Pathological features of intrathoracic histiocytic sarcoma in an Amami spiny rat (Tokudaia osimensis).

A 4-year 9-month-old Amami spiny rat reared in a zoo died following a history of anorexia, weight loss, and respiratory distress. At necropsy, neoplastic tissues were found along the pleura and adhered to the thoracic wall, heart, and lungs. Histologically, the tumor was composed of diffuse, patternless sheets of large round to polygonal neoplastic cells with abundant eosinophilic cytoplasm, and multinucleated giant cells were often present. Metastatic lesions were observed in the abdominal lymph nodes. Neoplastic cells were immunopositive for vimentin, Iba-1, and CD204, and negative for E-cadherin and S100. Based on these findings, the tumor was diagnosed as histiocytic sarcoma. Compression of the lungs by the tumor may have caused respiratory failure and led to death.

Investigation of the mutations in the genes involved in Janus kinase/signal transducer and activator of transcription pathway in canine large cell gastrointestinal lymphoma.

Canine gastrointestinal lymphoma is known to be of T-cell origin in most cases, but the molecular biological aberrations have not been clarified. In human intestinal T-cell lymphoma, the mutations in the genes associated with Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway have been frequently observed. In this study, the gene mutations were investigated in 31 dogs with large cell gastrointestinal lymphoma (LCGIL) by focusing on the genes involved in JAK-STAT pathway. Next-generation sequencing analysis to examine the mutations in STAT3, STAT5B, and JAK1 genes throughout the exon regions revealed the mutations in STAT3 gene in two dogs and JAK1 gene in one dog. In conclusion, this study could not indicate the associations of gene mutations in JAK-STAT pathway with LCGIL in most canine cases.

Area under the inspiratory flow-volume curve (AIN): Proposed normative values.

RATIONALE: Area under expiratory flow-volume curve (AEX) has been shown to be a valuable functional measurement in respiratory physiology. Area under inspiratory flow-volume loop (AIN) also shows promise in characterizing upper and/or lower airflow obstruction. OBJECTIVES: we aimed here to develop normative reference values for AIN, able to ascertain deviations from normal. METHODS: We analyzed AIN in 4,980 spirometry tests recorded in non-smoking, healthy individuals in the Pulmonary Function Testing Laboratory. RESULTS: The mean (95% confidence interval, CI), standard deviation and median (25th-75th interquartile range) AIN were 16.05 (15.79-16.31), 9.08 and 14.72 (9.12-21.42) L2·sec-1, respectively. The mean (95% CI) and standard deviation of the best-trial measurements for square root of AIN (Sqrt AIN) were 3.84 (3.81-3.87) and 1.14; 4.15 (4.12-4.18) and 1.03 in men, and 2.68 (2.63-2.72) and 0.72 L·sec-1/2 in women. The mean (standard deviation) of pre- and post-bronchodilator Sqrt AIN were 3.71 (1.17) and 3.81 (1.19) L·sec-1/2, respectively. The mean (95% CI), standard deviation and lowest 5th percentile (lower limit of normal, LLN) of Sqrt AIN/Sqrt AEX (%) were 101.3 (100.82-101.88), 18.7, and 71.8%; stratified by gender, it was 102.2 (101.6-102.8), 18.6, and 72.8% in men, and 98 (96.9-99.2), 18.8, and 68.6% in women, respectively. CONCLUSIONS: The availability of area under the inspiratory flow-volume curve (AIN) and the derived indices offers a promising opportunity to assess upper airway disease (e.g., involvement of larynx, trachea or major bronchi), especially because some of these measurements appear to be independent of age, race, height, and weight.

Atherosclerosis quantification and cardiovascular risk: the ISCHEMIA trial.

BACKGROUND AND AIMS: The aim of this study was to determine the prognostic value of coronary computed tomography angiography (CCTA)-derived atherosclerotic plaque analysis in ISCHEMIA. METHODS: Atherosclerosis imaging quantitative computed tomography (AI-QCT) was performed on all available baseline CCTAs to quantify plaque volume, composition, and distribution. Multivariable Cox regression was used to examine the association between baseline risk factors (age, sex, smoking, diabetes, hypertension, ejection fraction, prior coronary disease, estimated glomerular filtration rate, and statin use), number of diseased vessels, atherosclerotic plaque characteristics determined by AI-QCT, and a composite primary outcome of cardiovascular death or myocardial infarction over a median follow-up of 3.3 (interquartile range 2.2-4.4) years. The predictive value of plaque quantification over risk factors was compared in an area under the curve (AUC) analysis. RESULTS: Analysable CCTA data were available from 3711 participants (mean age 64 years, 21% female, 79% multivessel coronary artery disease). Amongst the AI-QCT variables, total plaque volume was most strongly associated with the primary outcome (adjusted hazard ratio 1.56, 95% confidence interval 1.25-1.97 per interquartile range increase [559 mm3]; P = .001). The addition of AI-QCT plaque quantification and characterization to baseline risk factors improved the model's predictive value for the primary outcome at 6 months (AUC 0.688 vs. 0.637; P = .006), at 2 years (AUC 0.660 vs. 0.617; P = .003), and at 4 years of follow-up (AUC 0.654 vs. 0.608; P = .002). The findings were similar for the other reported outcomes. CONCLUSIONS: In ISCHEMIA, total plaque volume was associated with cardiovascular death or myocardial infarction. In this highly diseased, high-risk population, enhanced assessment of atherosclerotic burden using AI-QCT-derived measures of plaque volume and composition modestly improved event prediction.

Esoteric beliefs and CAM impact SARS-CoV-2 immunization drivers, uptake and pediatric immunization views in Germany.

Recent studies demonstrate that sociopolitical attitudes partially explain variance in (SARS-CoV-2) vaccine hesitancy and uptake. Other attitudes, such as those towards esoteric beliefs, complementary and alternative medicine (CAM), and religion, have also been proposed. However, pertinent studies provide limited direction for public health efforts, as the impact of such attitudes has been tested in isolation or on different outcomes. Moreover, related associations between SARS-CoV-2 immunization drivers as well as views towards other modes of immunization (e.g., routine pediatric immunization), remain unclear. Based on a sample of ~7400 survey participants (Germany), where esoteric belief systems and CAM (Waldorf, homeopathy) are rather prevalent, and controlling for other sociological factors, we found that (i) individuals with positive attitudes towards Waldorf education and homeopathy are significantly less likely to have received a (further) dose of SARS-CoV-2 vaccine compared to those with positive views of mainstream medicine; (ii) for the former, immunization decisions are primarily driven by external pressures, and for the latter overwhelmingly by voluntary considerations; (iii) attitudes influencing adult SARS-CoV-2 vaccine uptake similarly influence views towards routine pediatric immunization. Our findings provide significant evidence informing a more nuanced design of public health and communication campaigns, and pertinent policies.

Multiple promoter and enhancer differences likely contribute to augmented G6PC2 expression in human versus mouse pancreatic islet alpha cells.

G6PC2 encodes a glucose-6-phosphatase catalytic subunit that opposes the action of glucokinase in pancreatic islets thereby modulating the sensitivity of insulin and glucagon secretion to glucose. In mice, G6pc2 is expressed at ~20-fold higher levels in ß-cells versus α-cells, whereas in humans G6PC2 is expressed at only ~5-fold higher levels in ß-cells. We therefore hypothesize that G6PC2 likely influences glucagon secretion to a greater degree in humans. With a view to generating a humanized mouse that re-capitulates augmented G6PC2 expression levels in α-cells, we sought to identify the genomic regions that confer differential mouse G6pc2 expression in α-cells versus ß-cells as well as the evolutionary changes that have altered this ratio in humans. Studies in islet-derived cell lines suggest that the elevated G6pc2 expression in mouse ß-cells versus α-cells is mainly due to a difference in the relative activity of the proximal G6pc2 promoter in these cell types. Similarly, the smaller difference in G6PC2 expression between α-cells versus ß-cells in humans is potentially explained by a change in relative proximal G6PC2 promoter activity. However, we show that both glucocorticoid levels and multiple differences in the relative activity of eight transcriptional enhancers between mice and humans likely contribute to differential G6PC2 expression. Finally, we show that a mouse-specific non-coding RNA, Gm13613, whose expression is controlled by G6pc2 enhancer I, does not regulate G6pc2 expression, indicating that altered expression of Gm13613 in a humanized mouse that contains both the human promoter and enhancers, should not affect G6PC2 function.

The minimal computational substrate of fluid intelligence.

The quantification of cognitive powers rests on identifying a behavioural task that depends on them. Such dependence cannot be assured, for the powers a task invokes cannot be experimentally controlled or constrained a priori, resulting in unknown vulnerability to failure of specificity and generalisability. Evaluating a compact version of Raven's Advanced Progressive Matrices (RAPM), a widely used clinical test of fluid intelligence, we show that LaMa, a self-supervised artificial neural network trained solely on the completion of partially masked images of natural environmental scenes, achieves representative human-level test scores a prima vista, without any task-specific inductive bias or training. Compared with cohorts of healthy and focally lesioned participants, LaMa exhibits human-like variation with item difficulty, and produces errors characteristic of right frontal lobe damage under degradation of its ability to integrate global spatial patterns. LaMa's narrow training and limited capacity suggest matrix-style tests may be open to computationally simple solutions that need not necessarily invoke the substrates of reasoning.

The INVISION Talar Component in Revision Total Ankle Arthroplasty: Analysis of Early Outcomes.

INTRODUCTION: Launched in 2018 for revision total ankle arthroplasty (rTAA), the INVISION talar component addresses subsidence when poor talar bone stock is present. Due to the recency of the market-availability of the INVISION, studies evaluating its efficacy are lacking. This study presents the first analysis of early-term outcomes of patients undergoing rTAA with the INVISION talar component. METHODS: This was a single-center, retrospective review of 28 patients undergoing rTAA with the INVISION talar component and INBONE II tibial component performed between 2018 and 2022. Data on preoperative characteristics, postoperative complications, secondary procedures, and survivorship were collected. The primary outcome measures were rates of major complications, re-operation, and implant failure. Secondary outcomes included post-operative changes in varus and valgus alignment of the tibia and talus. RESULTS: The most common secondary procedures performed with rTAA were medial malleolus fixation (n = 22, 78.6%) and gastrocnemius recession (n = 14, 50%). Overall, 10.7% (n = 3) of patients underwent reoperation and 14.3% (n = 4) suffered major complications. Incidence of implant failure was 10.7% (n = 3). All reoperations were caused by infection. Mean varus alignment of the tibia and talus improved from 4.07 degrees and 4.83 degrees to 1.67 degrees and 1.23 degrees, respectively. Mean valgus alignment of the tibia and talus improved from 3.67 degrees and 4.22 degrees to 2.00 degrees and 2.32 degrees, respectively. CONCLUSIONS: In a series of 28 patients undergoing rTAA with the INVISION talar component, we discovered comparatively low rates of reoperation, major complication, and implant failure (10.7%, 14.3%, and 10.7%). The INVISION system appears to have a reasonable safety profile, but further studies evaluating long-term outcomes are required to assess the efficacy of the INVISION system.

An optimised CRISPR Cas9 and Cas12a mutagenesis toolkit for Barley and Wheat.

BACKGROUND: CRISPR Cas9 and Cas12a are the two most frequently used programmable nucleases reported in plant systems. There is now a wide range of component parts for both which likely have varying degrees of effectiveness and potentially applicability to different species. Our aim was to develop and optimise Cas9 and Cas12a based systems for highly efficient genome editing in the monocotyledons barley and wheat and produce a user-friendly toolbox facilitating simplex and multiplex editing in the cereal community. RESULTS: We identified a Zea mays codon optimised Cas9 with 13 introns in conjunction with arrayed guides driven by U6 and U3 promoters as the best performer in barley where 100% of T0 plants were simultaneously edited in all three target genes. When this system was used in wheat > 90% of T0 plants were edited in all three subgenome targets. For Cas12a, an Arabidopsis codon optimised sequence with 8 introns gave the best editing efficiency in barley when combined with a tRNA based multiguide array, resulting in 90% mutant alleles in three simultaneously targeted genes. When we applied this Cas12a system in wheat 86% & 93% of T0 plants were mutated in two genes simultaneously targeted. We show that not all introns contribute equally to enhanced mutagenesis when inserted into a Cas12a coding sequence and that there is rationale for including multiple introns. We also show that the combined effect of two features which boost Cas12a mutagenesis efficiency (D156R mutation and introns) is more than the sum of the features applied separately. CONCLUSION: Based on the results of our testing, we describe and provide a GoldenGate modular cloning system for Cas9 and Cas12a use in barley and wheat. Proven Cas nuclease and guide expression cassette options found in the toolkit will facilitate highly efficient simplex and multiplex mutagenesis in both species. We incorporate GRF-GIF transformation boosting cassettes in wheat options to maximise workflow efficiency.

Catalytic asymmetric synthesis of meta benzene isosteres.

Although aromatic rings are common elements in pharmaceutically active compounds, the presence of these motifs brings several liabilities with respect to the developability of a drug1. Nonoptimal potency, metabolic stability, solubility and lipophilicity in pharmaceutical compounds can be improved by replacing aromatic rings with non-aromatic isosteric motifs2. Moreover, whereas aromatic rings are planar and lack three-dimensionality, the binding pockets of most pharmaceutical targets are chiral. Thus, the stereochemical configuration of the isosteric replacements may offer an added opportunity to improve the affinity of derived ligands for target receptors. A notable impediment to this approach is the lack of simple and scalable catalytic enantioselective syntheses of candidate isosteres from readily available precursors. Here we present a previously unknown palladium-catalysed reaction that converts hydrocarbon-derived precursors to chiral boron-containing nortricyclanes and we show that the shape of these nortricyclanes makes them plausible isosteres for meta disubstituted aromatic rings. With chiral catalysts, the Pd-catalysed reaction can be accomplished in an enantioselective fashion and subsequent transformation of the boron group provides access to a broad array of structures. We also show that the incorporation of nortricyclanes into pharmaceutical motifs can result in improved biophysical properties along with stereochemistry-dependent activity. We anticipate that these features, coupled with the simple, inexpensive synthesis of the functionalized nortricyclane scaffold, will render this platform a useful foundation for the assembly of new biologically active agents.

Rapidly progressive cystic lung disease in a patient with a scalp lesion.

We describe an elderly patient presenting with pneumothorax, cystic lung disease and a scalp lesion. The pneumothorax resolved after placing a chest tube and suction but recurred within a week. Progression of cystic features was also seen, and biopsies of the lung and scalp lesions were performed. Immunohistochemistry was positive for markers of endothelial cells (CD31 and ERG) and negative for markers expected to be positive in alveolar cells (keratin AE1/AE3 and TTF-1), supporting the diagnosis of metastatic angiosarcoma. Palliative chemotherapy did not prevent progression and the patient expired soon after. In describing the clinico-radiological correlation of metastatic angiosarcoma, we also briefly describe the approach to cystic lung disease. Understanding the pathophysiology of cyst formation in metastatic angiosarcoma may help clinicians to better appreciate and manage the full spectrum of cystic lung disease, especially with atypical features.

Location-Specific Prognostic Significance of Plaque Burden, Stenosis, and Plaque Morphology in Coronary Artery Disease.

AIMS: To investigate the location-specific prognostic significance of plaque burden, diameter stenosis and plaque morphology. METHODS AND RESULTS: Patients without a documented cardiac history who underwent coronary computed tomography angiography (CCTA) for suspected coronary artery disease were included. Percentage atheroma volume (PAV), maximum diameter stenosis, and plaque morphology were assessed and classified into proximal, mid, or distal segments of the coronary tree. Major adverse cardiac events (MACE) were defined as death or non-fatal myocardial infarction. Among 2819 patients 267 events (9.5%) occurred during a median follow-up of 6.9 years. When adjusted for traditional risk factors and presence of PAV on other locations, only proximal PAV was independently associated with MACE. However, PAV of the proximal segments was strongly correlated to PAV localized at the mid (R= 0.76) and distal segments (R=0.74, p<0.01 for both). When only adjusted for cardiovascular risk factors, the area under the curve (AUC) to predict MACE for proximal PAV was 0.73 (95%CI 0.69-0.76), which was similar compared to mid PAV (AUC 0.72, 95%CI 0.68-0.76) and distal PAV (AUC 0.72, 95%CI 0.68-0.76). Similar results were obtained using diameter stenosis instead of PAV. The presence of proximal low-attenuation plaque had borderline additional prognostic value. CONCLUSIONS: Proximal PAV was the strongest predictor of MACE when adjusted for cardiovascular risk factors and plaque at other locations. However, when presence of plaque was only adjusted for cardiovascular risk factors, proximal, mid, and distal plaque localization showed a similar predictive ability for MACE.

Ubiquitinated histone H2B as gatekeeper of the nucleosome acidic patch.

Monoubiquitination of histones H2B-K120 (H2BK120ub) and H2A-K119 (H2AK119ub) play opposing roles in regulating transcription and chromatin compaction. H2BK120ub is a hallmark of actively transcribed euchromatin, while H2AK119ub is highly enriched in transcriptionally repressed heterochromatin. Whereas H2BK120ub is known to stimulate the binding or activity of various chromatin-modifying enzymes, this post-translational modification (PTM) also interferes with the binding of several proteins to the nucleosome H2A/H2B acidic patch via an unknown mechanism. Here, we report cryoEM structures of an H2BK120ub nucleosome showing that ubiquitin adopts discrete positions that occlude the acidic patch. Molecular dynamics simulations show that ubiquitin remains stably positioned over this nucleosome region. By contrast, our cryoEM structures of H2AK119ub nucleosomes show ubiquitin adopting discrete positions that minimally occlude the acidic patch. Consistent with these observations, H2BK120ub, but not H2AK119ub, abrogates nucleosome interactions with acidic patch-binding proteins RCC1 and LANA, and single-domain antibodies specific to this region. Our results suggest a mechanism by which H2BK120ub serves as a gatekeeper to the acidic patch and point to distinct roles for histone H2AK119 and H2BK120 ubiquitination in regulating protein binding to nucleosomes.

Defining optimal left ventricular assist device short-term outcomes may provide insight into programmatic quality assessment.

BACKGROUND: Patients have substantial variability in perioperative outcomes after left ventricular assist device (LVAD) implant. A perioperative multidimensional tool integrating mortality, adverse events (AEs), and patient-reported outcomes to assist in quality improvement initiatives is needed. METHODS: Patients undergoing HeartMate 3 LVAD implant (January 1, 2017 to January 31, 2024) in the Society of Thoracic Surgeons' Intermacs registry were studied. Cox proportional hazard multivariable analyses incorporating AEs as time-varying covariates for mortality out to 180 days was used to generate the INtermacs Short term composITE quality score (INSITE score derivation), reflecting the adjusted hazard ratio (HR) for mortality contributed by each AE, applying the global ranking methodology. In those alive and on support at 6 months, multivariable logistic regression (odds ratio) was used to examine the impact of AEs on health-related quality of life (QOL) at 180 days, captured through the INSITE-QOL score. Failure to achieve ≥1 point increase in visual analog scale from baseline was the event. RESULTS: Of 13,148 patients, 4,389 (33.4%) suffered at least 1 AE or death through 180 days. Stroke (survival: HR 13.1; QOL: HR 1.7), dialysis (survival: HR 31.4; QOL: HR 4.2), prolonged respiratory failure (survival: HR 5.7; QOL: HR 2.3), reoperation (survival: HR 3.4; QOL: HR 1.6), and right heart failure (survival: 5.0; QOL: HR 1.4), contributed to both mortality and failure to improve QOL at 180 days (all p < 0.05). The median INSITE and INSITE-QOL scores were 0.0 [0.0, 1.6] and 0.0 [0.0, 0.0], respectively. At 9.4% (n = 17) of centers, a high INSITE score (≥13) was present in 15% of patients, while the top 25% of centers had perfect INSITE-QOL scores in at least 75% of patients. CONCLUSIONS: AEs after LVAD confer differential impact on mortality and QOL, enabling the development of global rank outcome scores. Given the high mortality hazard conferred by 180-day AEs, center-specific quality interventions aimed at reducing early complications provide the greatest opportunity to improve long-term survival and QOL.

Genome sequence of bacteriophage GiJojo, isolated using Streptomyces mirabilis in Catonsville, Maryland.

Bacteriophage GiJojo is a myovirus isolated from soil that infects Streptomyces mirabilis NRRL B-2400, with a genome length of 115,161 bp containing 180 genes and 29 tRNAs. Of those genes, 59 have been assigned functions. GiJojo is a member of the BS cluster of actinobacteriophages.

Predicting 35-Cl electric field gradient tensors in crystalline solids using cluster and fragment-corrected planewave density functional theory.

Planewave-corrected methods have proven effective for accurately modeling nuclear magnetic resonance (NMR) parameters in crystalline systems. Recent work extended the application of planewave-corrected calculations beyond the second row, predicting EFG tensor parameters for 35Cl using a simple molecular correction to projector augmented-wave (PAW) density functional theory (DFT). Here we extend this work using fragment and cluster-based calculations coupled with polarizable continuum (PCM) methods to improve further the accuracy of planewave-corrected 35Cl EFG tensor calculations. Benchmark data from a test set comprised of 105 individual 35Cl EFG tensor principal components for chlorine-containing molecular crystals and crystalline chloride salts shows fragment-corrected planewave calculations using the PBE0 hybrid density functional improve the accuracy of predicted EFG tensor components by 30 % relative to traditional planewave calculations. We compare the influence of different geometry optimization methods and density functionals on the accuracy of predicted 35Cl EFG tensor parameters. Four cases of spectral assignment are presented to demonstrate the utility of improving the accuracy of predicted 35Cl EFG tensor parameters.

Characterization of faecal microbiota and serum inflammatory markers in dogs diagnosed with chronic enteropathy or small-cell lymphoma: a pilot study.

Dogs diagnosed with chronic enteropathy (CE) or small-cell lymphoma (SCL) exhibit marked differences in faecal microbiota and organic acid profiles compared with healthy dogs, as well as immune abnormalities in intestinal mucosal tissue. However, few studies have analysed trace organic acids, such as succinic acid, which have been suggested to be associated with IBD in humans. Therefore, in this study, we compared the faecal microbiota and organic acid profiles as well as serum inflammatory markers between dogs with disease (n = 11; 6 with CE and 5 with SCL) and healthy controls (n = 16). We also performed machine learning and correlation analysis to obtain more detailed insights into the characteristics of affected dogs. These results revealed that dogs with CE and SCL had lower levels of Erysipelotrichaceae (e.g. Turicibacter and Allobaculum), exhibited abnormalities in the succinic acid metabolism (i.e. succinic acid accumulation and decreased levels of Phascolarctobacterium as succinic acid-utilising bacteria) and increased levels of pathobiont bacteria such as Escherichia-Shigella. Additionally, the presence of Dubosiella was significantly negatively correlated with Canine Inflammatory Bowel Disease Activity Index scores. These findings are expected to aid the development of microbiome-based medications and/or supplements, although further verification is needed.

Essential/precursor chemical control research: Giommoni's review, understanding multi-replication interrupted time series analysis, and next steps.

Controls on essential/precursor chemicals from commercial companies have been associated with many large downturns in illicit drug markets and attendant problems. My colleagues and I brought this to light in the studies that are the subject of Giommoni's review. McKetin et al. in an earlier review considered several of our studies on chemical controls for methamphetamine, all centered in North America. Giommoni discusses not only those studies but also our later work on chemical controls for cocaine and heroin. This later work evaluates US essential/precursor chemical policies targeting illicit drug producers outside of North America, and it examines impacts on illicit drug availability and use (the studies reviewed by McKetin et al. predominantly focused on outcomes such as drug-related hospitalizations, arrests, and treatment). Giommoni's review is a new resource that will help make the varied topics in essential/precursor chemical control research more accessible to many readers. After noting this, I discuss some common methodological misconceptions about our studies. For example, our studies generally used multi-replication interrupted time series analysis, a research design among the most powerful of all quasi-experimental designs. Authors, however, typically discuss the studies as if they used single-intervention interrupted time series analysis, a less powerful design. Multi-replication and single-intervention interrupted time series analyses also differ regarding likely confounders; awareness of this is critical to accurately assessing our findings and critiquing alternative explanations. Finally, I note that commercial chemical companies function as the silent, albeit usually unwitting, partners in the large-scale production of several illicit drugs, including fentanyl. And many governments are implementing essential/precursor chemical controls to help stymie this partnership. But they are doing so largely without evaluation and study-a poor policy practice. To remedy this, I suggest establishing multi-disciplinary applied research teams to help assess, guide and improve essential/precursor chemical control efforts.