Acute mesenteric haematoma and hematoperitoneum following a coughing episode induced by COVID-19.

Acute mesenteric haematoma (AMH) is a rare condition and established causes include blunt trauma, aneurysmal rupture, acute pancreatitis and anticoagulant use. A male patient in his 50s presented with abdominal pain and loss of consciousness that was immediately preceded by a prolonged coughing episode. A computed tomography (CT) abdomen-pelvis revealed two acute mesenteric haematomas and haematoperitoneum and admission swabs diagnosed coronavirus disease 2019 (COVID-19). The patient had no other acute clinical issues and was not taking anticoagulants. The haematomas were managed conservatively and a follow up computed tomography (CT) 4 weeks post-discharge revealed significant improvement. No clear vessel was identified as the source of the bleed in any of the investigations. This case represents a rare instance of AMH and haematoperitoneum with no established cause. We theorize that the combination of the patient's systemic response to COVID-19 and raised intra-abdominal pressure caused by coughing contributed to the bleeding.

Systematic Review of the Prevalence of Long COVID.

Background: Long COVID occurs in those infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) whose symptoms persist or develop beyond the acute phase. We conducted a systematic review to determine the prevalence of persistent symptoms, functional disability, or pathological changes in adults or children at least 12 weeks postinfection. Methods: We searched key registers and databases from January 1, 2020 to November 2, 2021, limited to publications in English and studies with at least 100 participants. Studies in which all participants were critically ill were excluded. Long COVID was extracted as prevalence of at least 1 symptom or pathology, or prevalence of the most common symptom or pathology, at 12 weeks or later. Heterogeneity was quantified in absolute terms and as a proportion of total variation and explored across predefined subgroups (PROSPERO ID CRD42020218351). Results: One hundred twenty studies in 130 publications were included. Length of follow-up varied between 12 weeks and 12 months. Few studies had low risk of bias. All complete and subgroup analyses except 1 had I2 ≥90%, with prevalence of persistent symptoms range of 0%-93% (pooled estimate [PE], 42.1%; 95% prediction interval [PI], 6.8% to 87.9%). Studies using routine healthcare records tended to report lower prevalence (PE, 13.6%; PI, 1.2% to 68%) of persistent symptoms/pathology than self-report (PE, 43.9%; PI, 8.2% to 87.2%). However, studies systematically investigating pathology in all participants at follow up tended to report the highest estimates of all 3 (PE, 51.7%; PI, 12.3% to 89.1%). Studies of hospitalized cases had generally higher estimates than community-based studies. Conclusions: The way in which Long COVID is defined and measured affects prevalence estimation. Given the widespread nature of SARS-CoV-2 infection globally, the burden of chronic illness is likely to be substantial even using the most conservative estimates.

A case report of recurrent takotsubo cardiomyopathy including the rare 'inverted' form.

Background: Takotsubo cardiomyopathy (TC) is a disease that causes transient left ventricular (LV) dysfunction in multiple vascular territories in the absence of coronary artery disease. Takotsubo cardiomyopathy is typically associated with dilation and dyskinesia of the apical and mid-LV segments induced by acute emotional and/or physical stress. Here, we present a case of recurrent TC including one episode of inverted TC, which is a rare form where dyskinesia occurs in the basal segments with sparing of the apical segments. Case summary: A 53-year-old female patient with a background history of chronic stress and anxiety was admitted with three episodes of recurrent TC over 4 years. The first episode in 2017 was triggered by an acute stressful event, but no major triggers were identified for the subsequent episodes. Although the first and third episodes displayed the signs of classical TC, the second episode was an inverted TC. Full cardiac function was restored after each episode. She now takes prognostic heart failure medications long term and mental health teams are trying to support her emotional wellbeing. Discussion: This patient displayed a rare disease course involving three recurrent episodes of TC, including one instance of its inverted form. Although psychiatric conditions and emotional stress are acknowledged as risk factors for TC, further research is needed to assess whether mental health treatment following TC can prevent disease recurrence.

Metatranscriptome Analysis of Sympatric Bee Species Identifies Bee Virus Variants and a New Virus, Andrena-Associated Bee Virus-1.

Bees are important plant pollinators in agricultural and natural ecosystems. High average annual losses of honey bee (Apis mellifera) colonies in some parts of the world, and regional population declines of some mining bee species (Andrena spp.), are attributed to multiple factors including habitat loss, lack of quality forage, insecticide exposure, and pathogens, including viruses. While research has primarily focused on viruses in honey bees, many of these viruses have a broad host range. It is therefore important to apply a community level approach in studying the epidemiology of bee viruses. We utilized high-throughput sequencing to evaluate viral diversity and viral sharing in sympatric, co-foraging bees in the context of habitat type. Variants of four common viruses (i.e., black queen cell virus, deformed wing virus, Lake Sinai virus 2, and Lake Sinai virus NE) were identified in honey bee and mining bee samples, and the high degree of nucleotide identity in the virus consensus sequences obtained from both taxa indicates virus sharing. We discovered a unique bipartite + ssRNA Tombo-like virus, Andrena-associated bee virus-1 (AnBV-1). AnBV-1 infects mining bees, honey bees, and primary honey bee pupal cells maintained in culture. AnBV-1 prevalence and abundance was greater in mining bees than in honey bees. Statistical modeling that examined the roles of ecological factors, including floral diversity and abundance, indicated that AnBV-1 infection prevalence in honey bees was greater in habitats with low floral diversity and abundance, and that interspecific virus transmission is strongly modulated by the floral community in the habitat. These results suggest that land management strategies that aim to enhance floral diversity and abundance may reduce AnBV-1 spread between co-foraging bees.

A PAX5-OCT4-PRDM1 developmental switch specifies human primordial germ cells.

Dysregulation of genetic pathways during human germ cell development leads to infertility. Here, we analysed bona fide human primordial germ cells (hPGCs) to probe the developmental genetics of human germ cell specification and differentiation. We examined the distribution of OCT4 occupancy in hPGCs relative to human embryonic stem cells (hESCs). We demonstrated that development, from pluripotent stem cells to germ cells, is driven by switching partners with OCT4 from SOX2 to PAX5 and PRDM1. Gain- and loss-of-function studies revealed that PAX5 encodes a critical regulator of hPGC development. Moreover, an epistasis analysis indicated that PAX5 acts upstream of OCT4 and PRDM1. The PAX5-OCT4-PRDM1 proteins form a core transcriptional network that activates germline and represses somatic programmes during human germ cell differentiation. These findings illustrate the power of combined genome editing, cell differentiation and engraftment for probing human developmental genetics that have historically been difficult to study.

Intensive herbicide use has selected for constitutively elevated levels of stress-responsive mRNAs and proteins in multiple herbicide-resistant Avena fatua L.

BACKGROUND: Intensive use of herbicides has led to the evolution of two multiple herbicide-resistant (MHR) Avena fatua (wild oat) populations in Montana that are resistant to members of all selective herbicide families available for A. fatua control in US small grain crops. We used transcriptome and proteome surveys to compare constitutive changes in MHR and herbicide-susceptible (HS) plants associated with non-target site resistance. RESULTS: Compared to HS plants, MHR plants contained constitutively elevated levels of differentially expressed genes (DEGs) with functions in xenobiotic catabolism, stress response, redox maintenance and transcriptional regulation that are similar to abiotic stress-tolerant phenotypes. Proteome comparisons identified similarly elevated proteins including biosynthetic and multifunctional enzymes in MHR plants. Of 25 DEGs validated by RT-qPCR assay, differential regulation of 21 co-segregated with flucarbazone-sodium herbicide resistance in F3 families, and a subset of 10 of these were induced or repressed in herbicide-treated HS plants. CONCLUSION: Although the individual and collective contributions of these DEGs and proteins to MHR remain to be determined, our results support the idea that intensive herbicide use has selected for MHR populations with altered, constitutively regulated patterns of gene expression that are similar to those in abiotic stress-tolerant plants. © 2017 Society of Chemical Industry.

ChIP-seq and in vivo transcriptome analyses of the Aspergillus fumigatus SREBP SrbA reveals a new regulator of the fungal hypoxia response and virulence.

The Aspergillus fumigatus sterol regulatory element binding protein (SREBP) SrbA belongs to the basic Helix-Loop-Helix (bHLH) family of transcription factors and is crucial for antifungal drug resistance and virulence. The latter phenotype is especially striking, as loss of SrbA results in complete loss of virulence in murine models of invasive pulmonary aspergillosis (IPA). How fungal SREBPs mediate fungal virulence is unknown, though it has been suggested that lack of growth in hypoxic conditions accounts for the attenuated virulence. To further understand the role of SrbA in fungal infection site pathobiology, chromatin immunoprecipitation followed by massively parallel DNA sequencing (ChIP-seq) was used to identify genes under direct SrbA transcriptional regulation in hypoxia. These results confirmed the direct regulation of ergosterol biosynthesis and iron uptake by SrbA in hypoxia and revealed new roles for SrbA in nitrate assimilation and heme biosynthesis. Moreover, functional characterization of an SrbA target gene with sequence similarity to SrbA identified a new transcriptional regulator of the fungal hypoxia response and virulence, SrbB. SrbB co-regulates genes involved in heme biosynthesis and demethylation of C4-sterols with SrbA in hypoxic conditions. However, SrbB also has regulatory functions independent of SrbA including regulation of carbohydrate metabolism. Loss of SrbB markedly attenuates A. fumigatus virulence, and loss of both SREBPs further reduces in vivo fungal growth. These data suggest that both A. fumigatus SREBPs are critical for hypoxia adaptation and virulence and reveal new insights into SREBPs' complex role in infection site adaptation and fungal virulence.

In situ gene expression profiling of the thermoacidophilic alga Cyanidioschyzon in relation to visible and ultraviolet irradiance.

Ultraviolet and high-intensity visible radiation generate reactive intermediates that damage phototrophic microorganisms. In Yellowstone National Park, the thermoacidophilic alga Cyanidioschyzon exhibits an annual seasonal biomass fluctuation referred to as 'mat decline', where algal viability decreases as ultraviolet and visible irradiances increase during summer. We examined the role irradiance might play in mat decline using irradiance filters that uncouple ultraviolet and visible effects along with custom microarrays to study gene expression in situ. Of the 6507 genes, 88% showed no response to ultraviolet or visible, implying that at the biomolecular level, these algae inhabit a chemostat-like environment and is consistent with the near constant aqueous chemistry measured. The remaining genes exhibited expression changes linked to ultraviolet exposure, to increased visible radiation, or to the apparent combined effects of ultraviolet and visible. Expression of DNA repetitive elements was synchronized, being repressed by visible but also influenced by ultraviolet. At highest irradiance levels, these algae reduced transcription of genes encoding functions involved with DNA replication, photosynthesis and cell cycle progression but exhibited an uptick in activities related to repairing DNA damage. This corroborates known physiological responses to ultraviolet and visible radiation, and leads us to provisionally conclude that mat decline is linked to photoinhibition.

Modularity and intrinsic evolvability of Hsp90-buffered change.

Hsp90 controls dramatic phenotypic transitions in a wide array of morphological features of many organisms. The genetic-background dependence of specific abnormalities and their response to laboratory selection suggested Hsp90 could be an 'evolutionary capacitor', allowing developmental variation to accumulate as neutral alleles under normal conditions and manifest selectable morphological differences during environmental stress. The relevance of Hsp90-buffered variation for evolution has been most often challenged by the idea that large morphological changes controlled by Hsp90 are unconditionally deleterious. To address this issue, we tested an Hsp90-buffered abnormality in Drosophila for unselected pleiotropic effects and correlated fitness costs. Up to 120-fold differences in penetrance among six highly related selection lines, started from an initially small number of flies and rapidly selected for and against a deformed eye trait (dfe), did not translate into measurable differences in any of several tests of viability, lifespan or competitive fitness. Nor were 17 dfe Quantitative Trait Loci (QTL) associated with fitness effects in over 1,400 recombinant lines. Our ability to detect measurable effects of inbreeding, media environment and the white mutation in the selection line backgrounds independent of dfe penetrance suggests that, within the limitations of laboratory tests of fitness, this large morphological change controlled by Hsp90 was selectable independent of strong, correlated and unconditionally deleterious effects--abundant, polygenic variation hidden by Hsp90 allows potentially deleterious alleles to be readily replaced during selection by less deleterious alleles with similar phenotypic effects. Hsp90 links environmental stress with the expression of developmental variation controlling unprecedented morphological plasticity. As outlined here and in the companion paper of this issue, the complex genetic architecture of Hsp90-buffered variation supports a remarkable modularity of Hsp90 effects on quantitative and qualitative phenotypes, consistent with the 'Hsp90 capacitor hypothesis' and standard quantitative genetic models of threshold traits.

Transcriptionally silenced transgenes in maize are activated by three mutations defective in paramutation.

Plants with mutations in one of three maize genes, mop1, rmr1, and rmr2, are defective in paramutation, an allele-specific interaction that leads to meiotically heritable chromatin changes. Experiments reported here demonstrate that these genes are required to maintain the transcriptional silencing of two different transgenes, suggesting that paramutation and transcriptional silencing of transgenes share mechanisms. We hypothesize that the transgenes are silenced through an RNA-directed chromatin mechanism, because mop1 encodes an RNA-dependent RNA polymerase. In all the mutants, DNA methylation was reduced in the active transgenes relative to the silent transgenes at all of the CNG sites monitored within the transgene promoter. However, asymmetrical methylation persisted at one site within the reactivated transgene in the rmr1-1 mutant. With that one mutant, rmr1-1, the transgene was efficiently resilenced upon outcrossing to reintroduce the wild-type protein. In contrast, with the mop1-1 and rmr2-1 mutants, the transgene remained active in a subset of progeny even after the wild-type proteins were reintroduced by outcrossing. Interestingly, this immunity to silencing increased as the generations progressed, consistent with a heritable chromatin state being formed at the transgene in plants carrying the mop1-1 and rmr2-1 mutations that becomes more resistant to silencing in subsequent generations.

Effects of angiotensin-converting enzyme inhibition on mitral regurgitation severity, left ventricular size, and functional capacity.

BACKGROUND: Mitral regurgitation (MR) is a progressive disorder that leads to left ventricular (LV) dilatation and dysfunction. Previous small studies have shown conflicting results regarding the benefits of afterload reduction for MR. METHODS: We assessed by serial echocardiography the effects of ramipril on MR severity and LV size by a number of quantitative methods in 26 asymptomatic patients with moderate to severe MR at baseline and again after 6 months of ramipril treatment. We also evaluated exercise capacity, neurohormonal levels, and the Minnesota Living With Heart Failure score. RESULTS: Despite a significant reduction in blood pressure with ramipril, there was no change in MR severity. MR severity, as assessed by effective regurgitant orifice area, was reduced in individuals with baseline systolic blood pressure (SBP) > or = 140 mm Hg (55.1 +/- 26 vs 37.4 +/- 35.4 mm2, P = .03), but not in individuals with SBP < 140 mm Hg (39.7 +/- 37.7 vs 46.1 +/- 34.1 mm2, P = not significant). Neither LV cavity size, exercise capacity, nor the Minnesota Living With Heart Failure score exhibited a significant change. CONCLUSIONS: Patients with MR do not experience significant changes in MR severity, LV size, or functional status after 6 months of treatment with angiotensin-converting enzyme inhibition. However, patients with SBP > or = 140 mm Hg represent a subgroup that shows reduction in MR. These data are consistent with current American College of Cardiology/American Heart Association guidelines, which reserve the use of afterload reduction for MR patients with systemic hypertension or LV dysfunction.

Mutations in the pale aleurone color1 regulatory gene of the Zea mays anthocyanin pathway have distinct phenotypes relative to the functionally similar TRANSPARENT TESTA GLABRA1 gene in Arabidopsis thaliana.

The pale aleurone color1 (pac1) locus, required for anthocyanin pigment in the aleurone and scutellum of the Zea mays (maize) seed, was cloned using Mutator transposon tagging. pac1 encodes a WD40 repeat protein closely related to anthocyanin regulatory proteins ANTHOCYANIN11 (AN11) (Petunia hybrida [petunia]) and TRANSPARENT TESTA GLABRA1 (TTG1) (Arabidopsis thaliana). Introduction of a 35S-Pac1 transgene into A. thaliana complemented multiple ttg1 mutant phenotypes, including ones nonexistent in Z. mays. Hybridization of Z. mays genomic BAC clones with the pac1 sequence identified an additional related gene, mp1. PAC1 and MP1 deduced protein sequences were used as queries to build a phylogenetic tree of homologous WD40 repeat proteins, revealing an ancestral gene duplication leading to two clades in plants, the PAC1 clade and the MP1 clade. Subsequent duplications within each clade have led to additional WD40 repeat proteins in particular species, with all mutants defective in anthocyanin expression contained in the PAC1 clade. Substantial differences in pac1, an11, and ttg1 mutant phenotypes suggest the evolutionary divergence of regulatory mechanisms for several traits that cannot be ascribed solely to divergence of the dicot and monocot protein sequences.

Double valve replacement in a patient with osteogenesis imperfecta.

Valvular heart disease (predominantly aortic and mitral valve disease) has been well documented in patients with osteogenesis imperfecta. Twenty-two prior reports of valve replacement and/or repair have been published. Mortality from cardiac surgery in these patients has been high, particularly in those receiving double valve prostheses. Here, a patient is described with advanced cardiovascular disease who underwent successful aortic and mitral valve replacement. This represents the second reported survival of double valve replacement in osteogenesis imperfecta and a reduced mortality rate for this procedure.

A mutation that prevents paramutation in maize also reverses Mutator transposon methylation and silencing.

Both paramutation and Mutator (Mu) transposon inactivation involve heritable changes in gene expression without concomitant changes in DNA sequence. The mechanisms by which these shifts in gene activity are achieved are unknown. Here we present evidence that these two phenomena are linked mechanistically. We show that mutation of a gene, modifier of paramutation 1 (mop1), which prevents paramutation at three different loci in maize, can reverse methylation of Mutator elements reliably. In mop1 mutant backgrounds, methylation of nonautonomous Mu elements can be reversed even in the absence of the regulatory MuDR element. Previously silenced MuDR elements are reactivated sporadically after multiple generations of exposure to mop1 mutations. MuDR methylation is separable from MuDR silencing, because removal of methylation does not cause immediate reactivation. The mop1 mutation does not alter the methylation of certain other transposable elements including those just upstream of a paramutable b1 gene. Our results suggest that the mop1 gene acts on a subset of epigenetically regulated sequences in the maize genome and paramutation and Mu element methylation require a common factor, which we hypothesize influences chromatin structure.