cardiovascular mortality. However, most studies evaluated hypertensive patients with a relatively short follow-up. We investigated in male workers the association between BPV and long-term all-cause and specific-cause mortality. METHODS Among 10 059 men, aged 40-65, tenured civil servants and municipal employees in Israel, 9398 participants who were examined in 1963, 1965 and 1968 had assessment of diabetic and coronary morbidity status and SBP levels. Participants underwent clinical and biochemical evaluations and BP measured in the recumbent position on the right arm. We conducted analysis for SD-SBP across study visits. Hazard ratios were calculated for 18 years all-cause mortality, coronary heart disease (CHD) and stroke mortality associated with quintile of SD-SBP, with the lowest quintile serving as a reference. RESULTS Multivariate analysis yielded a significant association between SD-SBP and all-cause, CHD and stroke mortality. Age and SBP-adjusted hazard ratios of all-cause mortality was 1.02 [95% confidence interval (CI), 0.90-1.17], 1.06 (95% CI, 0.94-1.20), 1.20 (95% CI, 1.06-1.35) and 1.36 (95% CI, 1.21-1.53) (for quintile 2-5, respectively). The results of CHD and stroke mortality similarly and strongly indicated increasing age-adjusted mortality risk with increasing SD-SBP. Further adjustment for smoking, BMI, diabetes mellitus and coronary heart disease yielded similar results. CONCLUSION In this cohort of tenured male workers, BPV taken over 5 years was clearly associated with 18-year all-cause, CHD and stroke mortality.
The effect on consent rates for deceased organ donation in Wales after the introduction of an opt‐out system

Organ transplantation saves and transforms lives. Failure to secure consent for organ retrieval is widely regarded as the single most important obstacle to transplantation. A soft opt‐out system of consent for deceased organ donation was introduced into Wales in December 2015, whilst England maintained the existing opt‐in system. Cumulative data on consent rates in Wales were compared with those in England, using a two‐sided sequential procedure that was powered to detect an absolute difference in consent rates between England and Wales of 10%. Supplementary risk‐adjusted logistic regression analysis examined whether any difference in consent rates between the two nations could be attributed to variations in factors known to influence UK consent rates. Between 1 January 2016 and 31 December 2018, 8192 families of eligible donors in England and 474 in Wales were approached regarding organ donation, with overall consent rates of 65% and 68%, respectively. There was a steady upward trend in the proportion of families consenting to donation after brain death in Wales as compared with England and after 33 months, this reached statistical significance. No evidence of any change in the donation after circulatory death consent rate was observed. Risk‐adjusted logistic regression analysis revealed that by the end of the study period the probability of consent to organ donation in Wales was higher than in England (OR [95%CI] 2.1 [1.26–3.41]). The introduction of a soft opt‐out system of consent in Wales significantly increased organ donation consent though the impact was not immediate.
Development of a Highly Proliferated Bilayer Coating on 316L Stainless Steel Implants

In this research, a bilayer coating has been applied on the surface of 316 L stainless steel (316LSS) to provide highly proliferated metallic implants for bone regeneration. The first layer was prepared using electrophoretic deposition of graphene oxide (GO), while the top layer was coated utilizing electrospinning of poly (ε-caprolactone) (PCL)/gelatin (Ge)/forsterite solutions. The morphology, porosity, wettability, biodegradability, bioactivity, cell attachment and cell viability of the prepared coatings were evaluated. The Field Emission Scanning Electron Microscopy (FESEM) results revealed the formation of uniform, continuous, and bead-free nanofibers. The Energy Dispersive X-ray (EDS) results confirmed well-distributed forsterite nanoparticles in the structure of the top coating. The porosity of the electrospun nanofibers was found to be above 70%. The water contact angle measurements indicated an improvement in the wettability of the coating by increasing the amount of nanoparticles. Furthermore, the electrospun nanofibers containing 1 and 3 wt. % of forsterite nanoparticles showed significant bioactivity after soaking in the simulated body fluid (SBF) solution for 21 days. In addition, to investigate the in vitro analysis, the MG-63 cells were cultured on the PCL/Ge/forsterite and GO-PCL/Ge/forsterite coatings. The results confirmed an excellent cell adhesion along with considerable cell growth and proliferation. It should be also noted that the existence of the forsterite nanoparticles and the GO layer substantially enhanced the cell proliferation of the coatings.
Response to Anthracnose in a Tarwi (Lupinus mutabilis) Collection Is Influenced by Anthocyanin Pigmentation

Anthracnose, caused by Colletotrichum lupini, is a major limiting factor for lupin production. Tarwi or Andean Lupin (Lupinus mutabilis) is generally regarded as susceptible to anthracnose, but the high protein and oil content of its seeds raise interest in promoting its cultivation in Europe. In this study we evaluated the response to anthracnose of 10 tarwi accessions contrasting in anthocyanin pigmentation, by comparison to white lupin (Lupinus albus), using a contemporary Portuguese fungal isolate. A severity rating scale was optimized, including weighted parameters considering the type of symptoms and organs affected. All tarwi accessions were classified as susceptible, exhibiting sporulating necroses on the main stem from seven days after inoculation. Anthracnose severity was lower on anthocyanin-rich tarwi plants, with accession LM34 standing out as the less susceptible. Accession I82 better combines anthracnose response and yield. In global terms, disease severity was lower on white lupin than on tarwi. Although based on a limited collection, the results of the study show the existence of genetic variability among L. mutabilis towards anthracnose response relatable with anthocyanin pigmentation, providing insights for more detailed and thorough characterization of tarwi resistance to anthracnose.
Post-hoc assessment of the immunogenicity of three antibodies reveals distinct immune stimulatory mechanisms

ABSTRACT Biologics have the potential to induce an immune response when used therapeutically. A number of in vitro assays are currently used preclinically to predict the risk of immunogenicity, but the validation of these preclinical tools suffers from the relatively small number of accessible immunogenic molecules and the limited understanding of the mechanisms underlying the immunogenicity of biologics. Here, we present the post-hoc analysis of three monoclonal antibodies with high immunogenicity in the clinic. Two of the three antibodies elicited a CD4 T cell proliferative response in multiple donors in a peripheral blood mononuclear cell assay, but required different experimental conditions to induce these responses. The third antibody did not trigger any T cell response in this assay. These distinct capacities to promote CD4 T cell responses in vitro were mirrored by different capacities to stimulate innate immune cells. Only one of the three antibodies was capable of inducing human dendritic cell (DC) maturation; the second antibody promoted monocyte activation while the third one did not induce any innate cell activation in vitro. All three antibodies exhibited a moderate to high internalization by human DCs and MHC-associated peptide proteomics analysis revealed the presence of potential T cell epitopes that were confirmed by a T-cell proliferation assay. Collectively, these findings highlight the existence of distinct immune stimulatory mechanisms for immunogenic antibodies. These findings have implications for the preclinical immunogenicity risk assessment of biologics.
Toward digital-based interventions for medication adherence and safety

ABSTRACT Introduction Adherence to the prescribed use of medications is a major problem for many patients. Whether intentional or unintentional, the failure to take medications as prescribed results in an array of health problems, hospitalizations, and increased health expenditures. Areas covered The paper reviews the different types of interventions to promote the appropriate use of medications from provider-based to digital-based interventions. These interventions often combine passive and interactive approaches and may include bio-surveillance/monitoring. Many studies have evaluated these interventions in a variety of conditions and patient population, demonstrating mixed outcomes. Expert opinion The complexity of the underlying causes of poor medication adherence may warrant personalized interventions that combine passive/interactive and personal/digital options. Enriching patient trials may enable observation of larger effect sizes.
Arabidopsis in the Wild—The Effect of Seasons on Seed Performance

Climate changes play a central role in the adaptive life histories of organisms all over the world. In higher plants, these changes may impact seed performance, both during seed development and after dispersal. To examine the plasticity of seed performance as a response to environmental fluctuations, eight genotypes known to be affected in seed dormancy and longevity were grown in the field in all seasons of two years. Soil and air temperature, day length, precipitation, and sun hours per day were monitored. We show that seed performance depends on the season. Seeds produced by plants grown in the summer, when the days began to shorten and the temperature started to decrease, were smaller with deeper dormancy and lower seed longevity compared to the other seasons when seeds were matured at higher temperature over longer days. The performance of seeds developed in the different seasons was compared to seeds produced in controlled conditions. This revealed that plants grown in a controlled environment produced larger seeds with lower dormancy than those grown in the field. All together the results show that the effect of the environment largely overrules the genetic effects, and especially, differences in seed dormancy caused by the different seasons were larger than the differences between the genotypes.
Global burden of hypertension among people living with HIV in the era of increased life expectancy: a systematic review and meta-analysis.

BACKGROUND Although HIV infection and antiretroviral therapy (ART) increase the risk for hypertension in people living with HIV (PLHIV), the global and regional burden of hypertension in PLHIV is not well characterized. METHODS In this systematic review and meta-analysis, we searched multiple databases for studies reporting on hypertension in PLHIV and conducted between 2007 and 2018. Meta-analysis through random-effect models served to obtain the pooled prevalence estimates. Heterogeneity was assessed via the χ test on Cochran's Q statistic. RESULTS We included 194 studies (396 776 PLHIV from 61 countries). The global prevalence of hypertension was 23.6% [95% confidence interval (95% CI: 21.6-25.5)] with substantial heterogeneity. The regional distribution was Western and Central Europe and North America [28.1% (95% CI: 24.5-31.9)], West and Central Africa [23.5% (16.6-31.0)], Latin America and the Caribbean [22.0% (17.8-26.5)], Eastern and Southern Africa [19.9% (17.2-22.8)], and Asia and Pacific [16.5% (12.5-21.0)]; P = 0.0007. No study originated from the Middle East and North Africa, and Eastern Europe and Central Asia regions. The prevalence was higher in high-income countries than others (P = 0.0003) and higher in PLHIV taking ART than those ART-naive (P = 0.0003). The prevalence increased over time (mainly driven by Eastern and Southern Africa) and with age. There was no difference between men and women. We estimated that in 2018, there were 8.9 (95% CI: 8.3-9.6) million cases of hypertension in PLHIV globally, among whom 59.2% were living in Sub-Saharan Africa. CONCLUSION Cost-effective strategies to curb the dreadful burden of hypertension among PLHIV are needed.
Expanding the Spectrum of Adenoviral Vectors for Cancer Therapy

Adenoviral vectors (AdVs) have attracted much attention in the fields of vaccine development and treatment for diseases such as genetic disorders and cancer. In this review, we discuss the utility of AdVs in cancer therapies. In recent years, AdVs were modified as oncolytic AdVs (OAs) that possess the characteristics of cancer cell-specific replication and killing. Different carriers such as diverse cells and extracellular vesicles are being explored for delivering OAs into cancer sites after systemic administration. In addition, there are also various strategies to improve cancer-specific replication of OAs, mainly through modifying the early region 1 (E1) of the virus genome. It has been documented that oncolytic viruses (OVs) function through stimulating the immune system, resulting in the inhibition of cancer progression and, in combination with classical immune modulators, the anti-cancer effect of OAs can be even further enforced. To enhance the cancer treatment efficacy, OAs are also combined with other standard treatments, including surgery, chemotherapy and radiotherapy. Adenovirus type 5 (Ad5) has mainly been explored to develop vectors for cancer treatment with different modulations. Only a limited number of the more than 100 identified AdV types were converted into OAs and, therefore, the construction of an adenovirus library for the screening of potential novel OA candidates is essential. Here, we provide a state-of-the-art overview of currently performed and completed clinic trials with OAs and an adenovirus library, providing novel possibilities for developing innovative adenoviral vectors for cancer treatment.
The Impact of Mutations in the HvCPD and HvBRI1 Genes on the Physicochemical Properties of the Membranes from Barley Acclimated to Low/High Temperatures

(1) Background: The study characterized barley mutants with brassinosteroid (BR) biosynthesis and signaling disturbances in terms of the physicochemical/structural properties of membranes to enrich the knowledge about the role of brassinosteroids for lipid metabolism and membrane functioning. (2) Methods: The Langmuir method was used to investigate the properties of the physicochemical membranes. Langmuir monolayers were formed from the lipid fractions isolated from the plants growing at 20 °C and then acclimated at 5 °C or 27 °C. The fatty acid composition of the lipids was estimated using gas chromatography. (3) Results: The BR-biosynthesis and BR-signaling mutants of barley were characterized by a temperature-dependent altered molar percentage of fatty acids (from 14:0 to 20:1) in their galactolipid and phospholipid fractions in comparison to wild-type (WT). For example, the mutants had a lower molar percentage of 18:3 in the phospholipid (PL) fraction. The same regularity was observed at 5 °C. It resulted in altered physicochemical parameters of the membranes (Alim, πcoll, Cs−1). (4) Conclusions: BR may be involved in regulating fatty acid biosynthesis or their transport/incorporation into the cell membranes. Mutants had altered physicochemical parameters of their membranes, compared to the WT, which suggests that BR may have a multidirectional impact on the membrane-dependent physiological processes.
Affective lability across psychosis spectrum disorders

Abstract Background. Despite apparent clinical remission, individuals with psychotic disorders often experience significant impairments across functional domains. Thus, there is a need to search beyond management of core symptoms to optimize treatment outcomes. Affective dysregulation is considered a risk factor for poor clinical and functional outcomes in many mental disorders, but research investigating such features in psychosis, particularly in schizophrenia, is limited. We aimed to investigate the level of affective lability (AL) in participants with schizophrenia- and bipolar spectrum disorders (n = 222) compared to healthy controls (n = 140), as well as clinical correlates of AL in the diagnostic groups. Methods. The Affective Lability Scale (ALS-SF) was used to measure total score of AL and subscores covering the domains of anxiety/depression, depression/elation, and anger. An analysis of covariance was performed to compare the ALS-SF total score between groups, correcting for potential confounders, as well as standard multiple regression analyses for diagnosis-specific investigations of the relationship between AL and demographic and clinical features. Results. Both the schizophrenia- and bipolar spectrum group had significantly higher ALS-SF total score compared to controls (p < 0.001), and no significant differences between the patient groups were found. In the schizophrenia group, current psychotic and depressive symptoms were significantly and independently associated with AL (p = 0.012 and p = 0.024, respectively). Conclusions. The findings indicate that AL is elevated in psychotic disorders and that it transcends diagnostic boundaries. Further research into the causal relationship between psychotic and affective symptoms and AL, as well as its role as a potential therapeutic target in psychosis spectrum disorders, is warranted.
Toxicity and ovicidal activity of different plant extracts on two-spotted spider mite, Tetranychus urticae Koch (Acari: Tetranychidae)

The acaricidial, persistent and ovicidal activities of four methanolic extracts of Anisosciadium orientale DC. , Scaligeria meifolia Boiss. , Trigonella elliptica Boiss. and Ptelea viscosa L. were assessed against the two-spotted spider mite, Tetranychus urticae Koch, in a bioassay under laboratory conditions. All the extracts exhibited significant adult female mite mortality as compared to control and S. meifolia extract showed highest toxicity based on the LC50 when compared with the other extracts tested. In the persistence test, the mites were exposed to 1, 24, 48 and 72 h old residues of 50% lethal concentration of methanolic extracts. The results showed that the lethal concentration effects of plant extracts fade within two or three days. S. meifolia caused high ovicidal activity (45.84%) followed by A. orientale (41.40%), T. elliptica (40.11%) and P. viscosa (37.66%). The results suggest that the methanolic extracts of A. orientale, S. meifolia, T. elliptica and P. viscosa have the potential to be used in mite pest management.
Chronic pain and psychedelics: a review and proposed mechanism of action

The development of chronic pain is a complex mechanism that is still not fully understood. Multiple somatic and visceral afferent pain signals, when experienced over time, cause a strengthening of certain neural circuitry through peripheral and central sensitization, resulting in the physical and emotional perceptual chronic pain experience. The mind-altering qualities of psychedelics have been attributed, through serotonin 2A (5-HT2A) receptor agonism, to ‘reset’ areas of functional connectivity (FC) in the brain that play prominent roles in many central neuropathic states. Psychedelic substances have a generally favorable safety profile, especially when compared with opioid analgesics. Clinical evidence to date for their use for chronic pain is limited; however, several studies and reports over the past 50 years have shown potential analgesic benefit in cancer pain, phantom limb pain and cluster headache. While the mechanisms by which the classic psychedelics may provide analgesia are not clear, several possibilities exist given the similarity between 5-HT2A activation pathways of psychedelics and the nociceptive modulation pathways in humans. Additionally, the alterations in FC seen with psychedelic use suggest a way that these agents could help reverse the changes in neural connections seen in chronic pain states. Given the current state of the opioid epidemic and limited efficacy of non-opioid analgesics, it is time to consider further research on psychedelics as analgesics in order to improve the lives of patients with chronic pain conditions.