Discrete States in Light-Like Linear Dilaton Background

We study the spectrum of bosonic strings in the light-like linear dilaton background and find discrete states. These are physical states which exist only at specific values of momentum. All except one discrete states generate spacetime symmetries. The exceptional discrete state corresponds to constraints which are deformations of conservation laws. The constraints resemble those arising from symmetries, and are equally powerful, suggesting that our notion of symmetry should be generalized.Comment: Latex, 21 pages, minor change

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Canagliflozin and renal outcomes in type 2 diabetes and nephropathy

BACKGROUND Type 2 diabetes mellitus is the leading cause of kidney failure worldwide, but few effective long-term treatments are available. In cardiovascular trials of inhibitors of sodium–glucose cotransporter 2 (SGLT2), exploratory results have suggested that such drugs may improve renal outcomes in patients with type 2 diabetes. METHODS In this double-blind, randomized trial, we assigned patients with type 2 diabetes and albuminuric chronic kidney disease to receive canagliflozin, an oral SGLT2 inhibitor, at a dose of 100 mg daily or placebo. All the patients had an estimated glomerular filtration rate (GFR) of 30 to <90 ml per minute per 1.73 m2 of body-surface area and albuminuria (ratio of albumin [mg] to creatinine [g], >300 to 5000) and were treated with renin–angiotensin system blockade. The primary outcome was a composite of end-stage kidney disease (dialysis, transplantation, or a sustained estimated GFR of <15 ml per minute per 1.73 m2), a doubling of the serum creatinine level, or death from renal or cardiovascular causes. Prespecified secondary outcomes were tested hierarchically. RESULTS The trial was stopped early after a planned interim analysis on the recommendation of the data and safety monitoring committee. At that time, 4401 patients had undergone randomization, with a median follow-up of 2.62 years. The relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group, with event rates of 43.2 and 61.2 per 1000 patient-years, respectively (hazard ratio, 0.70; 95% confidence interval [CI], 0.59 to 0.82; P=0.00001). The relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34% (hazard ratio, 0.66; 95% CI, 0.53 to 0.81; P<0.001), and the relative risk of end-stage kidney disease was lower by 32% (hazard ratio, 0.68; 95% CI, 0.54 to 0.86; P=0.002). The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction, or stroke (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01) and hospitalization for heart failure (hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001). There were no significant differences in rates of amputation or fracture. CONCLUSIONS In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years

Abstracts from the 8th International Conference on cGMP Generators, Effectors and Therapeutic Implications

This work was supported by a restricted research grant of Bayer AG

Transport of germ cells across the seminiferous epithelium during spermatogenesis—The involvement of both actin- and microtubule-based cytoskeletons

The transport of germ cells from the base of the seminiferous epithelium towards the luminal edge of the tubule lumen in the adluminal compartment during the epithelial cycle is an essential cellular event to support spermatogenesis. Thus, fully developed elongated spermatids (i.e., spermatozoa) can be released at spermiation in late stage VIII in rodents versus late stage II in humans. Earlier studies to examine the molecular mechanism(s) that support germ cell transport, most notably the transport of preleptotene spermatocytes across the blood-testis barrier (BTB), and the transport of elongating spermatids across the adluminal compartment during spermiogenesis, is focused on the adhesion protein complexes at the cell-cell interface. It is generally accepted that cell junctions at the Sertoli cell-cell interface at the BTB, including the actin-based tight junction (TJ), basal ectoplasmic specialization (basal ES, a testis-specific adherens junction) and gap junction (GJ), as well as the intermediate filament-based desmosome undergo constant remodeling to accommodate the transport of preleptotene spermatocytes across the barrier. On the other hand, similar junction dynamics (i.e., disassembly, reassembly and stabilization/maintenance) take place at the Sertoli-spermatid interface. Emerging evidence has shown that junction dynamics at the Sertoli cell-cell vs. Sertoli-germ cell interface are supported by the two intriguingly coordinated cytoskeletons, namely the F-actin- and microtubule (MT)-based cytoskeletons. Herein, we provide a brief summary and critically evaluate the recent findings. We also provide an updated hypothetical concept regarding germ cell transport in the testis utilizing the MT-conferred tracks and the MT-specific motor proteins

Actin nucleator Spire 1 is a regulator of ectoplasmic specialization in the testis

Abstract Germ cell differentiation during the epithelial cycle of spermatogenesis is accompanied by extensive remodeling at the Sertoli cell–cell and Sertoli cell–spermatid interface to accommodate the transport of preleptotene spermatocytes and developing spermatids across the blood–testis barrier (BTB) and the adluminal compartment of the seminiferous epithelium, respectively. The unique cell junction in the testis is the actin-rich ectoplasmic specialization (ES) designated basal ES at the Sertoli cell–cell interface, and the apical ES at the Sertoli–spermatid interface. Since ES dynamics (i.e., disassembly, reassembly and stabilization) are supported by actin microfilaments, which rapidly converts between their bundled and unbundled/branched configuration to confer plasticity to the ES, it is logical to speculate that actin nucleation proteins play a crucial role to ES dynamics. Herein, we reported findings that Spire 1, an actin nucleator known to polymerize actins into long stretches of linear microfilaments in cells, is an important regulator of ES dynamics. Its knockdown by RNAi in Sertoli cells cultured in vitro was found to impede the Sertoli cell tight junction (TJ)-permeability barrier through changes in the organization of F-actin across Sertoli cell cytosol. Unexpectedly, Spire 1 knockdown also perturbed microtubule (MT) organization in Sertoli cells cultured in vitro. Biochemical studies using cultured Sertoli cells and specific F-actin vs. MT polymerization assays supported the notion that a transient loss of Spire 1 by RNAi disrupted Sertoli cell actin and MT polymerization and bundling activities. These findings in vitro were reproduced in studies in vivo by RNAi using Spire 1-specific siRNA duplexes to transfect testes with Polyplus in vivo-jetPEI as a transfection medium with high transfection efficiency. Spire 1 knockdown in the testis led to gross disruption of F-actin and MT organization across the seminiferous epithelium, thereby impeding the transport of spermatids and phagosomes across the epithelium and perturbing spermatogenesis. In summary, Spire 1 is an ES regulator to support germ cell development during spermatogenesis

Enhancing LED spectral output with perylene dye-based remote phosphor

Abstract LEDs offer a wide range of spectral output with high efficiencies. However, the efficiencies of solid-state LEDs with green and yellow wavelengths are rather low due to the lack of suitable direct bandgap materials. Here, we introduce and develop perylene-enhanced green LEDs that produce a higher wall-plug efficiency of 48% compared to 38% for a solid-state green LED. While the wall-plug efficiency of the perylene-enhanced red LED is still lower than that of a solid-state red LED, we demonstrate that remote phosphor colour converters are effective solutions for targeted spectral tuning across the visible spectrum for horticultural lighting. In this work, we retrofit existing white LEDs and augment photosynthesis via spectral output tuning to achieve a higher red-to-blue ratio. Our results show a significant improvement in plant growth by up to 39%, after a 4-month growth cycle. We observe no visible degradation of the colour converter even under continuous illumination with a current of 400 mA. This opens up new opportunities for using perylene-based colour converters for tuneable illumination with high brightness

Signaling pathways regulating blood-tissue barriers—Lesson from the testis

Signal pathways that regulate blood-tissue barriers are important for studying the biology of various blood-tissue barriers. This information, if deciphered and better understood, will provide better therapeutic management of diseases particularly in organs that are sealed by the corresponding blood-tissue barriers from systemic circulation, such as the brain and the testis. These barriers block the access of antibiotics and/or chemotherapeutical agents across the corresponding barriers. Studies in the last decade using the blood-testis barrier (BTB) in rats have demonstrated the presence of several signaling pathways that are crucial to modulate BTB function. Herein, we critically evaluate these findings and provide hypothetical models regarding the underlying mechanisms by which these signaling molecules/pathways modulate dynamics. This information should be carefully evaluated to examine their applicability in other tissue barriers which shall benefit future functional studies in the field