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.

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.

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.

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.

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.

Videoconference version of the Montreal Cognitive Assessment: normative data for Quebec-French people aged 50 years and older.

BACKGROUND: The COVID-19 pandemic forced health professionals to rapidly develop and implement telepractice and remote assessments. Recent reviews appear to confirm the validity of a wide range of neuropsychological tests for teleneuropsychology and among these, the Montreal Cognitive Assessment (MoCA), a cognitive screening test widely used in clinical settings. The normative data specific to the context of videoconference administration is essential, particularly that consider sociodemographic characteristics. AIMS: This study had for objective to develop French-Quebec normative data for videoconference-administration of the MoCA that consider sociodemographic characteristics. METHODS: A total of 230 community-dwelling adults aged 50 years and older taking part in clinical trials completed the MoCA by videoconference. Regression analyses were run with sex, education, and age as predictors of the total MoCA scores, based on previously published norms. As an exploratory analysis, a second regression analysis was also run with cardiovascular disease as a predictor. RESULTS: Regression analyses revealed that older age and lower education were associated with poorer total MoCA scores, for medium effect size (p < 0.001, R2 = 0.17). Neither sex nor cardiovascular disease, were significant predictors in our analyses. For clinicians, a regression equation was proposed to calculate Z scores. DISCUSSION: This study provides normative data for the MoCA administered via videoconference in Quebec-French individuals aged 50 years and over. CONCLUSIONS: The present normative data will not only allow clinicians to continue to perform assessments remotely in this pandemic period but will also allow them to perform cognitive assessments to patients located in remote areas.

Coronary artery disease and its impact on the pulsatile brain: A functional NIRS study.

Recent studies have reported that optical indices of cerebral pulsatility are associated with cerebrovascular health in older adults. Such indices, including cerebral pulse amplitude and the pulse relaxation function (PRF), have been previously applied to quantify global and regional cerebral pulsatility. The aim of the present study was to determine whether these indices are modulated by cardiovascular status and whether they differ between individuals with low or high cardiovascular risk factors (LCVRF and HCVRF) and coronary artery disease (CAD). A total of 60 older adults aged 57-79 were enrolled in the study. Participants were grouped as LCVRF, HCVRF, and CAD. Participants were asked to walk freely on a gym track while a near-infrared spectroscopy (NIRS) device recorded hemodynamics data. Low-intensity, short-duration walking was used to test whether a brief cardiovascular challenge could increase the difference of pulsatility indices with respect to cardiovascular status. Results indicated that CAD individuals have higher global cerebral pulse amplitude compared with the other groups. Walking reduced global cerebral pulse amplitude and PRF in all groups but did not increase the difference across the groups. Instead, walking extended the spatial distribution of cerebral pulse amplitude to the anterior prefrontal cortex when CAD was compared to the CVRF groups. Further research is needed to determine whether cerebral pulse amplitude extracted from data acquired with NIRS, which is a noninvasive, inexpensive method, can provide an index to characterize the cerebrovascular status associated with CAD.

[Thymoma and squamous thymic carcinoma diagnosis; experience from the RYTHMIC network]. / Diagnostic des thymomes et carcinomes thymiques malpighiens ; expérience du réseau RYTHMIC.

The RYTHMIC network, supported by the French National Cancer Institute is dedicated to the management of patients with thymic epithelial tumors through regional and national multidisciplinary tumor boards. Tumor board decisions are based on the initial pathology diagnoses. However, following clinical inclusion in the network, a central pathology review is organized, implicating a panel of pathologists, for histotype and stage classification, which is different from a classical second opinion from pathologist to pathologist for a difficult case. Thanks to the participation of all French pathologists, more than 1000 cases have been reviewed by the panel. The aim of this review is to share with the French pathology community, the experience of the group. It underlines the importance of macroscopy and surgeon-pathologist involvement to allow a good central review, the main histopathological and immunophenotypical patterns of the most frequent thymomas and thymic carcinoma types, the differential diagnoses, as well as the difficulties for the panel to reproducibly assess on slides, stage, for some cases.

Interplay of Plasma Membrane and Vacuolar Ion Channels, Together with BAK1, Elicits Rapid Cytosolic Calcium Elevations in Arabidopsis during Aphid Feeding.

A transient rise in cytosolic calcium ion concentration is one of the main signals used by plants in perception of their environment. The role of calcium in the detection of abiotic stress is well documented; however, its role during biotic interactions remains unclear. Here, we use a fluorescent calcium biosensor (GCaMP3) in combination with the green peach aphid (Myzus persicae) as a tool to study Arabidopsis thaliana calcium dynamics in vivo and in real time during a live biotic interaction. We demonstrate rapid and highly localized plant calcium elevations around the feeding sites of M. persicae, and by monitoring aphid feeding behavior electrophysiologically, we demonstrate that these elevations correlate with aphid probing of epidermal and mesophyll cells. Furthermore, we dissect the molecular mechanisms involved, showing that interplay between the plant defense coreceptor BRASSINOSTEROID INSENSITIVE-ASSOCIATED KINASE1 (BAK1), the plasma membrane ion channels GLUTAMATE RECEPTOR-LIKE 3.3 and 3.6 (GLR3.3 and GLR3.6), and the vacuolar ion channel TWO-PORE CHANNEL1 (TPC1) mediate these calcium elevations. Consequently, we identify a link between plant perception of biotic threats by BAK1, cellular calcium entry mediated by GLRs, and intracellular calcium release by TPC1 during a biologically relevant interaction.

Indigenous Arabs are descendants of the earliest split from ancient Eurasian populations.

An open question in the history of human migration is the identity of the earliest Eurasian populations that have left contemporary descendants. The Arabian Peninsula was the initial site of the out-of-Africa migrations that occurred between 125,000 and 60,000 yr ago, leading to the hypothesis that the first Eurasian populations were established on the Peninsula and that contemporary indigenous Arabs are direct descendants of these ancient peoples. To assess this hypothesis, we sequenced the entire genomes of 104 unrelated natives of the Arabian Peninsula at high coverage, including 56 of indigenous Arab ancestry. The indigenous Arab genomes defined a cluster distinct from other ancestral groups, and these genomes showed clear hallmarks of an ancient out-of-Africa bottleneck. Similar to other Middle Eastern populations, the indigenous Arabs had higher levels of Neanderthal admixture compared to Africans but had lower levels than Europeans and Asians. These levels of Neanderthal admixture are consistent with an early divergence of Arab ancestors after the out-of-Africa bottleneck but before the major Neanderthal admixture events in Europe and other regions of Eurasia. When compared to worldwide populations sampled in the 1000 Genomes Project, although the indigenous Arabs had a signal of admixture with Europeans, they clustered in a basal, outgroup position to all 1000 Genomes non-Africans when considering pairwise similarity across the entire genome. These results place indigenous Arabs as the most distant relatives of all other contemporary non-Africans and identify these people as direct descendants of the first Eurasian populations established by the out-of-Africa migrations.

Improving zinc accumulation in cereal endosperm using HvMTP1, a transition metal transporter.

Zinc (Zn) is essential for all life forms, including humans. It is estimated that around two billion people are deficient in their Zn intake. Human dietary Zn intake relies heavily on plants, which in many developing countries consists mainly of cereals. The inner part of cereal grain, the endosperm, is the part that is eaten after milling but contains only a quarter of the total grain Zn. Here, we present results demonstrating that endosperm Zn content can be enhanced through expression of a transporter responsible for vacuolar Zn accumulation in cereals. The barley (Hordeum vulgare) vacuolar Zn transporter HvMTP1 was expressed under the control of the endosperm-specific D-hordein promoter. Transformed plants exhibited no significant change in growth but had higher total grain Zn concentration, as measured by ICP-OES, compared to parental controls. Compared with Zn, transformants had smaller increases in concentrations of Cu and Mn but not Fe. Staining grain cross sections with the Zn-specific stain DTZ revealed a significant enhancement of Zn accumulation in the endosperm of two of three transformed lines, a result confirmed by ICP-OES in the endosperm of dissected grain. Synchrotron X-ray fluorescence analysis of longitudinal grain sections demonstrated a redistribution of grain Zn from aleurone to endosperm. We argue that this proof-of-principle study provides the basis of a strategy for biofortification of cereal endosperm with Zn.

Natural History of Localized and Locally Advanced Atypical Lung Carcinoids after Complete Resection: A Joined French-Italian Retrospective Multicenter Study.

BACKGROUND: The natural history and the best modality of follow-up of atypical lung carcinoids (AC) remain ill defined. The aim of this study was to analyze recurrence-free survival (RFS) after complete resection (R0) of stage I-III pulmonary AC. Secondary objectives were prognostic parameters, the location of recurrences, and the modality of follow-up. METHODS: A retrospective review of 540 charts of AC patients treated between 1998 and 2008 at 10 French and Italian centers with experience in lung neuroendocrine tumor management was undertaken. The exclusion criteria were MEN1-related tumor, history of another cancer, referral after tumor relapse, and being lost to follow-up. A central pathological review was performed in each country. RESULTS: Sixty-two patients were included. After a median follow-up time of 91 months (mean 85, range 6-165), 35% of the patients experienced recurrence: 16% were regional recurrences and 19% were distant metastases. Median RFS was not reached. The 1-, 3-, and 5-year RFS rate was 90, 79, and 68%, respectively. In univariate analysis, lymph node involvement (p = 0.0001), stage (p = 0.0001), mitotic count (p = 0.004), and type of surgery (p = 0.043) were significantly associated with RFS. In multivariate analysis, lymph node involvement was significantly associated with RFS (HR 95% CI: 0.000-0.151; p = 0.004). During follow-up, somatostatin receptor scintigraphy, fibroscopy, and abdominal examination results were available for 22, 12, and 25 patients, respectively. The median time interval for imaging follow-up was 10 months. CONCLUSIONS: After complete resection of AC, recurrences were observed mostly within the first 5 years of follow-up, within bronchi, mediastinal nodes, the liver, and bones. In R0 patients, lymph node involvement could help to stratify follow-up intervals. Suboptimal imaging is evidenced.

Unlimited niche packing in a Lotka-Volterra competition game.

A central question in the study of ecology and evolution is: "Why are there so many species?" It has been shown that certain forms of the Lotka-Volterra (L-V) competition equations lead to an unlimited number of species. Furthermore, these authors note how any change in the nature of competition (the competition kernel) leads to a finite or small number of coexisting species. Here we build upon these works by further investigating the L-V model of unlimited niche packing as a reference model and evolutionary game for understanding the environmental factors restricting biodiversity. We also examine the combined eco-evolutionary dynamics leading up to the species diversity and traits of the ESS community in both unlimited and finite niche-packing versions of the model. As an L-V game with symmetric competition, we let the strategies of individuals determine the strength of the competitive interaction (like competes most with like) and also the carrying capacity of the population. We use a mixture of analytic proofs (for one and two species systems) and numerical simulations. For the model of unlimited niche packing, we show that a finite number of species will evolve to specific convergent stable minima of the adaptive landscape (also known as species archetypes). Starting with a single species, faunal buildup can proceed either through species doubling as each diversity-specific set of minima are reached, or through the addition of species one-by-one by randomly assigning a speciation event to one of the species. Either way it is possible for an unlimited number or species to evolve and coexist. We examine two simple and biologically likely ways for breaking the unlimited niche-packing: (1) some minimum level of competition among species, and (2) constrain the fundamental niche of the trait space to a finite interval. When examined under both ecological and evolutionary dynamics, both modifications result in convergent stable ESSs with a finite number of species. When the number of species is held below the number of species in an ESS coalition, we see a diverse array of convergent stable niche archetypes that consist of some species at maxima and some at minima of the adaptive landscape. Our results support those of others and suggest that instead of focusing on why there are so many species we might just as usefully ask, why are there so few species?

Pulmonary Abnormalities in Young, Light-Use Waterpipe (Hookah) Smokers.

RATIONALE: Waterpipes, also called hookahs, are currently used by millions of people worldwide. Despite the increasing use of waterpipe smoking, there is limited data on the health effects of waterpipe smoking and there are no federal regulations regarding its use. OBJECTIVES: To assess the effects of waterpipe smoking on the human lung using clinical and biological parameters in young, light-use waterpipe smokers. METHODS: We assessed young, light-use, waterpipe-only smokers in comparison with lifelong nonsmokers using clinical parameters of cough and sputum scores, lung function, and chest high-resolution computed tomography as well as biological parameters of lung epithelial lining fluid metabolome, small airway epithelial (SAE) cell differential and transcriptome, alveolar macrophage transcriptome, and plasma apoptotic endothelial cell microparticles. MEASUREMENTS AND MAIN RESULTS: Compared with nonsmokers, waterpipe smokers had more cough and sputum as well as a lower lung diffusing capacity, abnormal epithelial lining fluid metabolome profile, increased proportions of SAE secretory and intermediate cells, reduced proportions of SAE ciliated and basal cells, markedly abnormal SAE and alveolar macrophage transcriptomes, and elevated levels of apoptotic endothelial cell microparticles. CONCLUSIONS: Young, light-use, waterpipe-only smokers have a variety of abnormalities in multiple lung-related biological and clinical parameters, suggesting that even limited waterpipe use has broad consequences on human lung biology and health. We suggest that large epidemiological studies should be initiated to investigate the harmful effects of waterpipe smoking.

Osteopontin and thrombospondin-1 play opposite roles in promoting tumor aggressiveness of primary resected non-small cell lung cancer.

BACKGROUND: Osteopontin (OPN) and thrombospondin-1 (TSP-1) are extracellular matrix proteins secreted by stromal and tumor cells. These proteins appear to have a key role in the tumor microenvironment for cancer development and metastasis. There is little information regarding the prognostic value of the combination of these two proteins in human cancers. Our aim was to clarify clinical significance and prognostic value of each circulating protein and their combination in primary resected non-small cell lung cancer (NSCLC) patients. METHODS: We retrospectively reviewed 171 patients with NSCLC following curative intent surgery from January to December of 2012. Preoperative serums, demographics, clinical and pathological data and molecular profiling were analyzed. Pre-treatment OPN and TSP-1 serum levels were measured by ELISA. Tissue protein expression in primary tumor samples was determined by immunohistochemical analysis. RESULTS: OPN and TSP-1 serum levels were inversely correlated with survival rates. For each 50 units increment of serum OPN, an increased risk of metastasis by 69 % (unadjusted HR 1.69, 95 % CI 1.12-2.56, p = 0.01) and an increased risk of death by 95 % (unadjusted HR 1.95, 95 % CI 1.15-3.32, p = 0.01) were observed. Conversely, for each 10 units increment in TSP-1, the risk of death was decreased by 85 % (unadjusted HR 0.15, 95 % CI 0.03-0.89; p = 0.04). No statistically significant correlation was found between TSP-1 serum level and distant metastasis-free survival (p = 0.2). On multivariate analysis, OPN and TSP-1 serum levels were independent prognostic factors of overall survival (HR 1.71, 95 % CI 1.04-2.82, p = 0.04 for an increase of 50 ng/mL in OPN; HR 0.18, 95 % CI 0.04-0.87, p = 0.03 for an increase of 10 ng/mL in TSP-1). In addition, the combination of OPN and TSP-1 serum levels remained an independent prognostic factor for overall survival (HR 1.31, 95 % CI 1.03-1.67, p = 0.03 for an increase of 6 ng/mL in OPN/TSP-1 ratio). CONCLUSIONS: Our results show that pre-treatment OPN and TSP-1 serum levels may reflect the aggressiveness of the tumor and might serve as prognostic markers in patients with primary resected NSCLC.

Risk of COPD with obstruction in active smokers with normal spirometry and reduced diffusion capacity.

Smokers are assessed for chronic obstructive pulmonary disease (COPD) using spirometry, with COPD defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) as airflow limitation that is not fully reversible with bronchodilators. There is a subset of smokers with normal spirometry (by GOLD criteria), who have a low diffusing capacity of the lung for carbon monoxide (DLCO), a parameter linked to emphysema and small airway disease. The natural history of these "normal spirometry/low DLCO" smokers is unknown.From a cohort of 1570 smokers in the New York City metropolitian area, all of whom had normal spirometry, two groups were randomly selected for lung function follow-up: smokers with normal spirometry/normal DLCO (n=59) and smokers with normal spirometry/low DLCO (n=46). All had normal history, physical examination, complete blood count, urinalysis, HIV status, α1-antitrypsin level, chest radiography, forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC ratio and total lung capacity. Throughout the study, all continued to be active smokers.In the normal spirometry/normal DLCO group assessed over 45±20 months, 3% developed GOLD-defined COPD. In contrast, in the normal spirometry/low DLCO group, followed over 41±31 months, 22% developed GOLD-defined COPD.Despite appearing "normal" according to GOLD, smokers with normal spirometry but low DLCO are at significant risk of developing COPD with obstruction to airflow.

Thoracic endometriosis: clinicopathologic updates and issues about 18 cases from a tertiary referring center.

Thoracic endometriosis is defined as the ectopic presence of endometrial glands and stroma in lung or pleura and constitutes an uncommon cause of spontaneous pneumothorax in nonsmoker women in childbearing age. From 2000 to 2014, 18 (7.3%) women of 246 had a histologically proven endometriosis-related pneumothorax. The examination of thoracic samples was performed on formalin-fixed, paraffin-embedded hematoxylin and eosin-stained slides. Immunohistochemistry was carried out on all samples. The pathologic findings included endometriosis foci appearing as a triad of endometrial glands, stroma, and hemosiderin-laden macrophages in 8 patients. In the remaining 10 patients, minute nests of endometrial stroma were recognized at histologic examination and immunohistochemistry. One patient displayed diaphragmatic endometriosis and pulmonary lymphangioleiomyomatosis. Thoracic endometriosis is an uncommon cause of recurrent pneumothorax necessitating histologic confirmation. The histologic diagnosis of endometriosis may be challenging on small pleural or lung biopsies because endometriosis mostly appears as minute nests of endometrial stromal cells. Here, we present our experience on thoracic endometriosis: considering frequent interpretation difficulties of biopsy samples, we propose a multidisciplinary diagnostic algorithm.

LOGICOIL--multi-state prediction of coiled-coil oligomeric state.

MOTIVATION: The coiled coil is a ubiquitous α-helical protein-structure domain that directs and facilitates protein-protein interactions in a wide variety of biological processes. At the protein-sequence level, the coiled coil is readily recognized via a conspicuous heptad repeat of hydrophobic and polar residues. However, structurally coiled coils are more complicated, existing in a wide range of oligomer states and topologies. As a consequence, predicting these various states from sequence remains an unmet challenge. RESULTS: This work introduces LOGICOIL, the first algorithm to address the problem of predicting multiple coiled-coil oligomeric states from protein-sequence information alone. By covering >90% of the known coiled-coil structures, LOGICOIL is a net improvement compared with other existing methods, which achieve a predictive coverage of ∼31% of this population. This leap in predictive power offers better opportunities for genome-scale analysis, and analyses of coiled-coil containing protein assemblies. AVAILABILITY: LOGICOIL is available via a web-interface at http://coiledcoils.chm.bris.ac.uk/LOGICOIL. Source code, training sets and supporting information can be downloaded from the same site.

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.

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.