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The mitochondrial calcium uniporter channel (MCUC) mediates mitochondrial calcium entry, regulating energy metabolism and cell death. Although several MCUC components have been identified, the molecular basis of mitochondrial calcium signaling networks and their remodeling upon changes in uniporter activity have not been assessed. Here, we map the MCUC interactome under resting conditions and upon chronic loss or gain of mitochondrial calcium uptake. We identify 89 high-confidence interactors that link MCUC to several mitochondrial complexes and pathways, half of which are associated with human disease. As a proof-of-concept, we validate the mitochondrial intermembrane space protein EFHD1 as a binding partner of the MCUC subunits MCU, EMRE, and MCUB. We further show a MICU1-dependent inhibitory effect of EFHD1 on calcium uptake. Next, we systematically survey compensatory mechanisms and functional consequences of mitochondrial calcium dyshomeostasis by analyzing the MCU interactome upon EMRE, MCUB, MICU1, or MICU2 knockdown. While silencing EMRE reduces MCU interconnectivity, MCUB loss-of-function leads to a wider interaction network. Our study provides a comprehensive and high-confidence resource to gain insights into players and mechanisms regulating mitochondrial calcium signaling and their relevance in human diseases. Synopsis: Mitochondrial calcium uptake through the uniporter channel MCUC is critical to cell signaling, metabolism, physiology, and disease. This study provides an unbiased and quantitative map of the MCUC interactome and its remodelling, both under resting conditions and after genetic perturbations. Tandem affinity purification/mass-spectrometry-based approach identifies the MCUC protein interaction network. Mitochondrial inner membrane protein EFHD1 interacts with MCUC and inhibits mitochondrial calcium uptake. Loss of MCUB subunit results in an expansion and greater interconnection of the MCU protein network. A dynamic map of the MCUC interaction landscape reveals inhibition of mitochondrial calcium uptake by the mitochondrial intermembrane space protein EFHD1. [ABSTRACT FROM AUTHOR]

In December 2019 Malaysia submitted information on the outer limits of its continental shelf beyond 200 miles (OL) in the South China Sea (SCS) to the Commission on the Limits of the Continental Shelf (CLCS). According to Article 76(8) of the UN Convention on the Law of the Sea, Malaysia shall seek CLCS recommendations as the basis for establishing its OL. If notified of a land or maritime dispute, the CLCS shall not consider the submission unless consent is given by all disputants. As of 16 March 2022, the CLCS has received 28 note verbales (NVs) concerning Malaysia's submission. Apart from those challenging the submission, there are 12 NVs invoking the 2016 SCS Arbitration award to oppose territorial and maritime claims by China in its NVs initially objecting the submission. This article reviews relevant CLCS rules and practice, analyses all 28 NVs, and examines the disputes reflected in the NVs. [ABSTRACT FROM AUTHOR]

Background: Unproven cellular therapies are being offered to patients for a variety of conditions and diseases for which other treatments have failed. The use of untested cellular therapies is a worldwide problem. Practitioners (e.g., physicians, scientists, QA/QI facility managers, and policy advocates) are perhaps unaware of the risks involved with such therapies. Therefore, a critical need exists to bring attention to the potential limitations and adverse effects of these therapies to inform and limit misinformation. Study Design and Methods: We describe the extent of the unproven cellular therapy problem through a search of scientific literature and social media coverage. We also describe the regulatory framework that can be used by the practitioner to review and evaluate both proven and unproven cellular therapies. Results: We report on the current state of unproven cellular therapies across the globe. A workflow to facilitate an understanding of the regulatory processes involved in the approval of cellular therapies is provided as well as a list of warnings required by regulatory agencies on various products. It is hoped that this article will serve as a tool kit to educate the practitioner on navigating the field of unproven cellular therapy products. Discussion: Increasing awareness of the issues associated with unproven therapies through education is important to help in reducing misinformation and risks to patients. [ABSTRACT FROM AUTHOR]

The United Nations Convention on the Law of the Sea (LOSC) regulates the establishment of the outer limits of its continental shelf beyond 200 miles by a coastal State. Such limits are legitimised when based on the recommendations of the Commission on the Limits of the Continental Shelf (CLCS) under LOSC Article 76(8). The coastal State must first submit the information for delineating the limits to the CLCS, which will evaluate the information before providing recommendations. The CLCS shall not consider the submission made by any State concerned in a land or maritime dispute unless consent from all disputing parties is given under paragraph 5(a) of Annex I to the CLCS Rules of Procedure. This article interprets paragraph 5(a) and examines the subsequent practice of States sending submissions and/or notifying the CLCS of disputes, and the CLCS in handling various submissions involved in these disputes. [ABSTRACT FROM AUTHOR]

PGF implies persistent cytopenia in the presence of predominant donor chimerism. We examined contributors to PGF in 104 HCT recipients who survived ≥100 days without relapse or major complications. Surrogate parameters for PGF were: Hg <10 g/dl, RBC transfusion dependence, platelet count <20 × 109/L or ANC < 0.5 × 109/L. All patients received T cell depletion with alemtuzumab or ATG. The 2-year OS and PFS probabilities were 66%, 95%CI (56 − 75%) and 51%, 95%CI (41–60%) respectively. Fifty-four patients (52%) met one or more PGF criteria. There was significant association between major ABO incompatibility and platelet <20 × 109/L (OR = 4.7, 95%CI 1.05–21.26, p =.043), acute GVHD and Hg <10 g/dl (OR 3.7, 95%CI 1.4–9.6, p =.005) and CMV viremia and ANC < 0.5 × 109/L (OR 3.0, 95% CI 1.0, 8.7, p =.043). NRM was significantly higher in the PGF group compared to patients with adequate graft function (45.5% vs 16.7%, p =.014). [ABSTRACT FROM AUTHOR]

Rationale: Studies identified kininogen as a potential biomarker of preeclampsia, a major cause of adverse maternal outcomes. High‐molecular‐weight kininogen (HK) and its activated form participate in numerous pathways associated with establishing and maintaining pregnancy. However, dynamic changes in HK and naturally occurring HK‐derived peptides during the natural course of pregnancy are largely unknown. Methods: Longitudinal serum samples during the course of normal pregnancy (trimesters T1, T2, T3) from 60 pregnant women were analyzed by western blot with an anti‐HK antibody. Circulating peptides in longitudinal serum specimens derived from 50 participants were enriched using nanoporous silica thin films. Peptides were identified by liquid chromatography/tandem mass spectrometry (LC/MS/MS) and database searching. Relative quantification was performed using MaxQuant and in‐house scripts. Normality was evaluated by either ANOVA or Friedman tests with p < 0.05 for statistical significance. Results: Western blotting revealed that HK significantly decreased during normal pregnancy (T1 vs T2, p < 0.05; T1 vs T3, p < 0.0001). A 100 kDa intermediate increased during pregnancy (T1 vs T2, p < 0.005; T1 vs T3, p < 0.01). Moreover, the heavy chain (T1 vs T2, p < 0.0001; T1 vs T3, p < 0.0001; T2 vs T3, p < 0.01) and light chain (T1 vs T2, p < 0.0001; T1 vs T3, p < 0.0001; T2 vs T3, p < 0.05) significantly increased during pregnancy. LC/MS/MS analysis identified 180 kininogen‐1 peptides, of which 167 mapped to domain 5 (D5). Seventy‐three peptides with ten or more complete data sets were included for further analysis. Seventy peptides mapped to D5, and 3, 24, and 43 peptides showed significant decrease, no trend, and significant increase, respectively, during pregnancy. Conclusions: This study demonstrates dynamic changes in HK and naturally occurring HK‐derived peptides during pregnancy. Our study sheds light on the gestational changes of HK and its peptides for further validation of them as potential biomarkers for pregnancy‐related complications. [ABSTRACT FROM AUTHOR]

The interpretation of Article 121(3) of the 1982 U.N. Convention on the Law of the Sea (UNCLOS) was a key part of the Sino-Philippine Arbitration on the South China Sea Award issued in July 2016. This article uses the principles of treaty interpretation codified in Article 31 of the 1969 Vienna Convention on the Law of Treaties to evaluate the interpretation process. The Tribunal paid little attention to the text such as "rocks" in the plural form and overlooked the context of Article 121(3). The travaux préparatoires identified by the Tribunal was based on materials of doubtful weight. [ABSTRACT FROM AUTHOR]

The article focuses on several aspects of jurisdictional rulings of the South China Sea arbitration. It mentions that Philippine Submissions 3, 4, 6, and 7 claimed that Johnson, Cuarteron and Fiery Cross Reefs, as well as Scarborough Shoal were only rocks incapable of generating an exclusive economic zone (EEZ) or CS under Article 121(3) of United Nations Convention on the Law of the Sea (UNCLOS).

This paper examines the evidences used by the Tribunal for the South China Sea Arbitration to conclude that Philippines' Submissions 3-4 and 6-7 reflect disputes. The Jurisdictional Award uses certain notes verbales sent by the Philippines and China in April 2011 for this purpose. However, the plain wording of these notes verbales negates the existence of disputes concerning the legal status of nine maritime features identified by those four Submissions. The Tribunal overlooks the agreement reached in these notes verbales that some geological features in the Kalayaan Islands Group may generate Exclusive Economic Zone and continental shelf, which serve to defeat Philippines' Submissions 5, 8, and 9 as well as the Philippines' theory that China invokes historical rights to justify its law enforcement activities in the entire region within the U-Shaped Line. [ABSTRACT FROM AUTHOR]

In April 2012 the Commission on the Limits of the Continental Shelf (CLCS) adopted certain decisions and recommendations regarding Japan's 2008 outer continental shelf submission. The Japanese and Chinese differing interpretations of these recommendations demonstrate the still controversial legal status of Oki-no-Tori Shima under Article 121(3) of the United Nations Convention on the Law of the Sea (UNCLOS). Such a contradiction enlarges another dispute on the legal status of the surrounding maritime zone proclaimed by Japan as its Exclusive Economic Zone (EEZ). This article examines the decisions and recommendations of the CLCS as well as Japan's Submission so as to clarify the confusing situation. The decisions by the CLCS have wider implications on the unsettled scope of disputes under Rule 46 of and Annex I to the Rules of Procedure (ROP) of the CLCS, affecting submissions by other States. These implications will be explored by this article. Finally, the author offers his views on the future of such confrontational situations. [ABSTRACT FROM PUBLISHER]

This article addresses how the CLCS can curb the situations prohibited by Article 137(1) of UNCLOS, i.e. encroachment upon the Area. The CLCS is mandated by Article 76 to consider the submitted information that coastal States intend to use in establishing limits of outer continental shelves. When the inconsistency of the Submission with Article 76 is mishandled by the CLCS, encroachment may materialize. Being critical of the CLCS's decisions as to when to disqualify a controversial Submission, the scope of disputes under the CLCS Rules of Procedure has been unreasonably narrowed by practice and rendered inconsistent with Article 76(1). Consequently, encroachment is not discouraged. The author argues that a proper interpretation and application of Article 76(1) by the CLCS, while taking Article 121 as context, may prevent such an encroachment. [ABSTRACT FROM PUBLISHER]