Requirement of argininosuccinate lyase for systemic nitric oxide production

Nitric oxide (NO) is crucial in diverse physiological and pathological processes. We show that a hypomorphic mouse model of argininosuccinate lyase (encoded by Asl) deficiency has a distinct phenotype of multiorgan dysfunction and NO deficiency. Loss of Asl in both humans and mice leads to reduced NO synthesis, owing to both decreased endogenous arginine synthesis and an impaired ability to use extracellular arginine for NO production. Administration of nitrite, which can be converted into NO in vivo, rescued the manifestations of NO deficiency in hypomorphic Asl mice, and a nitric oxide synthase (NOS)-independent NO donor restored NO-dependent vascular reactivity in humans with ASL deficiency. Mechanistic studies showed that ASL has a structural function in addition to its catalytic activity, by which it contributes to the formation of a multiprotein complex required for NO production. Our data demonstrate a previously unappreciated role for ASL in NOS function and NO homeostasis. Hence, ASL may serve as a target for manipulating NO production in experimental models, as well as for the treatment of NO-related diseases

Recent advances in gastrointestinal oncology - updates and insights from the 2009 annual meeting of the American Society of Clinical Oncology

We have reviewed the pivotal presentations related to gastrointestinal malignancies from 2009 annual meeting of the American Society of Clinical Oncology with the theme of "personalizing cancer care". We have discussed the scientific findings and the impact on practice guidelines and ongoing clinical trials. Adding trastuzumab to chemotherapy improved the survival of patients with advanced gastric cancer overexpressing human epidermal growth factor receptor 2. Gemcitabine plus cisplatin has become a new standard for first-line treatment of advanced biliary cancer. Octreotide LAR significantly lengthened median time to tumor progression compared with placebo in patients with metastatic neuroendocrine tumors of the midgut. Addition of oxaliplatin to fluoropyrimidines for preoperative chemoradiotherapy in patients with stage II or III rectal cancer did not improve local tumor response but increased toxicities. Bevacizumab did not provide additional benefit to chemotherapy in adjuvant chemotherapy for stage II or III colon cancer. In patients with resected stage II colon cancer, recurrence score estimated by multigene RT-PCR assay has been shown to provide additional risk stratification. In stage IV colorectal cancer, data have supported the routine use of prophylactic skin treatment in patients receiving antibody against epidermal growth factor receptor, and the use of upfront chemotherapy as initial management in patients with synchronous metastasis without obstruction or bleeding from the primary site

Landscapes of Urbanization and De-Urbanization: A Large-Scale Approach to Investigating the Indus Civilization's Settlement Distributions in Northwest India.

Survey data play a fundamental role in studies of social complexity. Integrating the results from multiple projects into large-scale analyses encourages the reconsideration of existing interpretations. This approach is essential to understanding changes in the Indus Civilization's settlement distributions (ca. 2600-1600 b.c.), which shift from numerous small-scale settlements and a small number of larger urban centers to a de-nucleated pattern of settlement. This paper examines the interpretation that northwest India's settlement density increased as Indus cities declined by developing an integrated site location database and using this pilot database to conduct large-scale geographical information systems (GIS) analyses. It finds that settlement density in northwestern India may have increased in particular areas after ca. 1900 b.c., and that the resulting landscape of de-urbanization may have emerged at the expense of other processes. Investigating the Indus Civilization's landscapes has the potential to reveal broader dynamics of social complexity across extensive and varied environments.ER

Changing the prehistory of Sindh and Las Bela coast: twenty-five years of Italian contribution

The paper discusses the prehistory of Lowr Sindh and Las Bela Coast, and the role played by the Italian archaeologists since the 1980's. New date are presented regarding mainly the radiocarbon chronology the Indus Delta settlement on rocky outcrops and the shell middens of Las Bela

International Consensus Statement on Rhinology and Allergy: Rhinosinusitis

Background: The 5 years since the publication of the first International Consensus Statement on Allergy and Rhinology: Rhinosinusitis (ICAR‐RS) has witnessed foundational progress in our understanding and treatment of rhinologic disease. These advances are reflected within the more than 40 new topics covered within the ICAR‐RS‐2021 as well as updates to the original 140 topics. This executive summary consolidates the evidence‐based findings of the document. Methods: ICAR‐RS presents over 180 topics in the forms of evidence‐based reviews with recommendations (EBRRs), evidence‐based reviews, and literature reviews. The highest grade structured recommendations of the EBRR sections are summarized in this executive summary. Results: ICAR‐RS‐2021 covers 22 topics regarding the medical management of RS, which are grade A/B and are presented in the executive summary. Additionally, 4 topics regarding the surgical management of RS are grade A/B and are presented in the executive summary. Finally, a comprehensive evidence‐based management algorithm is provided. Conclusion: This ICAR‐RS‐2021 executive summary provides a compilation of the evidence‐based recommendations for medical and surgical treatment of the most common forms of RS

Spotting the “small eyes”: using photo-ID methodology to study a wild population of smalleye stingrays (Megatrygon microps) in southern Mozambique

Background The smalleye stingray (Megatrygon microps) is a large and rare dasyatid ray, patchily distributed across the Indo-West Pacific. Free-swimming individuals have regularly been recorded in Southern Mozambican coastal waters utilizing different inshore environments. Distinctive features of the species include latitudinal rows of white spots on the dorsal surface of their pectoral disc. Methods This study aimed to determine if the natural spot patterns on M. microps are sufficiently unique and stable to use in photo-identification studies of wild populations. Research dive logs were combined with opportunistic photographs from local dive centers and recreational divers to create a photographic database from the Inhambane Province coastline. Results Seventy different individuals were identified over a 15-year period, all exhibiting uniquely identifiable patterns. Stingrays were easily identifiable over a period of six years with multiple re-sightings of the same individuals recorded. Analysis of encounters across the Inhambane coastline revealed that individual rays regularly use inshore reefs along a 350 km stretch of coastline. Fifteen stingrays were re-sighted during the study period, including one showing a 400 km return movement between Tofo Beach and the Bazaruto Archipelago, which is the longest distance traveled by a dasyatid ray on record. Several presumably pregnant females have also been recorded in the Bazaruto Archipelago National Park