Psi promotes Drosophila wing growth via direct transcriptional activation of cell cycle targets and repression of growth inhibitors.

The first characterised FUSE Binding Protein family member, FUBP1, binds single-stranded DNA to activate MYC transcription. Psi, the sole FUBP protein in Drosophila, binds RNA to regulate P-element and mRNA splicing. Our previous work revealed pro-growth functions for Psi, which depend, in part, on transcriptional activation of Myc. Genome-wide functions for FUBP family proteins in transcriptional control remain obscure. Here, through the first genome-wide binding and expression profiles obtained for a FUBP family protein, we demonstrate that, in addition to being required to activate Myc to promote cell growth, Psi also directly binds and activates stg to couple growth and cell division. Thus, Psi knockdown results in reduced cell division in the wing imaginal disc. In addition to activating these pro-proliferative targets, Psi directly represses transcription of the growth inhibitor tolkin (tok, a metallopeptidase implicated in TGFß signalling). We further demonstrate tok overexpression inhibits proliferation, while tok loss of function increases mitosis alone and suppresses impaired cell division caused by Psi knockdown. Thus, Psi orchestrates growth through concurrent transcriptional activation of the pro-proliferative genes Myc and stg, in combination with repression of the growth inhibitor tok.

Investigation of the causal relationships between human IgG N-glycosylation and 12 common diseases associated with changes in the IgG N-glycome.

Changes in the N-glycosylation of immunoglobulin G (IgG) are often observed in pathological states, such as autoimmune, inflammatory, neurodegenerative, cardiovascular diseases and some types of cancer. However, in most cases, it is not clear if the disease onset causes these changes, or if the changes in IgG N-glycosylation are among the risk factors for the diseases. The aim of this study was to investigate the casual relationships between IgG N-glycosylation traits and 12 diseases, in which the alterations of IgG N-glycome were previously reported, using two sample Mendelian randomization (MR) approach. We have performed two sample MR using publicly available summary statistics of genome-wide association studies of IgG N-glycosylation and disease risks. Our results indicate positive causal effect of systemic lupus erythematosus (SLE) on the abundance of N-glycans with bisecting N-acetylglucosamine in the total IgG N-glycome. Therefore, we suggest regarding this IgG glycosylation trait as a biomarker of SLE. We also emphasize the need for more powerful GWAS studies of IgG N-glycosylation to further elucidate the causal effect of IgG N-glycome on the diseases.

Multivariate genome-wide analysis of immunoglobulin G N-glycosylation identifies new loci pleiotropic with immune function.

The N-glycosylation of immunoglobulin G (IgG) affects its structure and function. It has been demonstrated that IgG N-glycosylation patterns are inherited as complex quantitative traits. Genome-wide association studies identified loci harboring genes encoding enzymes directly involved in protein glycosylation as well as loci likely to be involved in regulation of glycosylation biochemical pathways. Many of these loci could be linked to immune functions and risk of inflammatory and autoimmune diseases. The aim of the present study was to discover and replicate new loci associated with IgG N-glycosylation and to investigate possible pleiotropic effects of these loci onto immune function and the risk of inflammatory and autoimmune diseases. We conducted a multivariate genome-wide association analysis of 23 IgG N-glycosylation traits measured in 8090 individuals of European ancestry. The discovery stage was followed up by replication in 3147 people and in silico functional analysis. Our study increased the total number of replicated loci from 22 to 29. For the discovered loci, we suggest a number of genes potentially involved in the control of IgG N-glycosylation. Among the new loci, two (near RNF168 and TNFRSF13B) were previously implicated in rare immune deficiencies and were associated with levels of circulating immunoglobulins. For one new locus (near AP5B1/OVOL1), we demonstrated a potential pleiotropic effect on the risk of asthma. Our findings underline an important link between IgG N-glycosylation and immune function and provide new clues to understanding their interplay.

Transcriptional repression of Myc underlies the tumour suppressor function of AGO1 in Drosophila.

Here, we report novel tumour suppressor activity for the Drosophila Argonaute family RNA-binding protein AGO1, a component of the miRNA-dependent RNA-induced silencing complex (RISC). The mechanism for growth inhibition does not, however, involve canonical roles as part of the RISC; rather, AGO1 controls cell and tissue growth by functioning as a direct transcriptional repressor of the master regulator of growth, Myc. AGO1 depletion in wing imaginal discs drives a significant increase in ribosome biogenesis, nucleolar expansion and cell growth in a manner dependent on Myc abundance. Moreover, increased Myc promoter activity and elevated Myc mRNA in AGO1-depleted animals requires RNA polymerase II transcription. Further support for transcriptional AGO1 functions is provided by physical interaction with the RNA polymerase II transcriptional machinery (chromatin remodelling factors and Mediator Complex), punctate nuclear localisation in euchromatic regions and overlap with Polycomb Group transcriptional silencing loci. Moreover, significant AGO1 enrichment is observed on the Myc promoter and AGO1 interacts with the Myc transcriptional activator Psi. Together, our data show that Drosophila AGO1 functions outside of the RISC to repress Myc transcription and inhibit developmental cell and tissue growth.This article has an associated 'The people behind the papers' interview.

EXPERIMENTAL AND MORPHOLOGICAL ASSESSMENT OF THE INFLUENCE OF HYDROXYAPATITE-CONTAINING OSTEOTROPIC MATERIAL AND ELECTRICAL STIMULATION ON REPARATIVE OSTEOGENESIS OF THE LOWER JAW.

OBJECTIVE: Aim: The aim of the study was to reveal the peculiarities of reparative osteogenesis in experimental lower jaw defect under the conditions of hydroxyapatite-containing osteotropic material application and electrical stimulation. PATIENTS AND METHODS: Materials and Methods: An experiment was conducted on 48 mature male rats of the WAG population. All animals were divided into 4 groups (12 animals in each group). Group 1 included rats that were not subjected to any manipulations. Group 2 included rats that were modeled with a perforated defect of the lower jaw body. Group 3 included rats that were modeled with a perforated defect similar to group 2, the cavity of which was filled with synthetic bone graft "Biomin GT" (RAPID, Ukraine). Group 4 included animals that were modeled with a perforated defect similar to groups 2-3, the cavity of which was filled with synthetic bone graft "Biomin GT". In animals of group 4, a microdevice for electrical action was implanted subcutaneously in the neck area on the side of the simulated bone defect. Morphological and statistical methods were used. RESULTS: Results: The research carried out by the authors proved that the use of the above-mentioned bone replacement material helps to increase the regenerative potential of the bone tissue of the lower jaw, but does not lead to the formation of a full-fledged bone regenerate, as evidenced by the results of the morphometry of the regenerate (the specific volume of lamellar bone tissue accounted for 54.9%); disordered localization of bone beams, which were characterized by reduced signs of mineralization; the presence in connective, osteogenic fibroreticular and lamellar bone tissues the encapsulated bone graft granules with the presence of inflammatory cell infiltration. In cases the combined use of synthetic bone graft "Biomin GT" and electrical stimulation, the authors noted more intensive reparative osteogenesis processes in the bone defect of the lower jaw compared to cases when only one bone graft was used, but they also did not lead to the formation of a full-fledged bone regenerate. CONCLUSION: Conclusions: The experimental and morphological study conducted by the authors proved that the use of hydroxyapatite-containing osteotropic material ("Biomin GT"), especially in cases of its combined use with electrical stimulation, significantly activates reparative osteogenesis in the bone defect of the lower jaw, which does not lead to the formation of a full-fledged bone regenerate.

MORPHOLOGICAL ASSESSMENT OF THE LUNGS IN POST-COVID-19 SYNDROME: ANALYSIS OF AUTOPSY MATERIAL.

OBJECTIVE: The aim was to reveal the morphological features of the lungs in post-COVID-19 syndrome. PATIENTS AND METHODS: Materials and methods: The material of the study was autopsy material - fragments of the lung tissue from 96 deceased (59 men and 37 women). During the lifetime, all patients had in anamnesis COVID-19 of varying severity, and after the treatment of this infection, they had various manifestations of respiratory failure until death. The average duration of the post-COVID-19 period was 148.6±9.5 days. Based on the severity of COVID-19 in anamnesis, all cases were divided into three groups. Group 1 included 39 cases with mild COVID-19 in anamnesis. Group 2 included 24 cases with moderate severity of COVID-19 in an-amnesis. Group 3 included 33 cases with severe COVID-19 in anamnesis. Histological, histochemical, morphometric and statistical research methods were used. RESULTS: Results: Morphological features of the lungs in post-COVID-19 syndrome were the presence of pneumosclerosis; focal-diffuse immune cells infiltration; emphysematous and atelectatic changes; degenerative-desquamatic changes in the alveolar epithelium; metaplastic changes of connective tissue; dystrophic calcification; dystrophic, metaplastic and dysplastic changes in the epithelial layer of bronchial tree; hemodynamic disorders. Pneumosclerosis, focal-diffuse immune cells infiltration, alterative changes in the alveolar epithelium, emphysematous and atelectatic changes, hemodynamic disorders increased with an increase the severity of COVID-19. Metaplastic changes of connective tissue, dystrophic calcification, dystrophic, metaplastic and dysplastic changes in epithelial layer of bronchial tree did not depend on the severity of the infection. CONCLUSION: Conclusions: The changes identified by the authors help to explain pulmonary manifestations of post-COVID-19 syndrome. They should be the basis for the oncological alertness formation among doctors, the development of rehabilitation and treatment measures for such category of patients.

Causal effects of psychosocial factors on chronic back pain: a bidirectional Mendelian randomisation study.

PURPOSE: Risk factors for chronic back pain (CBP) may share underlying genetic factors, making them difficult to study using conventional methods. We conducted a bi-directional Mendelian randomisation (MR) study to examine the causal effects of risk factors (education, smoking, alcohol consumption, physical activity, sleep and depression) on CBP and the causal effect of CBP on the same risk factors. METHODS: Genetic instruments for risk factors and CBP were obtained from the largest published genome-wide association studies (GWAS) of risk factor traits conducted in individuals of European ancestry. We used inverse weighted variance meta-analysis (IVW), Causal Analysis Using Summary Effect (CAUSE) and sensitivity analyses to examine evidence for causal associations. We interpreted exposure-outcome associations as being consistent with a causal relationship if results with IVW or CAUSE were statistically significant after accounting for multiple statistical testing (p < 0.003), and the direction and magnitude of effect estimates were concordant between IVW, CAUSE, and sensitivity analyses. RESULTS: We found evidence for statistically significant causal associations between greater education (OR per 4.2 years of schooling = 0.54), ever smoking (OR = 1.27), greater alcohol consumption (OR = 1.29 per consumption category increase) and major depressive disorder (OR = 1.41) and risk of CBP. Conversely, we found evidence for significant causal associations between CBP and greater alcohol consumption (OR = 1.19) and between CBP and smoking (OR = 1.21). Other relationships did not meet our pre-defined criteria for causal association. CONCLUSION: Fewer years of schooling, smoking, greater alcohol consumption, and major depressive disorder increase the risk of CBP. CBP increases the risk of greater alcohol consumption and smoking.

MORPHOLOGICAL AND FUNCTIONAL FEATURES OF THE MUCOUS MEMBRANE OF SMALL AND LARGE INTESTINE IN PATIENTS WITH COVID-19 AND IN POST-COVID-19 PERIOD.

OBJECTIVE: The aim: To reveal the morphological and functional features of the mucous membrane of small and large intestine in patients with COVID-19 and in post-COVID-19 period. PATIENTS AND METHODS: Materials and methods: In the present study, the authors used biopsy and autopsy material represented by the fragments of the mucous membrane of small and large intestine. All studied material was divided into 10 groups. Group 1 (comparison group) included autopsy material from the deceased who did not have COVID-19 during their lifetime. Groups 2-4 included autopsy material from the deceased who had COVID-19 of varying severity during their lifetime. Groups 5-7 included biopsy material from patients who had recovered from COVID-19 of varying severity, while the duration of the post-COVID period ranged from 1 to 50 days. Groups 8-10 included biopsy material from patients who had in anamnesis COVID-19 of varying severity (the duration of the post-COVID period lasted from 51 to 100 days). Histological, immunohistochemical, morphometric and statistical research methods were used. RESULTS: Results: The comparative analysis showed a more expressed deficiency of ACE2 in the mucous membrane of small and large intestine in patients with moderate and severe COVID-19 compared with patients in post-COVID-19 period of different duration. In patients who had moderate and severe COVID-19 in anamnesis, ACE2 deficiency decreases with increasing duration of post-COVID-19 period. In patients recovered from mild COVID-19, the ACE2 content increases with the duration of post-COVID-19 period from 1 to 50 days and corresponds to the norm with the duration of this period from 51 to 100 days. CONCLUSION: Conclusions: The comprehensive morphological study conducted by the authors made it possible, firstly, to clarify the morphological and functional features of the mucous membrane of small and large intestine in patients with COVID-19 of various degrees of severity; secondly, to obtain new data about the morpho-functional state of the mucous membrane of small and large intestine in patients, taking into account different duration of the post-COVID-19 period and the severity of the infection.

Replication of 15 loci involved in human plasma protein N-glycosylation in 4802 samples from four cohorts.

Human protein glycosylation is a complex process, and its in vivo regulation is poorly understood. Changes in glycosylation patterns are associated with many human diseases and conditions. Understanding the biological determinants of protein glycome provides a basis for future diagnostic and therapeutic applications. Genome-wide association studies (GWAS) allow to study biology via a hypothesis-free search of loci and genetic variants associated with a trait of interest. Sixteen loci were identified by three previous GWAS of human plasma proteome N-glycosylation. However, the possibility that some of these loci are false positives needs to be eliminated by replication studies, which have been limited so far. Here, we use the largest set of samples so far (4802 individuals) to replicate the previously identified loci. For all but one locus, the expected replication power exceeded 95%. Of the 16 loci reported previously, 15 were replicated in our study. For the remaining locus (near the KREMEN1 gene), the replication power was low, and hence, replication results were inconclusive. The very high replication rate highlights the general robustness of the GWAS findings as well as the high standards adopted by the community that studies genetic regulation of protein glycosylation. The 15 replicated loci present a good target for further functional studies. Among these, eight loci contain genes encoding glycosyltransferases: MGAT5, B3GAT1, FUT8, FUT6, ST6GAL1, B4GALT1, ST3GAL4 and MGAT3. The remaining seven loci offer starting points for further functional follow-up investigation into molecules and mechanisms that regulate human protein N-glycosylation in vivo.

Luminescent Analysis of Blood Serum for Diagnostics of Pathological and Pre-Pathological States of Cancer Patients.

This study is devoted to the development of a methodological approach to mathematical analysis and data interpretation of blood serum phosphorescence intensity in cancer patients for determining the pathological states and differential diagnostics of oncological process stages. The purpose of the study is blood serum phosphorescence research in patients with colorectal cancer (CRC) and stomach adenocarcinoma (SAC) and determination of the ultraweak luminescence role for diagnostics of the disease, determining its stages, control of pathogenetic therapy efficiency and forecast of recovery. The values of phosphorescence intensity of blood serum films in patients with CRC and SAC are significantly higher than the corresponding values for the control group. Contrary to the absolute intensity, the relative intensity increase compared to the control group is much more informative for oncoprocess diagnostics, since it exhibits three times increase even at the first stage of tumoral process. Serum phosphorescence intensity continues to increase with progressing of the disease. As the result of our study, the relative intensity increase compared to the first stage can be recommended as an informative indicator for differential diagnostics of oncological process stages. As a conclusion, determination of blood serum phosphorescence intensity can be considered as a sensitive and specific diagnostic method in oncology. With a correct methodological approach to data processing and interpretation, this method can be used in clinical practice for determining the oncopathological states, differential diagnostics of oncoprocess stages and diagnostics of precancer changes, which precede tumoral process development.

Heritability of Human Plasma N-Glycome.

The N-glycosylation profile of total human plasma proteins could be a useful biomarker for various pathological states. Reliable high-throughput methods for such profiling have been developed. However, studies of relative importance of genetic and environmental factors in regulating plasma N-glycome are scarce. The aim of our study was to determine the role of genetic factors in phenotypic variation of plasma N-glycan profile through the estimates of its heritability. Thirty-nine total plasma N-glycome traits were analyzed in 2816 individuals from the TwinsUK data set. For the majority of the traits, high heritability estimates (>50%) were obtained pointing at a significant contribution of genetic factors in plasma N-glycome variation, especially for glycans mostly attached to immunoglobulins. We have also found several structures with higher environmental contribution to their variation.

Profiling and genetic control of the murine immunoglobulin G glycome.

Immunoglobulin G (IgG) glycosylation is essential for function of the immune system, but the genetic and environmental factors that underlie its inter-individual variability are not well defined. The Collaborative Cross (CC) genetic resource harnesses over 90% of the common genetic variation of the mouse. By analyzing the IgG glycome composition of 95 CC strains, we made several important observations: (i) glycome variation between mouse strains was higher than between individual humans, despite all mice having the same environmental influences; (ii) five genetic loci were found to be associated with murine IgG glycosylation; (iii) variants outside traditional glycosylation site motifs affected glycome variation; (iv) bisecting N-acetylglucosamine (GlcNAc) was produced by several strains although most previous studies have reported the absence of glycans containing the bisecting GlcNAc on murine IgGs; and (v) common laboratory mouse strains are not optimal animal models for studying effects of glycosylation on IgG function.

DNA Conformation Regulates Gene Expression: The MYC Promoter and Beyond.

Emerging evidence suggests that DNA topology plays an instructive role in cell fate control through regulation of gene expression. Transcription produces torsional stress, and the resultant supercoiling of the DNA molecule generates an array of secondary structures. In turn, local DNA architecture is harnessed by the cell, acting within sensory feedback mechanisms to mediate transcriptional output. MYC is a potent oncogene, which is upregulated in the majority of cancers; thus numerous studies have focused on detailed understanding of its regulation. Dissection of regulatory regions within the MYC promoter provided the first hint that intimate feedback between DNA topology and associated DNA remodeling proteins is critical for moderating transcription. As evidence of such regulation is also found in the context of many other genes, here we expand on the prototypical example of the MYC promoter, and also explore DNA architecture in a genome-wide context as a global mechanism of transcriptional control.

MYC in Brain Development and Cancer.

The MYC family of transcriptional regulators play significant roles in animal development, including the renewal and maintenance of stem cells. Not surprisingly, given MYC's capacity to promote programs of proliferative cell growth, MYC is frequently upregulated in cancer. Although members of the MYC family are upregulated in nervous system tumours, the mechanisms of how elevated MYC promotes stem cell-driven brain cancers is unknown. If we are to determine how increased MYC might contribute to brain cancer progression, we will require a more complete understanding of MYC's roles during normal brain development. Here, we evaluate evidence for MYC family functions in neural stem cell fate and brain development, with a view to better understand mechanisms of MYC-driven neural malignancies.

Detection of BRCA1 gross rearrangements by droplet digital PCR.

PURPOSE: Large genomic rearrangements (LGRs) constitute a significant share of pathogenic BRCA1 mutations. Multiplex ligation-dependent probe amplification (MLPA) is a leading method for LGR detection; however, it is entirely based on the use of commercial kits, includes relatively time-consuming hybridization step, and is not convenient for large-scale screening of recurrent LGRs. MATERIALS AND METHODS: We developed and validated the droplet digital PCR (ddPCR) assay, which covers the entire coding region of BRCA1 gene and is capable to precisely quantitate the copy number for each exon. RESULTS: 141 breast cancer (BC) patients, who demonstrated evident clinical features of hereditary BC but turned out to be negative for founder BRCA1/2 mutations, were subjected to the LGR analysis. Four patients with LGR were identified, with three cases of exon 8 deletion and one women carrying the deletion of exons 5-7. Excellent concordance with MLPA test was observed. Exon 8 copy number was tested in additional 720 BC and 184 ovarian cancer (OC) high-risk patients, and another four cases with the deletion were revealed; MLPA re-analysis demonstrated that exon 8 loss was a part of a larger genetic alteration in two cases, while the remaining two patients had isolated defect of exon 8. Long-range PCR and next generation sequencing of DNA samples carrying exon 8 deletion revealed two types of recurrent LGRs. CONCLUSION: Droplet digital PCR is a reliable tool for the detection of large genomic rearrangements.

Comparative morphology of the nervous system in three phylactolaemate bryozoans.

BACKGROUND: Though some elements of the bryozoan nervous system were discovered 180 years ago, few studies of their neuromorphology have been undertaken since that time. As a result the general picture of the bryozoan nervous system structure is incomplete in respect of details and fragmentary in respect of taxonomic coverage. RESULTS: The nervous system of three common European freshwater bryozoans - Cristatella mucedo, Plumatella repens (both with a horseshoe-shaped lophophore) and Fredericella sultana (with a circular lophophore) had numerous differences in the details of the structure but the general neuroarchitecture is similar. The nervous system of the zooid consists of the cerebral ganglion, a circumpharyngeal ring and lophophoral nerve tracts (horns), both sending numerous nerves to the tentacles, and the nerve plexuses of the body wall and of the gut. A number of the important details (distal branching of the additional radial nerve, pattern of distribution of nerve cells and neurites in the ganglion, etc.) were described for the first time. The number and position of the tentacle nerves in Cristatella mucedo was ascertained and suggestions about their function were made. The revealed distribution of various neuromediators in the nervous system allowed us to suggest functional affinities of some major nerves. CONCLUSIONS: Despite the basic similarity, both the ganglion and the lophophore nervous system in Phylactolaemata have a more complex structure than in marine bryozoans (classes Gymnolaemata and Stenolaemata). First of all, their neuronal network has a denser and more complex branching pattern: most phylactolaemates have two large nerve tracts associated with lophophore arms, they have more nerves in the tentacles, additional and basal branches emitting from the main radial nerves, etc. This, in part, can be explained by the horseshoe shape of the lophophore and a larger size of the polypide in freshwater species. The structure of the nervous system in Fredericella sultana suggests that it underwent a secondary simplification following the reduction of the lophophore arms. Colony locomotion in Cristatella mucedo is based on co-ordinated activity of two perpendicular muscle layers of the sole and the plexus of motor neurons sandwiched between them. The trigger of this activity and the co-ordination mechanism remain enigmatic.

The Ecdysone receptor constrains wingless expression to pattern cell cycle across the Drosophila wing margin in a Cyclin B-dependent manner.

BACKGROUND: Ecdysone triggers transcriptional changes via the ecdysone receptor (EcR) to coordinate developmental programs of apoptosis, cell cycle and differentiation. Data suggests EcR affects cell cycle gene expression indirectly and here we identify Wingless as an intermediary factor linking EcR to cell cycle. RESULTS: We demonstrate EcR patterns cell cycle across the presumptive Drosophila wing margin by constraining wg transcription to modulate CycB expression, but not the previously identified Wg-targets dMyc or Stg. Furthermore co-knockdown of Wg restores CycB patterning in EcR knockdown clones. Wg is not a direct target of EcR, rather we demonstrate that repression of Wg by EcR is likely mediated by direct interaction between the EcR-responsive zinc finger transcription factor Crol and the wg promoter. CONCLUSIONS: Thus we elucidate a critical mechanism potentially connecting ecdysone with patterning signals to ensure correct timing of cell cycle exit and differentiation during margin wing development.

Bidirectional Mendelian Randomization Study of Personality Traits Reveals a Positive Feedback Loop Between Neuroticism and Back Pain.

We conducted a bidirectional Mendelian randomization study to examine the causal effects of six personality traits (anxiety, neuroticism, extraversion, openness to experience, agreeableness, and conscientiousness) on back pain associated with health care use and the causal effect of back pain on the same risk factors. Genetic instruments for the personality traits and back pain were obtained from the largest published genome-wide association studies conducted in individuals of European ancestry. We used inverse weighted variance meta-analysis and Causal Analysis Using Summary Effect for primary analyses and sensitivity analyses to examine evidence for causal associations. We interpreted exposure-outcome associations as being consistent with a causal relationship if results of at least one primary analysis were statistically significant after accounting for multiple statistical testing (P-value < .0042), and the direction and magnitude of effect estimates were concordant between primary and sensitivity analyses. We found evidence for statistically significant bidirectional causal associations between neuroticism and back pain, with odds ratio 1.51 (95% confidence interval 1.37; 1.67) of back pain per neuroticism sum score standard deviation, P-value = 7.80e-16; and beta = .12, se = .04 of neuroticism sum score standard deviation per log odds of back pain, P-value = 2.48e-03. Other relationships did not meet our predefined criteria for causal association. PERSPECTIVE: The significant positive feedback loop between neuroticism and back pain highlights the importance of considering neuroticism in the management of patients with back pain.

Evidence of causal effects of blood pressure on back pain and back pain on type II diabetes provided by a bidirectional Mendelian randomization study.

BACKGROUND CONTEXT: Cardiovascular risk factors (hypertension, dyslipidemia, and type II diabetes) have been proposed as risk factors for back pain. However, few longitudinal studies have found significant associations between cardiovascular risk factors and back pain, and these may be explained by confounding or reverse causation. PURPOSE: To examine potential causal effects of cardiovascular risk factors on back pain, and vice versa. STUDY DESIGN: Bidirectional Mendelian randomization (MR) study. PATIENT SAMPLES: Genome-wide association studies (GWAS) with sample sizes between 173,082 and 1,028,947 participants. OUTCOME MEASURES: Outcomes included (1) back pain associated with health care use (BP-HC) in the forward MR; and (2) seven cardiovascular phenotypes in the reverse MR, including 2 measurements used for the evaluation of hypertension (diastolic blood pressure and systolic blood pressure), 4 phenotypes related to dyslipidemia (LDL cholesterol, HDL cholesterol, total cholesterol, and triglycerides), and type II diabetes. METHODS: We used summary statistics from large, publicly available GWAS for BP-HC and the 7 cardiovascular phenotypes to obtain genetic instrumental variables. We examined MR evidence for causal associations using inverse-variance weighted (IVW) analysis, Causal Analysis Using Summary Effect (CAUSE), and sensitivity analyses. RESULTS: In forward MR analyses of seven cardiovascular phenotypes, diastolic blood pressure was associated with BP-HC across all analyses (IVW estimate: OR = 1.10 per 10.5 mm Hg increase [1.04-1.17], p-value = .001), and significant associations of systolic blood pressure with BP-HC were also found (IVW estimate: OR = 1.09 per 19.3 mm Hg increase [1.04-1.15], p-value = .0006). In reverse MR analyses, only type II diabetes was associated with BP-HC across all analyses (IVW estimate: OR = 1.40 [1.13-1.73], p-value = .002). CONCLUSIONS: These findings from analyses of large, population-based samples indicate that higher blood pressure increases the risk of BP-HC, and BP-HC itself increases the risk of type II diabetes.

Polymorphism in a histone H1 subtype with a short N-terminal domain in three legume species (Fabaceae, Fabaeae).

A number of alleles of an orthologous gene His6 encoding histone H1 subtype f (H1-6 in pea) accumulated in chromatin of old tissues were sequenced in three legume species: seven alleles in Pisum sativum, four in Vicia unijuga and eight in Lathyrus gmelinii. In the total of 19 alleles sequenced in the three species, 29 non-synonymous substitutions and six indels were found in the coding region; most of amino acid substitutions (26 of 29) and all indels occurred in the C-terminal hydrophilic domain of the encoded protein. All species were polymorphic for some non-synonymous substitutions, V. unijuga was also polymorphic for one and P. sativum for two indels. Three near-isogenic lines of P. sativum bearing different alleles showed differences in many quantitative traits; that in the growth dynamic could be tentatively attributed to the allelic substitution of subtype H1-6. The frequencies of four electromorphs in a sampled locality of V. unijuga were found to be close to those observed 25 years ago, although their rapid change in the past was supposed in the previous study.