Pentamethylquercetin attenuates angiotensin II-induced abdominal aortic aneurysm formation by blocking nuclear translocation of C/EBPß at Lys253.

BACKGROUND: Pentamethylquercetin (PMQ) is a natural polymethyl flavonoid that possesses anti-apoptotic and other biological properties. Abdominal aortic aneurysm (AAA), a fatal vascular disease with a high risk of rupture, is associated with phenotypic switching and apoptosis of medial vascular smooth muscle cells (VSMCs). This study aimed to investigate the protective effects of PMQ on the development of AAA and the underlying mechanism. METHODS: ApoE-/- mice were continuously infused with angiotensin II (Ang II) for 4 weeks to develop the AAA model. Intragastric administration of PMQ was initiated 5 days before Ang II infusion and continued for 4 weeks. In vitro, VSMCs were cultured and pretreated with PMQ, stimulated with Ang II. Real-time PCR, western blotting, and immunofluorescence staining were used to examine the roles and mechanisms of PMQ on the phenotypic switching and apoptosis of VSMCs. RESULTS: PMQ dose-dependently reduced the incidence of Ang II-induced AAA, aneurysm diameter enlargement, elastin degradation, VSMCs phenotypic switching and apoptosis. Furthermore, PMQ also inhibited phenotypic switching and apoptosis in Ang II-stimulated VSMCs. PMQ exerted protective effects by regulating the C/EBPß/PTEN/AKT/GSK-3ß axis. AAV-mediated overexpression of PTEN reduced the therapeutic effects of PMQ in the AAA model mice, suggesting that the effects of PMQ on Ang II-mediated AAA formation were related to the PTEN/AKT/GSK-3ß axis. PMQ inhibited VSMCs phenotypic switching and apoptosis by bounding to C/EBPß at Lys253 with hydrogen bond to regulate C/EBPß nuclear translocation and PTEN/AKT/GSK-3ß axis, thereby inhibiting Ang II-induced AAA formation. CONCLUSIONS: Pentamethylquercetin inhibits angiotensin II-induced abdominal aortic aneurysm formation by bounding to C/EBPß at Lys253. Therefore, PMQ prevents the formation of AAA and reduces the incidence of AAA.

Description of an anaerobic actinobacterium, Kribbibacterium absianum gen. nov., sp. nov., a new member of the novel family Kribbibacteriaceae fam. nov., and reclassification of the genera Granulimonas and Leptogranulimonas.

Two rod-shaped, obligate anaerobic, Gram-stain-positive bacteria isolated from the pig faeces were designated YH-ols2216 and YH-ols2217T. Analysis of 16S rRNA gene sequences revealed that these isolates were most related to the members of the family Atopobiaceae, within the order Coriobacteriales, and Granulimonas faecalis KCTC 25474T with 92.0 and 92.5% similarities, respectively. The 16S rRNA gene sequence similarity within isolates was 99.9 %; and those between isolates YH-ols2216 and YH-ols2217T, and Atopobium minutum DSM 20586T, the type species of the type genus Atopobium within the family Atopobiaceae, were 88.5 and 88.7 %, respectively. Those between isolates and Coriobacterium glomerans PW2T, the type species of the type genus Coriobacterium within the family Coriobacteriaceae, were 88.7 and 89.1 %, respectively. The multi-locus sequence tree revealed that the isolates, alongside the genera Granulimonas and Leptogranulimonas, formed a distinct cluster between the families Atopobiaceae and Coriobacteriaceae. The average nucleotide identities and digital DNA-DNA hybridization values for the isolates and their most closely related strains ranged from 67.7 to 76.2 % and from 18.4 to 23.3 %, respectively. The main cellular fatty acids of the isolates were C18 : 0 DMA, C18 : 1 ω9c, C18 : 0 12OH, C18 : 0, and C16 : 0. The cell wall contained the peptidoglycan meso-diaminopimelic acid. Lactate was the main end-product of the isolates. The major polar lipids of isolate YH-ols2217T were aminophospholipid, aminolipids, and lipids. Menaquinones were not identified in the cells of the isolates. The DNA G+C contents of isolates YH-ols2216 and YH-ols2217T were 67.5 and 67.6 mol%, respectively. Considering these chemotaxonomic, phenotypic, and phylogenetic properties, Kribbibacteriaceae fam. nov. is proposed within the order Coriobacteriales. YH-ols2216 (=KCTC 25708=NBRC 116429) and YH-ols2217T (=KCTC 25709T=NBRC 116430T) represent a novel taxon within this new family and the name Kribbibacterium absianum gen. nov., sp. nov. is proposed. In addition, the genera Granulimonas and Leptogranulimonas are transferred to the family Kribbibacteriaceae fam. nov.

Plasticity of Gene Expression and Thermal Tolerance: Implications for Climate Change Vulnerability in a Tropical Forest Lizard.

AbstractTropical ectotherms are thought to be especially vulnerable to climate change because they have evolved in temporally stable thermal environments and therefore have decreased tolerance for thermal variability. Thus, they are expected to have narrow thermal tolerance ranges, live close to their upper thermal tolerance limits, and have decreased thermal acclimation capacity. Although models often predict that tropical forest ectotherms are especially vulnerable to rapid environmental shifts, these models rarely include the potential for plasticity of relevant traits. We measured phenotypic plasticity of thermal tolerance and thermal preference as well as multitissue transcriptome plasticity in response to warmer temperatures in a species that previous work has suggested is highly vulnerable to climate warming, the Panamanian slender anole lizard (Anolis apletophallus). We found that many genes, including heat shock proteins, were differentially expressed across tissues in response to short-term warming. Under long-term warming, the voluntary thermal maxima of lizards also increased, although thermal preference exhibited only limited plasticity. Using these data, we modeled changes in the activity time of slender anoles through the end of the century under climate change and found that plasticity should delay declines in activity time by at least two decades. Our results suggest that slender anoles, and possibly other tropical ectotherms, can alter the expression of genes and phenotypes when responding to shifting environmental temperatures and that plasticity should be considered when predicting the future of organisms under a changing climate.

Complex nitrogen sources from agro-industrial byproducts: impact on production, multi-stress tolerance, virulence, and quality of Beauveria bassiana blastospores.

We investigated the impact of various complex organic nitrogen sources on the submerged liquid fermentation of Beauveria bassiana, a versatile entomopathogenic fungus known for producing hydrophilic yeast-like single cells called blastospores. Specifically, we examined yeast extract, autolyzed yeast, inactive yeast, cottonseed flour, corn bran, and corn gluten meal as nitrogen compounds with different carbon-to-nitrogen (C:N) ratios. Our comprehensive analysis encompassed blastospore production, tolerance to abiotic stresses, shelf stability after drying, and virulence against mealworm larvae, crucial attributes for developing effective blastospore-based biopesticides. Notably, cottonseed flour emerged as the optimal nitrogen source, yielding up to 2.5 × 109 blastospores/mL within 3 days in a bioreactor. These blastospores exhibited the highest tolerance to heat stress and UV-B radiation exposure. The endogenous C:N ratio in blastospore composition was also impacted by nitrogen sources. Bioassays with mealworm larvae demonstrated that blastospores from cottonseed flour were the most virulent, achieving faster lethality (lower LT50) and requiring a lower inoculum (LC50). Importantly, blastospores produced with cottonseed flour displayed extended viability during storage, surpassing the retention of viability compared to those from autolyzed yeast over 180 days at 4°C. Despite differences in storage viability, both nitrogen sources conferred similar long-term blastospore bioactivity against mealworms. In summary, this research advances our understanding of the crucial impact of complex organic nitrogen selection on the phenotypic traits of blastospores in association with their intracellular C:N ratio, contributing to the production of ecologically fit, shelf-stable, and virulent propagules for effective pest biocontrol programs. IMPORTANCE: Biological control through entomopathogenic fungi provides essential ecological services in the integrated management of agricultural pests. In the context of submerged liquid fermentation, the nutritional composition significantly influences the ecological fitness, virulence and quality of these fungi. This study specifically explores the impact of various complex organic nitrogen sources derived from agro-industrial byproducts on the submerged liquid fermentation of Beauveria bassiana, a versatile entomopathogenic fungus known for producing hydrophilic yeast-like blastospores. Notably, manipulating the nitrogen source during submerged cultivation can influence the quality, fitness, and performance of blastospores. This research identifies cottonseed flour as the optimal low-cost nitrogen source, contributing to increased production yields, enhanced multi-stress tolerance, heightened virulence with extended shelf life and long-term bioactivity. These findings deepen our understanding of the critical role of nitrogen compound selection in liquid media formulation, facilitating the production of ecologically fit and virulent blastospores for more effective pest biocontrol programs.

Resource-based trade-offs and the adaptive significance of seasonal plasticity in butterfly wing melanism.

Phenotypic plasticity is the ability of an organism to alter its phenotype in response to environmental cues. This can be adaptive if the cues are reliable predictors of impending conditions and the alterations enhance the organism's ability to capitalize on those conditions. However, since traits do not exist in isolation but as part of larger interdependent systems of traits (phenotypic integration), trade-offs between correlated plastic traits can make phenotypic plasticity non- or maladaptive. We examine this problem in the seasonally plastic wing melanism of a pierid (Order Lepidoptera, Family Pieridae) butterfly, Pieris rapae L. Several wing pattern traits are more melanized in colder than in warmer seasons, resulting in effective thermoregulation through solar absorption. However, other wing pattern traits, the spots, are less melanized during colder seasons than in warmer seasons. Although spot plasticity may be adaptive, reduced melanism of these spots could also be explained by resource-based trade-offs. Theory predicts that traits involved in resource-based trade-offs will be positively correlated when variation among individuals in resource acquisition is greater than variation among individuals in resource allocation strategies, and negatively correlated when variation in allocation is greater than variation in acquisition. Using data from both field studies and laboratory studies that manipulate dietary tyrosine, a melanin precursor, we show that when allocation to thermoregulatory melanism (ventral hindwing, and basal dorsal fore- and hindwing "shading") varies substantially this trait is negatively correlated with spot melanism. However, when there is less variation in allocation to thermoregulatory melanism we find these traits to be positively correlated; these findings are consistent with the resource-based trade-off hypothesis, which may provide a non- or maladaptive hypothesis to explain spot plasticity. We also show that increased dietary tyrosine results in increased spot melanism under some conditions, supporting the more general idea that melanism may involve resource-based costs.

Phenotypic and Functional Characterization of Bovine Adipose-Derived Mesenchymal Stromal Cells.

BACKGROUND: Mesenchymal stem cells (MSCs) are increasingly trialed in cellular therapy applications in humans. They can also be applied to treat a range of diseases in animals, particularly in cattle to combat inflammatory conditions and aging-associated degenerative disorders. We sought to demonstrate the feasibility of obtaining MSCs from adipose tissue and characterizing them using established assays. METHODS: Bovine adipose MSCs (BvAdMSCs) were isolated using in-house optimized tissue digestion protocols and characterized by performing a colony formation assay, cell growth assessments, cell surface marker analysis by immunocytochemistry and flow cytometry, osteogenic and adipogenic differentiation, and secretion of indoleamine 2,3-dioxygenease (IDO). RESULTS: Our results demonstrate the feasibility of successful MSC isolation and culture expansion from bovine adipose tissues with characteristic features of colony formation, in vitro multilineage differentiation into osteogenic and adipogenic lineages, and cell surface marker expression of CD105, CD73, CD90, CD44, and CD166 with negative expression of CD45. BvAdMSCs secreted significant amounts of IDO with or without interferon-gamma stimulation, indicating ability for immunomodulation. CONCLUSIONS: We report a viable approach to obtaining autologous adipose-derived MSCs that can be applied as potential adjuvant cell therapy for tissue repair and regeneration in cattle. Our methodology can be utilized by veterinary cell therapy labs for preparing MSCs for disease management in cattle.

Variable Penetrance and Expressivity of a Rare Pore Loss-of-Function Mutation (p.L889V) of Nav1.5 Channels in Three Spanish Families.

A novel rare mutation in the pore region of Nav1.5 channels (p.L889V) has been found in three unrelated Spanish families that produces quite diverse phenotypic manifestations (Brugada syndrome, conduction disease, dilated cardiomyopathy, sinus node dysfunction, etc.) with variable penetrance among families. We clinically characterized the carriers and recorded the Na+ current (INa) generated by p.L889V and native (WT) Nav1.5 channels, alone or in combination, to obtain further insight into the genotypic-phenotypic relationships in patients carrying SCN5A mutations and in the molecular determinants of the Nav1.5 channel function. The variant produced a strong dominant negative effect (DNE) since the peak INa generated by p.L889V channels expressed in Chinese hamster ovary cells, either alone (-69.4 ± 9.0 pA/pF) or in combination with WT (-62.2 ± 14.6 pA/pF), was significantly (n ≥ 17, p < 0.05) reduced compared to that generated by WT channels alone (-199.1 ± 44.1 pA/pF). The mutation shifted the voltage dependence of channel activation and inactivation to depolarized potentials, did not modify the density of the late component of INa, slightly decreased the peak window current, accelerated the recovery from fast and slow inactivation, and slowed the induction kinetics of slow inactivation, decreasing the fraction of channels entering this inactivated state. The membrane expression of p.L889V channels was low, and in silico molecular experiments demonstrated profound alterations in the disposition of the pore region of the mutated channels. Despite the mutation producing a marked DNE and reduction in the INa and being located in a critical domain of the channel, its penetrance and expressivity are quite variable among the carriers. Our results reinforce the argument that the incomplete penetrance and phenotypic variability of SCN5A loss-of-function mutations are the result of a combination of multiple factors, making it difficult to predict their expressivity in the carriers despite the combination of clinical, genetic, and functional studies.

Physiological and Structural Changes in Leaves of Platycrater arguta Seedlings Exposed to Increasing Light Intensities.

Understanding the light adaptation of plants is critical for conservation. Platycrater arguta, an endangered deciduous shrub endemic to East Asia, possesses high ornamental and phylogeographic value. However, the weak environmental adaptability of P. arguta species has limited its general growth and conservation. To obtain a deeper understanding of the P. arguta growth conditions, we examined the leaf morphology and physiology via anatomical and chloroplast ultrastructural analyses following exposure to different natural light intensities (full light, 40%, and 10%). The findings indicated that P. arguta seedings in the 10% light intensity had significantly improved leaf morphological characteristics and specific leaf area compared to those exposed to other intensities. The net photosynthetic rate, chlorophyll (Chl) content, photosynthetic nitrogen use efficiency (PNUE), and photosynthetic phosphorus use efficiency (PPUE) exhibited marked increases at a 10% light intensity compared to both 40% light and full light intensities, whereas the light compensation point and dark respiration levels reached their lowest values under the 10% light condition. With reduced light, leaf thickness, palisade tissue, spongy tissue, and stomatal density significantly decreased, whereas the stomatal length, stomatal width, and stomatal aperture were significantly elevated. When exposed to 10% light intensity, the ultrastructure of chloroplasts was well developed, chloroplasts and starch grain size, the number of grana, and thylakoids all increased significantly, while the number of plastoglobules was significantly reduced. Relative distance phenotypic plasticity index analysis exhibited that P. arguta adapts to varying light environments predominantly by adjusting PPUE, Chl b, PNUE, chloroplast area, and the activity of PSII reaction centers. We proposed that P. arguta efficiently utilizes low light to reconfigure its energy metabolism by regulating its leaf structure, photosynthetic capacity, nutrient use efficiency, and chloroplast development.

Christensenella strain resources, genomic/metabolomic profiling, and association with host at species level.

The gut commensal bacteria Christensenellaceae species are negatively associated with many metabolic diseases, and have been seen as promising next-generation probiotics. However, the cultured Christensenellaceae strain resources were limited, and their beneficial mechanisms for improving metabolic diseases have yet to be explored. In this study, we developed a method that enabled the enrichment and cultivation of Christensenellaceae strains from fecal samples. Using this method, a collection of Christensenellaceae Gut Microbial Biobank (ChrisGMB) was established, composed of 87 strains and genomes that represent 14 species of 8 genera. Seven species were first described and the cultured Christensenellaceae resources have been significantly expanded at species and strain levels. Christensenella strains exerted different abilities in utilization of various complex polysaccharides and other carbon sources, exhibited host-adaptation capabilities such as acid tolerance and bile tolerance, produced a wide range of volatile probiotic metabolites and secondary bile acids. Cohort analyses demonstrated that Christensenellaceae and Christensenella were prevalent in various cohorts and the abundances were significantly reduced in T2D and OB cohorts. At species level, Christensenellaceae showed different changes among healthy and disease cohorts. C. faecalis, F. tenuis, L. tenuis, and Guo. tenuis significantly reduced in all the metabolic disease cohorts. The relative abundances of C. minuta, C. hongkongensis and C. massiliensis showed no significant change in NAFLD and ACVD. and C. tenuis and C. acetigenes showed no significant change in ACVD, and Q. tenuis and Geh. tenuis showed no significant change in NAFLD, when compared with the HC cohort. So far as we know, this is the largest collection of cultured resource and first exploration of Christensenellaceae prevalences and abundances at species level.

Variation and plasticity in life-history traits and fitness of wild Arabidopsis thaliana populations are not related to their genotypic and ecological diversity.

BACKGROUND: Despite its implications for population dynamics and evolution, the relationship between genetic and phenotypic variation in wild populations remains unclear. Here, we estimated variation and plasticity in life-history traits and fitness of the annual plant Arabidopsis thaliana in two common garden experiments that differed in environmental conditions. We used up to 306 maternal inbred lines from six Iberian populations characterized by low and high genotypic (based on whole-genome sequences) and ecological (vegetation type) diversity. RESULTS: Low and high genotypic and ecological diversity was found in edge and core Iberian environments, respectively. Given that selection is expected to be stronger in edge environments and that ecological diversity may enhance both phenotypic variation and plasticity, we expected genotypic diversity to be positively associated with phenotypic variation and plasticity. However, maternal lines, irrespective of the genotypic and ecological diversity of their population of origin, exhibited a substantial amount of phenotypic variation and plasticity for all traits. Furthermore, all populations harbored maternal lines with canalization (robustness) or sensitivity in response to harsher environmental conditions in one of the two experiments. CONCLUSIONS: Overall, we conclude that the environmental attributes of each population probably determine their genotypic diversity, but all populations maintain substantial phenotypic variation and plasticity for all traits, which represents an asset to endure in changing environments.

Meta QTL analysis for dissecting abiotic stress tolerance in chickpea.

BACKGROUND: Chickpea is prone to many abiotic stresses such as heat, drought, salinity, etc. which cause severe loss in yield. Tolerance towards these stresses is quantitative in nature and many studies have been done to map the loci influencing these traits in different populations using different markers. This study is an attempt to meta-analyse those reported loci projected over a high-density consensus map to provide a more accurate information on the regions influencing heat, drought, cold and salinity tolerance in chickpea. RESULTS: A meta-analysis of QTL reported to be responsible for tolerance to drought, heat, cold and salinity stress tolerance in chickpeas was done. A total of 1512 QTL responsible for the concerned abiotic stress tolerance were collected from literature, of which 1189 were projected on a chickpea consensus genetic map. The QTL meta-analysis predicted 59 MQTL spread over all 8 chromosomes, responsible for these 4 kinds of abiotic stress tolerance in chickpea. The physical locations of 23 MQTL were validated by various marker-trait associations and genome-wide association studies. Out of these reported MQTL, CaMQAST1.1, CaMQAST4.1, CaMQAST4.4, CaMQAST7.8, and CaMQAST8.2 were suggested to be useful for different breeding approaches as they were responsible for high per cent variance explained (PVE), had small intervals and encompassed a large number of originally reported QTL. Many putative candidate genes that might be responsible for directly or indirectly conferring abiotic stress tolerance were identified in the region covered by 4 major MQTL- CaMQAST1.1, CaMQAST4.4, CaMQAST7.7, and CaMQAST6.4, such as heat shock proteins, auxin and gibberellin response factors, etc. CONCLUSION: The results of this study should be useful for the breeders and researchers to develop new chickpea varieties which are tolerant to drought, heat, cold, and salinity stresses.

Genotype-specific nonphotochemical quenching responses to nitrogen deficit are linked to chlorophyll a to b ratios.

Non-photochemical quenching (NPQ) protects plants from photodamage caused by excess light energy. Substantial variation in NPQ has been reported among different genotypes of the same species. However, comparatively little is known about how environmental perturbations, including nutrient deficits, impact natural variation in NPQ kinetics. Here, we analyzed a natural variation in NPQ kinetics of a diversity panel of 225 maize (Zea mays L.) genotypes under nitrogen replete and nitrogen deficient field conditions. Individual maize genotypes from a diversity panel exhibited a range of changes in NPQ in response to low nitrogen. Replicated genotypes exhibited consistent responses across two field experiments conducted in different years. At the seedling and pre-flowering stages, a similar portion of the genotypes (∼33%) showed decrease, no-change or increase in NPQ under low nitrogen relative to control. Genotypes with increased NPQ under low nitrogen also showed greater reductions in dry biomass and photosynthesis than genotypes with stable NPQ when exposed to low nitrogen conditions. Maize genotypes where an increase in NPQ was observed under low nitrogen also exhibited a reduction in the ratio of chlorophyll a to chlorophyll b. Our results underline that since thermal dissipation of excess excitation energy measured via NPQ helps to balance the energy absorbed with energy utilized, the NPQ changes are the reflection of broader molecular and biochemical changes which occur under the stresses such as low soil fertility. Here, we have demonstrated that variation in NPQ kinetics resulted from genetic and environmental factors, are not independent of each other. Natural genetic variation controlling plastic responses of NPQ kinetics to environmental perturbation increases the likelihood it will be possible to optimize NPQ kinetics in crop plants for different environments.

Clinical and genetic characteristics and natural history of Finnish families with familial exudative vitreoretinopathy due to pathogenic FZD4 variants.

PURPOSE: To report clinical and genetic characteristics of familial exudative vitreoretinopathy (FEVR) in the Finnish population. METHODS: Detailed clinical and genetic data of 35 individuals with heterozygous pathogenic variants in FZD4 were gathered and analysed. RESULTS: Thirty-two individuals with FZD4 c.313A>G variant and three individuals with FZD4 c.40_49del were included in the study. The clinical phenotype was variable even among family members with the same FZD4 variant. Only 34% (N = 12/35) of variant-positive individuals had been clinically diagnosed with FEVR. The median age of the onset of symptoms was 2.3 years, ranging between 0 to 25 years. Median visual acuity was 0.1 logMAR (0.8 Snellen decimal), ranging between light perception and -0.1 logMAR (1.25 Snellen decimal). Most (N = 33/35, 94%) were classified as not visually impaired. Despite unilateral visual loss present in some, they did not meet the criteria of visual impairment according to the WHO classification. Two study patients (N = 2/35, 6%) had severe visual impairment. The most common FEVR stage in study patient's eyes (N = 28/70 eyes, 40%) was FEVR stage 1, that is, avascular periphery or abnormal vascularisation. Most of FZD4-variant-positive study patient's eyes (N = 31/50 eyes, 62%) were myopic. Two individuals presented with persistent hyperplastic primary vitreous expanding the phenotypic spectrum of FEVR. Shared haplotypes extending approximately 0.9 Mb around the recurrent FZD4 c.313A>G variant were identified. CONCLUSION: Most study patients were unaffected or had mild clinical manifestations by FEVR. Myopia seemed to be overly common in FZD4-variant-positive individuals.

Comparison of the Phenotypic Flexibility of Muscle and Body Condition of Migrant and Resident White-Crowned Sparrows.

AbstractSeasonally breeding birds express variations of traits (phenotypic flexibility) throughout their life history stages that represent adaptations to environmental conditions. Changes of body condition during migration have been well studied, whereas alterations of skeletal and cardiac muscles, body mass, and fat scores have yet to be characterized throughout the spring or fall migratory stages. Additionally, we examined flexible patterns of muscle, body mass, and fat score in migrant white-crowned sparrows (Zonotrichia leucophrys gambelii) in comparison with those in a resident subspecies (Zonotrichia leucophrys nuttalli) during the stages they share to evaluate the influence of different life histories. Migrants showed hypertrophy of the pectoralis muscle fiber area on the wintering grounds in late prealternate molt, yet increased pectoralis muscle mass was not detected until birds readied for spring departure. While pectoralis profile and fat scores enlarged at predeparture in spring and fall, pectoralis, cardiac, and body masses were greater only in spring stages, suggesting seasonal differences for migratory preparation. Gastrocnemius mass showed little change throughout all stages, whereas gastrocnemius fiber area declined steadily but rebounded in fall on the wintering grounds, where migrants become more sedentary. In general, residents are heavier birds with larger leg structures, while migrants sport longer wings and greater heart mass. Phenotypic flexibility was most prominent among residents with peaks of pectoralis, gastrocnemius, and body masses during the winter stage, when local weather is most severe. Thus, the subspecies express specific patterns of phenotypic flexibility with peaks coinciding with the stages of heightened energy demands: the winter stage for residents and the spring stages for migrants.

Interpretation of 10 years of Alzheimer's disease genetic findings in the perspective of statistical heterogeneity.

Common genetic variants and susceptibility loci associated with Alzheimer's disease (AD) have been discovered through large-scale genome-wide association studies (GWAS), GWAS by proxy (GWAX) and meta-analysis of GWAS and GWAX (GWAS+GWAX). However, due to the very low repeatability of AD susceptibility loci and the low heritability of AD, these AD genetic findings have been questioned. We summarize AD genetic findings from the past 10 years and provide a new interpretation of these findings in the context of statistical heterogeneity. We discovered that only 17% of AD risk loci demonstrated reproducibility with a genome-wide significance of P < 5.00E-08 across all AD GWAS and GWAS+GWAX datasets. We highlighted that the AD GWAS+GWAX with the largest sample size failed to identify the most significant signals, the maximum number of genome-wide significant genetic variants or maximum heritability. Additionally, we identified widespread statistical heterogeneity in AD GWAS+GWAX datasets, but not in AD GWAS datasets. We consider that statistical heterogeneity may have attenuated the statistical power in AD GWAS+GWAX and may contribute to explaining the low repeatability (17%) of genome-wide significant AD susceptibility loci and the decreased AD heritability (40-2%) as the sample size increased. Importantly, evidence supports the idea that a decrease in statistical heterogeneity facilitates the identification of genome-wide significant genetic loci and contributes to an increase in AD heritability. Collectively, current AD GWAX and GWAS+GWAX findings should be meticulously assessed and warrant additional investigation, and AD GWAS+GWAX should employ multiple meta-analysis methods, such as random-effects inverse variance-weighted meta-analysis, which is designed specifically for statistical heterogeneity.

PRESTIGIO RING "a 59-year-old man with multidrug resistant HIV-1 infection failing a regimen including dolutegravir, rilpivirine, atazanavir/cobicistat: successful treatment tailoring based on genotypic and phenotypic resistance tests".

Management of virological failure in heavily treatment-experienced people with multidrug-resistant (MDR) HIV infection is a serious clinical challenge. New drugs with novel mechanisms of action have recently been approved, and their use has improved the outcome of subjects with limited treatment options (LTO). In this setting, the choice of antiretroviral therapy (ART) should be tailored based on the pattern of resistance, treatment history and patients' individual characteristics. While genotypic resistance testing is the reference method for analysing residual drug susceptibility, phenotypic resistance testing can provide additional support when facing LTO. Herein, we present the case of a patient with MDR HIV-1 infection on virological failure enrolled in the PRESTIGIO Registry. The salvage ART regimen, which included drugs with novel mechanisms of action (MoA), was tailored to the patient's clinical characteristics and on the resistance pattern explored with genotypic and phenotypic investigation, allowing the achievement of viro-immunological success. The use of recently approved drugs with novel MoA, combined with an optimized background regimen, may also achieve virological suppression in people with LTO.

Phenotypic and genetic effect of carotid intima-media thickness on the risk of stroke.

While carotid intima-media thickness (cIMT) as a noninvasive surrogate measure of atherosclerosis is widely considered a risk factor for stroke, the intrinsic link underlying cIMT and stroke has not been fully understood. We aimed to evaluate the clinical value of cIMT in stroke through the investigation of phenotypic and genetic relationships between cIMT and stroke. We evaluated phenotypic associations using observational data from UK Biobank (N = 21,526). We then investigated genetic relationships leveraging genomic data conducted in predominantly European ancestry for cIMT (N = 45,185) and any stroke (AS, Ncase/Ncontrol=40,585/406,111). Observational analyses suggested an increased hazard of stroke per one standard deviation increase in cIMT (cIMTmax-AS: hazard ratio (HR) = 1.39, 95%CI = 1.09-1.79; cIMTmean-AS: HR = 1.39, 95%CI = 1.09-1.78; cIMTmin-AS: HR = 1.32, 95%CI = 1.04-1.68). A positive global genetic correlation was observed (cIMTmax-AS: [Formula: see text]=0.23, P=9.44 × 10-5; cIMTmean-AS: [Formula: see text]=0.21, P=3.00 × 10-4; cIMTmin-AS: [Formula: see text]=0.16, P=6.30 × 10-3). This was further substantiated by five shared independent loci and 15 shared expression-trait associations. Mendelian randomization analyses suggested no causal effect of cIMT on stroke (cIMTmax-AS: odds ratio (OR)=1.12, 95%CI=0.97-1.28; cIMTmean-AS: OR=1.09, 95%CI=0.93-1.26; cIMTmin-AS: OR=1.03, 95%CI = 0.90-1.17). A putative association was observed for genetically predicted stroke on cIMT (AS-cIMTmax: beta=0.07, 95%CI = 0.01-0.13; AS-cIMTmean: beta=0.08, 95%CI = 0.01-0.15; AS-cIMTmin: beta = 0.08, 95%CI = 0.01-0.16) in the reverse direction MR, which attenuated to non-significant in sensitivity analysis. Our work does not find evidence supporting causal associations between cIMT and stroke. The pronounced cIMT-stroke association is intrinsic, and mostly attributed to shared genetic components. The clinical value of cIMT as a surrogate marker for stroke risk in the general population is likely limited.

The diversity of endophytic fungi in Tartary buckwheat (Fagopyrum tataricum) and its correlation with flavonoids and phenotypic traits.

Tartary buckwheat (Fagopyrum tataricum) is a significant medicinal crop, with flavonoids serving as a crucial measure of its quality. Presently, the artificial cultivation of Tartary buckwheat yields low results, and the quality varies across different origins. Therefore, it is imperative to identify an effective method to enhance the yield and quality of buckwheat. Endophytic fungi reside within plants and form a mutually beneficial symbiotic relationship, aiding plants in nutrient absorption, promoting host growth, and improving secondary metabolites akin to the host. In this study, high-throughput sequencing technology was employed to assess the diversity of endophytic fungi in Tartary buckwheat. Subsequently, a correlation analysis was performed between fungi and metabolites, revealing potential increases in flavonoid content due to endophytic fungi such as Bipolaris, Hymenula, and Colletotrichum. Additionally, a correlation analysis between fungi and phenotypic traits unveiled the potential influence of endophytic fungi such as Bipolaris, Buckleyzyma, and Trichosporon on the phenotypic traits of Tartary buckwheat. Notably, the endophytic fungi of the Bipolaris genus exhibited the potential to elevate the content of Tartary buckwheat metabolites and enhance crop growth. Consequently, this study successfully identified the resources of endophytic fungi in Tartary buckwheat, explored potential functional endophytic fungi, and laid a scientific foundation for future implementation of biological fertilizers in improving the quality and growth of Tartary buckwheat.

Plasticity-led and mutation-led evolutions are different modes of the same developmental gene regulatory network.

The standard theory of evolution proposes that mutations cause heritable variations, which are naturally selected, leading to evolution. However, this mutation-led evolution (MLE) is being questioned by an alternative theory called plasticity-led evolution (PLE). PLE suggests that an environmental change induces adaptive phenotypes, which are later genetically accommodated. According to PLE, developmental systems should be able to respond to environmental changes adaptively. However, developmental systems are known to be robust against environmental and mutational perturbations. Thus, we expect a transition from a robust state to a plastic one. To test this hypothesis, we constructed a gene regulatory network (GRN) model that integrates developmental processes, hierarchical regulation, and environmental cues. We then simulated its evolution over different magnitudes of environmental changes. Our findings indicate that this GRN model exhibits PLE under large environmental changes and MLE under small environmental changes. Furthermore, we observed that the GRN model is susceptible to environmental or genetic fluctuations under large environmental changes but is robust under small environmental changes. This indicates a breakdown of robustness due to large environmental changes. Before the breakdown of robustness, the distribution of phenotypes is biased and aligned to the environmental changes, which would facilitate rapid adaptation should a large environmental change occur. These observations suggest that the evolutionary transition from mutation-led to plasticity-led evolution is due to a developmental transition from robust to susceptible regimes over increasing magnitudes of environmental change. Thus, the GRN model can reconcile these conflicting theories of evolution.