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BRCA2 plays a central role in facilitating DNA repair by homologous recombination (HR). Here the authors describe how BRCA2 forms a complex with the protein phosphatase PP2A-B56 in response to DNA damage, which is required for HR.

Pleiotropy and genetic correlation are widespread features in genome-wide association studies (GWAS), but they are often difficult to interpret at the molecular level. Here, we perform GWAS of 16 metabolites clustered at the intersection of amino acid catabolism, glycolysis, and ketone body metabolism in a subset of UK Biobank. We utilize the well-documented biochemistry jointly impacting these metabolites to analyze pleiotropic effects in the context of their pathways. Among the 213 lead GWAS hits, we find a strong enrichment for genes encoding pathway-relevant enzymes and transporters. We demonstrate that the effect directions of variants acting on biology between metabolite pairs often contrast with those of upstream or downstream variants as well as the polygenic background. Thus, we find that these outlier variants often reflect biology local to the traits. Finally, we explore the implications for interpreting disease GWAS, underscoring the potential of unifying biochemistry with dense metabolomics data to understand the molecular basis of pleiotropy in complex traits and diseases.

Abstract Introduction Allogeneic hematopoietic stem cell transplantation (aHSCT) is a curative treatment for hematopoietic malignancies. Graft‐versus‐host disease (GVHD) is a major complication of aHSCT. After transplantation, the balance of immune conditions, such as proinflammatory cytokine level and T‐cell subset count, influences GVHD magnitude. Lenalidomide (LEN) is an immunomodulatory drug used for treating several hematological malignancies such as multiple myeloma, adult T‐cell lymphoma/leukemia, and follicular lymphoma. However, the impact of LEN on immune responses after aHSCT has not been elucidated. Methods We analyzed the lymphocyte composition in naïve mice treated with LEN. Subsequently, we treated host mice with LEN, soon after aHSCT, and analyzed GVHD severity as well as the composition and characteristics of lymphocytes associated with GVHD. Results Using a mouse model, we demonstrated the beneficial effects of LEN for treating acute GVHD. Although natural killer cells were slightly increased by LEN, it did not significantly change T‐cell proliferation and the balance of the T‐cell subset in naïve mice. LEN did not modulate the suppressive function of regulatory T cells (Tregs). Unexpectedly, LEN prevented severe GVHD in a mouse acute GVHD model. Donor‐derived lymphocytes were more numerous in host mice treated with LEN than in host mice treated with vehicle. Lymphocyte infiltration of the gastrointestinal tract in host mice treated with LEN was less severe compared to that in host mice treated with vehicle. The percentage of LPAM‐1 (α4β7‐integrin)‐expressing Foxp3−CD4+ T cells was significantly lower in host mice treated with LEN than in host mice treated with vehicle, whereas that of LPAM‐1‐expressing Tregs was comparable. Conclusions LEN may be useful as a prophylactic agent for acute GVHD‐induced mortality through the inhibition of lymphocyte migration to the gastrointestinal tract. Our data show the effect of LEN on immune responses early after aHSCT and suggest that cereblon, a molecular target of LEN, may be a therapeutic target for preventing acute GVHD‐induced mortality.

Abstract Background Prostate cancer is caused by genomic aberrations in normal epithelial cells, however clinical translation of findings from analyses of cancer cells alone has been very limited. A deeper understanding of the tumour microenvironment is needed to identify the key drivers of disease progression and reveal novel therapeutic opportunities. Results In this study, the experimental enrichment of selected cell-types, the development of a Bayesian inference model for continuous differential transcript abundance, and multiplex immunohistochemistry permitted us to define the transcriptional landscape of the prostate cancer microenvironment along the disease progression axis. An important role of monocytes and macrophages in prostate cancer progression and disease recurrence was uncovered, supported by both transcriptional landscape findings and by differential tissue composition analyses. These findings were corroborated and validated by spatial analyses at the single-cell level using multiplex immunohistochemistry. Conclusions This study advances our knowledge concerning the role of monocyte-derived recruitment in primary prostate cancer, and supports their key role in disease progression, patient survival and prostate microenvironment immune modulation.

Abstract A molecular-level understanding of the structure of the polymeric network formed upon the curing of air-drying artists’ oil paints still represents a challenge. In this study we used a set of analytical methodologies classically employed for the characterisation of a paint film—based on infrared spectroscopy and mass spectrometry—in combination with solid state NMR (SSNMR), to characterise model paint layers which present different behaviours towards surface cleaning with water, a commonly applied procedure in art conservation. The study demonstrates, with the fundamental contribution of SSNMR, a relationship between the painting stability and the chemical structure of the polymeric network. In particular, it is demonstrated for the first time that a low degree of cross-linking in combination with a high degree of oxidation of the polymeric network render the oil paint layer sensitive to water.

The present study focused on the entropy generation as well as the heat transfer rate and velocity profiles of a nanofluid of the Jeffery-Hamel flow, especially for convergent-divergent channels. First, the governing dimensional partial differential equations have been transformed into a system of non-dimensional ordinary differential equations. The Power series method has been used to solve these non-dimensional governing equations and the Hermite-Pade approximation has been applied for analyzing them. The effect of various physical parameters such as channel angle, Reynolds number, Hartmann number, nanoparticle solid volume frictions and Eckert number have been investigated for the velocity profiles, heat transfer and entropy generation. Here, Cu has been used as the solid nanoparticle and water has been used as the base fluid. It is interesting to remark that the entropy generation of the whole system increased at the two walls and a significant effect could be noticed on the heat transfer rate and velocity profiles.

Abstract Background Coronavirus disease 2019 (COVID-19) pandemic has caused unprecedented pressure on healthcare system globally. Lack of high-quality evidence on the respiratory management of COVID-19-related acute respiratory failure (C-ARF) has resulted in wide variation in clinical practice. Methods Using a Delphi process, an international panel of 39 experts developed clinical practice statements on the respiratory management of C-ARF in areas where evidence is absent or limited. Agreement was defined as achieved when > 70% experts voted for a given option on the Likert scale statement or > 80% voted for a particular option in multiple-choice questions. Stability was assessed between the two concluding rounds for each statement, using the non-parametric Chi-square (χ 2) test (p

Abstract Among the artists’ materials of the nineteenth century, pastel crayons merit scientific interest since their early commercial formulations are mostly unknown and, until now, have been considerably less studied with respect to other contemporary painting materials. In this framework, research herein reports the results of a comprehensive multi-analytical study of 44 pastel crayons of two recognized brands (LeFranc and Dr. F. Schoenfeld) from the Munch museum collection of original materials belonging to Edvard Munch. The integrated use of complementary spectroscopic and hyphenated mass-spectrometry techniques allowed the compositional profiles of the crayons to be traced providing the identification of the inorganic and organic pigments, the fillers/extenders and the binders. All crayons resulted to be oil- based and the binder was identified to be a mixture of a drying oil (safflower or linseed oil), palm oil or Japan wax and beeswax. Among others, pigments such as ultramarine, chrome yellows, Prussian blue, manganese violet, viridian and madder lake have been identified. A significant alignment in formulations of the brands was observed with the only exception of the greens which showed distinctive pigment and filler compositions. The analytical information provided for these commercial artists’ materials will be of great interest for academia, museum and other institutions hosting art collections dating from the same period and it will be used by the Munch museum to draw proper conservation strategies of its own artwork collections.

Among the innovative materials used by 20th-century artists, polyurethane (PUR) has been shown to be highly unstable, and therefore artworks made of it are now in need of careful conservation strategies. This study presents a multi-analytical investigation of PUR foam scenic objects originally made between the 1960s and 1970s during the Italian Arte Viva movement. The main components in the foam and additives were characterized through micro attenuated total reflectance infrared spectroscopy (μ-ATR-FTIR) and pyrolysis coupled with gas chromatography and mass spectrometry (Py-GC/MS). Painted samples were further investigated through μ-FTIR and Raman spectroscopy to define binders and pigments. The use of μ-ATR-FTIR in combination with evolved gas analysis-mass spectrometry (EGA-MS) allowed the variable conditions of the artworks to be assessed and attained some insights into the chemical processes responsible for aging. At the same time, morphological changes due to the degradation phenomena were recorded through optical (OM) and scanning electron microscopy (SEM). The detailed characterization of the PUR foam and painting materials was helpful in attaining some insights into harmful environmental parameters for the artworks, thus informing preventive conservation.

Sol LeWitt, a pioneer of conceptual art, created during his career over 1350 wall drawings, including the Wall Drawing #736 (1993) at the Center for Contemporary Art Luigi Pecci in Prato (Prato, Italy). The painting, executed by Andrea Marescalchi and Antony Sansotta under LeWitt's instructions, features a grid of coloured rectangles obtained by overlapping different layers of inks. During a 2021 restoration by the Wall Paintings and Stuccoes Department of the Opificio delle Pietre Dure (Firenze, Italy), an in-depth investigation of the composition and the materials used by LeWitt's assistants in producing Wall Drawing #736 was performed. A multi-analytical approach entailing Raman spectroscopy, high-performance liquid chromatography coupled to diode array and high-resolution mass spectrometry, gas chromatography–mass spectrometry (GC–MS), and pyrolysis coupled with GC–MS was applied. Our results revealed the use of animal glue, shellac resin, paraffin wax, linseed oil, and various organic pigments. The binder in the preparation layer was identified as poly(vinyl acetate), while poly(n-butyl methacrylate) was determined as a fixative. This research provided valuable insights into LeWitt's techniques. The acquired knowledge on the paint technique is highly relevant in supporting conservators in restoration and consolidating the many wall drawings produced exploiting the same technique all over the world. [ABSTRACT FROM AUTHOR]

China has a 9000-year-long history of cereal-based alcohol production, with the use of molds (filamentous fungi) likely being one of the earliest fermentation techniques. This method later developed into the uniquely East Asian qu (koji) starter compound, containing grains, molds, yeasts, and bacteria. Recent studies have revealed that this method was already widely applied during the Neolithic period. However, much less is known about its development during the early dynastic times, and our knowledge of this innovation has mainly relied on textual materials. Here, we present direct evidence, based on microbotanical, microbial, and chemical analyses, for the fermentation method of a 2300-year-old liquid preserved in a sealed bronze bottle unearthed in a Qin tomb at Yancun, Shaanxi. The results of this research suggest that this liquid is likely a fermented beverage made from wheat/barley, rice, Job's tears, broomcorn millet, and pulses. The fermentation starter may have been a cereal-based qu, consisting of a wide range of microorganisms, including molds (Aspergillus and Monascus), yeasts, and bacteria. Our findings suggest that the tradition of selecting suitable grains and microbial communities for brewing alcohol, possibly with a maiqu starter (primarily wheat/barley-based qu), may have been well established more than two thousand years ago. [ABSTRACT FROM AUTHOR]

Pooled nucleic acid amplification tests for severe acute respiratory syndrome coronavirus 2 could increase availability of testing at decreased cost. However, the effect of dilution on analytical sensitivity through sample pooling has not been well characterized. We tested 1,648 prospectively pooled specimens by using 3 nucleic acid amplification tests for severe acute respiratory syndrome coronavirus 2: a laboratory-developed real-time reverse transcription PCR targeting the envelope gene, and 2 commercially available Panther System assays targeting open reading frame 1ab. Positive percent agreement (PPA) of pooled versus individual testing ranged from 71.7% to 82.6% for pools of 8 and from 82.9% to 100.0% for pools of 4. We developed and validated an independent stochastic simulation model to estimate effects of dilution on PPA and efficiency of a 2-stage pooled real-time reverse transcription PCR testing algorithm. PPA was dependent on the proportion of tests with positive results, cycle threshold distribution, and assay limit of detection.

Abstract Two types of materials were sampled as part of an investigation of the relics of the Holy Catholic Church of the Apostles St Philip and St James in the Basilica dei Santi Apostoli in Rome: bone- and mummy-materials and architectural samples. The analyses encompassed radiocarbon dating, thermoluminescence dating, gas and liquid chromatographic separation with mass spectrometric detection, X-Ray fluorescence, X-Ray diffraction, inductively coupled plasma mass spectrometry, Raman spectroscopy, and Fourier transform infrared spectroscopy. The results show that the samples were subjected to a number of conservational and exhibition-related treatments. The alleged femoral bone of St James was dated between AD 214 and 340 (2σ confidence), which shows that this cannot be the bone of St James. An encrustation found in a canal in the reliquary in the high altar construction showed the presence of heavily oxidized rapeseed oil, which was radiocarbon dated between AD 267 and 539 (2σ confidence), and a ceramic shard also found in the high altar construction was TL-dated to AD 314–746 (2σ confidence). The two latter dates are consistent with a translation of the relics following the erection of the church at the time of Pope Pelagius I in AD 556–561.

Acute disseminated encephalomyelitis (ADEM) is an uncommon disease generally with a preceding history of infectious illness. Here, we report a rare case of ADEM following influenza A infection with transient detection of anti-myelin oligodendrocyte glycoprotein (MOG) antibody in a young male patient who presented with extensive demyelination of brain and spinal cord, likely the result of dysregulated immune response from previous influenza A infection. The patient presented to the emergency with urinary retention and progressive ascending weakness of lower limbs. Magnetic resonance imaging (MRI) of the brain and spinal cord showed multiple ill-defined hyperintensities, suggestive of demyelination. The clinical presentation, MRI findings, cerebrospinal fluid examination, negative anti-aquaporin-4 antibody and metabolic and other viral infectious screening supported the diagnosis of ADEM. The patient had transiently positive anti-MOG antibodies (for 3 months) and was treated with intravenous immunoglobulin followed by oral prednisolone for 3 months. There was a significant recovery in the upper limb weakness and brainstem function. This case highlights the association of anti-MOG antibody with ADEM following viral infections and the need for prolonged follow-up to differentiate between transient antibodies from relapsing MOG antibody disease.

Mendelian randomization is a popular method to detect causal relationships between traits, but can be confounded by instances of horizontal pleiotropy. Here, the authors present a Mendelian randomization workflow which includes causal discovery analysis and filtering of genetic instruments based on their conditional independencies.

Gastrointestinal cytomegalovirus (GI-CMV) infection is well-reported in immunocompromised individuals and those on chemotherapy or other immunosuppressive medications. Rarely, CMV infection of gastrointestinal tract (GIT) occurs in immunocompetent individuals. Colon is the most common site of GI involvement with CMV. However, in immunocompetent individuals, upper GIT involvement is more common. Clinical spectrum of GI-CMV disease is variable and depends on the location and severity of the disease. Prompt diagnosis and treatment aids in reducing morbidity and mortality related to CMV involvement in GI tract. We present two interesting cases of CMV-induced GI ulcers in immunocompetent individuals with brief review of diagnostic and treatment challenges associated with CMV disease in immunocompetent individuals.

Studies of early life stress (ELS) demonstrate the long-lasting effects of acute and chronic stress on developmental trajectories. Such experiences can become biologically consolidated, creating individual vulnerability to psychological and psychiatric issues later in life. The hippocampus, amygdala, and the medial prefrontal cortex are all important limbic structures involved in the processes that undermine mental health. Hyperarousal of the sympathetic nervous system with sustained allostatic load along the Hypothalamic Pituitary Adrenal (HPA) axis and its connections has been theorized as the basis for adult psychopathology following early childhood trauma. In this review we synthesize current understandings and hypotheses concerning the neurobiological link between childhood trauma, the HPA axis, and adult psychiatric illness. We examine the mechanisms at play in the brain of the developing child and discuss how adverse environmental stimuli may become biologically incorporated into the structure and function of the adult brain via a discussion of the neurosequential model of development, sensitive periods and plasticity. The HPA connections and brain areas implicated in ELS and psychopathology are also explored. In a targeted review of HPA activation in mood and psychotic disorders, cortisol is generally elevated across mood and psychotic disorders. However, in bipolar disorder and psychosis patients with previous early life stress, blunted cortisol responses are found to awakening, psychological stressors and physiological manipulation compared to patients without previous early life stress. These attenuated responses occur in bipolar and psychosis patients on a background of increased cortisol turnover. Although cortisol measures are generally raised in depression, the evidence for a different HPA activation profile in those with early life stress is inconclusive. Further research is needed to explore the stress responses commonalities between bipolar disorder and psychosis in those patients with early life stress.

Sardinia has one of the lowest incidences of hospitalization and related mortality in Europe and yet a very high frequency of the Neanderthal risk locus variant on chromosome 3 (rs35044562), considered to be a major risk factor for a severe SARS-CoV-2 disease course. We evaluated 358 SARS-CoV-2 patients and 314 healthy Sardinian controls. One hundred and twenty patients were asymptomatic, 90 were pauci-symptomatic, 108 presented a moderate disease course and 40 were severely ill. All patients were analyzed for the Neanderthal-derived genetic variants reported as being protective (rs1156361) or causative (rs35044562) for severe illness. The β°39 C>T Thalassemia variant (rs11549407), HLA haplotypes, KIR genes, KIRs and their HLA class I ligand combinations were also investigated. Our findings revealed an increased risk for severe disease in Sardinian patients carrying the rs35044562 high risk variant [OR 5.32 (95% CI 2.53 - 12.01), p = 0.000]. Conversely, the protective effect of the HLA-A*02:01, B*18:01, DRB*03:01 three-loci extended haplotype in the Sardinian population was shown to efficiently contrast the high risk of a severe and devastating outcome of the infection predicted for carriers of the Neanderthal locus [OR 15.47 (95% CI 5.8 – 41.0), p < 0.0001]. This result suggests that the balance between risk and protective immunogenetic factors plays an important role in the evolution of COVID-19. A better understanding of these mechanisms may well turn out to be the biggest advantage in the race for the development of more efficient drugs and vaccines.

The ability of clinical laboratories to meet the demand for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) testing is critical for reducing coronavirus disease (COVID-19)-related illness, death, and economic impact. [...]