126 research outputs found
The Alzheimer’s Disease Drug Development Landscape
Background: Alzheimer’s disease (AD) is a devastating neurodegenerative disease leading to dementia. The field has made significant progress over the last 15 years. AD diagnosis has shifted from syndromal, based on signs and symptoms, to a biomarker construct based on the pathological hallmarks of the disease: amyloid β deposition, pathologic tau, and neurodegeneration. Numerous genetic risk factors for sporadic AD have been identified, providing further insight into the molecular underpinnings of the disease. For the last two decades, however, drug development for AD has been proven to be particularly challenging. Here, we provide a unique overview of the drug development landscape for AD. By comparing preclinical and clinical drug development pipelines, we aim to describe trends and differences regarding target classes and therapeutic modalities in preclinical and clinical development. Methods: We analyzed proprietary and public databases and company websites for drugs in preclinical development for AD by the pharmaceutical industry and major clinical trial registries for drugs in clinical development for AD. Drugs were categorized by target class and treatment modality. Results: We found a higher proportion of preclinical interventions targeting molecular pathways associated with sporadic AD genetic risk variants, compared to clinical stage interventions. These include apolipoprotein E (ApoE) and lipids, lysosomal/endosomal targets, and proteostasis. Further, we observed a trend suggesting that more traditional therapeutic modalities are developed for these novel targets, while more novel treatment modalities such as gene therapies and enzyme treatments are in development for more traditional targets such as amyloid β and tau. Interestingly, the percentage of amyloid β targeting therapies in preclinical development (19.2%) is even higher than the percentage in clinical development (10.7%), indicating that diversification away from interventions targeting amyloid-beta has not materialized. Inflammation is the second most popular target class in both preclinical and clinical development. Conclusions: Our observations show that the AD drug development pipeline is diversifying in terms of targets and treatment modalities, while amyloid-targeting therapies remain a prominent avenue of development as well. To further advance AD drug development, novel companion diagnostics are needed that are directed at disease mechanisms related to genetic risk factors of AD, both for patient stratification and assessment of therapeutic efficacy in clinical trials
Herd immunity drives the epidemic fadeout of avian cholera in Arctic-nesting seabirds
Avian cholera, caused by the bacterium Pasteurella multocida, is a common and important infectious disease of wild birds in North America. Between 2005 and 2012, avian cholera caused annual mortality of widely varying magnitudes in Northern common eiders (Somateria mollissima borealis) breeding at the largest colony in the Canadian Arctic, Mitivik Island, Nunavut. Although herd immunity, in which a large proportion of the population acquires immunity to the disease, has been suggested to play a role in epidemic fadeout, immunological studies exploring this hypothesis have been missing. We investigated the role of three potential drivers of fadeout of avian cholera in eiders, including immunity, prevalence of infection, and colony size. Each potential driver was examined in relation to the annual real-time reproductive number (Rt) of P. multocida, previously calculated for eiders at Mitivik Island. Each year, colony size was estimated and eiders were closely monitored, and evaluated for infection and serological status. We demonstrate that acquired immunity approximated using antibody titers to P. multocida in both sexes was likely a key driver for the epidemic fadeout. This study exemplifies the importance of herd immunity in influencing the dynamics and fadeout of epidemics in a wildlife population
Multimode solutions of first-order elliptic quasilinear systems obtained from Riemann invariants
Two new approaches to solving first-order quasilinear elliptic systems of
PDEs in many dimensions are proposed. The first method is based on an analysis
of multimode solutions expressible in terms of Riemann invariants, based on
links between two techniques, that of the symmetry reduction method and of the
generalized method of characteristics. A variant of the conditional symmetry
method for constructing this type of solution is proposed. A specific feature
of that approach is an algebraic-geometric point of view, which allows the
introduction of specific first-order side conditions consistent with the
original system of PDEs, leading to a generalization of the Riemann invariant
method for solving elliptic homogeneous systems of PDEs. A further
generalization of the Riemann invariants method to the case of inhomogeneous
systems, based on the introduction of specific rotation matrices, enables us to
weaken the integrability condition. It allows us to establish a connection
between the structure of the set of integral elements and the possibility of
constructing specific classes of simple mode solutions. These theoretical
considerations are illustrated by the examples of an ideal plastic flow in its
elliptic region and a system describing a nonlinear interaction of waves and
particles. Several new classes of solutions are obtained in explicit form,
including the general integral for the latter system of equations
Towards evidence-based marketing: The case of childhood obesity
Contentious commodities such as tobacco, alcohol and fatty foods are bringing marketing under scrutiny from consumers and policymakers. Yet there is little agreement on whether marketing is harmful to society. Systematic review (SR), a methodology derived from clinical medicine, offers marketers a tool for providing resolution and allowing policymakers to proceed with greater confidence. This article describes how SR methods were applied for the first time to a marketing problem -- the effects of food promotion to children. The review withstood scrutiny and its findings were formally ratified by government bodies and policymakers, demonstrating that SR methods can transfer from clinical research to marketing
The COMPARE Data Hubs
Data sharing enables research communities to exchange findings and build upon the knowledge that arises from their discoveries. Areas of public and animal health as well as food safety would benefit from rapid data sharing when it comes to emergencies. However, ethical, regulatory and institutional challenges, as well as lack of suitable platforms which provide an infrastructure for data sharing in structured formats, often lead to data not being shared or at most shared in form of supplementary materials in journal publications. Here, we describe an informatics platform that includes workflows for structured data storage, managing and pre-publication sharing of pathogen sequencing data and its analysis interpretations with relevant stakeholders
The evolution of metallicity and metallicity gradients from z = 2.7 to 0.6 with KMOS<sup>3D</sup>
We present measurements of the [NII]/Ha ratio as a probe of gas-phase oxygen
abundance for a sample of 419 star-forming galaxies at z=0.6-2.7 from the
KMOS3D near-IR multi-IFU survey. The mass-metallicity relation (MZR) is
determined consistently with the same sample selection, metallicity tracer, and
methodology over the wide redshift range probed by the survey. We find good
agreement with long-slit surveys in the literature, except for the low-mass
slope of the relation at z~2.3, where this sample is less biased than previous
samples based on optical spectroscopic redshifts. In this regime we measure a
steeper slope than some literature results. Excluding the AGN contribution from
the MZR reduces sensitivity at the high mass end, but produces otherwise
consistent results. There is no significant dependence of the [NII]/Ha ratio on
SFR or environment at fixed redshift and stellar mass. The IFU data allow
spatially resolved measurements of [NII]/Ha, from which we can infer abundance
gradients for 180 galaxies, thus tripling the current sample in the literature.
The observed gradients are on average flat, with only 15 gradients
statistically offset from zero at >3sigma. We have modelled the effect of
beam-smearing, assuming a smooth intrinsic radial gradient and known seeing,
inclination and effective radius for each galaxy. Our seeing-limited
observations can recover up to 70% of the intrinsic gradient for the largest,
face-on disks, but only 30% for the smaller, more inclined galaxies. We do not
find significant trends between observed or corrected gradients and any stellar
population, dynamical or structural galaxy parameters, mostly in agreement with
existing studies with much smaller sample sizes. In cosmological simulations,
strong feedback is generally required to produce flat gradients at high
redshift.Comment: submitted to Ap
Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk
BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7×10-8, HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4×10-8, HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4×10-8, HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific associat
Histone H3.3 beyond cancer: Germline mutations in Histone 3 Family 3A and 3B cause a previously unidentified neurodegenerative disorder in 46 patients
Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A (H3F3A) or H3F3B with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation
Genome-wide association meta-analyses and fine-mapping elucidate pathways influencing albuminuria
Increased levels of the urinary albumin-to-creatinine ratio (UACR) are associated with higher risk of kidney disease progression and cardiovascular events, but underlying mechanisms are incompletely understood. Here, we conduct trans-ethnic (n = 564,257) and European-ancestry specific meta-analyses of genome-wide association studies of UACR, including ancestry- and diabetes-specific analyses, and identify 68 UACR-associated loci. Genetic correlation analyses and risk score associations in an independent electronic medical records database (n = 192,868) reveal connections with proteinuria, hyperlipidemia, gout, and hypertension. Fine-mapping and trans-Omics analyses with gene expression in 47 tissues and plasma protein levels implicate genes potentially operating through differential expression in kidney (including TGFB1, MUC1, PRKCI, and OAF), and allow coupling of UACR associations to altered plasma OAF concentrations. Knockdown of OAF and PRKCI orthologs in Drosophila nephrocytes reduces albumin endocytosis. Silencing fly PRKCI further impairs slit diaphragm formation. These results generate a priority list of genes and pathways for translational research to reduce albuminuria
- …