Integrating targeted genetic markers to genotyping-by-sequencing for an ultimate genotyping tool.

New selection methods, using trait-specific markers (marker-assisted selection (MAS)) and/or genome-wide markers (genomic selection (GS)), are becoming increasingly widespread in breeding programs. This new era requires innovative and cost-efficient solutions for genotyping. Reduction in sequencing cost has enhanced the use of high-throughput low-cost genotyping methods such as genotyping-by-sequencing (GBS) for genome-wide single-nucleotide polymorphism (SNP) profiling in large breeding populations. However, the major weakness of GBS methodologies is their inability to genotype targeted markers. Conversely, targeted methods, such as amplicon sequencing (AmpSeq), often face cost constraints, hindering genome-wide genotyping across a large cohort. Although GBS and AmpSeq data can be generated from the same sample, an efficient method to achieve this is lacking. In this study, we present the Genome-wide & Targeted Amplicon (GTA) genotyping platform, an innovative way to integrate multiplex targeted amplicons into the GBS library preparation to provide an all-in-one cost-effective genotyping solution to breeders and research communities. Custom primers were designed to target 23 and 36 high-value markers associated with key agronomical traits in soybean and barley, respectively. The resulting multiplex amplicons were compatible with the GBS library preparation enabling both GBS and targeted genotyping data to be produced efficiently and cost-effectively. To facilitate data analysis, we have introduced Fast-GBS.v3, a user-friendly bioinformatic pipeline that generates comprehensive outputs from data obtained following sequencing of GTA libraries. This high-throughput low-cost approach will greatly facilitate the application of DNA markers as it provides required markers for both MAS and GS in a single assay.

Platelet aggregates in lung capillaries in severely decompensated pulmonary hypertension.

The mechanism of thrombocytopenia during acute pulmonary hypertension (PH) decompensation may be partly due to platelet aggregation in the lung. Platelet aggregates in explanted lung from 16 lung transplant patients during acute PH decompensation with and without thrombocytopenia were identified by immunohistochemistry. Scanning electron microscopy (SEM) was performed. 7 explant lung controls without PH and thrombocytopenia were also examined. Compared with controls, the median number of platelet aggregates was higher in patients with acute PH decompensation with thrombocytopenia (19.4 [IQR 3.4-38.3] vs 147.5 [IQR 26.5-203.2]). SEM showed capillaries filled with platelet aggregates. Our study suggests that platelets may aggregate in the lungs during acute PH decompensation.

Association Between Emergency Medical Services Intervention Volume and Out-of-Hospital Cardiac Arrest Survival: A Propensity Score Matching Analysis.

BACKGROUND: Out of hospital cardiac arrest (OHCA) survival rates are very low. An association between institutional OHCA case volume and patient outcomes has been documented. However, whether this applies to prehospital emergency medicine services (EMS) is unknown. OBJECTIVES: To investigate the association between the volume of interventions by mobile intensive care units (MICU) and outcomes of patients experiencing an OHCA. METHODS: A retrospective cohort study including adult patients with OHCA managed by medical EMS in five French centers between 2013 and 2020. Two groups were defined depending on the overall annual numbers of MICU interventions: low and high-volume MICU. Primary endpoint was 30-day survival. Secondary endpoints were prehospital return of spontaneous circulation (ROSC), ROSC at hospital admission and favorable neurological outcome. Patients were matched 1:1 using a propensity score. Conditional logistic regression was then used. RESULTS: 2,014 adult patients (69% male, median age 68 [57-79] years) were analyzed, 50.5% (n = 1,017) were managed by low-volume MICU and 49.5% (n = 997) by high-volume MICU. Survival on day 30 was 3.6% in the low-volume group compared to 5.1% in the high-volume group. There was no significant association between MICU volume of intervention and survival on day 30 (OR = 0.92, 95%CI [0.55;1.53]), prehospital ROSC (OR = 1.01[0.78;1.3]), ROSC at hospital admission (OR = 0.92 [0.69;1.21]), or favorable neurologic prognosis on day 30 (OR = 0.92 [0.53;1.62]).

DNA methylation as a new tool for the differential diagnosis between T-LBL and lymphocyte-rich thymoma.

T-lymphoblastic lymphoma (T-LBL) and thymoma are two rare primary tumors of the thymus deriving either from T-cell precursors or from thymic epithelial cells, respectively. Some thymoma subtypes (AB, B1, and B2) display numerous reactive terminal deoxynucleotidyl transferase-positive (TdT+) T-cell precursors masking epithelial tumor cells. Therefore, the differential diagnosis between T-LBL and TdT+ T-lymphocyte-rich thymoma could be challenging, especially in the case of needle biopsy. To distinguish between T-LBL and thymoma-associated lymphoid proliferations, we analyzed the global DNA methylation using two different technologies, namely MeDIP array and EPIC array, in independent samples series [17 T-LBLs compared with one TdT+ lymphocyte-rich thymoma (B1 subtype) and three normal thymi, and seven lymphocyte-rich thymomas compared with 24 T-LBLs, respectively]. In unsupervised principal component analysis (PCA), T-LBL and thymoma samples clustered separately. We identified differentially methylated regions (DMRs) using MeDIP-array and EPIC-array datasets and nine overlapping genes between the two datasets considering the top 100 DMRs including ZIC1, TSHZ2, CDC42BPB, RBM24, C10orf53, and MACROD2. In order to explore the DNA methylation profiles in larger series, we defined a classifier based on these six differentially methylated gene promoters, developed an MS-MLPA assay, and demonstrated a significant differential methylation between thymomas (hypomethylated; n = 48) and T-LBLs (hypermethylated; n = 54) (methylation ratio median 0.03 versus 0.66, respectively; p < 0.0001), with MACROD2 methylation status the most discriminating. Using a machine learning strategy, we built a prediction model trained with the EPIC-array dataset and defined a cumulative score taking into account the weight of each feature. A score above or equal to 0.4 was predictive of T-LBL and conversely. Applied to the MS-MLPA dataset, this prediction model accurately predicted diagnoses of T-LBL and thymoma. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Modulation of FGF pathway signaling and vascular differentiation using designed oligomeric assemblies.

Many growth factors and cytokines signal by binding to the extracellular domains of their receptors and driving association and transphosphorylation of the receptor intracellular tyrosine kinase domains, initiating downstream signaling cascades. To enable systematic exploration of how receptor valency and geometry affect signaling outcomes, we designed cyclic homo-oligomers with up to 8 subunits using repeat protein building blocks that can be modularly extended. By incorporating a de novo-designed fibroblast growth factor receptor (FGFR)-binding module into these scaffolds, we generated a series of synthetic signaling ligands that exhibit potent valency- and geometry-dependent Ca2+ release and mitogen-activated protein kinase (MAPK) pathway activation. The high specificity of the designed agonists reveals distinct roles for two FGFR splice variants in driving arterial endothelium and perivascular cell fates during early vascular development. Our designed modular assemblies should be broadly useful for unraveling the complexities of signaling in key developmental transitions and for developing future therapeutic applications.

Effects of Cardiopulmonary Rehabilitation on Cardiorespiratory Fitness and Clinical Symptom Burden in Long COVID: Results from the COVID-Rehab Randomized Controlled Trial.

OBJECTIVE: To investigate the effectiveness of an eight-week cardiopulmonary rehabilitation program on cardiorespiratory fitness (VO2peak) and key cardiopulmonary exercise test measures, quality of life, and symptom burden in individuals with Long COVID. DESIGN: Forty individuals with Long COVID (mean age 53 ± 11 years), were randomized into 2 groups: 1/ Rehabilitation group: centre-based individualized clinical rehabilitation program (8 weeks, 3 sessions per week of aerobic and resistance exercises, and daily inspiratory muscle training) and 2/ Control group: individuals maintained their daily habits during an eight-week period. RESULTS: There was a significant difference between groups in mean VO2peak improvement (p = 0.003). VO2peak improved significantly in the rehab group (+2.7 mL.kg.min 95%IC:+1.6 to +3.8 p < 0.001) compared to the control group (+0.3 mL.kg.min 95%IC:-0.8 to +1.3 p = 0.596), along withVE/VCO2 slope (p = 0.032) (-2.4 95%IC:-4.8 to +0.01 p = 0.049 and + 1.3 95%IC:-1.0 to +3.6 p = 0.272 respectively) and VO2 at first ventilatory threshold (p = 0.045). Furthermore, all symptom impact scales improved significantly in the rehabilitation group compared to the control group (p < 0.05). CONCLUSION: An individualized and supervised cardiopulmonary rehabilitation program was effective in improving cardiorespiratory fitness, ventilatory efficiency, and symptom burden in individuals with Long COVID. Careful monitoring of symptoms is important to appropriately tailor and adjust rehabilitation sessions.

Genetics of cystogenesis in base-edited human organoids reveal therapeutic strategies for polycystic kidney disease.

In polycystic kidney disease (PKD), microscopic tubules expand into macroscopic cysts. Among the world's most common genetic disorders, PKD is inherited via heterozygous loss-of-function mutations but is theorized to require additional loss of function. To test this, we establish human pluripotent stem cells in allelic series representing four common nonsense mutations, using CRISPR base editing. When differentiated into kidney organoids, homozygous mutants spontaneously form cysts, whereas heterozygous mutants (original or base corrected) express no phenotype. Using these, we identify eukaryotic ribosomal selective glycosides (ERSGs) as PKD therapeutics enabling ribosomal readthrough of these same nonsense mutations. Two different ERSGs not only prevent cyst initiation but also limit growth of pre-formed cysts by partially restoring polycystin expression. Furthermore, glycosides accumulate in cyst epithelia in organoids and mice. Our findings define the human polycystin threshold as a surmountable drug target for pharmacological or gene therapy interventions, with relevance for understanding disease mechanisms and future clinical trials.

New Oldowan locality Sare-Abururu (ca. 1.7 Ma) provides evidence of diverse hominin behaviors on the Homa Peninsula, Kenya.

The Homa Peninsula, in southwestern Kenya, continues to yield insights into Oldowan hominin landscape behaviors. The Late Pliocene locality of Nyayanga (∼3-2.6 Ma) preserves some of the oldest Oldowan tools. At the Early Pleistocene locality of Kanjera South (∼2 Ma) toolmakers procured a diversity of raw materials from over 10 km away and strategically reduced them in a grassland-dominated ecosystem. Here, we report findings from Sare-Abururu, a younger (∼1.7 Ma) Oldowan locality approximately 12 km southeast of Kanjera South and 18 km east of Nyayanga. Sare-Abururu has yielded 1754 artifacts in relatively undisturbed low-energy silts and sands. Stable isotopic analysis of pedogenic carbonates suggests that hominin activities were carried out in a grassland-dominated setting with similar vegetation structure as documented at Kanjera South. The composition of a nearby paleo-conglomerate indicates that high-quality stone raw materials were locally abundant. Toolmakers at Sare-Abururu produced angular fragments from quartz pebbles, representing a considerable contrast to the strategies used to reduce high quality raw materials at Kanjera South. Although lithic reduction at Sare-Abururu was technologically simple, toolmakers proficiently produced cutting edges, made few mistakes and exhibited a mastery of platform management, demonstrating that expedient technical strategies do not necessarily indicate a lack of skill or suitable raw materials. Lithic procurement and reduction patterns on the Homa Peninsula appear to reflect variation in local resource contexts rather than large-scale evolutionary changes in mobility, energy budget, or toolmaker cognition.

Prefrontal engagement predicts the effect of museum visit on psychological well-being: an fNIRS exploration.

Recent research suggests that museum visits can benefit psychological well-being by reducing symptoms of stress and anxiety. However, these reported relaxing effects remain inconsistent between studies. Shedding light on the underlying cerebral mechanisms of museum visits might support a better understanding of how it affects psychological well-being. This study aimed to investigate the prefrontal engagement evoked by artwork analysis during a museum visit and to determine if these prefrontal substrates are associated with the museum's effect on psychological well-being in older adults. Nineteen adults aged between 65 and 79, toured a Baroque-style exhibit at the Montreal Museum of Fine Arts for approximately 20 minutes while equipped with a near-infrared spectroscopy system measuring the prefrontal cortex's hemodynamic activity. For each painting, participants received the instruction to either (1): analyze the painting and produce a personal interpretation of its signification (analytic condition) or (2) visualize the painting without any specific thoughts (visualization condition). Questionnaires measuring stress, anxiety, and well-being were administered before and after the visit. Sixteen older women (71.5 ± 4 years) were included in the analyses. Results showed that, at the group level, the analytic condition was associated with an increased activation pattern in the left ventrolateral prefrontal region, typically related to attentional processes (not observed in the visualization condition). The activation associated with the analytic condition predicted pre-/post-visit reductions in self-reported anxiety and stress in the sample of older women. These observations suggest that the level of engagement of attentional processes during artwork analysis may play a major role in the effect of a museum's visit on self-reported symptoms of anxiety.

Immune checkpoints are predominantly co-expressed by clonally expanded CD4+FoxP3+ intratumoral T-cells in primary human cancers.

BACKGROUND: In addition to anti-PD(L)1, anti-CTLA-4 and anti-LAG-3, novel immune checkpoint proteins (ICP)-targeted antibodies have recently failed to demonstrate significant efficacy in clinical trials. In these trials, patients were enrolled without screening for drug target expression. Although these novel ICP-targeted antibodies were expected to stimulate anti-tumor CD8 + T-cells, the rationale for their target expression in human tumors relied on pre-clinical IHC stainings and transcriptomic data, which are poorly sensitive and specific techniques for assessing membrane protein expression on immune cell subsets. Our aim was to describe ICP expression on intratumoral T-cells from primary solid tumors to better design upcoming neoadjuvant cancer immunotherapy trials. METHODS: We prospectively performed multiparameter flow cytometry and single-cell RNA sequencing (scRNA-Seq) paired with TCR sequencing on freshly resected human primary tumors of various histological types to precisely determine ICP expression levels within T-cell subsets. RESULTS: Within a given tumor type, we found high inter-individual variability for tumor infiltrating CD45 + cells and for T-cells subsets. The proportions of CD8+ T-cells (~ 40%), CD4+ FoxP3- T-cells (~ 40%) and CD4+ FoxP3+ T-cells (~ 10%) were consistent across patients and indications. Intriguingly, both stimulatory (CD25, CD28, 4-1BB, ICOS, OX40) and inhibitory (PD-1, CTLA-4, PD-L1, CD39 and TIGIT) checkpoint proteins were predominantly co-expressed by intratumoral CD4+FoxP3+ T-cells. ScRNA-Seq paired with TCR sequencing revealed that T-cells with high clonality and high ICP expressions comprised over 80% of FoxP3+ cells among CD4+ T-cells. Unsupervised clustering of flow cytometry and scRNAseq data identified subsets of CD8+ T-cells and of CD4+ FoxP3- T-cells expressing certain checkpoints, though these expressions were generally lower than in CD4+ FoxP3+ T-cell subsets, both in terms of proportions among total T-cells and ICP expression levels. CONCLUSIONS: Tumor histology alone does not reveal the complete picture of the tumor immune contexture. In clinical trials, assumptions regarding target expression should rely on more sensitive and specific techniques than conventional IHC or transcriptomics. Flow cytometry and scRNAseq accurately characterize ICP expression within immune cell subsets. Much like in hematology, flow cytometry can better describe the immune contexture of solid tumors, offering the opportunity to guide patient treatment according to drug target expression rather than tumor histological type.

Single-cell census of human tooth development enables generation of human enamel.

Tooth enamel secreted by ameloblasts (AMs) is the hardest material in the human body, acting as a shield to protect the teeth. However, the enamel is gradually damaged or partially lost in over 90% of adults and cannot be regenerated due to a lack of ameloblasts in erupted teeth. Here, we use single-cell combinatorial indexing RNA sequencing (sci-RNA-seq) to establish a spatiotemporal single-cell census for the developing human tooth and identify regulatory mechanisms controlling the differentiation process of human ameloblasts. We identify key signaling pathways involved between the support cells and ameloblasts during fetal development and recapitulate those findings in human ameloblast in vitro differentiation from induced pluripotent stem cells (iPSCs). We furthermore develop a disease model of amelogenesis imperfecta in a three-dimensional (3D) organoid system and show AM maturation to mineralized structure in vivo. These studies pave the way for future regenerative dentistry.

Multiomic analysis of malignant pleural mesothelioma identifies molecular axes and specialized tumor profiles driving intertumor heterogeneity.

Malignant pleural mesothelioma (MPM) is an aggressive cancer with rising incidence and challenging clinical management. Through a large series of whole-genome sequencing data, integrated with transcriptomic and epigenomic data using multiomics factor analysis, we demonstrate that the current World Health Organization classification only accounts for up to 10% of interpatient molecular differences. Instead, the MESOMICS project paves the way for a morphomolecular classification of MPM based on four dimensions: ploidy, tumor cell morphology, adaptive immune response and CpG island methylator profile. We show that these four dimensions are complementary, capture major interpatient molecular differences and are delimited by extreme phenotypes that-in the case of the interdependent tumor cell morphology and adapted immune response-reflect tumor specialization. These findings unearth the interplay between MPM functional biology and its genomic history, and provide insights into the variations observed in the clinical behavior of patients with MPM.

Cardiorespiratory Fitness Moderates the Age-Related Association Between Executive Functioning and Mobility: Evidence From Remote Assessments.

Background and Objectives: In older adults, executive functions are important for daily-life function and mobility. Evidence suggests that the relationship between cognition and mobility is dynamic and could vary according to individual factors, but whether cardiorespiratory fitness reduces the age-related increase of interdependence between mobility and cognition remains unexplored. Research Design and Methods: One hundred eighty-nine participants (aged 50-87) were divided into 3 groups according to their age: middle-aged (MA; <65), young older adults (YOA; 65-74), and old older adults (OOA; ≥75). Participants performed Timed Up and Go and executive functioning assessments (Oral Trail Making Test and Phonologic verbal fluency) remotely by videoconference. Participants completed the Matthews questionnaire to estimate their cardiorespiratory fitness (VO2 max in ml/min/kg). A 3-way moderation was used to address whether cardiorespiratory fitness interacts with age to moderate the relationship between cognition and mobility. Results: Results showed that the cardiorespiratory fitness × age interaction moderated the association between executive functioning and mobility (ß = -0.05; p = .048; R 2 = 17.6; p < .001). At lower levels of physical fitness (<19.16 ml/min/kg), executive functioning significantly influenced YOA's mobility (ß = -0.48, p = .004) and to a greater extent OOA's mobility (ß = -0.96, p = .002). Discussion and Implications: Our results support the idea of a dynamic relationship between mobility and executive functioning during aging and suggest that physical fitness could play a significant role in reducing their interdependency.

Expanded geographic distribution and dietary strategies of the earliest Oldowan hominins and Paranthropus.

The oldest Oldowan tool sites, from around 2.6 million years ago, have previously been confined to Ethiopia's Afar Triangle. We describe sites at Nyayanga, Kenya, dated to 3.032 to 2.581 million years ago and expand this distribution by over 1300 kilometers. Furthermore, we found two hippopotamid butchery sites associated with mosaic vegetation and a C4 grazer-dominated fauna. Tool flaking proficiency was comparable with that of younger Oldowan assemblages, but pounding activities were more common. Tool use-wear and bone damage indicate plant and animal tissue processing. Paranthropus sp. teeth, the first from southwestern Kenya, possessed carbon isotopic values indicative of a diet rich in C4 foods. We argue that the earliest Oldowan was more widespread than previously known, used to process diverse foods including megafauna, and associated with Paranthropus from its onset.

Glucose absorption drives cystogenesis in a human organoid-on-chip model of polycystic kidney disease.

In polycystic kidney disease (PKD), fluid-filled cysts arise from tubules in kidneys and other organs. Human kidney organoids can reconstitute PKD cystogenesis in a genetically specific way, but the mechanisms underlying cystogenesis remain elusive. Here we show that subjecting organoids to fluid shear stress in a PKD-on-a-chip microphysiological system promotes cyst expansion via an absorptive rather than a secretory pathway. A diffusive static condition partially substitutes for fluid flow, implicating volume and solute concentration as key mediators of this effect. Surprisingly, cyst-lining epithelia in organoids polarize outwards towards the media, arguing against a secretory mechanism. Rather, cyst formation is driven by glucose transport into lumens of outwards-facing epithelia, which can be blocked pharmacologically. In PKD mice, glucose is imported through cysts into the renal interstitium, which detaches from tubules to license expansion. Thus, absorption can mediate PKD cyst growth in human organoids, with implications for disease mechanism and potential for therapy development.

Multiple routes to help you roam: A comparison of training interventions to improve cognitive-motor dual-tasking in healthy older adults.

Cognitive-motor dual-tasking is a complex activity that predicts falls risk and cognitive impairment in older adults. Cognitive and physical training can both lead to improvements in dual-tasking; however, less is known about what mechanisms underlie these changes. To investigate this, 33 healthy older adults were randomized to one of three training arms: Executive function (EF; n = 10), Aerobic Exercise (AE; n = 10), Gross Motor Abilities (GMA; n = 13) over 12 weeks (1 h, 3×/week). Single and dual-task performance (gait speed, m/s; cognitive accuracy, %) was evaluated before and after training, using the 2-back as concurrent cognitive load. Training arms were designed to improve cognitive and motor functioning, through different mechanisms (i.e., executive functioning - EF, cardiorespiratory fitness - CRF, and energy cost of walking - ECW). Compared to baseline, we observed few changes in dual-task gait speed following training (small effect). However, dual-task cognitive accuracy improved significantly, becoming facilitated by walking (large effect). There were no differences in the magnitude of improvements across training arms. We also found that older adults with lower cognitive ability (i.e., MoCA score < 26; n = 14) improved more on the dual-task cognitive accuracy following training, compared to older adults with higher cognitive ability (i.e., MoCA ≥26; n = 18). Taken together, the results suggest that regardless of the type of intervention, training appears to strengthen cognitive efficiency during dual-tasking, particularly for older adults with lower baseline cognitive status. These gains appear to occur via different mechanisms depending on the form of intervention. Implications of this research are paramount, as we demonstrate multiple routes for improving cognitive-motor dual-tasking in older adults, which may help reduce risk of cognitive impairment.

Diffusion and bulk flow of amino acids mediate calcium waves in plants.

In plants, a variety of stimuli trigger long-range calcium signals that travel rapidly along the vasculature to distal tissues via poorly understood mechanisms. Here, we use quantitative imaging and analysis to demonstrate that traveling calcium waves are mediated by diffusion and bulk flow of amino acid chemical messengers. We propose that wounding triggers release of amino acids that diffuse locally through the apoplast, activating the calcium-permeable channel GLUTAMATE RECEPTOR-LIKE 3.3 as they pass. Over long distances through the vasculature, the wound-triggered dynamics of a fluorescent tracer show that calcium waves are likely driven by bulk flow of a channel-activating chemical. We observed that multiple stimuli trigger calcium waves with similar dynamics, but calcium waves alone cannot initiate all systemic defense responses, suggesting that mobile chemical messengers are a core component of complex systemic signaling in plants.

Orai1 Inhibitors as Potential Treatments for Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is characterized by progressive distal pulmonary artery (PA) obstruction, leading to right ventricular hypertrophy and failure. Exacerbated intracellular calcium (Ca2+) signaling contributes to abnormalities in PA smooth muscle cells (PASMCs), including aberrant proliferation, apoptosis resistance, exacerbated migration, and arterial contractility. Store-operated Ca2+ entry is involved in Ca2+ homeostasis in PASMCs, but its properties in PAH are unclear. METHODS: Using a combination of Ca2+ imaging, molecular biology, in vitro, ex vivo, and in vivo approaches, we investigated the roles of the Orai1 SOC channel in PA remodeling in PAH and determined the consequences of pharmacological Orai1 inhibition in vivo using experimental models of pulmonary hypertension (PH). RESULTS: Store-operated Ca2+ entry and Orai1 mRNA and protein were increased in human PASMCs (hPASMCs) from patients with PAH (PAH-hPASMCs). We found that MEK1/2 (mitogen-activated protein kinase kinase 1/2), NFAT (nuclear factor of activated T cells), and NFκB (nuclear factor-kappa B) contribute to the upregulation of Orai1 expression in PAH-hPASMCs. Using small interfering RNA (siRNA) and Orai1 inhibitors, we found that Orai1 inhibition reduced store-operated Ca2+ entry, mitochondrial Ca2+ uptake, aberrant proliferation, apoptosis resistance, migration, and excessive calcineurin activity in PAH-hPASMCs. Orai1 inhibitors reduced agonist-evoked constriction in human PAs. In experimental rat models of PH evoked by chronic hypoxia, monocrotaline, or Sugen/hypoxia, administration of Orai1 inhibitors (N-{4-[3,5-bis(Trifluoromethyl)-1H-pyrazol-1-yl]phenyl}-4-methyl-1,2,3-thiadiazole-5-carboxamide [BTP2], 4-(2,5-dimethoxyphenyl)-N-[(pyridin-4-yl)methyl]aniline [JPIII], or 5J4) protected against PH. CONCLUSIONS: In human PAH and experimental PH, Orai1 expression and activity are increased. Orai1 inhibition normalizes the PAH-hPASMCs phenotype and attenuates PH in rat models. These results suggest that Orai1 should be considered as a relevant therapeutic target for PAH.

Exploring cognitive and brain oxygenation changes over a 1-year period in physically active individuals with mild cognitive impairment: a longitudinal fNIRS pilot study.

BACKGROUND: Aging is associated with an increased likelihood of developing dementia, but a growing body of evidence suggests that certain modifiable risk factors may help prevent or delay dementia onset. Among these, physical activity (PA) has been linked to better cognitive performance and brain functions in healthy older adults and may contribute to preventing dementia. The current pilot study investigated changes in behavioral and brain activation patterns over a 1-year period in individuals with mild cognitive impairment (MCI) and healthy controls taking part in regular PA. METHODS: Frontal cortical response during a dual-task walking paradigm was investigated at baseline, at 6 months (T6), and at 12 months (T12) by means of a portable functional Near-Infrared Spectroscopy (fNIRS) system. The dual-task paradigm included a single cognitive task (2-back), a single motor task (walking), and a dual-task condition (2-back whilst walking). RESULTS: Both groups showed progressive improvement in cognitive performance at follow-up visits compared to baseline. Gait speed remained stable throughout the duration of the study in the control group and increased at T6 for those with MCI. A significant decrease in cortical activity was observed in both groups during the cognitive component of the dual-task at follow-up visits compared to baseline, with MCI individuals showing the greatest improvement. CONCLUSIONS: The observations of this pilot study suggest that taking part in regular PA may be especially beneficial for both cognitive performance and brain functions in older adulthood and, especially, in individuals with MCI. Our findings may serve as preliminary evidence for the use of PA as a potential intervention to prevent cognitive decline in individuals at greater risk of dementia.

The construction of a high-density consensus genetic map for soybean based on SNP markers derived from genotyping-by-sequencing.

Genetic linkage maps are used to localize markers on the genome based on the recombination frequency. Most often, these maps are based on the segregation observed within a single biparental population of limited size (n < 300) where relatively few recombination events are sampled and in which some genomic regions are monomorphic because both parents carry the same alleles. Together, these two limitations affect both the resolution and extent of genome coverage of such maps. Consensus genetic maps overcome the limitations of individual genetic maps by merging the information from multiple segregating populations derived from a greater diversity of parental combinations, thus increasing the number of recombination events and reducing the number of monomorphic regions. The aim of this study was to construct a high-density consensus genetic map for single nucleotide polymorphism (SNP) markers obtained through a genotyping-by-sequencing (GBS) approach. Individual genetic maps were generated from six F4:5 mapping populations (n = 278-365), totaling 1857 individuals. The six linkage maps were then merged to produce a consensus map comprising a total of 16 311 mapped SNPs that jointly cover 99.5% of the soybean genome with only two gaps larger than 10 cM. Compared to previous soybean consensus maps, it offers a more extensive and uniform coverage.