The Global State of LGBTIQ Organizing: The Right to Register

It has become increasingly difficult for community-based organizations to operate, a phenomena frequently referred to as shrinking space for civil society. Yet, to fully understand the impact of new laws restricting organizations' access to funding, laws equating human rights with the corruption of youth, and laws written to equate activism with threats to national security, it is important to analyze exactly how LGBTIQ organizations are specifically impacted. LGBTIQ movements globally are relatively young, and so many LGBTIQ organizations have had little time to institutionalize. Are LGBTIQ organizations at heightened risk in the current environment, and what can be done to safeguard these young movements?OutRight Action International's report, The Global State of LGBTIQ Organizing: The Right to Register, seeks to answer these questions and determine the possibility of legal registration for LGBTIQ organizations globally. OutRight's research finds that legal registration for LGBTIQ organizations is severely restricted globally and the result is that LGBTIQ human rights defenders work with fewer resources and face more danger.In a survey of 194 countries, OutRight found that only 56%, 109 countries, permit LGBTIQ organizations to legally register as LGBTIQ organizations. In just 28%, 55 countries, LGBTIQ organizations exist but they cannot legally register as LGBTIQ organizations. In these countries disclosing an intention to serve LGBTIQ people sets up a barrier to legal registration. Thus, many organizations pursue registration using more neutral language about their aims and objectives that do not identify that they work with LGBTIQ people. In 15% of the countries studied, OutRight could not identify any organizations working on LGBTIQ issues, whether registered or unregistered. In these countries, LGBTIQ people don't have an organization operated by and for the community that can advocate for their rights. OutRight is concerned that LGBTIQ people in these countries may be at higher risk of discrimination and violence.The study collected data on thousands of organizations across 5 global regions and determined the registration status of a set of 864 organizations in Asia and the Pacific, the Caribbean, Eastern Europe, the Middle East and North Africa and sub-Saharan Africa. This report includes a summary of legal analysis undertaken in 41 countries to determine the laws allowing Non-Governmental Organizations (NGOs) to register. In certain countries, the law does not explicitly deny the existence of LGBTIQ organizations but authorities still find ways to reject registration applications and deny equal rights of recognition. Thus, the homophobic and/or transphobic biases of authorities can impede organizations from registering. Finally, the report provides in-depth case studies from Belize, China, Lebanon, Germany, Nigeria, Russia, St Lucia, Singapore, Tanzania and Tunisia on the experiences of 22 LGBTIQ organizations who have sought or obtained legal status in those countries

Countdown to 2015: changes in offi cial development assistance to reproductive, maternal, newborn, and child health, and assessment of progress between 2003 and 2012

Background Tracking of aid resources to reproductive, maternal, newborn, and child health (RMNCH) provides timely and crucial information to hold donors accountable. For the fi rst time, we examine fl ows in offi cial development assistance (ODA) and grants from the Bill & Melinda Gates Foundation (collectively termed ODA+) in relation to the continuum of care for RMNCH and assess progress since 2003. Methods We coded and analysed fi nancial disbursements for maternal, newborn, and child health (MNCH) and for reproductive health (R*) to all recipient countries worldwide from all donors reporting to the creditor reporting system database for the years 2011–12. We also included grants from the Bill & Melinda Gates Foundation. We analysed trends for MNCH for the period 2003–12 and for R* for the period 2009–12. Findings ODA+ to RMNCH from all donors to all countries worldwide amounted to US$12·2 billion in 2011 (an 11·8$12·8 billion in 2012 (a 5·0% increase relative to 2011). ODA+ to MNCH represents more than 60% of all aid to RMNCH. ODA+ to projects that have newborns as part of the target population has increased 34-fold since 2003. ODA to RMNCH from the 31 donors, which have reported consistently since 2003, to the 75 Countdown priority countries, saw a 3·2% increase in 2011 relative to 2010 ($8·3 billion in 2011), and an 11·8$9·3 billion in 2012). ODA to RMNCH projects has increased with time, whereas general budget support has continuously declined. Bilateral agencies are still the predominant source of ODA to RMNCH. Increased funding to family planning, nutrition, and immunisation projects were noted in 2011 and 2012. ODA+ has been targeted to RMNCH during the period 2005–12, although there is no evidence of improvements in targeting over time. Interpretation Despite a reduction in ODA+ in 2011, ODA+ to RMNCH increased in both 2011 and 2012. The increase in funding is encouraging, but continued increases are needed to accelerate progress towards achieving MDGs 4 and 5 and beyond

Countdown to 2015: changes in official development assistance to reproductive, maternal, newborn, and child health, and assessment of progress between 2003 and 2012.

BACKGROUND: Tracking of aid resources to reproductive, maternal, newborn, and child health (RMNCH) provides timely and crucial information to hold donors accountable. For the first time, we examine flows in official development assistance (ODA) and grants from the Bill & Melinda Gates Foundation (collectively termed ODA+) in relation to the continuum of care for RMNCH and assess progress since 2003. METHODS: We coded and analysed financial disbursements for maternal, newborn, and child health (MNCH) and for reproductive health (R*) to all recipient countries worldwide from all donors reporting to the creditor reporting system database for the years 2011-12. We also included grants from the Bill & Melinda Gates Foundation. We analysed trends for MNCH for the period 2003-12 and for R* for the period 2009-12. FINDINGS: ODA+ to RMNCH from all donors to all countries worldwide amounted to US$12·2 billion in 2011 (an 11·8$12·8 billion in 2012 (a 5·0% increase relative to 2011). ODA+ to MNCH represents more than 60% of all aid to RMNCH. ODA+ to projects that have newborns as part of the target population has increased 34-fold since 2003. ODA to RMNCH from the 31 donors, which have reported consistently since 2003, to the 75 Countdown priority countries, saw a 3·2% increase in 2011 relative to 2010 ($8·3 billion in 2011), and an 11·8$9·3 billion in 2012). ODA to RMNCH projects has increased with time, whereas general budget support has continuously declined. Bilateral agencies are still the predominant source of ODA to RMNCH. Increased funding to family planning, nutrition, and immunisation projects were noted in 2011 and 2012. ODA+ has been targeted to RMNCH during the period 2005-12, although there is no evidence of improvements in targeting over time. INTERPRETATION: Despite a reduction in ODA+ in 2011, ODA+ to RMNCH increased in both 2011 and 2012. The increase in funding is encouraging, but continued increases are needed to accelerate progress towards achieving MDGs 4 and 5 and beyond. FUNDING: Bill & Melinda Gates Foundation

Insulin resistance uncoupled from dyslipidemia due to C-terminal PIK3R1 mutations.

Obesity-related insulin resistance is associated with fatty liver, dyslipidemia, and low plasma adiponectin. Insulin resistance due to insulin receptor (INSR) dysfunction is associated with none of these, but when due to dysfunction of the downstream kinase AKT2 phenocopies obesity-related insulin resistance. We report 5 patients with SHORT syndrome and C-terminal mutations in PIK3R1, encoding the p85α/p55α/p50α subunits of PI3K, which act between INSR and AKT in insulin signaling. Four of 5 patients had extreme insulin resistance without dyslipidemia or hepatic steatosis. In 3 of these 4, plasma adiponectin was preserved, as in insulin receptor dysfunction. The fourth patient and her healthy mother had low plasma adiponectin associated with a potentially novel mutation, p.Asp231Ala, in adiponectin itself. Cells studied from one patient with the p.Tyr657X PIK3R1 mutation expressed abundant truncated PIK3R1 products and showed severely reduced insulin-stimulated association of mutant but not WT p85α with IRS1, but normal downstream signaling. In 3T3-L1 preadipocytes, mutant p85α overexpression attenuated insulin-induced AKT phosphorylation and adipocyte differentiation. Thus, PIK3R1 C-terminal mutations impair insulin signaling only in some cellular contexts and produce a subphenotype of insulin resistance resembling INSR dysfunction but unlike AKT2 dysfunction, implicating PI3K in the pathogenesis of key components of the metabolic syndrome.IHD was supported by the Raymond and Beverly Sackler Foundation via the University of Cambridge MB/PhD programme; RKS, IB, DBS, and SO were supported by the Wellcome Trust (grants WT098498, WT098051, WT107064, and WT095515, respectively and Strategic Award 100574/Z/12/Z), the MRC Metabolic Diseases Unit (MRC_MC_UU_12012/5), and the United Kingdom National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. The work was also supported by the Innovative Medicines Initiative Joint Undertaking under European Medical Information Framework (EMIF) grant agreement number 115372. UK10K was funded by the Wellcome Trust under award WT091310.This is the final version of the article. It first appeared from the American Society for Clinical Investigation via https://doi.org/10.1172/jci.insight.8876

Exome Sequencing Identifies Genes and Gene Sets Contributing to Severe Childhood Obesity, Linking PHIP Variants to Repressed POMC Transcription.

Obesity is genetically heterogeneous with monogenic and complex polygenic forms. Using exome and targeted sequencing in 2,737 severely obese cases and 6,704 controls, we identified three genes (PHIP, DGKI, and ZMYM4) with an excess burden of very rare predicted deleterious variants in cases. In cells, we found that nuclear PHIP (pleckstrin homology domain interacting protein) directly enhances transcription of pro-opiomelanocortin (POMC), a neuropeptide that suppresses appetite. Obesity-associated PHIP variants repressed POMC transcription. Our demonstration that PHIP is involved in human energy homeostasis through transcriptional regulation of central melanocortin signaling has potential diagnostic and therapeutic implications for patients with obesity and developmental delay. Additionally, we found an excess burden of predicted deleterious variants involving genes nearest to loci from obesity genome-wide association studies. Genes and gene sets influencing obesity with variable penetrance provide compelling evidence for a continuum of causality in the genetic architecture of obesity, and explain some of its missing heritability

X-linked primary ciliary dyskinesia due to mutations in the cytoplasmic axonemal dynein assembly factor PIH1D3

By moving essential body fluids and molecules, motile cilia and flagella govern respiratory mucociliary clearance, laterality determination and the transport of gametes and cerebrospinal fluid. Primary ciliary dyskinesia (PCD) is an autosomal recessive disorder frequently caused by non-assembly of dynein arm motors into cilia and flagella axonemes. Before their import into cilia and flagella, multi-subunit axonemal dynein arms are thought to be stabilized and pre-assembled in the cytoplasm through a DNAAF2–DNAAF4–HSP90 complex akin to the HSP90 co-chaperone R2TP complex. Here, we demonstrate that large genomic deletions as well as point mutations involving PIH1D3 are responsible for an X-linked form of PCD causing disruption of early axonemal dynein assembly. We propose that PIH1D3, a protein that emerges as a new player of the cytoplasmic pre-assembly pathway, is part of a complementary conserved R2TP-like HSP90 co-chaperone complex, the loss of which affects assembly of a subset of inner arm dyneins

Significant benefits of AIP testing and clinical screening in familial isolated and young-onset pituitary tumors

Context Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs). Objective To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients. Design 12-year prospective, observational study. Participants & Setting We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases. Interventions & Outcome AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310). Results Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650). Conclusions Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course

Improved imputation of low-frequency and rare variants using the UK10K haplotype reference panel

Imputing genotypes from reference panels created by whole-genome sequencing (WGS) provides a cost-effective strategy for augmenting the single-nucleotide polymorphism (SNP) content of genome-wide arrays. The UK10K Cohorts project has generated a data set of 3,781 whole genomes sequenced at low depth (average 7x), aiming to exhaustively characterize genetic variation down to 0.1% minor allele frequency in the British population. Here we demonstrate the value of this resource for improving imputation accuracy at rare and low-frequency variants in both a UK and an Italian population. We show that large increases in imputation accuracy can be achieved by re-phasing WGS reference panels after initial genotype calling. We also present a method for combining WGS panels to improve variant coverage and downstream imputation accuracy, which we illustrate by integrating 7,562 WGS haplotypes from the UK10K project with 2,184 haplotypes from the 1000 Genomes Project. Finally, we introduce a novel approximation that maintains speed without sacrificing imputation accuracy for rare variants

Targeting DNA Damage Response and Replication Stress in Pancreatic Cancer

Background and aims: Continuing recalcitrance to therapy cements pancreatic cancer (PC) as the most lethal malignancy, which is set to become the second leading cause of cancer death in our society. The study aim was to investigate the association between DNA damage response (DDR), replication stress and novel therapeutic response in PC to develop a biomarker driven therapeutic strategy targeting DDR and replication stress in PC. Methods: We interrogated the transcriptome, genome, proteome and functional characteristics of 61 novel PC patient-derived cell lines to define novel therapeutic strategies targeting DDR and replication stress. Validation was done in patient derived xenografts and human PC organoids. Results: Patient-derived cell lines faithfully recapitulate the epithelial component of pancreatic tumors including previously described molecular subtypes. Biomarkers of DDR deficiency, including a novel signature of homologous recombination deficiency, co-segregates with response to platinum (P < 0.001) and PARP inhibitor therapy (P < 0.001) in vitro and in vivo. We generated a novel signature of replication stress with which predicts response to ATR (P < 0.018) and WEE1 inhibitor (P < 0.029) treatment in both cell lines and human PC organoids. Replication stress was enriched in the squamous subtype of PC (P < 0.001) but not associated with DDR deficiency. Conclusions: Replication stress and DDR deficiency are independent of each other, creating opportunities for therapy in DDR proficient PC, and post-platinum therapy

Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10-5) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10-5). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10-10, odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression