Feedback control of gene expression variability in the Caenorhabditis elegans Wnt pathway.

Variability in gene expression contributes to phenotypic heterogeneity even in isogenic populations. Here, we used the stereotyped, Wnt signaling-dependent development of the Caenorhabditis elegans Q neuroblast to probe endogenous mechanisms that control gene expression variability. We found that the key Hox gene that orients Q neuroblast migration exhibits increased gene expression variability in mutants in which Wnt pathway activity has been perturbed. Distinct features of the gene expression distributions prompted us on a systematic search for regulatory interactions, revealing a network of interlocked positive and negative feedback loops. Interestingly, positive feedback appeared to cooperate with negative feedback to reduce variability while keeping the Hox gene expression at elevated levels. A minimal model correctly predicts the increased gene expression variability across mutants. Our results highlight the influence of gene network architecture on expression variability and implicate feedback regulation as an effective mechanism to ensure developmental robustness.

Structural insights into the regulation of RyR1 by S100A1.

S100A1, a small homodimeric EF-hand Ca2+-binding protein (~21 kDa), plays an important regulatory role in Ca2+ signaling pathways involved in various biological functions including Ca2+ cycling and contractile performance in skeletal and cardiac myocytes. One key target of the S100A1 interactome is the ryanodine receptor (RyR), a huge homotetrameric Ca2+ release channel (~2.3 MDa) of the sarcoplasmic reticulum. Here, we report cryoelectron microscopy structures of S100A1 bound to RyR1, the skeletal muscle isoform, in absence and presence of Ca2+. Ca2+-free apo-S100A1 binds beneath the bridging solenoid (BSol) and forms contacts with the junctional solenoid and the shell-core linker of RyR1. Upon Ca2+-binding, S100A1 undergoes a conformational change resulting in the exposure of the hydrophobic pocket known to serve as a major interaction site of S100A1. Through interactions of the hydrophobic pocket with RyR1, Ca2+-bound S100A1 intrudes deeper into the RyR1 structure beneath BSol than the apo-form and induces sideways motions of the C-terminal BSol region toward the adjacent RyR1 protomer resulting in tighter interprotomer contacts. Interestingly, the second hydrophobic pocket of the S100A1-dimer is largely exposed at the hydrophilic surface making it prone to interactions with the local environment, suggesting that S100A1 could be involved in forming larger heterocomplexes of RyRs with other protein partners. Since S100A1 interactions stabilizing BSol are implicated in the regulation of RyR-mediated Ca2+ release, the characterization of the S100A1 binding site conserved between RyR isoforms may provide the structural basis for the development of therapeutic strategies regarding treatments of RyR-related disorders.

Differentiable partition function calculation for RNA.

Ribonucleic acid (RNA) is an essential molecule in a wide range of biological functions. In 1990, McCaskill introduced a dynamic programming algorithm for computing the partition function of an RNA sequence. McCaskill's algorithm is widely used today for understanding the thermodynamic properties of RNA. In this work, we introduce a generalization of McCaskill's algorithm that is well-defined over continuous inputs. Crucially, this enables us to implement an end-to-end differentiable partition function calculation. The derivative can be computed with respect to the input, or to any other fixed values, such as the parameters of the energy model. This builds a bridge between RNA thermodynamics and the tools of differentiable programming including deep learning as it enables the partition function to be incorporated directly into any end-to-end differentiable pipeline. To demonstrate the effectiveness of our new approach, we tackle the inverse folding problem directly using gradient optimization. We find that using the gradient to optimize the sequence directly is sufficient to arrive at sequences with a high probability of folding into the desired structure. This indicates that the gradients we compute are meaningful.

Biological differences between adult and perinatal human mesenchymal stromal cells and their impact on the manufacturing processes.

The biological properties of human mesenchymal stromal cells (hMSCs) have been explored in over a thousand clinical trials in the last decade. Although hMSCs can be isolated from multiple sources, the degree of biological similarity between cell populations from these sources remains to be determined. A comparative study was performed investigating the growth kinetics and functionality of hMSCs isolated from adipose tissue (AT), bone marrow (BM) and umbilical cord tissue (UCT) expanded in monolayer over five passages. Adult hMSCs (AT, BM) had a slower proliferation ability than the UCT-hMSCs, with no apparent differences in their glucose consumption profile. BM-hMSCs produced higher concentrations of endogenous vascular endothelial growth factor (VEGF) compared to AT- and UCT-hMSCs. This study also revealed that UCT-hMSCs were more efficiently transduced by a lentiviral vector carrying a VEGF gene than their adult counterparts. Following cellular immunophenotypic characterization, no differences across the sources were found in the expression levels of the typical markers used to identify hMSCs. This work established a systematic approach for cell source selection depending on the hMSC's intended clinical application.

The rhythms of histones in regeneration: The epigenetic modifications determined by clock genes.

The evolutionary establishment of an internal biological clock is a primordial event tightly associated with a 24-h period. Changes in the circadian rhythm can affect cellular functions, including proliferation, DNA repair and redox state. Even isolated organs, tissues and cells can maintain an autonomous circadian rhythm. These cell-autonomous molecular mechanisms are driven by intracellular clock genes, such as BMAL1. Little is known about the role of core clock genes and epigenetic modifications in the skin. Our focus was to identify BMAL1-driven epigenetic modifications associated with gene transcription by mapping the acetylation landscape of histones in epithelial cells responding to injury. We explored the role of BMAL1 in epidermal wound and tissue regeneration using a loss-of-function approach in vivo. We worked with BMAL1 knockout mice and a contraction-resistance wound healing protocol, determining the histone modifications using specific antibodies to detect the acetylation levels of histones H3 and H4. We found significant differences in the acetylation levels of histones in both homeostatic and injured skin with deregulated BMAL1. The intact skin displayed varied acetylation levels of histones H3 and H4, including hyperacetylation of H3 Lys 9 (H3K9). The most pronounced changes were observed at the repair site, with notable alterations in the acetylation pattern of histone H4. These findings reveal the importance of histone modifications in response to injury and indicate that modulation of BMAL1 and its associated epigenetic events could be therapeutically harnessed to improve skin regeneration.

The relevance of the superior cervical ganglion for cardiac autonomic innervation in health and disease: a systematic review.

PURPOSE: The heart receives cervical and thoracic sympathetic contributions. Although the stellate ganglion is considered the main contributor to cardiac sympathetic innervation, the superior cervical ganglia (SCG) is used in many experimental studies. The clinical relevance of the SCG to cardiac innervation is controversial. We investigated current morphological and functional evidence as well as controversies on the contribution of the SCG to cardiac innervation. METHODS: A systematic literature review was conducted in PubMed, Embase, Web of Science, and COCHRANE Library. Included studies received a full/text review and quality appraisal. RESULTS: Seventy-six eligible studies performed between 1976 and 2023 were identified. In all species studied, morphological evidence of direct or indirect SCG contribution to cardiac innervation was found, but its contribution was limited. Morphologically, SCG sidedness may be relevant. There is indirect functional evidence that the SCG contributes to cardiac innervation as shown by its involvement in sympathetic overdrive reactions in cardiac disease states. A direct functional contribution was not found. Functional data on SCG sidedness was largely unavailable. Information about sex differences and pre- and postnatal differences was lacking. CONCLUSION: Current literature mainly supports an indirect involvement of the SCG in cardiac innervation, via other structures and plexuses or via sympathetic overdrive in response to cardiac diseases. Morphological evidence of a direct involvement was found, but its contribution seems limited. The relevance of SCG sidedness, sex, and developmental stage in health and disease remains unclear and warrants further exploration.

TAPVR: Molecular Pathways and Animal Models.

The venous pole of the heart where the pulmonary veins will develop encompasses the sinus venosus and the atrium. In the fourth week of development, the sinus venosus consists of a left and a right part receiving blood from the common cardinal vein, the omphalomesenteric and umbilical veins. Asymmetrical expansion of the common atrium corresponds with a rightward shift of the connection of the sinus to the atrium. The right-sided part of the sinus venosus including its tributing cardinal veins enlarges to form the right superior and inferior vena cava that will incorporate into the right atrium. The left-sided part in human development largely obliterates and remodels to form the coronary sinus in adults. In approximately the same time window (4th-fifth weeks), a splanchnic vascular plexus surrounds the developing lung buds (putative lungs) with a twofold connection. Of note, during early developmental stages, the primary route of drainage from the pulmonary plexus is toward the systemic veins and not to the heart. After lumenization of the so-called mid-pharyngeal endothelial strand (MPES), the first anlage of the pulmonary vein, the common pulmonary vein can be observed in the dorsal mesocardium, and the primary route of drainage will gradually change toward a cardiac drainage. The splanchnic pulmonary venous connections with the systemic cardinal veins will gradually disappear during normal development. In case of absence or atresia of the MPES, the pulmonary-to-systemic connections will persist, clinically resulting in total anomalous pulmonary venous return (TAPVR). This chapter describes the developmental processes and molecular pathways underlying anomalous pulmonary venous connections.

A switch from noncanonical to canonical Wnt signaling stops neuroblast migration through a Slt-Robo and RGA-9b/ARHGAP-dependent mechanism.

Members of the Wnt family of secreted glycoproteins regulate cell migration through distinct canonical and noncanonical signaling pathways. Studies of vertebrate development and disease have shown that these pathways can have opposing effects on cell migration, but the mechanism of this functional interplay is not known. In the nematode Caenorhabditis elegans, a switch from noncanonical to canonical Wnt signaling terminates the long-range migration of the QR neuroblast descendants, providing a tractable system to study this mechanism in vivo. Here, we show that noncanonical Wnt signaling acts through PIX-1/RhoGEF, while canonical signaling directly activates the Slt-Robo pathway component EVA-1/EVA1C and the Rho GTPase-activating protein RGA-9b/ARHGAP, which are required for migration inhibition. Our results support a model in which cross-talk between noncanonical and canonical Wnt signaling occurs through antagonistic regulation of the Rho GTPases that drive cell migration.

Effects of Exposure to Conflicting Health Information on Topic-Specific Information Sharing and Seeking Intentions.

Despite considerable evidence that exposure to conflicting health information can have undesirable effects on outcomes including public understanding about and trust in health recommendations, comparatively little is known about whether such exposure influences intentions to engage in two communication behaviors central to public health promotion: information sharing and information seeking. The purpose of the current study is to test whether exposure to conflicting information influences intentions to share and seek information about six health topics. We analyzed data from two waves of a longitudinal survey experiment with a nationally representative sample of U.S. adults (N = 3,920). Participants were randomly assigned to either a conflict or no-conflict message condition, in which they read news stories and social media posts about three (of six) randomly selected health topics at Time 1 and the remaining three at Time 2. The dependent variables, which were measured at Time 2, asked participants whether they intended to share or seek information about the three topics they had just viewed. Linear mixed effects models showed that exposure to conflict reduced intentions to share and seek information, regardless of health topic. These findings suggest that exposure to conflicting health information discourages two important types of health information engagement, thus adding to the growing evidence base documenting the adverse consequences of conflicting information for public health.

Top 100 most-cited scientific articles in regenerative endodontics 2019-2023: A bibliometric analysis.

BACKGROUND: Bibliometric analysis is a critical indicator of the influence and relevance of scientific papers, whilst also highlighting key contributors and gaps in knowledge in a scientific field. OBJECTIVES: To update and analyse the 100 most-cited papers in regenerative endodontics from 2019 to 2023. METHODS: A search of the most-cited recent papers focusing on regenerative endodontics using journals included in the category, 'Dentistry, Oral Surgery & Medicine', in the Clarivate Web of Science database from 2019 to 2023 was performed. Three researchers conducted the study selection and data extraction. Data extraction included publication title and year, authors, number and mean number of citations, institution, country and continent, study design, journal title, keywords and research topic. Citation counts were also collected in Google Scholar and Scopus databases. Graphical bibliometric networks were created using VOSviewer software. RESULTS: The number of citations of the 100 most-cited articles ranged from 6 to 85. Most were published in 2020 (n = 48), principally in the Journal of Endodontics (47%), followed by International Endodontic Journal (13%), Journal of Dental Research (6%) and Dental Materials (6%). Laboratory study was the most common study design amongst the included papers (n = 47), followed by narrative reviews (n = 17) and observational studies (n = 16). The most frequent first author on the top three most-cited papers was Hacer Aksel, whilst Adham A. Azim (n = 6; 89 citations) contributed most to the top 100 articles. The institution from which most articles originated was the University of Hong Kong (China) (n = 5; 81 citations), whereas the corresponding authors were predominantly from the United States of America (USA) (n = 31; 560 citations). The VOSviewer map of co-authorship demonstrated research collaborative clusters. 'Regenerative endodontics' and 'stem-cells' were the most employed keywords (37 and 36 occurrences respectively). DISCUSSION: The current study was designed not only to showcase the most influential papers in regenerative endodontics since 2019 but also to provide a better understanding of global research in this area over the last five years. CONCLUSIONS: This bibliometric analysis highlighted papers, authors, institutions and keywords in regenerative endodontics. The 100 most-cited papers primarily consisted of laboratory studies published in the USA, focusing on evaluating biomaterials and scaffold design strategies in contact with stem cells. Clinical studies and systematic reviews representing higher levels of scientific evidence are currently not the most influential in the regenerative endodontic field.

Balloon pulmonary angioplasty for chronic thromboembolic pulmonary hypertension: a clinical consensus statement of the ESC working group on pulmonary circulation and right ventricular function.

The current treatment algorithm for chronic thromboembolic pulmonary hypertension (CTEPH) as depicted in the 2022 European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines on the diagnosis and treatment of pulmonary hypertension (PH) includes a multimodal approach of combinations of pulmonary endarterectomy (PEA), balloon pulmonary angioplasty (BPA) and medical therapies to target major vessel pulmonary vascular lesions, and microvasculopathy. Today, BPA of >1700 patients has been reported in the literature from centers in Asia, the US, and also Europe; many more patients have been treated outside literature reports. As BPA becomes part of routine care of patients with CTEPH, benchmarks for safe and effective care delivery become increasingly important. In light of this development, the ESC Working Group on Pulmonary Circulation and Right Ventricular Function has decided to publish a document that helps standardize BPA to meet the need of uniformity in patient selection, procedural planning, technical approach, materials and devices, treatment goals, complications including their management, and patient follow-up, thus complementing the guidelines. Delphi methodology was utilized for statements that were not evidence based. First, an anatomical nomenclature and a description of vascular lesions are provided. Second, treatment goals and definitions of complete BPA are outlined. Third, definitions of complications are presented which may be the basis for a standardized reporting in studies involving BPA. The document is intended to serve as a companion to the official ESC/ERS guidelines.

The effect of air-free administration of intravenous drugs on microemboli during cardiopulmonary bypass.

OBJECTIVE: During cardiopulmonary bypass (CPB), gaseous microemboli (GME) that originate from the extracorporeal circuit are released into the arterial blood stream of the patient. Gaseous microemboli may contribute to adverse outcome after cardiac surgery with CPB. Possibly, air may be collected in the right atrium during induction of anesthesia and released during CPB start. The aim of this study was to assess if the GME load entering the venous line of the CPB circuit could be reduced by training of anesthesia personal in avoiding air introduction during administration of intravenous medication. METHODS: In 94 patients undergoing coronary artery bypass grafting with CPB, GME number and volume were measured intraoperatively with a bubble counter (BCC300). The quantity and the relationship between GME number and volume in the venous and arterial line were determined in 2 periods before and after education of the anesthesiologists and nurses. RESULTS: In the venous line no significant differences were observed between numbers and volumes of GME between groups. Comparing patients with low versus high GME load, showed significantly more patients from the intervention group in the low GME-load group, namely 29 versus 18. Administration of medication by anesthesia was confirmed as a clear cause of GME/air-introduction into the venous circulation. Scavenging properties of the CPB circuit including the oxygenator showed a 99.9% reduction of GME. CONCLUSIONS: A wide spread of GME generation during perfusion was present with no difference in generation of GME between groups. Lower GME load observed in patients (intervention group) and examples of air introduction during drug administration suggest that air introduced by anesthesia contributes to the GME load during CPB. Scavenging properties of the CPB circuit contribute very much to patient safety regarding reduction of venous air. Awareness and education create the possibilities for further reduction of GME during cardiopulmonary bypass.

Effect of desensitizing agents on the resin bond strength to sound dentin.

This study aimed to evaluate the effect of dentin hypersensitivity treatments on immediate and long-term shear bond strength (SBS) of composite restorations. Ninety non-carious extracted human molars were cut to expose dentin, which was embedded in acrylic resin, and randomly divided into three groups (n = 30/group) according to surface treatment: 1) no treatment (C and C*; control); 2) silver diamine fluoride with potassium iodide (SDF/KI and SDF/KI*; Riva Star); and 3) nano-hydroxyapatite (nHAp and nHAp*; PrevDent). The specimens were etched through the etch-and-rinse technique, followed by universal adhesive application and resin composite cylinders (2.38 mm in diameter × 3.5 mm high). The SBS was tested immediately (24 h after the restoration) and after thermocycling (*) (5000 cycles, 5 °C to 55 °C) at a 0.5 mm/min crosshead speed using a universal testing machine. A stereomicroscope was used to evaluate the mode of failure, and representative scanning electron microscopy (SEM) images were also acquired. Data normality was verified, and two-way ANOVA and Tukey's post hoc tests were performed for multiple comparisons (α = 0.05). The control group presented the highest SBS (27.10 MPa), while SDF/KI* had the lowest values (6.87 MPa). nHAp-based desensitizer exhibited higher SBS than SDF/KI for both immediate (22.6 MPa) and thermocycled (19.03 MPa) conditions. No intragroup difference was evidenced between immediate and thermocycled samples for any group. Most specimens for the C and nHAp groups presented mixed failure, while the SDF/KI groups presented comparable adhesive and mixed failures. The SBS of adhesive restorations after the application of desensitizing agents is material dependent, where SDF/KI reduces SBS values below the acceptable minimum bond strength, while the nHAp application meets the minimally required bond strength.

Latent Pulmonary Vascular Disease May Alter the Response to Therapeutic Atrial Shunt Device in Heart Failure.

BACKGROUND: In REDUCE LAP-HF II (A Study to Evaluate the Corvia Medical, Inc IASD System II to Reduce Elevated Left Atrial Pressure in Patients With Heart Failure), implantation of an atrial shunt device did not provide overall clinical benefit for patients with heart failure with preserved or mildly reduced ejection fraction. However, prespecified analyses identified differences in response in subgroups defined by pulmonary artery systolic pressure during submaximal exercise, right atrial volume, and sex. Shunt implantation reduces left atrial pressures but increases pulmonary blood flow, which may be poorly tolerated in patients with pulmonary vascular disease (PVD). On the basis of these results, we hypothesized that patients with latent PVD, defined as elevated pulmonary vascular resistance during exercise, might be harmed by shunt implantation, and conversely that patients without PVD might benefit. METHODS: REDUCE LAP-HF II enrolled 626 patients with heart failure, ejection fraction ≥40%, exercise pulmonary capillary wedge pressure ≥25 mm Hg, and resting pulmonary vascular resistance <3.5 Wood units who were randomized 1:1 to atrial shunt device or sham control. The primary outcome-a hierarchical composite of cardiovascular death, nonfatal ischemic stroke, recurrent HF events, and change in health status-was analyzed using the win ratio. Latent PVD was defined as pulmonary vascular resistance ≥1.74 Wood units (highest tertile) at peak exercise, measured before randomization. RESULTS: Compared with patients without PVD (n=382), those with latent PVD (n=188) were older, had more atrial fibrillation and right heart dysfunction, and were more likely to have elevated left atrial pressure at rest. Shunt treatment was associated with worse outcomes in patients with PVD (win ratio, 0.60 [95% CI, 0.42, 0.86]; P=0.005) and signal of clinical benefit in patients without PVD (win ratio, 1.31 [95% CI, 1.02, 1.68]; P=0.038). Patients with larger right atrial volumes and men had worse outcomes with the device and both groups were more likely to have pacemakers, heart failure with mildly reduced ejection fraction, and increased left atrial volume. For patients without latent PVD or pacemaker (n=313; 50% of randomized patients), shunt treatment resulted in more robust signal of clinical benefit (win ratio, 1.51 [95% CI, 1.14, 2.00]; P=0.004). CONCLUSIONS: In patients with heart failure with preserved or mildly reduced ejection fraction, the presence of latent PVD uncovered by invasive hemodynamic exercise testing identifies patients who may worsen with atrial shunt therapy, whereas those without latent PVD may benefit.

11ß-HSD1 determines the extent of muscle atrophy in a model of acute exacerbation of COPD.

Muscle atrophy is an extrapulmonary complication of acute exacerbations (AE) in chronic obstructive pulmonary disease (COPD). The endogenous production and therapeutic application of glucocorticoids (GCs) have been implicated as drivers of muscle loss in AE-COPD. The enzyme 11 ß-hydroxysteroid dehydrogenase 1 (11ß-HSD1) activates GCs and contributes toward GC-induced muscle wasting. To explore the potential of 11ßHSD1 inhibition to prevent muscle wasting here, the objective of this study was to ascertain the contribution of endogenous GC activation and amplification by 11ßHSD1 in skeletal muscle wasting during AE-COPD. Emphysema was induced by intratracheal (IT) instillation of elastase to model COPD in WT and 11ßHSD1/KO mice, followed by vehicle or IT-LPS administration to mimic AE. µCT scans were obtained prior and at study endpoint 48 h following IT-LPS, to assess emphysema development and muscle mass changes, respectively. Plasma cytokine and GC profiles were determined by ELISA. In vitro, myonuclear accretion and cellular response to plasma and GCs were determined in C2C12 and human primary myotubes. Muscle wasting was exacerbated in LPS-11ßHSD1/KO animals compared with WT controls. RT-qPCR and western blot analysis showed elevated catabolic and suppressed anabolic pathways in muscle of LPS-11ßHSD1/KO animals relative to WTs. Plasma corticosterone levels were higher in LPS-11ßHSD1/KO animals, whereas C2C12 myotubes treated with LPS-11ßHSD1/KO plasma or exogenous GCs displayed reduced myonuclear accretion relative to WT counterparts. This study reveals that 11ß-HSD1 inhibition aggravates muscle wasting in a model of AE-COPD, suggesting that therapeutic inhibition of 11ß-HSD1 may not be appropriate to prevent muscle wasting in this setting.

Long-term expanding human airway organoids for disease modeling.

Organoids are self-organizing 3D structures grown from stem cells that recapitulate essential aspects of organ structure and function. Here, we describe a method to establish long-term-expanding human airway organoids from broncho-alveolar resections or lavage material. The pseudostratified airway organoids consist of basal cells, functional multi-ciliated cells, mucus-producing secretory cells, and CC10-secreting club cells. Airway organoids derived from cystic fibrosis (CF) patients allow assessment of CFTR function in an organoid swelling assay. Organoids established from lung cancer resections and metastasis biopsies retain tumor histopathology as well as cancer gene mutations and are amenable to drug screening. Respiratory syncytial virus (RSV) infection recapitulates central disease features, dramatically increases organoid cell motility via the non-structural viral NS2 protein, and preferentially recruits neutrophils upon co-culturing. We conclude that human airway organoids represent versatile models for the in vitro study of hereditary, malignant, and infectious pulmonary disease.

Ecological network analysis of traits reveals variable response capacity to stress.

Response diversity increases the potential 'options' for ecological communities to respond to stress (i.e. response capacity). An indicator of community response diversity is the diversity of different traits associated with their capacity to be resistant to stress, to recover and to regulate ecosystem functions. We conducted a network analysis of traits using benthic macroinvertebrate community data from a large-scale field experiment to explore the loss of response diversity along environmental gradients. We elevated sediment nutrient concentrations (a process that occurs with eutrophication) at 24 sites (in 15 estuaries) with varying environmental conditions (water column turbidity and sediment properties). Macroinvertebrate community response capacity to nutrient stress was dependent on the baseline trait network complexity in the ambient community (i.e. non-enriched sediments). The greater the complexity of the baseline network, the less variable the network response to nutrient stress was; in contrast, more variable responses to nutrient stress occurred with simpler networks. Thus, stressors or environmental variables that shift baseline network complexity also shift the capacity for these ecosystems to respond to additional stressors. Empirical studies that explore the mechanisms responsible for loss of resilience are essential to inform our ability to predict changes in ecological states.

Selective vulnerability of brainstem and cervical spinal cord regions in people with non-progressive multiple sclerosis of Black or African American and European ancestry.

BACKGROUND: We evaluated imaging features suggestive of neurodegeneration within the brainstem and upper cervical spinal cord (UCSC) in non-progressive multiple sclerosis (MS). METHODS: Standardized 3-Tesla three-dimensional brain magnetic resonance imaging (MRI) studies were prospectively acquired. Rates of change in volume, surface texture, curvature were quantified at the pons and medulla-UCSC. Whole and regional brain volumes and T2-weighted lesion volumes were also quantified. Independent regression models were constructed to evaluate differences between those of Black or African ancestry (B/AA) and European ancestry (EA) with non-progressive MS. RESULTS: 209 people with MS (pwMS) having at least two MRI studies, 29% possessing 3-6 timepoints, resulted in 487 scans for analysis. Median follow-up time between MRI timepoints was 1.33 (25th-75th percentile: 0.51-1.98) years. Of 183 non-progressive pwMS, 88 and 95 self-reported being B/AA and EA, respectively. Non-progressive pwMS demonstrated greater rates of decline in pontine volume (p < 0.0001) in B/AA and in medulla-UCSC volume (p < 0.0001) for EA pwMS. Longitudinal surface texture and curvature changes suggesting reduced tissue integrity were observed at the ventral medulla-UCSC (p < 0.001), dorsal pons (p < 0.0001) and dorsal medulla (p < 0.0001) but not the ventral pons (p = 0.92) between groups. CONCLUSIONS: Selectively vulnerable regions within the brainstem-UCSC may allow for more personalized approaches to disease surveillance and management.

Organ involvement and assessment in sarcoidosis.

PURPOSE OF REVIEW: In recent years new recommendations have been published about organ assessment in the diagnosis of sarcoidosis. RECENT FINDINGS: Screening for pulmonary, cardiac, ocular, neurologic and renal involvement and hypercalcemia is recommended in the work-up for sarcoidosis, additionally, screening for hypercalciuria at the time of the diagnosis might be beneficial. SUMMARY: One of the goals in the work-up of sarcoidosis is to assess the extent and severity of organ involvement. Timely and accurate assessment leads to determination of treatment indication. Screening for pulmonary involvement should include pulmonary imaging and pulmonary function tests. Screening for cardiac involvement should include a clear history including palpitations and collapse and a baseline electrocardiogram or 24-h Holter monitoring. At diagnosis, ophthalmological assessment is recommended. Furthermore, serum calcium level and serum creatinine level should be obtained. Although routine 24-h urinary calcium excretion is not included in the guidelines, performing this test routinely can be considered. On indication, neurologic, rheumatologic or dermatologic assessment can be performed.

Niche evolution in a northern temperate tree lineage: biogeographical legacies in cork oaks (Quercus section Cerris).

BACKGROUND AND AIMS: Cork oaks (Quercus section Cerris) comprise 15 extant species in Eurasia. Despite being a small clade, they display a range of leaf morphologies comparable to the largest sections (>100 spp.) in Quercus. Their fossil record extends back to the Eocene. Here, we explore how cork oaks achieved their modern ranges and how legacy effects might explain niche evolution in modern species of section Cerris and its sister section Ilex, the holly oaks. METHODS: We inferred a dated phylogeny for cork and holly oaks using a reduced-representation next-generation sequencing method, restriction site-associated DNA sequencing (RAD-seq), and used D-statistics to investigate gene flow hypotheses. We estimated divergence times using a fossilized birth-death model calibrated with 47 fossils. We used Köppen profiles, selected bioclimatic parameters and forest biomes occupied by modern species to infer ancestral climatic and biotic niches. KEY RESULTS: East Asian and Western Eurasian cork oaks diverged initially in the Eocene. Subsequently, four Western Eurasian lineages (subsections) differentiated during the Oligocene and Miocene. Evolution of leaf size, form and texture was correlated, in part, with multiple transitions from ancestral humid temperate climates to mediterranean, arid and continental climates. Distantly related but ecologically similar species converged on similar leaf traits in the process. CONCLUSIONS: Originating in temperate (frost-free) biomes, Eocene to Oligocene ranges of the primarily deciduous cork oaks were restricted to higher latitudes (Siberia to north of Paratethys). Members of the evergreen holly oaks (section Ilex) also originated in temperate biomes but migrated southwards and south-westwards into then-(sub)tropical southern China and south-eastern Tibet during the Eocene, then westwards along existing pre-Himalayan mountain ranges. Divergent biogeographical histories and deep-time phylogenetic legacies (in cold and drought tolerance, nutrient storage and fire resistance) thus account for the modern species mosaic of Western Eurasian oak communities, which are composed of oaks belonging to four sections.