The paradigm that only 1% of microbes are culturable has had a profound impact on our understanding of microbial ecology and is still a major motivation for mostly using molecular tools to ...characterize microbial communities. However, this point is often expressed vaguely, suggesting that some scientists have different interpretations of the paradigm. In addition, there have been substantial advances in cultivation techniques suggesting that this paradigm may no longer be correct. To quantify bacterial culturability across six major biomes, I found that the median 16S rRNA similarity of bacteria to known cultured relatives was 97.3 ± 2.3% (s.d.). Furthermore, 52.0 ± 24% of sequences and 34.9 ± 23% of taxa (defined as >97% similar) had a closely related cultured relative. Thus, many cells and taxa across environments are culturable with known techniques, suggesting that the 1% paradigm is no longer correct.
Animal nutrition is profoundly influenced by the gut microbiota, but knowledge of the scope and core mechanisms of the underlying animal-microbiota interactions is fragmentary. To investigate the ...nutritional traits shaped by the gut microbiota of Drosophila, we determined the microbiota-dependent response of multiple metabolic and performance indices to systematically varied diet composition. Diet-dependent differences between Drosophila bearing its unmanipulated microbiota (conventional flies) and experimentally deprived of its microbiota (axenic flies) revealed evidence for: microbial sparing of dietary B vitamins, especially riboflavin, on low-yeast diets; microbial promotion of protein nutrition, particularly in females; and microbiota-mediated suppression of lipid/carbohydrate storage, especially on high sugar diets. The microbiota also sets the relationship between energy storage and body mass, indicative of microbial modulation of the host signaling networks that coordinate metabolism with body size. This analysis identifies the multiple impacts of the microbiota on the metabolism of Drosophila, and demonstrates that the significance of these different interactions varies with diet composition and host sex.
Apical constriction is a cell shape change that promotes tissue remodeling in a variety of homeostatic and developmental contexts, including gastrulation in many organisms and neural tube formation ...in vertebrates. In recent years, progress has been made towards understanding how the distinct cell biological processes that together drive apical constriction are coordinated. These processes include the contraction of actin-myosin networks, which generates force, and the attachment of actin networks to cell-cell junctions, which allows forces to be transmitted between cells. Different cell types regulate contractility and adhesion in unique ways, resulting in apical constriction with varying dynamics and subcellular organizations, as well as a variety of resulting tissue shape changes. Understanding both the common themes and the variations in apical constriction mechanisms promises to provide insight into the mechanics that underlie tissue morphogenesis.
Combination cancer therapies aim to improve the probability and magnitude of therapeutic responses and reduce the likelihood of acquired resistance in an individual patient. However, drugs are tested ...in clinical trials on genetically diverse patient populations. We show here that patient-to-patient variability and independent drug action are sufficient to explain the superiority of many FDA-approved drug combinations in the absence of drug synergy or additivity. This is also true for combinations tested in patient-derived tumor xenografts. In a combination exhibiting independent drug action, each patient benefits solely from the drug to which his or her tumor is most sensitive, with no added benefit from other drugs. Even when drug combinations exhibit additivity or synergy in pre-clinical models, patient-to-patient variability and low cross-resistance make independent action the dominant mechanism in clinical populations. This insight represents a different way to interpret trial data and a different way to design combination therapies.
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•Anti-cancer drugs have variable efficacy within patient populations•Drug combinations give each patient more chances that one drug could be effective•Clinical efficacy of many combinations is accurately predicted without drug synergy•Optimizing drug independence represents a new way to design cancer treatments
Patient-to-patient variability in response to single drugs is sufficient to explain the efficacy of a large number of combination cancer therapies without pharmacologically additive or synergistic effect in individual patients.
D'Arcy Thompson was a proponent of applying mathematical and physical principles to biological systems, an approach that is becoming increasingly common in developmental biology. Indeed, the recent ...integration of quantitative experimental data, force measurements and mathematical modeling has changed our understanding of morphogenesis - the shaping of an organism during development. Emerging evidence suggests that the subcellular organization of contractile cytoskeletal networks plays a key role in force generation, while on the tissue level the spatial organization of forces determines the morphogenetic output. Inspired by D'Arcy Thompson's
, we review our current understanding of how biological forms are created and maintained by the generation and organization of contractile forces at the cell and tissue levels. We focus on recent advances in our understanding of how cells actively sculpt tissues and how forces are involved in specific morphogenetic processes.
: Hepatitis B virus (HBV) reactivation has been documented in association with multiple immunotherapy regimens . These reactivations can be life-threatening and result in fulminant hepatic failure. ...There are currently no reports of HBV reactivation on nivolumab treatment. This is a case of a patient with known HIV infection and previous HBV workup that revealed him to be anti-hepatitis B core antibody positive, hepatitis B surface antigen negative, and HBV DNA negative. He experienced a HBV reactivation while on therapy with nivolumab for stage IIIa poorly differentiated carcinoma of the lung, which was a recurrence from a prior surgically resected stage Ia well differentiated adenocarcinoma of the lung. He is a long-term nonprogressor in regards to his HIV and had previously had a negative HBV DNA level and had declined antiretroviral therapy until just prior to starting nivolumab. This case is also of interest as antiprogrammed death-1 receptors are involved in CD4-related HIV control , and the effects of nivolumab in a patient who was an HIV long-term nonprogressor are unknown. There was concern that he would develop increased HIV viremia and CD4-related immune dysfunction without antiretroviral therapy, and thus, he agreed to treatment prior to starting antineoplastic immunotherapy.
Deep Learning in Chemistry Mater, Adam C; Coote, Michelle L
Journal of chemical information and modeling,
06/2019, Volume:
59, Issue:
6
Journal Article
Peer reviewed
Open access
Machine learning enables computers to address problems by learning from data. Deep learning is a type of machine learning that uses a hierarchical recombination of features to extract pertinent ...information and then learn the patterns represented in the data. Over the last eight years, its abilities have increasingly been applied to a wide variety of chemical challenges, from improving computational chemistry to drug and materials design and even synthesis planning. This review aims to explain the concepts of deep learning to chemists from any background and follows this with an overview of the diverse applications demonstrated in the literature. We hope that this will empower the broader chemical community to engage with this burgeoning field and foster the growing movement of deep learning accelerated chemistry.
Circadian rhythms refer to biologic processes that oscillate with a period of ∼24 hr. These rhythms are sustained by a molecular clock and provide a temporal matrix that ensures the coordination of ...homeostatic processes with the periodicity of environmental challenges. We demonstrate the circadian molecular clock controls the expression and function of Toll-like receptor 9 (TLR9). In a vaccination model using TLR9 ligand as adjuvant, mice immunized at the time of enhanced TLR9 responsiveness presented weeks later with an improved adaptive immune response. In a TLR9-dependent mouse model of sepsis, we found that disease severity was dependent on the timing of sepsis induction, coinciding with the daily changes in TLR9 expression and function. These findings unveil a direct molecular link between the circadian and innate immune systems with important implications for immunoprophylaxis and immunotherapy.
► The circadian molecular clock modulates Tlr9 expression and function ► There are in vivo daily variations in the responsiveness to CpG ODNs (TLR9 ligand) ► The time of day determines disease severity in a TLR9-dependent sepsis model ► Timing of immunization determines TLR9 ligand-adjuvanted vaccine responsiveness
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