Single-cell analysis reveals regional reprogramming during adaptation to massive small bowel resection in mice

BACKGROUND & AIMS: The small intestine (SI) displays regionality in nutrient and immunological function. Following SI tissue loss (as occurs in short gut syndrome, or SGS), remaining SI must compensate, or adapt ; the capacity of SI epithelium to reprogram its regional identity has not been described. Here, we apply single-cell resolution analyses to characterize molecular changes underpinning adaptation to SGS. METHODS: Single-cell RNA sequencing was performed on epithelial cells isolated from distal SI of mice following 50% proximal small bowel resection (SBR) vs sham surgery. Single-cell profiles were clustered based on transcriptional similarity, reconstructing differentiation events from intestinal stem cells (ISCs) through to mature enterocytes. An unsupervised computational approach to score cell identity was used to quantify changes in regional (proximal vs distal) SI identity, validated using immunofluorescence, immunohistochemistry, qPCR, western blotting, and RNA-FISH. RESULTS: Uniform Manifold Approximation and Projection-based clustering and visualization revealed differentiation trajectories from ISCs to mature enterocytes in sham and SBR. Cell identity scoring demonstrated segregation of enterocytes by regional SI identity: SBR enterocytes assumed more mature proximal identities. This was associated with significant upregulation of lipid metabolism and oxidative stress gene expression, which was validated via orthogonal analyses. Observed upstream transcriptional changes suggest retinoid metabolism and proximal transcription factor Creb3l3 drive proximalization of cell identity in response to SBR. CONCLUSIONS: Adaptation to proximal SBR involves regional reprogramming of ileal enterocytes toward a proximal identity. Interventions bolstering the endogenous reprogramming capacity of SI enterocytes-conceivably by engaging the retinoid metabolism pathway-merit further investigation, as they may increase enteral feeding tolerance, and obviate intestinal failure, in SGS

Proteome sequence features carry signatures of the environmental niche of prokaryotes

<p>Abstract</p> <p>Background</p> <p>Prokaryotic environmental adaptations occur at different levels within cells to ensure the preservation of genome integrity, proper protein folding and function as well as membrane fluidity. Although specific composition and structure of cellular components suitable for the variety of extreme conditions has already been postulated, a systematic study describing such adaptations has not yet been performed. We therefore explored whether the environmental niche of a prokaryote could be deduced from the sequence of its proteome. Finally, we aimed at finding the precise differences between proteome sequences of prokaryotes from different environments.</p> <p>Results</p> <p>We analyzed the proteomes of 192 prokaryotes from different habitats. We collected detailed information about the optimal growth conditions of each microorganism. Furthermore, we selected 42 physico-chemical properties of amino acids and computed their values for each proteome. Further, on the same set of features we applied two fundamentally different machine learning methods, Support Vector Machines and Random Forests, to successfully classify between bacteria and archaea, halophiles and non-halophiles, as well as mesophiles, thermophiles and mesothermophiles. Finally, we performed feature selection by using Random Forests.</p> <p>Conclusions</p> <p>To our knowledge, this is the first time that three different classification cases (domain of life, halophilicity and thermophilicity) of proteome adaptation are successfully performed with the same set of 42 features. The characteristic features of a specific adaptation constitute a signature that may help understanding the mechanisms of adaptation to extreme environments.</p

Another Shipment of Six Short-Period Giant Planets from TESS

We present the discovery and characterization of six short-period, transiting giant planets from NASA's Transiting Exoplanet Survey Satellite (TESS) -- TOI-1811 (TIC 376524552), TOI-2025 (TIC 394050135), TOI-2145 (TIC 88992642), TOI-2152 (TIC 395393265), TOI-2154 (TIC 428787891), & TOI-2497 (TIC 97568467). All six planets orbit bright host stars (8.9 <G< 11.8, 7.7 <K< 10.1). Using a combination of time-series photometric and spectroscopic follow-up observations from the TESS Follow-up Observing Program (TFOP) Working Group, we have determined that the planets are Jovian-sized (R$_{P}$ = 1.00-1.45 R$_{J}$), have masses ranging from 0.92 to 5.35 M$_{J}$, and orbit F, G, and K stars (4753 $<$ T$_{eff}$ $<$ 7360 K). We detect a significant orbital eccentricity for the three longest-period systems in our sample: TOI-2025 b (P = 8.872 days, $e$ = $0.220\pm0.053$), TOI-2145 b (P = 10.261 days, $e$ = $0.182^{+0.039}_{-0.049}$), and TOI-2497 b (P = 10.656 days, $e$ = $0.196^{+0.059}_{-0.053}$). TOI-2145 b and TOI-2497 b both orbit subgiant host stars (3.8 $<$ $\log$ g $<$4.0), but these planets show no sign of inflation despite very high levels of irradiation. The lack of inflation may be explained by the high mass of the planets; $5.35^{+0.32}_{-0.35}$ M$_{\rm J}$ (TOI-2145 b) and $5.21\pm0.52$ M$_{\rm J}$ (TOI-2497 b). These six new discoveries contribute to the larger community effort to use {\it TESS} to create a magnitude-complete, self-consistent sample of giant planets with well-determined parameters for future detailed studies.Comment: 20 Pages, 6 Figures, 8 Tables, Accepted by MNRA

The genetic architecture of type 2 diabetes

The genetic architecture of common traits, including the number, frequency, and effect sizes of inherited variants that contribute to individual risk, has been long debated. Genome-wide association studies have identified scores of common variants associated with type 2 diabetes, but in aggregate, these explain only a fraction of heritability. To test the hypothesis that lower-frequency variants explain much of the remainder, the GoT2D and T2D-GENES consortia performed whole genome sequencing in 2,657 Europeans with and without diabetes, and exome sequencing in a total of 12,940 subjects from five ancestral groups. To increase statistical power, we expanded sample size via genotyping and imputation in a further 111,548 subjects. Variants associated with type 2 diabetes after sequencing were overwhelmingly common and most fell within regions previously identified by genome-wide association studies. Comprehensive enumeration of sequence variation is necessary to identify functional alleles that provide important clues to disease pathophysiology, but large-scale sequencing does not support a major role for lower-frequency variants in predisposition to type 2 diabetes

Chest CT Diagnosis and Clinical Management of Drug-related Pneumonitis in Patients Receiving Molecular Targeting Agents and Immune Checkpoint Inhibitors: A Position Paper from the Fleischner Society

Use of molecular targeting agents and immune checkpoint inhibitors (ICIs) has increased the frequency and broadened the spectrum of lung toxicity, particularly in patients with cancer. The diagnosis of drug-related pneumonitis (DRP) is usually achieved by excluding other potential known causes. Awareness of the incidence and risk factors for DRP is becoming increasingly important. The severity of symptoms associated with DRP may range from mild or none to life-threatening with rapid progression to death. Imaging features of DRP should be assessed in consideration of the distribution of lung parenchymal abnormalities (radiologic pattern approach). The CT patterns reflect acute (diffuse alveolar damage) interstitial pneumonia and transient (simple pulmonary eosinophilia) lung abnormality, subacute interstitial disease (organizing pneumonia and hypersensitivity pneumonitis), and chronic interstitial disease (nonspecific interstitial pneumonia). A single drug can be associated with multiple radiologic patterns. Treatment of a patient suspected of having DRP generally consists of drug discontinuation, immunosuppressive therapy, or both, along with supportive measures eventually including supplemental oxygen and intensive care. In this position paper, the authors provide diagnostic criteria and management recommendations for DRP that should be of interest to radiologists, clinicians, clinical trialists, and trial sponsors, among others