Evolving Therapeutic Strategies for the Classic Philadelphia-Negative Myeloproliferative Neoplasms

AbstractDespite the emergence of JAK inhibitors, there is a need for disease-modifying treatments for Philadelphia-negative myeloproliferative neoplasms (MPNs). JAK inhibitors ameliorate symptoms and address splenomegaly, but because of the heterogeneous contributors to the disease process, JAK inhibitor monotherapy incompletely addresses the burden of disease. The ever-growing understanding of MPN pathogenesis has provided the rationale for testing novel and targeted therapeutic agents, as monotherapies or in combination, in preclinical and clinical settings. A number of intriguing options have emerged, and it is hoped that further progress will lead to significant changes in the natural history of MPNs

Symptom profiles and illness course among Anabaptist and Non-Anabaptist adults with major mood disorders

Background: Anabaptists comprise large and growing Amish and Mennonite populations with a unique genetic heritage and cultural background. Little is known about the symptoms and course of major mood disorders in Anabaptists. Even less is known about the impact of potential moderators on symptom severity and course. Methods: A sample of Amish and Mennonite participants with bipolar, recurrent unipolar, or schizoaffective bipolar disorder (n = 155) were systematically evaluated with a well-validated instrument. Cases were compared with non-Anabaptist participants (n = 155) matched for age, sex, and psychiatric diagnosis and evaluated by the same methods. Results: Despite substantial cultural differences, the profile of manic and depressive symptoms during illness episodes did not significantly differ between the two groups. Alcohol use disorder (AUD) was significantly less frequent among Anabaptists, and was associated with more major depressive episodes and more hospitalizations for major depression in Anabaptist, but not non-Anabaptist participants. Lifetime history of head injury showed a trend toward association with more episodes of major depression in both Anabaptist and non-Anabaptist groups that did not withstand multiple test correction. Conclusions: The presentation of a highly heritable psychiatric illness such as bipolar disorder does not differ in cases drawn from genetically unique Anabaptist populations. However, alcohol comorbidity, head injury, and their effects on illness course suggest some differences that deserve further investigation

Amino-terminal dimerization of an erythropoietin mimetic peptide results in increased erythropoietic activity

AbstractBackground: Erythropoietin (EPO), the hormone involved in red blood cell production, activates its receptor by binding to the receptor's extracellular domain and presumably dimerizing two receptor monomers to initiate signal transduction. EPO-mimetic peptides, such as EMP1, also bind and activate the receptor by dimerization. These mimetic peptides are not as potent as EPO, however. The crystal structure of the EPO receptor (EBP) bound to EMP1 reveals the formation of a complex consisting of two peptides bound to two receptors, so we sought to improve the biological activity of EPO-mimetic peptides by constructing covalent dimers of EMP1 and other peptide mimetics linked by polyethylene glycol (PEG).Results: The potency of the PEG-dimerized EPO peptide mimetics both in vitro and in vivo was improved up to 1,000-fold compared to the corresponding peptide monomers. The dinners were constructed using peptide monomers which have only one reactive amine per molecule, allowing us to conclude that the increase in potency can be attributed to a structure in which two peptides are linked through their respective amino termini to the difunctional PEG molecule. In addition, an inactive peptide was converted into a weak agonist by PEG-induced dimerization.Conclusions: The potency of previously isolated peptides that are modest agonists of the EPO receptor was dramatically increased by PEG-induced dimerization. The EPO receptor is thought to be dimerized during activation, so our results are consistent with the proposed 2:2 receptor : peptide stoichiometry. The conversion of an inactive peptide into an agonist further supports the idea that dimerization can mediate receptor activation

Finding Rare, Disease-Associated Variants in Isolated Groups: Potential Advantages of Mennonite Populations

Large-scale genotyping and next-generation sequencing techniques have allowed great advances in the field of molecular genetics. Numerous common variants of low impact have been associated with many complex human traits and diseases, such as bipolar disorder and schizophrenia. Although they may exert a greater impact on risk, few rare disease variants have been found, owing to the greatly increased sample sizes that are typically necessary to demonstrate association with rarer variants. One alternative strategy is to study isolated populations, where historical bottlenecks reduce genetic diversity and some otherwise rare variants may drift to higher frequencies. Here we describe the Mennonite population settlements, considering their history of multiple bottlenecks followed by demographic expansion and a currently widespread geographical distribution. We argue that Mennonite populations are valuable partners for studies seeking genetic variants that exert a high impact on risk for a variety of common disorders, including mental illnesses

Genetic Overlap Profiles of Cognitive Ability in Psychotic and Affective Illnesses: A Multisite Study of Multiplex Pedigrees

Background: Cognitive impairment is a key feature of psychiatric illness, making cognition an important tool for exploring of the genetics of illness risk. It remains unclear which measures should be prioritized in pleiotropy-guided research. Here, we generate profiles of genetic overlap between psychotic and affective disorders and cognitive measures in Caucasian and Hispanic groups. Methods: Data were from 4 samples of extended pedigrees (N = 3046). Coefficient of relationship analyses were used to estimate genetic overlap between illness risk and cognitive ability. Results were meta-analyzed. Results: Psychosis was characterized by cognitive impairments on all measures with a generalized profile of genetic overlap. General cognitive ability shared greatest genetic overlap with psychosis risk (average endophenotype ranking value [ERV] across samples from a random-effects meta-analysis = 0.32), followed by verbal memory (ERV = 0.24), executive function (ERV = 0.22), and working memory (ERV = 0.21). For bipolar disorder, there was genetic overlap with processing speed (ERV = 0.05) and verbal memory (ERV = 0.11), but these were confined to select samples. Major depressive disorder was characterized by enhanced working and face memory performance, as reflected in significant genetic overlap in 2 samples. Conclusions: There is substantial genetic overlap between risk for psychosis and a range of cognitive abilities (including general intelligence). Most of these effects are largely stable across of ascertainment strategy and ethnicity. Genetic overlap between affective disorders and cognition, on the other hand, tends to be specific to ascertainment strategy, ethnicity, and cognitive test battery

Birds and people: from conflict to coexistence

Negative interactions between humans and animals are becoming increasingly frequent, as wild habitats shrink and human presence and activities expand throughout the world. Conflicts between people over conservation are one of the outcomes of this increased interaction, with severe consequences for both wildlife and people. Globally, conflicts can arise across diverse ecosystems, species and circumstances. Even if most attention in wildlife-related conflicts has been on mammals, birds are also often at the centre of such conflicts, but conflict research is still not explicitly present in ornithological literature. Examples of such conflicts include those related to birds and agriculture, forestry, hunting, fishing and public health interests. Conflicts are often more complex than initial assessments might suggest, involving ecological, economic, cultural, social and political elements. Reflecting the complexity of these issues and their increasing relevance to bird conservation, a British Ornithologists' Union conference was organized in November 2021 that aimed to highlight examples of conflicts that exist between people over birds and their conservation. Building on this conference, we provide here a review of key themes relating to the understanding of conflicts, including the importance of conflict perceptions, the collaboration between multiple disciplines and the different types of knowledge needed to better understand conflicts. We then consider the management of bird conservation conflicts, including the key issues of dealing with uncertainty, the role of technical solutions and the importance of collaboration and building trust, illustrating each theme with real-world examples. Finally, we outline potential future conflicts around bird conservation and how best to address them proactively

The evolution of Omega(HI) and the epoch of formation of damped Lyman-alpha absorbers

We present a study of the evolution of the column density distribution, f(N,z), and total neutral hydrogen mass in high-column density quasar absorbers using candidates from a recent high-redshift survey for damped Lyman-alpha (DLA) and Lyman limit system (LLS) absorbers. The observed number of LLS (N(HI)> 1.6 * 10^{17} atom/cm^2) is used to constrain f(N,z) below the classical DLA Wolfe et al. (1986) definition of 2 * 10^{20} atom/cm^2. The joint LLS-DLA analysis shows unambiguously that f(N,z) deviates significantly from a single power law and that a Gamma-law distribution of the form f(N,z)=(f_*/N_*)(N/N_*)^{-Beta} exp(-N/N_*) provides a better description of the observations. These results are used to determine the amount of neutral gas contained in DLAs and in systems with lower column density. Whilst in the redshift range 2 to 3.5, ~90% of the neutral HI mass is in DLAs, we find that at z>3.5 this fraction drops to only 55% and that the remaining 'missing' mass fraction of the neutral gas lies in sub-DLAs with N(HI) 10^{19} - 2 * 10^{20} atom/cm^2. The characteristic column density, N_*, changes from 1.6 * 10^{21} atom/cm^2 at z3.5, supporting a picture where at z>3.5, we are directly observing the formation of high column density neutral hydrogen DLA systems from lower column density units. Moreover since current metallicity studies of DLA systems focus on the higher column density systems they may be giving a biased or incomplete view of global galactic chemical evolution at z>3. After correcting the observed mass in HI for the ``missing'' neutral gas the comoving mass density now shows no evidence for a decrease above z=2. (abridged)Comment: Replaced to match version published in MNRAS. One figure and appendix added, analysis and conclusions unchange

ImpZ: a new photometric redshift code for galaxies and quasars

We present a combined galaxy-quasar approach to template-fitting photometric redshift techniques and show the method to be a powerful one. The code (ImpZ) is presented, developed and applied to two spectroscopic redshift catalogues, namely the Isaac Newton Telescope Wide Angle Survey ELAIS N1 and N2 fields and the Chandra Deep Field North. In particular, optical size information is used to improve the redshift determination. The success of the code is shown to be very good with Delta z/(1+z) constrained to within 0.1 for 92 per cent of the galaxies in our sample. The extension of template-fitting to quasars is found to be reasonable with Delta z/(1+z) constrained to within 0.25 for 68 per cent of the quasars in our sample. Various template extensions into the far-UV are also tested.Comment: 21 pages. MNRAS in press. Minor alterations to match MNRAS final proo

Author Correction: A population-specific reference panel empowers genetic studies of Anabaptist populations.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper

Characterisation of age and polarity at onset in bipolar disorder

BACKGROUND Studying phenotypic and genetic characteristics of age at onset (AAO) and polarity at onset (PAO) in bipolar disorder can provide new insights into disease pathology and facilitate the development of screening tools. AIMS To examine the genetic architecture of AAO and PAO and their association with bipolar disorder disease characteristics. METHOD Genome-wide association studies (GWASs) and polygenic score (PGS) analyses of AAO (n = 12 977) and PAO (n = 6773) were conducted in patients with bipolar disorder from 34 cohorts and a replication sample (n = 2237). The association of onset with disease characteristics was investigated in two of these cohorts. RESULTS Earlier AAO was associated with a higher probability of psychotic symptoms, suicidality, lower educational attainment, not living together and fewer episodes. Depressive onset correlated with suicidality and manic onset correlated with delusions and manic episodes. Systematic differences in AAO between cohorts and continents of origin were observed. This was also reflected in single-nucleotide variant-based heritability estimates, with higher heritabilities for stricter onset definitions. Increased PGS for autism spectrum disorder (β = -0.34 years, s.e. = 0.08), major depression (β = -0.34 years, s.e. = 0.08), schizophrenia (β = -0.39 years, s.e. = 0.08), and educational attainment (β = -0.31 years, s.e. = 0.08) were associated with an earlier AAO. The AAO GWAS identified one significant locus, but this finding did not replicate. Neither GWAS nor PGS analyses yielded significant associations with PAO. CONCLUSIONS AAO and PAO are associated with indicators of bipolar disorder severity. Individuals with an earlier onset show an increased polygenic liability for a broad spectrum of psychiatric traits. Systematic differences in AAO across cohorts, continents and phenotype definitions introduce significant heterogeneity, affecting analyses