Differentiation Process Research Articles

Recent advances in the understanding of gonadotrope lineage differentiation in the developing pituitary

Background: The pituitary gland is a vital endocrine organ regulating body homeostasis through six hormone-secreting cell types. Among these, pituitary gonadotrope cells are essential for reproductive function. Throughout pituitary ontogenesis, gonadotrope cells differentiate in a stepwise process, involving both morphogenic cues and transcription factors, which drives specification of progenitor cells into specialized endocrine cells. It is crucial to understand the mechanisms underlying gonadotrope differentiation, as developmental defects and abnormalities in this process can lead to many reproductive pathologies. Summary: This review offers a detailed overview of the latest advances in gonadotrope cell differentiation. We addressed this question with a specific focus on three important aspects of gonadotrope differentiation: the identification of the progenitor population giving rise to gonadotrope cells, the early mechanisms that initiate Nr5a1 expression and thus gonadotrope fate commitment and finally, the mechanisms driving the formation of physical and functional gonadotrope networks. Key Messages: Overall, this review aims to provide new insights into three aspects of the gonadotrope differentiation process by reconsidering pioneering studies in the light of data gained from latest technological developments. Firstly, we re-investigated the long debated developmental trajectory of pituitary gonadotrope cells. Secondly, we reported new regulatory mechanisms of Nr5a1 expression, focusing on the involvement of ERα. Finally, we highlighted the molecular and cellular mechanisms driving gonadotrope network formation during embryogenesis, a process that seems essential for regulation of gonadotrope activity.

Coexistence of complete intestinal tract, prostatic tissue, prostatic urethra and bladder structure in ovarian mature cystic teratoma: a case report

AbstractMature cystic teratomas (MCTs) of the ovary comprise tissues from all three germ layers. The coexistence of the complete intestinal tract, prostatic tissue, and bladder component within the same ovarian MCT is unprecedented. Here, we report the diagnosis and management of such a rare case. A 26-year-old woman presented with a right ovarian mass, which was later confirmed as an MCT by histopathological examination. The patient underwent a successful laparoscopic cystectomy with no evidence of malignancy or postoperative complications. Histological examination revealed that this MCT contained the complete organ structures including a lower intestinal tract and male genital tract with prostate, urethra, and bladder components, which is unusual. This case underscores the importance of understanding the pathogenesis of extensive organogenesis in MCTs and raises questions about the differentiation processes leading to such unique presentations.

Identifying and optimizing critical process parameters for large-scale manufacturing of iPSC derived insulin-producing β-cells

BackgroundType 1 diabetes, an autoimmune disorder leading to the destruction of pancreatic β-cells, requires lifelong insulin therapy. Islet transplantation offers a promising solution but faces challenges such as limited availability and the need for immunosuppression. Induced pluripotent stem cells (iPSCs) provide a potential alternative source of functional β-cells and have the capability for large-scale production. However, current differentiation protocols, predominantly conducted in hybrid or 2D settings, lack scalability and optimal conditions for suspension culture.MethodsWe examined a range of bioreactor scaleup process parameters and quality target product profiles that might affect the differentiation process. This investigation was conducted using an optimized High Dimensional Design of Experiments (HD-DoE) protocol designed for scalability and implemented in 0.5L (PBS-0.5 Mini) vertical wheel bioreactors.ResultsA three stage suspension manufacturing process is developed, transitioning from adherent to suspension culture, with TB2 media supporting iPSC growth during scaling. Stage-wise optimization approaches and extended differentiation times are used to enhance marker expression and maturation of iPSC-derived islet-like clusters. Continuous bioreactor runs were used to study nutrient and growth limitations and impact on differentiation. The continuous bioreactors were compared to a Control media change bioreactor showing metabolic shifts and a more β-cell-like differentiation profile. Cryopreserved aggregates harvested from the runs were recovered and showed maintenance of viability and insulin secretion capacity post-recovery, indicating their potential for storage and future transplantation therapies.ConclusionThis study demonstrated that stage time increase and limited media replenishing with lactate accumulation can increase the differentiation capacity of insulin producing cells cultured in a large-scale suspension environment.

Risk assessment of homologous variants of biotech trait proteins using a bridging approach

ABSTRACT A transgenic protein is frequently expressed as different homologous variants in genetically modified crops due to differential processing of targeting peptides or optimization of activity and specificity. The aim of this study was to develop a science-based approach for risk assessment of homologous protein variants using dicamba mono-oxygenase (DMO) as a case study. In this study, DMO expressed in the next-generation dicamba-tolerant maize, sugar beet and soybean crops exhibited up to 27 amino acid sequence differences in the N-terminus. Structure modeling using AlphaFold, ESMFold and OpenFold demonstrates that these small N-terminal extensions lack an ordered secondary structure and do not disrupt the DMO functional structure. Three DMO variants were demonstrated to have equivalent immunoreactivity and functional activity ranging from 214 to 331 nmol/min/mg. Repeated toxicity studies using each DMO variant found no test substance-related adverse effects. These results support that homologous protein variants, which have demonstrated physicochemical and functional equivalence, can leverage existing safety data from one variant without requiring additional de novo safety assessments.

Deciphering transcriptome patterns in porcine mesenchymal stem cells promoting phenotypic maintenance and differentiation by key driver genes

Mesenchymal stem cells (MSC) are fibroblast-like non-hematopoietic cells with self-renewal and differentiation capacity, and thereby great potential in regeneration and wound healing. MSC populations are heterogeneous not only inherently, but also among different model species. In particular, porcine MSC serve as a frequently used resource for translational research, due to pigs’ distinctive closeness to human anatomy and physiology. However, information on gene expression profiles from porcine MSC and its dynamics during differentiation is sparse, especially with regard to cell surface and inner cell markers. In this study, we investigated the transcriptome of bone marrow-derived MSC and its differentiated cell types in a minipig breed for experimental research, known as Mini-LEWE, using bulk mRNA sequencing. Our data highlighted Rap1 signaling and downstream pathways PI3K-Akt and MAPK signaling as potential players for the maintenance of stemness of BM-MSC. In addition, we were able to link the process of differentiation to changes in the regulation of actin cytoskeleton. A total of 18 “BM-MSC differentiation driver markers” were identified, potentially promoting the process of differentiation into adipocytes, chondrocytes as well as osteocytes. Our results offer a new perspective on the molecular phenotype of porcine BM-MSC and the transcriptional responses in new differentiated progeny.

Network Architecture Search Methods for Constructing Efficient Fault Diagnosis Models in Rotating Machinery

Abstract The development of high-performance fault diagnosis models for specific tasks requires substantial expertise. Neural Architecture Search (NAS) offers a promising solution, but most NAS methodologies are hampered by lengthy search durations and low efficiency, and few researchers have applied these methods within the fault diagnosis domain. This paper introduces a novel differentiable architecture search (DARTS) method tailored for constructing efficient fault diagnosis models for rotating machinery, designed to rapidly and effectively search for network models suitable for specific datasets. Specifically, this study constructs a completely new and advanced search space, incorporating various efficient, lightweight convolutional operations to reduce computational complexity. To enhance the stability of the differentiable network architecture search process and reduce fluctuations in model accuracy, this study proposes a novel Multi-scale Pyramid Squeeze Attention (MPSA) module. This module aids in the learning of richer multi-scale feature representations and adaptively recalibrates the weights of multi-dimensional channel attention. The proposed method was validated on two rotating machinery fault datasets, demonstrating superior performance compared to manually designed networks and general network search methods, with notably improved diagnostic effectiveness.

Effect of Astaxanthin in Cytoprotection and Maturation in Vitro Differentiation Process to Insulin-Producing Cells

Asx is a fat-soluble xanthophyll carotenoid, one of its most relevant properties is its antioxidant activity. Depending on the dose and environment, it participates in an adequate regulation of ROS/RNS at optimal levels, either directly scavenger or indirectly through the stimulation of “antioxidant” pathways such as NRF2. This regulation and interactions within the signaling pathways are studied here in order to find information that provides data to elucidate the effects that may influence the processes of obtaining IPC and the study of the effect of molecules that increase the efficiency of the cellular response during the trans differentiation process. We found that adding Asx to a cocktail of differentiation molecules to obtain IPC from DPSC increases the efficiency of insulin production, as well as the expression of important markers for the maturity and identity of pancreatic β-type cells (NGN3, PDX1, MAFA). It was also revealed that Asx favors the proper regulation of oxidative stress caused during the process of cellular trans differentiation of DPSC towards IPC, through the direct inactivation of ROS and the increase in the expression of NRF2 as well as the decrease of their principal inhibitor KEAP1, favoring the maturity of the IPC. These results suggest the potential use of Asx to deepen the knowledge of its interaction with other signaling pathways that favor the generation of IPC and other cells sensitive to oxidative stress, and thereby lay the foundations for a possible cell replacement therapy as in DM1.

Deciphering the role of NcRNAs in Pancreatic Cancer immune evasion and drug resistance: a new perspective for targeted therapy

Pancreatic cancer (PC) is a very aggressive digestive system tumor, known for its high mortality rate, low cure rate, low survival rate and poor prognosis. In particular, pancreatic ductal adenocarcinoma (PADC), which accounts for more than 90% of PC cases, has an overall 5-year survival rate of only 5%, which is an extremely critical situation. Early detection and effective treatment of PC is extremely difficult, which leads many patients to despair. In the current medical context, targeted therapy, as an important strategy for cancer treatment, is expected. However, the problems of immune escape and drug resistance in PC have become two major obstacles that are difficult to be overcome by targeted therapy. How to break through these two difficulties has become a key issue to be solved in the field of PC therapy. In recent years, non-coding RNAs (ncRNAs) have continued to heat up in the field of cancer research. NcRNAs play a pivotal role in gene regulation, cell differentiation, development, and disease processes, and their important roles in the genesis, development, and therapeutic response of PC have been gradually revealed. More importantly, ncRNAs have many advantages as therapeutic targets, such as high specificity and low side effects, making them a new favorite in the field of PC therapy. Therefore, the aim of this paper is to provide new ideas and methods for the targeted therapy of PC by reviewing the mechanism of action of four major ncRNAs (circRNAs, lncRNAs, miRNAs, siRNAs) in both immune escape and drug resistance of PC. It is expected that an effective way to overcome immune escape and drug resistance can be found through in-depth study of ncRNA, bringing a ray of hope to PC patients.

A 3D-Printed Microdevice Encapsulates Vascularized Islets Composed of iPSC-derived β-like Cells and Microvascular Fragments for Type 1 Diabetes Treatment

Tranplantation of insulin-secreting cells provides a promising method for re-establishing the autonomous blood glucose control ability of type 1 diabetes (T1D) patients, but the low survival of the tranlplanted cells hinder the therapeutic efficacy. In this study, we 3D-printed an encapsulation system contraining β-like cells and microvascular fragments (MVF), to create a retrivable microdevice with vascularized islets in vivo for T1D therapy. The functional β-like cells were differentiated from the urine epithelial cell-derived induced pluripotent stem cells (UiPSCs). Single-cell RNA sequencing provided an integrative study and macroscopic developmental analyses of the entire process of differentiation, which revealed the developmental trajectory of differentiation in vitro follows the developmental pattern of embryonic pancreas in vivo. The MVF were isolated from the epididymal fat pad. The microdevice with a groove structure were rapidly fabricated by the digital light processing (DLP)-3D printing technology. The β-like cells and MVF were uniformly distributed in the device. After subcutaneous transplantation into C57BL/6 mice, the microdevice have less collagen accumulation and low immune cell infiltration. Moerover, the microdevice encapsulated vascularized islets reduced hyperglycemica in 33% of the treated mice for up to 100 days without immunosuppressants, and the humanized C-peptide was also detected in the serum of the mice. In summary, we described the microdevice-protecd vasculared islets for long-term treatment of T1D, with high safety and potential clinical transformative value, and may therefore provide a translatable solution to advance the research progress of β cell replacement therapy for T1D.

Understanding density fluctuations in supersonic, isothermal turbulence.

Supersonic turbulence occurs in many environments, particularly in astrophysics. In the crucial case of isothermal turbulence, the probability density function (PDF) of the logarithmic density, s, is well measured, but a theoretical understanding of the processes leading to this distribution remains elusive. We investigate these processes using Lagrangian tracer particles to track s and [Formula: see text] in direct numerical simulations, and we show that their evolution can be modeled as a stochastic differential process with time-correlated noise. The temporal correlation functions of s and [Formula: see text] decay exponentially, as predicted by the model, and the decay timescale is ≈1/6 the eddy turnover time. The behaviors of the conditional averages of [Formula: see text] and [Formula: see text] are also well explained by the model, which shows that the density PDF arises from a balance between stochastic compressions/expansions, which tend to broaden the PDF, and the acceleration/deceleration of shocks by density gradients, which tends to narrow it.

Kynurenine’s Effect on the Different Stages of Osteoblastic Differentiation

This study focuses on the dynamics of age-related changes in osteoblasts’ matrix production, with a specific focus on the involvement of the aryl hydrocarbon receptor (AhR). The AhR is activated by kynurenine, a metabolite of the amino acid tryptophan that tends to increase with age. Kynurenine has been known to impair osteoblasts’ bone formation ability, however, the point at which this occurs is unknown. The study utilizes a 21-day differentiation process of mesenchymal stem cells. “Window experiments” that vary the intervals of kynurenine treatment to explore its impact at different stages of osteoblast development were utilized. The experimental setup involves four distinct conditions: a control group with a vehicle, a group treated with kynurenine, a group with an AhR antagonist (BAY), and a group treated with both kynurenine and BAY. The AhR antagonist, specifically BAY2416964, serves to investigate whether any observed effects of kynurenine are mediated through AhR signaling. Results, analyzed through alizarin red staining, demonstrate a notable negative impact of kynurenine on matrix production, particularly in the middle stages of osteoblast differentiation. The study further employs crystal violet staining to confirm the presence of cells in the experimental wells, provid-ing assurance of the reliability of the alizarin staining procedure. Importantly, this staining procedure also suggests that the effects of kynurenine on mineralized matrix production are largely independent of any potential impacts on cell viability.

Vedic Sutras Mathematics with Application in Differentiation

Vedic Mathematics, rooted in ancient Indian texts, offers a unique and efficient approach to solving complex mathematical problems. This paper explores the application of Vedic principles in modern calculus, specifically focusing on derivatives and integration. By applying Vedic methods, such as the Urdhva Tiryak Sutra (vertical and crosswise multiplication) and Paravartya Sutra (transposition), we demonstrate how these can simplify and expedite processes in differentiation and integration. The study provides practical examples where these techniques are applied to common calculus problems, highlighting their potential to enhance problem-solving efficiency in higher mathematics.

Giant plagioclase in the Steens Basalt, southeast Oregon, USA: Tracking the balance of differentiation processes in continental flood basalt evolution

Giant plagioclase basalts (GPBs), flows that contain abundant and conspicuous plagioclase crystals ≥1 cm in length, exist at many continental flood basalt provinces, and their presence can provide a window into the crustal differentiation processes and storage conditions that produced the magmas prior to eruption. GPB flows occur in the Steens Basalt of southeast Oregon, USA, one of the earliest members of the Columbia River Flood Basalt Group, but their origin in this province has not been studied in detail. We conducted quantitative textural analysis utilizing crystal size distributions (CSDs) at the outcrop and thin section scale, as well as in situ plagioclase trace element and isotopic compositional analysis, in order to elucidate the processes responsible for generating two end-member textural types of GPB found in the Steens Basalt: daisy stone glomerocryst clusters composed of radiating plagioclase laths and single isolated plagioclase. CSD patterns suggest a changing balance of multiple differentiation processes affected the magmas that created each GPB textural type. In the daisy stone plagioclase, crystals rarely exhibit resorption textures, trace element abundances are comparatively low with minimal variability, and Sr isotopes are commonly in equilibrium with groundmass. In the single isolated plagioclase, resorption textures are common, trace element abundances are generally higher and display within crystal variation, and Sr isotopes are typically not in equilibrium with groundmass. These distinctive characteristics require separate mechanisms to generate each end-member GPB texture. Daisy stone GPBs form by growth of large crystals following mafic recharge events that completely resorb entrained cumulate plagioclase. A large amount of plagioclase may then grow with minimal cooling following recharge due to saturation in plagioclase components. In contrast, single isolated GPBs are the result of partial resorption of both entrained and resident plagioclase following less voluminous and less primitive recharge events; regrowth then occurs on the partially resorbed cores when cooling resumes. Both GPB types are formed by thermal cycling, but each texture reflects the differentiation processes that were prevalent during different eruptive stages of the Steens Basalt, as the balance between recharge, crystal fractionation, and assimilation varied in time.

DLK1 and DLK2, two non-canonical ligands of NOTCH receptors, differentially modulate the osteogenic differentiation of mesenchymal C3H10T1/2 cells

BackgroundC3H10T1/2 is a mesenchymal cell line capable of differentiating into osteoblasts, adipocytes and chondrocytes. The differentiation of these cells into osteoblasts is modulated by various transcription factors, such as RUNX2. Additionally, several interconnected signaling pathways, including the NOTCH pathway, play a crucial role in modulating their differentiation into mature bone cells. We have investigated the roles of DLK1 and DLK2, two non-canonical inhibitory ligands of NOTCH receptors, in the osteogenic differentiation of C3H10T1/2 cells.ResultsOur results corroborate existing evidence that DLK1 acts as an inhibitor of osteogenesis. In contrast, we demonstrate for the first time that DLK2 enhances this differentiation process. Additionally, our data suggest that NOTCH2, 3 and 4 receptors may promote osteogenesis, as indicated by their increased expression during this process, whereas NOTCH1 expression, which decreases during cell differentiation, might inhibit osteogenesis. Moreover, treatment with DAPT, a NOTCH signaling inhibitor, impeded osteogenic differentiation. We have confirmed the increase in ERK1/2 MAPK and p38 MAPK phosphorylation in C3H10T1/2 cells induced to differentiate to osteoblasts. Our new findings reveal increased ERK1/2 MAPK phosphorylation in differentiated C3H10T1/2 cells with a decrease in DLK1 expression or an overexpression of DLK2, which is coincident with the behavior of those transfectants where we have detected an increase in osteogenic differentiation. Additionally, p38 MAPK phosphorylation increases in differentiated C3H10T1/2 cells with reduced DLK1 levels.ConclusionsOur results suggest that DLK1 may inhibit osteogenesis, while DLK2 may promote it, by modulating NOTCH signaling and the phosphorylation of ERK1/2 and p38 MAPK pathways. Given the established inhibitory effect of DLK proteins on NOTCH signaling, these new insights could pave the way for developing future therapeutic strategies aimed at treating bone diseases.

Single-cell analysis of nasal epithelial cell development in domestic pigs

The nasal mucosa forms a critical barrier against the invasion of respiratory pathogens. Composed of a heterogeneous assortment of cell types, the nasal mucosa relies on the unique characteristics and complex intercellular dynamics of these cells to maintain their structural integrity and functional efficacy. In this study, single-cell RNA sequencing (scRNA-seq) of porcine nasal mucosa was performed, and nineteen distinct nasal cell types, including nine epithelial cell types, five stromal cell types, and five immune cell types, were identified. The distribution patterns of three representative types of epithelial cells (basal cells, goblet cells, and ciliated cells) were subsequently detected by immunofluorescence. We conducted a comparative analysis of these data with published human single-cell data, revealing consistent differentiation trajectories among porcine and human nasal epithelial cells. Specifically, basal cells serve as the initial stage in the differentiation process of nasal epithelial cells, which then epithelial cells. This research not only enhances our understanding of the composition and transcriptional signature of porcine nasal mucosal cells but also offers a theoretical foundation for developing alternative models for human respiratory diseases.

Slow H2S-Releasing Donors and 3D Printable Arrays Cellular Models in Osteo-Differentiation of Mesenchymal Stem Cells for Personalized Therapies

The effects of the hydrogen sulfide (H2S) slow-releasing donor, named GSGa, a glutathione-conjugate water-soluble garlic extract, on human mesenchymal stem cells (hMSCs) in both bidimensional (2D) and three-dimensional (3D) cultures were investigated, demonstrating increased expression of the antioxidant enzyme HO-1 and decreased expression of the pro-inflammatory cytokine interleukin-6 (IL-6). The administration of the H2S donor can therefore increase the expression of antioxidant enzymes, which may have potential therapeutic applications in osteoarthritis (OA). Moreover, GSGa was able to promote the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), but not of cardiac mesenchymal stem cells (cMSCs) in a 2D culture system. This result highlights the varying sensitivity of hMSCs to the H2S donor GSGa, suggesting that the induction of osteogenic differentiation in stem cells by chemical factors is dependent on the tissue of origin. Additionally, a 3D-printable mesenchymal stem cells–bone matrix array (MSCBM), designed to closely mimic the stiffness of bone tissue, was developed to serve as a versatile tool for evaluating the effects of drugs and stem cells on bone repair in chronic diseases, such as OA. We demonstrated that the osteogenic differentiation process in cMSCs can be induced just by simulating bone stiffness in a 3D system. The expression of osteocalcin, RUNX2, and antioxidant enzymes was also assessed after treating MSCs with GSGa and/or increasing the stiffness of the culture environment. The printability of the array may enable better customization of the cavities, enabling an accurate replication of real bone defects. This could optimize the BM array to mimic bone defects not only in terms of stiffness, but also in terms of shape. This culture system may enable a rapid screening of antioxidant and anti-inflammatory compounds, facilitating a more personalized approach to regenerative therapy.

In vitro bioprinted 3D model enhancing osteoblast-to-osteocyte differentiation

Abstract In vitro bone models are pivotal for understanding tissue behavior and cellular responses, particularly in unravelling certain pathologies' mechanisms and assessing the impact of new therapeutic interventions. A desirable in vitro bone model should incorporate primary human cells within a 3D environment that mimics the mechanical properties characteristics of osteoid and faithfully replicate all stages of osteogenic differentiation from osteoblasts to osteocytes. However, to date, no bio-printed model using primary osteoblasts has demonstrated the expression of osteocytic protein markers. This study aimed to develop bio-printed in vitro model that accurately captures the differentiation process of human primary osteoblasts into osteocytes. Given the considerable impact of hydrogel stiffness and relaxation behavior on osteoblast activity, we employed three distinct cross-linking solutions to fabricate hydrogels. These hydrogels were designed to exhibit either similar elastic behavior with different elastic moduli, or similar elastic moduli with varying relaxation behavior. These hydrogels, composed of gelatin (5% w/v), alginate (1%w/v) and fibrinogen (2%w/v), were designed to be compatible with micro-extrusion bioprinting and proliferative. The modulation of their biomechanical properties, including stiffness and viscoelastic behavior, was achieved by applying various concentrations of cross-linkers targeting both gelatin covalent bonding (transglutaminase) and alginate chains’ ionic cross-linking (calcium). Among the conditions tested, the hydrogel with a low elastic modulus of 8 kPa and a viscoelastic behavior over time exhibited promising outcomes regarding osteoblast-to-osteocyte differentiation. The cessation of cell proliferation coincided with a significant increase in alkaline phosphatase (ALP) activity, the development of dendrites, and the expression of the osteocyte marker PHEX. Within this hydrogel, cells actively influenced their environment, as evidenced by hydrogel contraction and the secretion of collagen I. This bio-printed model, demonstrating primary human osteoblasts expressing an osteocyte-specific protein, marks a significant achievement. We envision its substantial utility in advancing research on bone pathologies, including osteoporosis and bone tumors.

Overcoming Product Catalog Challenges in Telecom : A Technical Perspective

This comprehensive article explores the intricate challenges telecom providers face in managing complex product catalogs across multiple customer touchpoints. With the global telecom market projected to reach $2.47 trillion by 2028, efficient catalog management is crucial for maintaining competitiveness and customer satisfaction. The article delves into the multifaceted complexities of telecom product catalogs, including regional pricing variations, dynamic promotional offers, and the need for real-time synchronization across platforms. It outlines key challenges such as catalog complexity, slow data retrieval, frequent updates, third-party integration latencies, high traffic spikes, and campaign management inconsistencies. The article then presents innovative technical solutions and best practices, including the adoption of industry-leading catalog solutions, leveraging ElasticSearch for faster data retrieval, implementing differential processing for updates, preprocessing third-party integrations, utilizing dynamic UI templates, employing advanced campaign management tools, and implementing inventory prefetching. These solutions aim to enhance operational efficiency, improve customer experiences, and accelerate time-to-market in the rapidly evolving telecom industry.

Opening the species box: What parsimonious microscopic models of speciation have to say about macroevolution.

In the last two decades, lineage-based models of diversification, where species are viewed as particles that can divide (speciate) or die (become extinct) at rates depending on some evolving trait, have been very popular tools to study macroevolutionary processes. Here, we argue that this approach cannot be used to break down the inner workings of species diversification and that "opening the species box" is necessary to understand the causes of macroevolution, but that too detailed speciation models also fail to make robust macroevolutionary predictions. We set up a general framework for parsimonious models of speciation that rely on a minimal number of mechanistic principles: (i) reproductive isolation is caused by excessive dissimilarity between genotypes; (ii) dissimilarity results from a balance between differentiation processes and homogenizing processes; and (iii) dissimilarity can feed back on these processes by decelerating homogenization. We classify such models according to the main homogenizing process : (1) clonal evolution models (ecological drift), (2) models of genetic isolation (gene flow) and (3) models of isolation by distance (spatial drift). We review these models and their specific predictions on macroscopic variables such as species abundances, speciation rates, interfertility relationships or phylogenetic tree structure. We propose new avenues of research by displaying conceptual questions remaining to be solved and new models to address them: the failure of speciation at secondary contact, the feedback of dissimilarity on homogenization, the emergence in space of breeding barriers.

Development and validation of a smartphone based app to guide the differential diagnosis in patients with primary left ventricular hypertrophy: the Thick Heart App

Abstract Introduction Patients presenting with primary Left Ventricular Hypertrophy (LVH) suffers from a diagnostic delay quantified in years. They are often misdiagnosed because of both physician-related and disease-related reasons including fragmented knowledge among different specialties and rarity of the conditions. Purpose We developed and validate a free digital support tool in the form of an App to provide support and to guide the physician in the differential diagnostic process of patients presenting with primary LVH. Methods We studied 712 patients with definitive diagnosis of sarcomeric HCM or one of its genocopies (414 (58%) males, 48±24 years) referred to four tertiary centers in Europe. Pre-specified RF were categorized into five domains: family history; signs/symptoms; electrocardiography, echocardiographic and laboratory. Each patient’s characteristics were inserted by two independent and blind investigators on the App of the digital support tool. The possible diagnostic outcome was categorized as follows: (a) most likely diagnosis (age range for the condition, at least 1 extremely specific RFs or >1 specific RF; (b) possible diagnosis (age range, 1 specific RF); (c) less likely diagnosis (outside age range, no RF selected). Results Ris were common in patients presenting with a genotyped HCM (2568 RFs, 3.5 per patient). RF on physical examination was associated with non sarcomeric aetiology (318/319 physical examination RF identified in non-sarcomeric HCM), whereas 68% of RF associated with sarcomeric HCM were derived from accurate ECG and echocardiography analysis. Sarcomeric HCM, TTR-amyloidosis, Danon and PRKAG2 cardiomyopathy relied extensively on ECG and echocardiographic systematic analyisis (68%, 69%, 67% and 69% respectively). In contrast, AFD, Friederich’s ataxia, Noonan syndrome with multiple lentiges (NSML), mitochondrial, Pompe and Noonan cardiomyopathy presented red flags potentially identifiable in the general practioner setting by anamnesis, physical examination and routine laboratory (57%, 59%, 52%, 57%, 57% and 58% respectively) in the vast majority of case. A total of 697/712 (97.8%) were correctly categorized in the most likely and possible diagnosis section. The App proved to be sensible for sarcomeric HCM, FD (0.99 and 0.91, NPV 0.98 and 0.83) and extremely capable in the identification of rare causes of LVH (Danon, Friederich’s ataxia, LEOPARD, Pompe, Noonan and PRKAG2 diseases). By design, specificity was not high, in particular for sarcomeric HCM and FD. Conclusions The present validation of an App based free digital support tool in the form of an App proved to be extremely sensible in providing the support to the screening of different causes of primary LVH in patients presenting with a HCM phenotype. Further external and multicenter validation is warranted.