Mutations in GATA2 cause primary lymphedema associated with a predisposition to acute myeloid leukemia (Emberger syndrome).

We report an allelic series of eight mutations in GATA2 underlying Emberger syndrome, an autosomal dominant primary lymphedema associated with a predisposition to acute myeloid leukemia. GATA2 is a transcription factor that plays an essential role in gene regulation during vascular development and hematopoietic differentiation. Our findings indicate that haploinsufficiency of GATA2 underlies primary lymphedema and predisposes to acute myeloid leukemia in this syndrome

Infección por SARS-CoV-2 : implicaciones para la salud sexual y reproductiva. Una declaración de posición de la Asociación Española de Andrología, Medicina Sexual y Reproductiva (ASESA)

El objetivo de esta revisión es resumir la evidencia disponible sobre los posibles efectos adversos del SARS-CoV-2 en el sistema reproductor masculino y proporcionar una declaración de posición oficial de la Asociación Española de Andrología, Medicina Sexual y Reproductiva (ASESA). Se realizó una búsqueda exhaustiva en las bibliotecas Pubmed, Web of Science, Embase, Medline, Cochrane y MedRxiv. No se ha confirmado la orquitis como una posible complicación de la infección por SARS-CoV-2. Un estudio informó que el 19% de los hombres con COVID-19 presentaban molestias escrotales sugestivas de orquitis viral, que no se pudo confirmar. Es posible que el virus no infecte los testículos directamente, si no que desencadene una respuesta autoinmune secundaria y que cause una orquitis autoinmune. COVID-19 se ha asociado con anormalidades en la coagulación por lo que la orquitis podría ser el resultado de una vasculitis segmentaria. Los datos disponibles sobre la presencia del virus en semen son contradictorios. Sólo un estudio informó de la presencia de ARN en el 15,8% de enfermos de COVID-19. La presencia de ácido nucleico o antígeno en el semen no implica la existencia de virus con capacidad de replicación o infección. En hombres con COVID-19 se ha observado un incremento significativo de LH en suero y una drástica disminución de la ratio T/LH y FSH/LH, congruente con un hipogonadismo subclínico. Los datos disponibles y los hallazgos de los estudios recientes se basan en tamaños de muestra pequeños y proporcionan informaciones contradictorias. Existe la posibilidad teórica de que pueda producirse daño testicular y posterior infertilidad después de la infección por COVID-19, por lo que especialmente para aquellos hombres en edad reproductiva, se debe sugerir consulta y evaluación de la función gonadal y análisis de semen. En cuanto a la posibilidad de transmisión sexual, no hay evidencia suficiente para respaldar la necesidad de que las parejas asintomáticas eviten las relaciones sexuales para protegerse contra la transmisión del virus. Se necesita más investigación para comprender los impactos a largo plazo del SARS-CoV-2 en la función reproductiva masculina, incluidos sus posibles efectos sobre la fertilidad y la función endocrina testicular

Coordination of Cell Differentiation and Migration in Mathematical Models of Caudal Embryonic Axis Extension

Vertebrate embryos display a predominant head-to-tail body axis whose formation is associated with the progressive development of post-cranial structures from a pool of caudal undifferentiated cells. This involves the maintenance of active FGF signaling in this caudal region as a consequence of the restricted production of the secreted factor FGF8. FGF8 is transcribed specifically in the caudal precursor region and is down-regulated as cells differentiate and the embryo extends caudally. We are interested in understanding the progressive down-regulation of FGF8 and its coordination with the caudal movement of cells which is also known to be FGF-signaling dependent. Our study is performed using mathematical modeling and computer simulations. We use an individual-based hybrid model as well as a caricature continuous model for the simulation of experimental observations (ours and those known from the literature) in order to examine possible mechanisms that drive differentiation and cell movement during the axis elongation. Using these models we have identified a possible gene regulatory network involving self-repression of a caudal morphogen coupled to directional domain movement that may account for progressive down-regulation of FGF8 and conservation of the FGF8 domain of expression. Furthermore, we have shown that chemotaxis driven by molecules, such as FGF8 secreted in the stem zone, could underlie the migration of the caudal precursor zone and, therefore, embryonic axis extension. These mechanisms may also be at play in other developmental processes displaying a similar mode of axis extension coupled to cell differentiation

EPHB4 kinase-inactivating mutations cause autosomal dominant lymphatic-related hydrops fetalis.

Hydrops fetalis describes fluid accumulation in at least 2 fetal compartments, including abdominal cavities, pleura, and pericardium, or in body tissue. The majority of hydrops fetalis cases are nonimmune conditions that present with generalized edema of the fetus, and approximately 15% of these nonimmune cases result from a lymphatic abnormality. Here, we have identified an autosomal dominant, inherited form of lymphatic-related (nonimmune) hydrops fetalis (LRHF). Independent exome sequencing projects on 2 families with a history of in utero and neonatal deaths associated with nonimmune hydrops fetalis uncovered 2 heterozygous missense variants in the gene encoding Eph receptor B4 (EPHB4). Biochemical analysis determined that the mutant EPHB4 proteins are devoid of tyrosine kinase activity, indicating that loss of EPHB4 signaling contributes to LRHF pathogenesis. Further, inactivation of Ephb4 in lymphatic endothelial cells of developing mouse embryos led to defective lymphovenous valve formation and consequent subcutaneous edema. Together, these findings identify EPHB4 as a critical regulator of early lymphatic vascular development and demonstrate that mutations in the gene can cause an autosomal dominant form of LRHF that is associated with a high mortality rate

Realising superoscillations: A review of mathematical tools and their application

Superoscillations are making a growing impact on an ever-increasing number of real-world applications, as early theoretical analysis has evolved into wide experimental realisation. This is particularly true in optics: the first application area to have extensively embraced superoscillations, with much recent growth. This review provides a tool for anyone planning to expand the boundaries in an application where superoscillations have already been used, or to apply superoscillations to a new application. By reviewing the mathematical methods for constructing superoscillations, including their considerations and capabilities, we lay out the options for anyone wanting to construct a device that uses superoscillations. Superoscillations have inherent trade-offs: as the size of spot reduces, its relative intensity decreases as high-energy sidebands appear. Different methods provide solutions for optimising different aspects of these trade-offs, to suit different purposes. Despite numerous technological ways of realising superoscillations, the mathematical methods can be categorised into three approaches: direct design of superoscillatory functions, design of pupil filters and design of superoscillatory lenses. This categorisation, based on mathematical methods, is used to highlight the transferability of methods between applications. It also highlights areas for future theoretical development to enable the scientific and technological boundaries to be pushed even further in real-world applications

Response to Novel Drugs before and after Allogeneic Stem Cell Transplantation in Patients with Relapsed Multiple Myeloma

Multiple myeloma (MM) remains as an incurable disease and, although allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative approach, most patients ultimately relapse, and their treatment remains challenging. Because allo-HSCT can modify not only the biology of the disease, but also the immune system and the microenvironment, it can potentially enhance the response to rescue therapies. Information on the efficacy and safety of novel drugs in patients relapsing after allo-HSCT is lacking, however. The objectives of this study were to evaluate the efficacy and toxicity of rescue therapies in patients with MM who relapsed after allo-HSCT, as well as to compare their efficacy before and after allo-HSCT. This retrospective multicenter study included 126 consecutive patients with MM who underwent allo-HSCT between 2000 and 2013 at 8 Spanish centers. All patients engrafted. The incidence of grade II-IV acute graft-versus-host disease (GVHD) was 47%, and nonrelapse mortality within the first 100 days post-transplantation was 13%. After a median follow-up of 92 months, overall survival (OS) was 51% at 2 years and 43% at 5 years. The median progression-free survival after allo-HSCT was 7 months, whereas the median OS after relapse was 33 months. Patients relapsing in the first 6 months after transplantation had a dismal prognosis compared with those who relapsed later (median OS, 11 months versus 120 months; P <.001). The absence of chronic GVHD was associated with reduced OS after relapse (hazard ratio, 3.44; P <.001). Most patients responded to rescue therapies, including proteasome inhibitors (PIs; 62%) and immunomodulatory drugs (IMiDs; 77%), with a good toxicity profile. An in-depth evaluation, including the type and intensity of PI- and IMiD-based combinations used before and after allo-HSCT, showed that the overall response rate and duration of response after allo-HSCT were similar to those seen in the pretransplantation period. Patients with MM who relapse after allo-HSCT should be considered candidates for therapy with new drugs, which can achieve similar response rates with similar durability as seen in the pretransplantation period. This pattern does not follow the usual course of the disease outside the transplantation setting, where response rates and time to progression decreases with each consecutive line of treatment

Complement Factor H Is Expressed in Adipose Tissue in Association With Insulin Resistance

10 páginas, 5 figuras, 5 tablas -- PAGS nros. 200-209OBJECTIVE Activation of the alternative pathway of the complement system, in which factor H (fH; complement fH [CFH]) is a key regulatory component, has been suggested as a link between obesity and metabolic disorders. Our objective was to study the associations between circulating and adipose tissue gene expressions of CFH and complement factor B (fB; CFB) with obesity and insulin resistance. RESEARCH DESIGN AND METHODS Circulating fH and fB were determined by enzyme-linked immunosorbent assay in 398 subjects. CFH and CFB gene expressions were evaluated in 76 adipose tissue samples, in isolated adipocytes, and in stromovascular cells (SVC) (n = 13). The effects of weight loss and rosiglitazone were investigated in independent cohorts. RESULTS Both circulating fH and fB were associated positively with BMI, waist circumference, triglycerides, and inflammatory parameters and negatively with insulin sensitivity and HDL cholesterol. For the first time, CFH gene expression was detected in human adipose tissue (significantly increased in subcutaneous compared with omental fat). CFH gene expression in omental fat was significantly associated with insulin resistance. In contrast, CFB gene expression was significantly increased in omental fat but also in association with fasting glucose and triglycerides. The SVC fraction was responsible for these differences, although isolated adipocytes also expressed fB and fH at low levels. Both weight loss and rosiglitazone led to significantly decreased circulating fB and fH levels. CONCLUSIONS Increased circulating fH and fB concentrations in subjects with altered glucose tolerance could reflect increased SVC-induced activation of the alternative pathway of complement in omental adipose tissue linked to insulin resistance and metabolic disturbances.Obesity is closely associated with a cluster of metabolic diseases, such as dyslipidemia, hypertension, insulin resistance, type 2 diabetes, and atherosclerosis (1). Adipose tissue is well known for its essential role as an energy storage depot and for secreting adipokines that influence sites as diverse as brain, liver, muscle, β-cells, gonads, lymphoid organs, and systemic vasculature (2,3). Expression analysis of macrophage and nonmacrophage cell populations isolated from adipose tissue demonstrates that adipose tissue macrophages are responsible for most of the proinflammatory cytokines (4). In recent years, it has become evident that alterations in the function of the innate immune system are intrinsically linked to metabolic pathways in humans (5–8). The complement system is a major component of the innate immune system, defending the host against pathogens, coordinating various events during inflammation, and bridging innate and adaptive immune responses. Complement deficiency and abnormalities in the regulation of the complement system lead to increased susceptibility to infection and chronic inflammatory diseases (9,10,11). Factor H (fH) is a relatively abundant plasma glycoprotein that is essential to maintain complement homeostasis and to restrict the action of complement to activating surfaces. fH acts as a cofactor for factor I–mediated cleavage of C3b (the active fragment of the third component of complement C3), accelerates the dissociation of the alternative pathway C3 convertases (a bimolecular enzymatic complex formed by active fragments of C3 and factor B [fB]), and competes with fB for binding to C3b. fH regulates complement both in fluid phase and on cellular surfaces (12–16). It has been suggested that activation of the alternative pathway of the complement system could be a link between obesity and metabolic disorders (17–21). Moreover, fB and factor D (fD, adipsin) are produced by adipose tissue where they likely influence formation of the alternative pathway component C3 convertase and the production of the anaphylatoxin C3a and its carboxypeptidase B-anaphylatoxic–inactivated derivative C3adesArg (acylation-stimulating protein [ASP]). Both ASP/C3adesArg and C3a interact with the receptor C5L2 to effectively stimulate triglyceride synthesis in cultured adipocytes (22). C3 knockout (C3KO) mice are obligatorily ASP deficient and present lipid abnormalities (23). In humans, ASP levels are increased in obesity, type 2 diabetes, and in individuals at risk of arterial disease, including those with hypertension, type 2 diabetes, dyslipidemia, and coronary artery disease, whereas exercise or weight loss decreases ASP levels (24,25). These data suggest a relationship between these conditions and activation of the alternative pathway of complement. There is also a correlation between increased C3 concentration and decreased insulin action (26,27). Levels of C3 and fB were higher in subjects with insulin resistance and other features of the metabolic syndrome (28,29).Given these interactions among activation of the alternative pathway of complement, metabolic disturbances, and a chronic low-level inflammatory state, we designed experiments to study the associations among circulating fH, fB, insulin resistance, lipid parameters, and inflammatory markers. We found that circulating fH and fB are strongly associated with obesity. For that reason, we also studied whether adipose tissue could constitute a source of circulating fH and fBThis work was partially supported by research grants from the Ministerio de Educación y Ciencia (SAF2008-02073). CIBEROBN Fisiopatología de la Obesidad y Nutrición is an initiative from the Instituto de Salud Carlos III from SpainPeer reviewe

A note on comonotonicity and positivity of the control components of decoupled quadratic FBSDE

In this small note we are concerned with the solution of Forward-Backward Stochastic Differential Equations (FBSDE) with drivers that grow quadratically in the control component (quadratic growth FBSDE or qgFBSDE). The main theorem is a comparison result that allows comparing componentwise the signs of the control processes of two different qgFBSDE. As a byproduct one obtains conditions that allow establishing the positivity of the control process.Comment: accepted for publicatio