Autoimmunity and immune dysregulation may lead to cytopenia and represent key features of many primary immunodeficiencies (PIDs). Especially when cytopenia is the initial symptom of a PID, the order ...and depth of diagnostic steps have to be performed in accordance with both an immunologic and a hematologic approach and will help exclude disorders such as systemic lupus erythematosus, common variable immunodeficiency, and autoimmune lymphoproliferative syndromes, hemophagocytic disorders, lymphoproliferative diseases, and novel differential diagnoses such as MonoMac syndrome (GATA2 deficiency), CD27 deficiency, lipopolysaccharide-responsive beige-like anchor (LRBA) deficiency, activated PI3KD syndrome (APDS), X-linked immunodeficiency with magnesium defect (MAGT1 deficiency), and others. Immunosuppressive treatment often needs to be initiated urgently, which impedes further relevant immunologic laboratory analyses aimed at defining the underlying PID. Awareness of potentially involved disease spectra ranging from hematologic to rheumatologic and immunologic disorders is crucial for identifying a certain proportion of PID phenotypes and genotypes among descriptive diagnoses such as autoimmune hemolytic anemia, chronic immune thrombocytopenia, Evans syndrome, severe aplastic anemia/refractory cytopenia, and others. A synopsis of pathomechanisms, novel differential diagnoses, and advances in treatment options for cytopenias in PID is provided to facilitate multidisciplinary management and to bridge different approaches.
The technology in current use for sexing sperm represents remarkable feats of engineering. These flow cytometer/cell sorters can make over 30 000 consecutive evaluations of individual sperm each ...second for each nozzle and sort the sperm into three containers: X-sperm, Y-sperm and unsexable plus dead sperm. Even at these speeds it is not economical to package sperm at standard numbers per inseminate. However, with excellent management, pregnancy rates in cattle with 2 million sexed sperm per insemination dose are about 80% of those with conventional semen at normal sperm doses. This lowered fertility, in part due to damage to sperm during sorting, plus the extra cost of sexed semen limits the applications that are economically feasible. Even so, on the order of 2 million doses of bovine semen are sexed annually in the United States. The main application is for dairy heifers to have heifer calves, either for herd expansion or for sale as replacements, often for eventual export. Breeders of purebred cattle often use sexed semen for specific matings; thawing and then sexing frozen semen and immediately using the few resulting sexed sperm for in vitro fertilization is done with increasing frequency. Beef cattle producers are starting to use sexed semen to produce crossbred female replacements. Proprietary improvements in sperm sexing procedures, implemented in 2013, are claimed to improve fertility between 4 and 6 percentage points, or about 10%.
Successful sorting of sperm based on presence of the X- or Y-chromosome was first reported in the early 1980′s with the first live births reported in rabbits in 1988. Subsequent development of ...technological efficiencies resulted in commercialization of sex-sorted semen to cattle producers in 2003–2005. At product launch, low throughput dictated that reasonable prices to the producer could only be accomplished with extremely low sperm number dosages (2 × 106). Furthermore, conception rates were 70%–75% of those achieved by conventional unsorted product. Refinements in sorting equipment have enhanced the number of sperm that can be sorted from a semen sample and (or) aliquot of time, which translates into reduced production costs, while modifications to other aspects of sperm processing and freezing have facilitated maintenance of a conception potential more similar to that of conventional semen. More recently, strategic use of sex-sorted semen coupled with genomic technologies to identify superior females to satisfy replacement female needs has, by default, led to identification of a population of dairy cows from which replacements are not desired, leading to a tremendous increase in use of beef semen in dairy herds. Though exact numbers are unavailable, estimates indicate sex-sorted semen is rapidly approaching 30% of the total AI market share in North America. Though the primary application of sex-sorted semen is to accelerate genetic progress while enhancing biosecurity through in-house production of replacement animals, numerous other potential applications are evolving or are under consideration.
•From 2017–2020, sales of unsexed dairy semen declined ~20% in North America.•From 2017–2020, sales of unsexed beef semen increased ~64% in North America.•The market share of sexed semen in North America is approaching 30% of all sales.
The immune surveillance theory of cancer posits that the body's immune system detects and destroys randomly occurring malignant cells. This theory is based on the observation of the increased ...frequency of malignancies in primary and secondary immunodeficiencies, and is supported by the successful demonstration of immune augmentation in current oncological immune therapy approaches. We review this model in the context of Down syndrome (DS), a condition with a unique tumor profile and various immune defects. Children and adults with DS are more prone to infections due to anatomical reasons and a varying degree of T- and B-cell maturation defects, NK cell dysfunction, and chemotactic or phagocytic abnormalities. However, despite an increased incidence of lymphoblastic and myeloblastic leukemia of infants and children with DS, individuals with DS have a globally decreased incidence of solid tumors as compared to age-adjusted non-DS controls. Additionally, cancers that have been considered "proof of immune therapy principles," such as renal carcinoma, small cell lung carcinoma, and malignant melanoma, are less frequent in adults with DS compared to the general population. Thus, despite the combination of an increased risk of leukemia with detectable immune biological abnormalities and a clinical immunodeficiency, people with DS appear to be protected against many cancers. This observation does not support the immune surveillance theory in the context of DS and indicates a potential tumor-suppressive role for trisomy 21 in non-hematological malignancies.
Although the basic principles controlling the sex of mammalian offspring have been known for a relatively long time, recent application of certain modern cellular methodologies has led to development ...of a flow cytometric system capable of differentiating and separating living X- and Y-chromosome-bearing sperm in amounts suitable for AI and therefore, commercialization of this sexing technology. After a very long history of unsuccessful attempts to differentiate between mammalian sperm that produce males from those that produce females, a breakthrough came in 1981 when it was demonstrated that precise DNA content could be measured. Although these initial measurements of DNA content killed the sperm in the process, they led to the ultimate development of a sperm sorting system that was capable, not only of differentiating between live X- and Y-sperm, but of sorting them into relatively pure X- and Y-sperm populations without obvious cellular damage. Initial efforts to predetermine the sex of mammalian offspring in 1989 required surgical insemination, but later enhancements provided sex-sorted sperm in quantities suitable for use with IVF. Subsequent advances in flow sorting provided minimal numbers of sperm sufficient for use in AI. It was not until the flow cytometric sorting system was improved greatly and successful cryopreservation of sex-sorted bull sperm was developed that efficacious approaches to commercialization of sexed semen could be implemented worldwide in cattle. A number of companies now offer sex-sorted bovine sperm. Innovative approaches by a diverse group of scientists along with advances in computer science, biophysics, cell biology, instrumentation, and applied reproductive physiology provided the basis for commercializing sexed semen in cattle.
Time delayed dynamical systems have proven to be a fertile framework for the study of physical phenomena. In natural sciences, their uses have been limited to the study of dissipative dynamics. In ...this Letter, we demonstrate the existence of nonlinear reversible conservative time delayed systems. We consider the example of a dispersive microcavity containing a Kerr medium coupled to a distant external mirror. At low energies and in the long delay limit, a multiscale analysis shows the equivalence with the nonlinear Schrödinger equation. We unveil some of the symmetries and conserved quantities, as well as bright temporal solitons. While elastic collisions occur for shallow wave packets, we observe the lack of integrability at higher energies. We recover the Lugiato-Lefever equation in the weakly dissipative regime.
CD27, a tumor necrosis factor receptor family member, interacts with CD70 and influences T-, B- and NK-cell functions. Disturbance of this axis impairs immunity and memory generation against viruses ...including Epstein Barr virus (EBV), influenza, and others. CD27 is commonly used as marker of memory B cells for the classification of B-cell deficiencies including common variable immune deficiency. Flow cytometric immunophenotyping including expression analysis of CD27 on lymphoid cells was followed by capillary sequencing of CD27 in index patients, their parents, and non-affected siblings. More comprehensive genetic analysis employed single nucleotide polymorphism-based homozygosity mapping and whole exome sequencing. Analysis of exome sequencing data was performed at two centers using slightly different data analysis pipelines, each based on the Genome Analysis ToolKit Best Practice version 3 recommendations. A comprehensive clinical characterization was correlated to genotype. We report the simultaneous confirmation of human CD27 deficiency in 3 independent families (8 patients) due to a homozygous mutation (p. Cys53Tyr) revealed by whole exome sequencing, leading to disruption of an evolutionarily conserved cystein knot motif of the transmembrane receptor. Phenotypes varied from asymptomatic memory B-cell deficiency (n=3) to EBV-associated hemophagocytosis and lymphoproliferative disorder (LPD; n=3) and malignant lymphoma (n=2; +1 after LPD). Following EBV infection, hypogammaglobulinemia developed in at least 3 of the affected individuals, while specific anti-viral and anti-polysaccharide antibodies and EBV-specific T-cell responses were detectable. In severely affected patients, numbers of iNKT cells and NK-cell function were reduced. Two of 8 patients died, 2 others underwent allogeneic hematopoietic stem cell transplantation successfully, and one received anti-CD20 (rituximab) therapy repeatedly. Since homozygosity mapping and exome sequencing did not reveal additional modifying factors, our findings suggest that lack of functional CD27 predisposes towards a combined immunodeficiency associated with potentially fatal EBV-driven hemo-phagocytosis, lymphoproliferation, and lymphoma development.
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•MD characterization of load transfer of functionalized graphene-polymer interface.•Normal and sliding mode force-separation responses studied.•Functionalization density effect on ...interface load transfer studied parametrically.•MD derived cohesive zone laws implemented in FEA RVE to obtain elastic properties.•Improvement of shear load transfer with functionalization key to elastic properties.
The effects of functionalization of the interface between carbon nanotubes (CNTs) and the polymer matrix on the macroscale elastic mechanical material properties have been investigated using a multiscale model. Molecular dynamic (MD) simulations are used to investigate the influence of functionalization on the nanoscale load transfer ability of the interface between the CNT and the polymer matrix material in CNT–polyethylene (PE) nanocomposites. Graphene–polymer interface models with variable numbers of functional groups grafted between the graphene sheet and the polymer chains are adopted to represent the interface between the CNTs and the polymer matrix. Normal mode and sliding mode separations are performed using MD simulations in order to characterize the load transfer of the functionalized graphene–polymer interface in terms of force-separation responses. The influence of the functionalization density on the load transfer at the interface is studied parametrically. Two force field potentials, the consistent valence force field (CVFF) and adaptive intermolecular reactive empirical bond order (AIREBO) potential, are used to simulate the interactions between the atoms in the polymer matrix and the functional groups. An energy based bond breaking criteria is introduced into the CVFF potential such that both potentials allow for bond breaking. Comparison of the two potentials is conducted by comparing the MD simulation results where it is found that two potentials give different force-separation responses, but that in both cases, there is significant increase in load transfer capability and toughness of the interface with increasing degree of functionalization of the interface. With cohesive zone laws derived from MD results, a finite element implementation of the cohesive zone models is used to calculate the effective elastic mechanical properties of the CNT–PE nanocomposites in order to study the influence of functionalization at the nanoscale on their macroscale mechanical performance.
Hundreds of thousands of off springs have been born as a result of AI with sexed sperm. Although this technology has been used for many species, the overwhelming majority of pregnancies have been in ...cattle, nearly all as a result of sperm that were sexed and subsequently frozen. The technology for sexing sperm has not changed greatly in the past 7 years, but refinements have speeded up the process and reduced damage to sperm.
The process of commercialization of sexed sperm has accelerated recently. However, this technology is characterized by high costs, complexity of implementation and lower pregnancy rates than with control sperm. Nevertheless, sexed, frozen bovine sperm are being produced commercially in many countries, although from a limited number of bulls.
The main application of sexed sperm to date has been to breed dairy heifers to produce female calves. Because of the slow speed of sexing sperm, fewer sperm are used per insemination dose of sexed than conventional sperm, and pregnancy rates with this product are often only slightly decreased. Successful use of sexed sperm requires excellent management of cattle, careful handling of sperm and use of skilled inseminators. As costs decline, sexed sperm will be used increasingly for cattle breeding, horse breeding and niche applications in other species.
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