Genetic architecture of band neutrophil fraction in Iceland

Publisher Copyright: © 2022, The Author(s).The characteristic lobulated nuclear morphology of granulocytes is partially determined by composition of nuclear envelope proteins. Abnormal nuclear morphology is primarily observed as an increased number of hypolobulated immature neutrophils, called band cells, during infection or in rare envelopathies like Pelger-Huët anomaly. To search for sequence variants affecting nuclear morphology of granulocytes, we performed a genome-wide association study using band neutrophil fraction from 88,101 Icelanders. We describe 13 sequence variants affecting band neutrophil fraction at nine loci. Five of the variants are at the Lamin B receptor (LBR) locus, encoding an inner nuclear membrane protein. Mutations in LBR are linked to Pelger-Huët anomaly. In addition, we identify cosegregation of a rare stop-gain sequence variant in LBR and Pelger Huët anomaly in an Icelandic eight generation pedigree, initially reported in 1963. Two of the other loci include genes which, like LBR, play a role in the nuclear membrane function and integrity. These GWAS results highlight the role proteins of the inner nuclear membrane have as important for neutrophil nuclear morphology.Peer reviewe

Risks and benefits of lethal male fighting in the colonial, polygynous thrips Hoplothrips karnyi (Insecta: Thysanoptera)

Males of Hoplothrips karnyi (Hood) (Insecta: Thysanoptera), a colonial fungus-feeding thrips, fight each other in defense of communal egg mass sites, where they mate with females that come to oviposit. Fighting males stab each other with their enlarged, armed forelegs and hit each other with their abdomens. Escalated fights occur between large males of similar size. Fights are often lethal; males that died during observations fought more frequently than other males, were stabbed more often and more severely than other males, and were relatively large, but somewhat smaller than their opponents. Large males tend to win fights and guard egg masses, and they secure about 80% of last matings before ovipositions. Guarding males apparently assess female reproductive condition by putting their forelegs partially around females' abdomens; guarding males, but not nonguarding males, mate preferentially with females that have yet to oviposit. Non-guarding males mate with females away from egg masses, sneak matings at egg masses, and occasionally challenge guarding males. Challenges tend to follow matings by non-guarding males at egg masses. Each of four observed or inferred takeovers was followed by the death of the guarding male that lost. Male fighting strategies are discussed in terms of the consistency of lethal fighting with game theory models. Guardin males appear to pursue a classical “hawk” strategy of “escalate until injured or victorious”. This strategy may be advantageous because only large males become guarders, the mating success of guarders greatly exceeds that of non-guarders, and high population viscosity ensures that benefits from killing an opponent accrue directly to gaurders. The occurrence of challenges by large non-guarders implies that fighting ability and resource value asymmetries between males change over time; such changes may result from the energetic costs of guarding, injury to guarding males, or depletion of guarding males' supply of sperm.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46885/1/265_2004_Article_BF00299845.pd

Adaptation, compromise, and constraint: the development, morphometrics, and behavioral basis of a fighter-flier polymorphism in male Hoplothrips karnyi (Insecta: Thysanoptera)

Males of the colonial, wing-polymorphic thrips Hoplothrips karnyi (Hood) fight each other with their forelegs in defense of communal female oviposition areas. In this study, males were reared individually under varying conditions of food deprivation to investigate the developmental cues used in morph determination and the relationships between wing morph, developmental time in each instar, propupal weight, and five adult morphological characters associated with fighting ability and dispersal ability. Males deprived of food for five days midway through the second (final) larval instar had smaller propupal weights and were more likely to develop wings than males deprived of food in the first instar or control males. However, the mean propupal weight of all males that developed wings was not significantly less than that of wingless males. Wing morph of female parents had no measurable effect on this character in the offspring. Wingless males possess relatively larger fore-femora and prothoraces than do winged males, but winged males possess relatively larger pterothoraces (Fig. 1). Behavioral observations of wingless and winged males of similar weight as propupae showed that wingless males won fights and became dominant in oviposition areas. Thus, a trade-off exists between characters associated with male fighting and dispersal ability. The cost of wings, in terms of fore-femora size and prothorax size, increased with propupal weight. Wingless males that developed in the experimental treatment that produced a high proportion of winged males were relatively small in size, and were intermediate in body shape with respect to winged males and other wingless males (Fig. 2). This shape intermediacy indicates that there may be developmental constraints on alternative tactics of resource allocation. Total developmental time varied between wing morphs, but was not correlated with propupal weight or adult morphological characters of winged or wingless males. For wingless males that developed in the treatment that produced a high proportion of winged males, adult morphological characters were negatively correlated with the duration of the second instar. This correlation suggests that the development of small wingless males involves a compromise between the benefits of large adult size and the costs of prolonging the second instar to increase the probability of becoming larger.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/46886/1/265_2004_Article_BF00299892.pd

Genetic variants associated with mosaic Y chromosome loss highlight cell cycle genes and overlap with cancer susceptibility.

The Y chromosome is frequently lost in hematopoietic cells, which represents the most common somatic alteration in men. However, the mechanisms that regulate mosaic loss of chromosome Y (mLOY), and its clinical relevance, are unknown. We used genotype-array-intensity data and sequence reads from 85,542 men to identify 19 genomic regions (P < 5 × 10-8) that are associated with mLOY. Cumulatively, these loci also predicted X chromosome loss in women (n = 96,123; P = 4 × 10-6). Additional epigenome-wide methylation analyses using whole blood highlighted 36 differentially methylated sites associated with mLOY. The genes identified converge on aspects of cell proliferation and cell cycle regulation, including DNA synthesis (NPAT), DNA damage response (ATM), mitosis (PMF1, CENPN and MAD1L1) and apoptosis (TP53). We highlight the shared genetic architecture between mLOY and cancer susceptibility, in addition to inferring a causal effect of smoking on mLOY. Collectively, our results demonstrate that genotype-array-intensity data enables a measure of cell cycle efficiency at population scale and identifies genes implicated in aneuploidy, genome instability and cancer susceptibility.This research has been conducted using the UK Biobank Resource under Application Number 9905. This work was supported by the UK Medical Research Council (Unit Programme numbers MC_UU_12015/1 and MC_UU_12015/2). Research in the S. Jackson laboratory is funded by Cancer Research UK (CRUK; programme grant C6/A18796), with Institute core funding provided by CRUK (C6946/A14492) and the Wellcome Trust (WT092096). S. Jackson receives salary from the University of Cambridge, supplemented by CRUK

Preoperative medical treatment in Cushing&apos;s syndrome : frequency of use and its impact on postoperative assessment : data from ERCUSYN

Background: Surgery is the definitive treatment of Cushing's syndrome (CS) but medications may also be used as a first-line therapy. Whether preoperative medical treatment (PMT) affects postoperative outcome remains controversial. Objective: (1) Evaluate how frequently PMT is given to CS patients across Europe; (2) examine differences in preoperative characteristics of patients who receive PMT and those who undergo primary surgery and (3) determine if PMT influences postoperative outcome in pituitary-dependent CS (PIT-CS). Patients and methods: 1143 CS patients entered into the ERCUSYN database from 57 centers in 26 countries. Sixty-nine percent had PIT-CS, 25% adrenal-dependent CS (ADR-CS), 5% CS from an ectopic source (ECT-CS) and 1% were classified as having CS from other causes (OTH-CS). Results: Twenty per cent of patients took PMT. ECT-CS and PIT-CS were more likely to receive PMT compared to ADR-CS (P < 0.001). Most commonly used drugs were ketoconazole (62%), metyrapone (16%) and a combination of both (12%). Median (interquartile range) duration of PMT was 109 (98) days. PIT-CS patients treated with PMT had more severe clinical features at diagnosis and poorer quality of life compared to those undergoing primary surgery (SX) (P < 0.05). Within 7 days of surgery, PIT-CS patients treated with PMT were more likely to have normal cortisol (P < 0.01) and a lower remission rate (P < 0.01). Within 6 months of surgery, no differences in morbidity or remission rates were observed between SX and PMT groups. Conclusions: PMT may confound the interpretation of immediate postoperative outcome. Follow-up is recommended to definitely evaluate surgical results

Anaplasmosis in Pediatric Patients: Case Report and Review

Human granulocytic anaplasmosis (HGA) is a tick-borne infection, characterized as an acute and sometimes severe febrile illness which may be associated with leukopenia and thrombocytopenia. Most case reports of HGA have been in adults, with only 8 case reports of HGA in children. We add a ninth case of HGA, which occurred in a 5-year-old. The paucity of pediatric HGA case reports maybe because publication bias, or HGA in children is a mild illness and children with HGA are less likely than adults to seek medical care, or the diagnosis of HGA requires a blood draw and adults (versus children) are more likely to get diagnostic testing. The 9 case reports in children suggest that pediatric HGA is usually a mild infection and that doxycycline and rifampin are effective therapies. Like adults, children with HGA frequently present with fever, headache, and malaise; however, children are more likely than adults to have abdominal pain as a prominent complaint