Identification and optimization of small molecule antagonists of vasoactive intestinal peptide receptor-1 (VIPR1)

Identification, synthesis and structure-activity relationship of small-molecule VIPR1 antagonists encompassing two chemical series are described

Expression profiling of clonal lymphocyte cell cultures from Rett syndrome patients

BACKGROUND: More than 85% of Rett syndrome (RTT) patients have heterozygous mutations in the X-linked MECP2 gene which encodes methyl-CpG-binding protein 2, a transcriptional repressor that binds methylated CpG sites. Because MECP2 is subject to X chromosome inactivation (XCI), girls with RTT express either the wild type or mutant MECP2 in each of their cells. To test the hypothesis that MECP2 mutations result in genome-wide transcriptional deregulation and identify its target genes in a system that circumvents the functional mosaicism resulting from XCI, we performed gene expression profiling of pure populations of untransformed T-lymphocytes that express either a mutant or a wild-type allele. METHODS: Single T lymphocytes from a patient with a c.473C>T (p.T158M) mutation and one with a c.1308-1309delTC mutation were subcloned and subjected to short term culture. Gene expression profiles of wild-type and mutant clones were compared by oligonucleotide expression microarray analysis. RESULTS: Expression profiling yielded 44 upregulated genes and 77 downregulated genes. We compared this gene list with expression profiles of independent microarray experiments in cells and tissues of RTT patients and mouse models with Mecp2 mutations. These comparisons identified a candidate MeCP2 target gene, SPOCK1, downregulated in two independent microarray experiments, but its expression was not altered by quantitative RT-PCR analysis on brain tissues from a RTT mouse model. CONCLUSION: Initial expression profiling from T-cell clones of RTT patients identified a list of potential MeCP2 target genes. Further detailed analysis and comparison to independent microarray experiments did not confirm significantly altered expression of most candidate genes. These results are consistent with other reported data

Estimates of global, regional, and national incidence, prevalence, and mortality of HIV, 1980-2015: the Global Burden of Disease Study 2015

Timely assessment of the burden of HIV/AIDS is essential for policy setting and programme evaluation. In this report from the Global Burden of Disease Study 2015 (GBD 2015), we provide national estimates of levels and trends of HIV/AIDS incidence, prevalence, coverage of antiretroviral therapy (ART), and mortality for 195 countries and territories from 1980 to 2015.For countries without high-quality vital registration data, we estimated prevalence and incidence with data from antenatal care clinics and population-based seroprevalence surveys, and with assumptions by age and sex on initial CD4 distribution at infection, CD4 progression rates (probability of progression from higher to lower CD4 cell-count category), on and off antiretroviral therapy (ART) mortality, and mortality from all other causes. Our estimation strategy links the GBD 2015 assessment of all-cause mortality and estimation of incidence and prevalence so that for each draw from the uncertainty distribution all assumptions used in each step are internally consistent. We estimated incidence, prevalence, and death with GBD versions of the Estimation and Projection Package (EPP) and Spectrum software originally developed by the Joint United Nations Programme on HIV/AIDS (UNAIDS). We used an open-source version of EPP and recoded Spectrum for speed, and used updated assumptions from systematic reviews of the literature and GBD demographic data. For countries with high-quality vital registration data, we developed the cohort incidence bias adjustment model to estimate HIV incidence and prevalence largely from the number of deaths caused by HIV recorded in cause-of-death statistics. We corrected these statistics for garbage coding and HIV misclassification.Global HIV incidence reached its peak in 1997, at 3·3 million new infections (95% uncertainty interval [UI] 3·1-3·4 million). Annual incidence has stayed relatively constant at about 2·6 million per year (range 2·5-2·8 million) since 2005, after a period of fast decline between 1997 and 2005. The number of people living with HIV/AIDS has been steadily increasing and reached 38·8 million (95% UI 37·6-40·4 million) in 2015. At the same time, HIV/AIDS mortality has been declining at a steady pace, from a peak of 1·8 million deaths (95% UI 1·7-1·9 million) in 2005, to 1·2 million deaths (1·1-1·3 million) in 2015. We recorded substantial heterogeneity in the levels and trends of HIV/AIDS across countries. Although many countries have experienced decreases in HIV/AIDS mortality and in annual new infections, other countries have had slowdowns or increases in rates of change in annual new infections.Scale-up of ART and prevention of mother-to-child transmission has been one of the great successes of global health in the past two decades. However, in the past decade, progress in reducing new infections has been slow, development assistance for health devoted to HIV has stagnated, and resources for health in low-income countries have grown slowly. Achievement of the new ambitious goals for HIV enshrined in Sustainable Development Goal 3 and the 90-90-90 UNAIDS targets will be challenging, and will need continued efforts from governments and international agencies in the next 15 years to end AIDS by 2030.Bill & Melinda Gates Foundation, and National Institute of Mental Health and National Institute on Aging, National Institutes of Health

Measuring progress from 1990 to 2017 and projecting attainment to 2030 of the health-related Sustainable Development Goals for 195 countries and territories: a systematic analysis for the Global Burden of Disease Study 2017

Background Efforts to establish the 2015 baseline and monitor early implementation of the UN Sustainable Development Goals (SDGs) highlight both great potential for and threats to improving health by 2030. To fully deliver on the SDG aim of “leaving no one behind”, it is increasingly important to examine the health-related SDGs beyond national-level estimates. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017), we measured progress on 41 of 52 health-related SDG indicators and estimated the health-related SDG index for 195 countries and territories for the period 1990–2017, projected indicators to 2030, and analysed global attainment. Methods We measured progress on 41 health-related SDG indicators from 1990 to 2017, an increase of four indicators since GBD 2016 (new indicators were health worker density, sexual violence by non-intimate partners, population census status, and prevalence of physical and sexual violence [reported separately]). We also improved the measurement of several previously reported indicators. We constructed national-level estimates and, for a subset of health-related SDGs, examined indicator-level differences by sex and Socio-demographic Index (SDI) quintile. We also did subnational assessments of performance for selected countries. To construct the healthrelated SDG index, we transformed the value for each indicator on a scale of 0–100, with 0 as the 2·5th percentile and 100 as the 97·5th percentile of 1000 draws calculated from 1990 to 2030, and took the geometric mean of the scaled indicators by target. To generate projections through 2030, we used a forecasting framework that drew estimates from the broader GBD study and used weighted averages of indicator-specific and country-specific annualised rates of change from 1990 to 2017 to inform future estimates. We assessed attainment of indicators with defined targets in two ways: first, using mean values projected for 2030, and then using the probability of attainment in 2030 calculated from 1000 draws. We also did a global attainment analysis of the feasibility of attaining SDG targets on the basis of past trends. Using 2015 global averages of indicators with defined SDG targets, we calculated the global annualised rates of change required from 2015 to 2030 to meet these targets, and then identified in what percentiles the required global annualised rates of change fell in the distribution of country-level rates of change from 1990 to 2015. We took the mean of these global percentile values across indicators and applied the past rate of change at this mean global percentile to all health-related SDG indicators, irrespective of target definition, to estimate the equivalent 2030 global average value and percentage change from 2015 to 2030 for each indicator. Findings The global median health-related SDG index in 2017 was 59·4 (IQR 35·4–67·3), ranging from a low of 11·6 (95% uncertainty interval 9·6–14·0) to a high of 84·9 (83·1–86·7). SDG index values in countries assessed at the subnational level varied substantially, particularly in China and India, although scores in Japan and the UK were more homogeneous. Indicators also varied by SDI quintile and sex, with males having worse outcomes than females for non-communicable disease (NCD) mortality, alcohol use, and smoking, among others. Most countries were projected to have a higher health-related SDG index in 2030 than in 2017, while country-level probabilities of attainment by 2030 varied widely by indicator. Under-5 mortality, neonatal mortality, maternal mortality ratio, and malaria indicators had the most countries with at least 95% probability of target attainment. Other indicators, including NCD mortality and suicide mortality, had no countries projected to meet corresponding SDG targets on the basis of projected mean values for 2030 but showed some probability of attainment by 2030. For some indicators, including child malnutrition, several infectious diseases, and most violence measures, the annualised rates of change required to meet SDG targets far exceeded the pace of progress achieved by any country in the recent past. We found that applying the mean global annualised rate of change to indicators without defined targets would equate to about 19% and 22% reductions in global smoking and alcohol consumption, respectively; a 47% decline in adolescent birth rates; and a more than 85% increase in health worker density per 1000 population by 2030. Interpretation The GBD study offers a unique, robust platform for monitoring the health-related SDGs across demographic and geographic dimensions. Our findings underscore the importance of increased collection and analysis of disaggregated data and highlight where more deliberate design or targeting of interventions could accelerate progress in attaining the SDGs. Current projections show that many health-related SDG indicators, NCDs, NCD-related risks, and violence-related indicators will require a concerted shift away from what might have driven past gains—curative interventions in the case of NCDs—towards multisectoral, prevention-oriented policy action and investments to achieve SDG aims. Notably, several targets, if they are to be met by 2030, demand a pace of progress that no country has achieved in the recent past. The future is fundamentally uncertain, and no model can fully predict what breakthroughs or events might alter the course of the SDGs. What is clear is that our actions—or inaction—today will ultimately dictate how close the world, collectively, can get to leaving no one behind by 2030

Measurements of inclusive and differential Higgs boson production cross sections at √s = 13.6 TeV in the H → γγ decay channel

Data Availability Statement: This article has no associated data or the data will not be deposited. Release and preservation of data used by the CMS Collaboration as the basis for publications is guided by the CMS data preservation, re-use and open access policy.Code Availability Statement: This article has no associated code or the code will not be deposited. The CMS core software is publicly available on GitHub.A preprint version of the article is available at arXiv:2504.17755v2 [hep-ex], https://arxiv.org/abs/2504.17755 . Comments: Replaced with the published version. Added the journal reference and the DOI. All the figures and tables, including additional supplementary figures, can be found at https://cms-results.web.cern.ch/cms-results/public-results/publications/HIG-23-014 (CMS Public Pages). Report number: CMS-HIG-23-014, CERN-EP-2025-067. Journal reference: JHEP 09 (2025) 070.Inclusive and differential cross sections for Higgs boson production in proton-proton collisions at a centre-of-mass energy of 13.6 TeV are measured using data collected with the CMS detector at the LHC in 2022, corresponding to an integrated luminosity of 34.7 fb^-1. Events with the diphoton final state are selected, and the measured inclusive fiducial cross section is σfid = 74 ± 11 (stat) [+5 -4] (syst) fb, in agreement with the standard model prediction of 67.8 ± 3.8 fb. Differential cross sections are measured as functions of several observables: the Higgs boson transverse momentum and rapidity, the number of associated jets, and the transverse momentum of the leading jet in the event. Within the uncertainties, the differential cross sections agree with the standard model predictions.SCOAP3

Measuring progress from 1990 to 2017 and projecting attainment to 2030 of the health-related Sustainable Development Goals for 195 countries and territories: a systematic analysis for the Global Burden of Disease Study 2017

Background: Efforts to establish the 2015 baseline and monitor early implementation of the UN Sustainable Development Goals (SDGs) highlight both great potential for and threats to improving health by 2030. To fully deliver on the SDG aim of “leaving no one behind”, it is increasingly important to examine the health-related SDGs beyond national-level estimates. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2017 (GBD 2017), we measured progress on 41 of 52 health-related SDG indicators and estimated the health-related SDG index for 195 countries and territories for the period 1990–2017, projected indicators to 2030, and analysed global attainment. Methods: We measured progress on 41 health-related SDG indicators from 1990 to 2017, an increase of four indicators since GBD 2016 (new indicators were health worker density, sexual violence by non-intimate partners, population census status, and prevalence of physical and sexual violence [reported separately]). We also improved the measurement of several previously reported indicators. We constructed national-level estimates and, for a subset of health-related SDGs, examined indicator-level differences by sex and Socio-demographic Index (SDI) quintile. We also did subnational assessments of performance for selected countries. To construct the health-related SDG index, we transformed the value for each indicator on a scale of 0–100, with 0 as the 2·5th percentile and 100 as the 97·5th percentile of 1000 draws calculated from 1990 to 2030, and took the geometric mean of the scaled indicators by target. To generate projections through 2030, we used a forecasting framework that drew estimates from the broader GBD study and used weighted averages of indicator-specific and country-specific annualised rates of change from 1990 to 2017 to inform future estimates. We assessed attainment of indicators with defined targets in two ways: first, using mean values projected for 2030, and then using the probability of attainment in 2030 calculated from 1000 draws. We also did a global attainment analysis of the feasibility of attaining SDG targets on the basis of past trends. Using 2015 global averages of indicators with defined SDG targets, we calculated the global annualised rates of change required from 2015 to 2030 to meet these targets, and then identified in what percentiles the required global annualised rates of change fell in the distribution of country-level rates of change from 1990 to 2015. We took the mean of these global percentile values across indicators and applied the past rate of change at this mean global percentile to all health-related SDG indicators, irrespective of target definition, to estimate the equivalent 2030 global average value and percentage change from 2015 to 2030 for each indicator. Findings: The global median health-related SDG index in 2017 was 59·4 (IQR 35·4–67·3), ranging from a low of 11·6 (95% uncertainty interval 9·6–14·0) to a high of 84·9 (83·1–86·7). SDG index values in countries assessed at the subnational level varied substantially, particularly in China and India, although scores in Japan and the UK were more homogeneous. Indicators also varied by SDI quintile and sex, with males having worse outcomes than females for non-communicable disease (NCD) mortality, alcohol use, and smoking, among others. Most countries were projected to have a higher health-related SDG index in 2030 than in 2017, while country-level probabilities of attainment by 2030 varied widely by indicator. Under-5 mortality, neonatal mortality, maternal mortality ratio, and malaria indicators had the most countries with at least 95% probability of target attainment. Other indicators, including NCD mortality and suicide mortality, had no countries projected to meet corresponding SDG targets on the basis of projected mean values for 2030 but showed some probability of attainment by 2030. For some indicators, including child malnutrition, several infectious diseases, and most violence measures, the annualised rates of change required to meet SDG targets far exceeded the pace of progress achieved by any country in the recent past. We found that applying the mean global annualised rate of change to indicators without defined targets would equate to about 19% and 22% reductions in global smoking and alcohol consumption, respectively; a 47% decline in adolescent birth rates; and a more than 85% increase in health worker density per 1000 population by 2030. Interpretation: The GBD study offers a unique, robust platform for monitoring the health-related SDGs across demographic and geographic dimensions. Our findings underscore the importance of increased collection and analysis of disaggregated data and highlight where more deliberate design or targeting of interventions could accelerate progress in attaining the SDGs. Current projections show that many health-related SDG indicators, NCDs, NCD-related risks, and violence-related indicators will require a concerted shift away from what might have driven past gains—curative interventions in the case of NCDs—towards multisectoral, prevention-oriented policy action and investments to achieve SDG aims. Notably, several targets, if they are to be met by 2030, demand a pace of progress that no country has achieved in the recent past. The future is fundamentally uncertain, and no model can fully predict what breakthroughs or events might alter the course of the SDGs. What is clear is that our actions—or inaction—today will ultimately dictate how close the world, collectively, can get to leaving no one behind by 2030

Search for new Higgs bosons via same-sign top quark pair production in association with a jet in proton-proton collisions at √s = 13 TeV

Data availability: Release and preservation of data used by the CMS Collaboration as the basis for publications is guided by the CMS policy as stated in “CMS data preservation, re-use and open access policy” available online at: https://cms-docdb.cern.ch/cgi-bin/PublicDocDB/RetrieveFile?docid=6032&filename=CMSDataPolicyV1.2.pdf&version=2 .A preprint of this article is available online at arXiv:2311.03261v2 [hep-ex] https://arxiv.org/abs/2311.03261v2 . Comments: Replaced with the published version. Added the journal reference and the DOI. All the figures and tables can be found at https://cms-results.web.cern.ch/cms-results/public-results/publications/TOP-22-010 (CMS Public Pages)A search is presented for new Higgs bosons in proton-proton (pp) collision events in which a same-sign top quark pair is produced in association with a jet, via the pp → tH/A → tt¯c and pp → tH/A → tt¯u processes. Here, H and A represent the extra scalar and pseudoscalar boson, respectively, of the second Higgs doublet in the generalized two-Higgs-doublet model (g2HDM). The search is based on pp collision data collected at a center-of-mass energy of 13 TeV with the CMS detector at the LHC, corresponding to an integrated luminosity of 138 fb−1. Final states with a same-sign lepton pair in association with jets and missing transverse momentum are considered. New Higgs bosons in the 200-1000 GeV mass range and new Yukawa couplings between 0.1 and 1.0 are targeted in the search, for scenarios in which either H or A appear alone, or in which they coexist and interfere. No significant excess above the standard model prediction is observed. Exclusion limits are derived in the context of the g2HDM.SCOAP3

Energy-scaling behavior of intrinsic transverse-momentum parameters in Drell-Yan simulation

Data Availability: Release and preservation of data used by the CMS Collaboration as the basis for publications is guided by the CMS data preservation, re-use, and open access policy https://dx.doi.org/10.7483/OPENDATA.CMS.7347.JDWH .A preprint version of the article is available on arXiv, arXiv:2409.17770v2 [hep-ph] (https://arxiv.org/abs/2409.17770). [v2] Tue, 8 Apr 2025 23:23:48 UTC (450 KB). Comments: Replaced with the published version. Added the journal reference and the DOI. All the figures and tables can be found at https://cms-results.web.cern.ch/cms-results/public-results/publications/GEN-22-001 (CMS Public Pages). Subjects: High Energy Physics - Phenomenology (hep-ph); High Energy Physics - Experiment (hep-ex). Report numbers: CMS-GEN-22-001, CERN-EP-2024-216An analysis is presented based on models of the intrinsic transverse momentum (intrinsic ) of partons in nucleons by studying the dilepton transverse momentum in Drell-Yan events. Using parameter tuning in event generators and existing data from fixed-target experiments and from hadron colliders, our investigation spans 3 orders of magnitude in center-of-mass energy and 2 orders of magnitude in dilepton invariant mass. The results show an energy-scaling behavior of the intrinsic parameters, independent of the dilepton invariant mass at a given center-of-mass energy.We congratulate our colleagues in the CERN accelerator departments for the excellent performance of the LHC and thank the technical and administrative staffs at CERN and at other CMS institutes for their contributions to the success of the CMS effort. In addition, we gratefully acknowledge the computing centers and personnel of the Worldwide LHC Computing Grid and other centers for delivering so effectively the computing infrastructure essential to our analyses. Finally, we acknowledge the enduring support for the construction and operation of the LHC, the CMS detector, and the supporting computing infrastructure provided by the following funding agencies: SC (Armenia), BMBWF and FWF (Austria); FNRS and FWO (Belgium); CNPq, CAPES, FAPERJ, FAPERGS, and FAPESP (Brazil); MES and BNSF (Bulgaria); CERN; CAS, MoST, and NSFC (China); MINCIENCIAS (Colombia); MSES and CSF (Croatia); RIF (Cyprus); SENESCYT (Ecuador); ERC PRG, RVTT3 and MoER TK202 (Estonia); Academy of Finland, MEC, and HIP (Finland); CEA and CNRS/IN2P3 (France); SRNSF (Georgia); BMBF, DFG, and HGF (Germany); GSRI (Greece); NKFIH (Hungary); DAE and DST (India); IPM (Iran); SFI (Ireland); INFN (Italy); MSIP and NRF (Republic of Korea); MES (Latvia); LMTLT (Lithuania); MOE and UM (Malaysia); BUAP, CINVESTAV, CONACYT, LNS, SEP, and UASLP-FAI (Mexico); MOS (Montenegro); MBIE (New Zealand); PAEC (Pakistan); MES and NSC (Poland); FCT (Portugal); MESTD (Serbia); MCIN/AEI and PCTI (Spain); MOSTR (Sri Lanka); Swiss Funding Agencies (Switzerland); MST (Taipei); MHESI and NSTDA (Thailand); TUBITAK and TENMAK (Turkey); NASU (Ukraine); STFC (United Kingdom); DOE and NSF (USA)

Evidence for tWZ production in proton-proton collisions at √s=13 TeV in multilepton final states

Data availability - https://www.sciencedirect.com/science/article/pii/S0370269324003733?via%3Dihub#dav0001 [Release and preservation of data used by the CMS Collaboration as the basis for publications is guided by the CMS data preservation, re-use and open access policy (https://cms-docdb.cern.ch/cgi-bin/PublicDocDB/RetrieveFile?docid=6032&filename=CMSDataPolicyV1.2.pdf&version=2)]The first evidence for the standard model production of a top quark in association with a W boson and a Z boson is reported. The measurement is performed in multilepton final states, where the Z boson is reconstructed via its decays to electron or muon pairs. At least one W boson, associated or from top quark decay, decays leptonically, too. The analysed data were recorded by the CMS experiment at the CERN LHC in 2016–2018 in proton-proton collisions at √s=13 TeV, and correspond to an integrated luminosity of 138 fb−1. The measured cross section is 354±54(stat)±95(syst) fb, and corresponds to a statistical significance of 3.4 standard deviations.SCOAP

Measurement of energy correlators inside jets and determination of the strong coupling αS(mZ)

A preprint version of this article is available at arXiv:2402.13864v2 [hep-ex], https://arxiv.org/abs/2402.13864 . Comments: Replaced with the published version. Added the journal reference and the DOI. All the figures and tables can be found at https://cms-results.web.cern.ch/cms-results/public-results/publications/SMP-22-015 (CMS Public Pages). Report number: CMS-SMP-22-015, CERN-EP-2024-010 .Energy correlators that describe energy-weighted distances between two or three particles in a hadronic jet are measured using an event sample of √ = 13  TeV proton-proton collisions collected by the CMS experiment and corresponding to an integrated luminosity of 36.3  fb^−1. The measured distributions are consistent with the trends in the simulation that reveal two key features of the strong interaction: confinement and asymptotic freedom. By comparing the ratio of the measured three- and two-particle energy correlator distributions with theoretical calculations that resum collinear emissions at approximate next-to-next-to-leading-logarithmic accuracy matched to a next-to-leading-order calculation, the strong coupling is determined at the boson mass: ⁡() = 0.122⁢9+0.0040 −0.0050, the most precise ⁡() value obtained using jet substructure observables.SCOAP3