Enzymes are able to perform reactions under mild conditions, e.g., pH and temperature, with remarkable chemo-, regio-, and stereoselectivity. Due to this feature the number of biocatalysts used in ...organic synthesis has rapidly increased during the last decades, especially for the production of chiral compounds. The present review highlights biotechnological processes for the production of chiral alcohols by reducing prochiral ketones with whole cells. Microbial transformations feature different characteristics in comparison to isolated enzymes. Enzymes that are used in whole-cell biotransformations are often more stable due to the presence of their natural environment inside the cell. Because reductase-catalyzed reactions are dependent on cofactors, one major task in process development is to provide an effective method for regeneration of the consumed cofactors. Many whole-cell biocatalysts offer their internal cofactor regeneration that can be used by adding cosubstrates, glucose or, in the case of cyanobacteria, simply light. In this paper, various processes carried out on laboratory and industrial scales are presented. Thereby, attention is turned to process parameters, e.g., conversion, yield, enantiomeric excess, and process strategies, e.g., the application of biphasic systems. The biocatalytic production of chiral alcohols utilizing isolated enzymes is presented in part I of this review (Goldberg et al., Appl Microbiol Biotechnol, 2007).
Enzymes are able to perform reactions under mild conditions, e.g., pH and temperature, with remarkable chemo-, regio-, and stereoselectivity. Because of this feature, the number of biocatalysts used ...in organic synthesis has rapidly increased during the last decades, especially for the production of chiral compounds. The present review highlights biotechnological processes for the production of chiral alcohols by reducing prochiral ketones. These reactions can be catalyzed by either isolated enzymes or whole cells that exhibit ketone-reducing activity. The use of isolated enzymes is often preferred because of a higher volumetric productivity and the absence of side reactions. Both types of catalysts have also deficiencies limiting their use in synthesis of chiral alcohols. Because reductase-catalyzed reactions are dependent on cofactors, one major task in process development is to provide an effective method for regeneration of the consumed cofactors. In this paper, strategies for cofactor regeneration in biocatalytic ketone reduction are reviewed. Furthermore, different processes carried out on laboratory and industrial scales using isolated enzymes are presented. Attention is turned to process parameters, e.g., conversion, yield, enantiomeric excess, and process strategies, e.g., the application of biphasic systems or methods of in situ (co)product recovery. The biocatalytic production of chiral alcohols utilizing whole cells is presented in part II of this review (Goldberg et al., Appl Microbiol Biotechnol, 2007).
Immobilization of the alcohol dehydrogenase ADH-‘A’ from
Rhodococcus ruber DSM 44541 has been performed with different amino-functionalized carrier materials. The procedure included the activation of ...the carrier with glutaraldehyde and subsequent covalent binding to the enzyme. The porous glass beads TRISOPERL
® and TRISOPOR
®, magnetic particles, and detonation nanodiamonds were used as carriers in these experiments. In all cases, the immobilization was successful with almost quantitative immobilization yields; subsequently the activity for the reduction of acetophenone was lower compared to the activity of the free biocatalyst. Activity yields of 40% and 60% were obtained. The immobilized biocatalysts showed high stabilities in repetitive batches.
How ecological opportunity relates to diversification is a central question in evolutionary biology. However, there are few empirical examples of how ecological opportunity and morphological ...innovation open new adaptive zones, and promote diversification. We analyse data on diet, skull morphology and bite performance, and relate these traits to diversification rates throughout the evolutionary history of an ecologically diverse family of mammals (Chiroptera: Phyllostomidae). We found a significant increase in diversification rate driven by increased speciation at the most recent common ancestor of the predominantly frugivorous subfamily Stenodermatinae. The evolution of diet was associated with skull morphology, and morphology was tightly coupled with biting performance, linking phenotype to new niches through performance. Following the increase in speciation rate, the rate of morphological evolution slowed, while the rate of evolution in diet increased. This pattern suggests that morphology stabilized, and niches within the new adaptive zone of frugivory were filled rapidly, after the evolution of a new cranial phenotype that resulted in a certain level of mechanical efficiency. The tree-wide speciation rate increased non linearly with a more frugivorous diet, and was highest at measures of skull morphology associated with morphological extremes, including the most derived Stenodermatines. These results show that a novel stenodermatine skull phenotype played a central role in the evolution of frugivory and increasing speciation within phyllostomids.
We investigate a formalism for the conditions of a successful explanation of AI. We consider “success” to depend not only on what information the explanation contains, but also on what information ...the human explainee understands from it. Theory of mind literature discusses the folk concepts that humans use to understand and generalize behavior. We posit that folk concepts of behavior provide us with a “language” that humans understand behavior with. We use these folk concepts as a framework of social attribution by the human explainee—the information constructs that humans are likely to comprehend from explanations—by introducing a blueprint for an explanatory narrative (Figure 1) that explains AI behavior with these constructs. We then demonstrate that many XAI methods today can be mapped to folk concepts of behavior in a qualitative evaluation. This allows us to uncover their failure modes that prevent current methods from explaining successfully—i.e., the information constructs that are missing for any given XAI method, and whose inclusion can decrease the likelihood of misunderstanding AI behavior.
BackgroundNon-small cell lung cancer (NSCLC) patients bearing targetable oncogene alterations typically derive limited benefit from immune checkpoint blockade (ICB), which has been attributed to low ...tumor mutation burden (TMB) and/or PD-L1 levels. We investigated oncogene-specific differences in these markers and clinical outcome.MethodsThree cohorts of NSCLC patients with oncogene alterations (n=4189 total) were analyzed. Two clinical cohorts of advanced NSCLC patients treated with ICB monotherapy MD Anderson (MDACC; n=172) and Flatiron Health-Foundation Medicine Clinico-Genomic Database (CGDB; n=894 patients) were analyzed for clinical outcome. The FMI biomarker cohort (n=4017) was used to assess the association of oncogene alterations with TMB and PD-L1 expression.ResultsHigh PD-L1 expression (PD-L1 ≥50%) rate was 19%–20% in classic EGFR, EGFR exon 20 and HER2-mutant tumors, and 34%–55% in tumors with ALK, BRAF V600E, ROS1, RET, or MET alterations. Compared with KRAS-mutant tumors, BRAF non-V600E group had higher TMB (9.6 vs KRAS 7.8 mutations/Mb, p=0.003), while all other oncogene groups had lower TMB (p<0.001). In the two clinical cohorts treated with ICB, molecular groups with EGFR, HER2, ALK, ROS1, RET, or MET alterations had short progression-free survival (PFS; 1.8–3.7 months), while BRAF V600E group was associated with greater clinical benefit from ICB (CGDB cohort: PFS 9.8 months vs KRAS 3.7 months, HR 0.66, p=0.099; MDACC cohort: response rate 62% vs KRAS 24%; PFS 7.4 vs KRAS 2.8 months, HR 0.36, p=0.026). KRAS G12C and non-G12C subgroups had similar clinical benefit from ICB in both cohorts. In a multivariable analysis, BRAF V600E mutation (HR 0.58, p=0.041), PD-L1 expression (HR 0.57, p=0.022), and high TMB (HR 0.66, p<0.001) were associated with longer PFS.ConclusionsHigh TMB and PD-L1 expression are predictive for benefit from ICB treatment in oncogene-driven NSCLCs. NSCLC harboring BRAF mutations demonstrated superior benefit from ICB that may be attributed to higher TMB and higher PD-L1 expression in these tumors. Meanwhile EGFR and HER2 mutations and ALK, ROS1, RET, and MET fusions define NSCLC subsets with minimal benefit from ICB despite high PD-L1 expression in NSCLC harboring oncogene fusions. These findings indicate a TMB/PD-L1-independent impact on sensitivity to ICB for certain oncogene alterations.
Introduction
Breast cancer is a heterogeneous disease with different prognoses and responses to systemic treatment depending on its molecular characteristics, which makes it imperative to develop new ...biomarkers for an individualized diagnosis and personalized oncological treatment. Ex vivo high-resolution magic angle spinning proton magnetic resonance spectroscopy (HRMAS 1H MRS) is the most common technique for metabolic quantification in human surgical and biopsy tissue specimens.
Objective
To perform a review of the current available literature on the clinical applications of HRMAS 1H MRS metabolic analysis in tissue samples of breast cancer patients.
Methods
This systematic scoping review included original research papers published in the English language in peer-reviewed journals. Study selection was performed independently by two reviewers and preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines were followed.
Results
The literature search returned 159 studies and 26 papers were included as part of this systematic review. There was considerable variation regarding tissue type, aims, and statistical analysis methods across the different studies. To facilitate the interpretation of the results, the included studies were grouped according to their aims or main outcomes into: feasibility and tumor diagnosis (n = 6); tumor heterogeneity (n = 2); correlation with proteomics/transcriptomics (n = 3); correlation with prognostic factors (n = 11); and response evaluation to NAC (n = 4).
Conclusion
There is a lot of potential in including metabolic information of breast cancer tissue obtained with HRMAS 1H MRS. To date, studies show that metabolic concentrations quantified by this technique can be related to the diagnosis, prognosis, and treatment response in breast cancer patients.
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