Loss of UGP2 in brain leads to a severe epileptic encephalopathy, emphasizing that bi-allelic isoform-specific start-loss mutations of essential genes can cause genetic diseases.

Developmental and/or epileptic encephalopathies (DEEs) are a group of devastating genetic disorders, resulting in early-onset, therapy-resistant seizures and developmental delay. Here we report on 22 individuals from 15 families presenting with a severe form of intractable epilepsy, severe developmental delay, progressive microcephaly, visual disturbance and similar minor dysmorphisms. Whole exome sequencing identified a recurrent, homozygous variant (chr2:64083454A > G) in the essential UDP-glucose pyrophosphorylase (UGP2) gene in all probands. This rare variant results in a tolerable Met12Val missense change of the longer UGP2 protein isoform but causes a disruption of the start codon of the shorter isoform, which is predominant in brain. We show that the absence of the shorter isoform leads to a reduction of functional UGP2 enzyme in neural stem cells, leading to altered glycogen metabolism, upregulated unfolded protein response and premature neuronal differentiation, as modeled during pluripotent stem cell differentiation in vitro. In contrast, the complete lack of all UGP2 isoforms leads to differentiation defects in multiple lineages in human cells. Reduced expression of Ugp2a/Ugp2b in vivo in zebrafish mimics visual disturbance and mutant animals show a behavioral phenotype. Our study identifies a recurrent start codon mutation in UGP2 as a cause of a novel autosomal recessive DEE syndrome. Importantly, it also shows that isoform-specific start-loss mutations causing expression loss of a tissue-relevant isoform of an essential protein can cause a genetic disease, even when an organism-wide protein absence is incompatible with life. We provide additional examples where a similar disease mechanism applies

Advancing male age differentially alters levels and localization patterns of PLCzeta in sperm and testes from different mouse strains

Sperm-specific phospholipase C zeta (PLC) initiates intracellular calcium (Ca2+) transients which drive a series of concurrent events collectively termed oocyte activation. Numerous investigations have linked abrogation and absence/reduction of PLC with forms of male infertility in humans where oocyte activation fails. However, very few studies have examined potential relationships between PLC and advancing male age, both of which are increasingly considered to be major effectors of male fertility. Initial efforts in humans may be hindered by inherent PLC variability within the human population, alongside a lack of sufficient controllable repeats. Herein, utilizing immunoblotting, immunofluorescence, and quantitative reverse transcription PCR (qRT-PCR) we examined for the first time PLC protein levels and localization patterns in sperm, and PLC mRNA levels within testes, from mice at 8 weeks, 12 weeks, 24 weeks, and 36 weeks of age, from two separate strains of mice, C57BL/6 (B6; inbred) and CD1 (outbred). Collectively, advancing male age generally diminished levels and variability of PLC protein and mRNA in sperm and testes, respectively, when both strains were examined. Furthermore, advancing male age altered the predominant pattern of PLC localization in mouse sperm, with younger mice exhibiting predominantly post-Acrosomal, and older mice exhibiting both post-Acrosomal and acrosomal populations of PLC. However, the specific pattern of such decline in levels of protein and mRNA was strain-specific. Collectively, our results demonstrate a negative relationship between advancing male age and PLC levels and localization patterns, indicating that aging male mice from different strains may serve as useful models to investigate PLC in cases of male infertility and subfertility in humans

Increasing Traffic Flows with DSRC Technology: Field Trials and Performance Evaluation

As traffic congestion becomes a huge problem for most developing and developed countries across the world, intelligent transportation systems (ITS) are becoming a hot topic that is attracting attention of researchers and the general public alike. In this paper, we demonstrate a specific implementation of an ITS system whereby traffic lights are actuated by DSRC radios installed in vehicles. More specifically, we report the design of prototype of a DSRC-Actuated Traffic Lights (DSRC-ATL) system. It is shown that this system can reduce the travel time and commute time significantly, especially during rush hours. Furthermore, the results reported in this paper do NOT assume or require all vehicles to be equipped with DSCR radios. Even with low penetration ratios, e.g., when only 20% of all vehicles in a city are equipped with DSRC radios, the overall performance of the designed system is superior to the current traffic control systems

Safety concerns when using novel medications to treat alopecia

Introduction: Alopecia is often a cause of great concern to patients for cosmetic and psychologic reasons. The aim of treating non-scarring alopecias is to reduce hair loss and, to some extent, enhance hair regrowth. However, therapies for scarring alopecias are limited and aiming to halt disease progression. Nonetheless, available modalities of treatment come with numerous side effects. Areas covered: Many new treatments for non-scarring alopecias have been introduced in recent years. This review summarizes the safety concerns when using novel therapeutic modalities such as JAK inhibitors, hair transplantation, mesotherapy, oral minoxidil, platelet-rich plasma, microneedling, and 5α-reductase inhibitors for treating hair loss. A broad literature search was performed using PubMed and Google Scholar in April 2018 to compile published articles that reported the adverse effects of new therapeutic modalities for alopecia. Expert opinion: Although emerging therapeutic modalities for alopecia have demonstrated efficacy in hair regrowth and treating established disease, their safety profiles vary widely. When considering the new treatments for alopecia, physicians should weigh the potential benefits and risks of each treatment or combination treatment to ensure safe and successful outcomes

New Drugs for Alopecias

The new drugs in the development of AGA include PGF2 analogs, a PGD2 receptor antagonist, Wnt pathway activators, an androgen receptor antagonist, a topical JAK inhibitors, and topical finasteride. While many of these have already shown efficacy compared to placebo, none have shown superiority to topical minoxidil; however, they may still have future as an adjuvant treatment with topical minoxidil. For AA, oral JAK inhibitors are a promising new development, although other new drugs are in development as well. A particularly interesting one is BNZ-1, which has the potential to suppress the autoimmune response without causing systemic immunosuppression

Role of Oral Supplements: When and How to Choose

People commonly inquire about vitamin and mineral supplementation and diet as a means to prevent or manage dermatological diseases and, in particular, hair loss. Answering these queries is frequently challenging, given the enormous and conflicting evidence that exists on this subject. There are several reasons to suspect a role for micronutrients in non-scarring alopecia. Micronutrients are major elements in the normal hair follicle cycle, playing a role in cellular turnover. The role of nutrition and diet in treating hair loss represents a dynamic and growing area of inquiry. This chapter summarizes the role of vitamins and minerals in non-scarring alopecia. Micronutrients such as vitamins and minerals play an important, but not entirely clear role in normal hair follicle development and immune cell function. Deficiency of such micronutrients may represent a modifiable risk factor associated with development, prevention, and treatment of alopecia