Challenges of and Insights into Acid-Catalyzed Transformations of Sugars

The selective transformation of hexose and pentose sugars to intermediate platform chemicals, such as furans, is an essential step in the conversion of cellulosic and hemicellulosic biomass to biofuels and biochemicals. Yet, many challenges in achieving commercially viable processes remain. In this feature article, we outline challenges that need to be overcome to enable these transformations. Then, we present the newly introduced acid-catalyzed isomerization of aldose sugars to ketose sugars via a class of solid Lewis acid catalysts (e.g., Sn-Beta, Ti-Beta). We elucidate mechanistic insights arising from subnanometer cooperativity and solvent effects that can be controlled to tune reaction pathways and selectivity and draw parallels between heterogeneous and homogeneous Lewis acid catalysts. Subsequently, we discuss fructose dehydration to 5-hydroxyl-methylfurfural (HMF) via homogeneous and heterogeneous Brønsted acid-catalyzed chemistry. We show how fundamental insights arising from the combination of kinetics, spectroscopy, and multiscale simulations rationalize the improved yield of HMF in water–organic cosolvents. The stability of heterogeneous Lewis acid catalysts under low pH enables tandem Brønsted and Lewis acid-catalyzed reactions in a single pot that overcomes equilibrium limitations and gives a high HMF yield starting from sugar raw materials. Additionally, we provide an overview of multicomponent adsorption of biomass derivatives from solution in microporous materials and discuss how structure–property relations can lead to superior micro- and micromesoporous carbon adsorbents for reactive adsorption toward high HMF yield. Finally, we provide an outlook for the field

MINPP1 prevents intracellular accumulation of the chelator inositol hexakisphosphate and is mutated in Pontocerebellar Hypoplasia

Inositol polyphosphates are vital metabolic and secondary messengers, involved in diverse cellular functions. Therefore, tight regulation of inositol polyphosphate metabolism is essential for proper cell physiology. Here, we describe an early-onset neurodegenerative syndrome caused by loss-of-function mutations in the multiple inositol-polyphosphate phosphatase 1 gene (MINPP1). Patients are found to have a distinct type of Pontocerebellar Hypoplasia with typical basal ganglia involvement on neuroimaging. We find that patient-derived and genome edited MINPP1−/− induced stem cells exhibit an inefficient neuronal differentiation combined with an increased cell death. MINPP1 deficiency results in an intracellular imbalance of the inositol polyphosphate metabolism. This metabolic defect is characterized by an accumulation of highly phosphorylated inositols, mostly inositol hexakisphosphate (IP6), detected in HEK293 cells, fibroblasts, iPSCs and differentiating neurons lacking MINPP1. In mutant cells, higher IP6 level is expected to be associated with an increased chelation of intracellular cations, such as iron or calcium, resulting in decreased levels of available ions. These data suggest the involvement of IP6-mediated chelation on Pontocerebellar Hypoplasia disease pathology and thereby highlight the critical role of MINPP1 in the regulation of human brain development and homeostasis

Lethal Mutants and Truncated Selection Together Solve a Paradox of the Origin of Life

BACKGROUND: Many attempts have been made to describe the origin of life, one of which is Eigen's cycle of autocatalytic reactions [Eigen M (1971) Naturwissenschaften 58, 465-523], in which primordial life molecules are replicated with limited accuracy through autocatalytic reactions. For successful evolution, the information carrier (either RNA or DNA or their precursor) must be transmitted to the next generation with a minimal number of misprints. In Eigen's theory, the maximum chain length that could be maintained is restricted to 100-1000 nucleotides, while for the most primitive genome the length is around 7000-20,000. This is the famous error catastrophe paradox. How to solve this puzzle is an interesting and important problem in the theory of the origin of life. METHODOLOGY/PRINCIPAL FINDINGS: We use methods of statistical physics to solve this paradox by carefully analyzing the implications of neutral and lethal mutants, and truncated selection (i.e., when fitness is zero after a certain Hamming distance from the master sequence) for the critical chain length. While neutral mutants play an important role in evolution, they do not provide a solution to the paradox. We have found that lethal mutants and truncated selection together can solve the error catastrophe paradox. There is a principal difference between prebiotic molecule self-replication and proto-cell self-replication stages in the origin of life. CONCLUSIONS/SIGNIFICANCE: We have applied methods of statistical physics to make an important breakthrough in the molecular theory of the origin of life. Our results will inspire further studies on the molecular theory of the origin of life and biological evolution

Thermodynamic Basis for the Emergence of Genomes during Prebiotic Evolution

The RNA world hypothesis views modern organisms as descendants of RNA molecules. The earliest RNA molecules must have been random sequences, from which the first genomes that coded for polymerase ribozymes emerged. The quasispecies theory by Eigen predicts the existence of an error threshold limiting genomic stability during such transitions, but does not address the spontaneity of changes. Following a recent theoretical approach, we applied the quasispecies theory combined with kinetic/thermodynamic descriptions of RNA replication to analyze the collective behavior of RNA replicators based on known experimental kinetics data. We find that, with increasing fidelity (relative rate of base-extension for Watson-Crick versus mismatched base pairs), replications without enzymes, with ribozymes, and with protein-based polymerases are above, near, and below a critical point, respectively. The prebiotic evolution therefore must have crossed this critical region. Over large regions of the phase diagram, fitness increases with increasing fidelity, biasing random drifts in sequence space toward ‘crystallization.’ This region encloses the experimental nonenzymatic fidelity value, favoring evolutions toward polymerase sequences with ever higher fidelity, despite error rates above the error catastrophe threshold. Our work shows that experimentally characterized kinetics and thermodynamics of RNA replication allow us to determine the physicochemical conditions required for the spontaneous crystallization of biological information. Our findings also suggest that among many potential oligomers capable of templated replication, RNAs may have evolved to form prebiotic genomes due to the value of their nonenzymatic fidelity

MINPP1 prevents intracellular accumulation of the chelator inositol hexakisphosphate and is mutated in Pontocerebellar Hypoplasia

International audienceInositol polyphosphates are vital metabolic and secondary messengers, involved in diverse cellular functions. Therefore, tight regulation of inositol polyphosphate metabolism is essential for proper cell physiology. Here, we describe an early-onset neurodegenerative syndrome caused by loss-of-function mutations in the multiple inositol-polyphosphate phosphatase 1 gene (MINPP1). Patients are found to have a distinct type of Pontocerebellar Hypoplasia with typical basal ganglia involvement on neuroimaging. We find that patient-derived and genome edited MINPP1-/- induced stem cells exhibit an inefficient neuronal differentiation combined with an increased cell death. MINPP1 deficiency results in an intracellular imbalance of the inositol polyphosphate metabolism. This metabolic defect is characterized by an accumulation of highly phosphorylated inositols, mostly inositol hexakisphosphate (IP6), detected in HEK293 cells, fibroblasts, iPSCs and differentiating neurons lacking MINPP1. In mutant cells, higher IP6 level is expected to be associated with an increased chelation of intracellular cations, such as iron or calcium, resulting in decreased levels of available ions. These data suggest the involvement of IP6-mediated chelation on Pontocerebellar Hypoplasia disease pathology and thereby highlight the critical role of MINPP1 in the regulation of human brain development and homeostasis

Subjective right ventricle assessment by echo qualified intensive care specialists: assessing agreement with objective measures

International audienceBackgroundRight ventricle (RV) size and function assessment by echocardiography (echo) is a standard tool in the ICU. Frequently subjective assessment is performed, and guidelines suggest its utility in adequately trained clinicians. We aimed to compare subjective (visual) assessment of RV size and function by ICU physicians, with advanced qualifications in echocardiography, vs objective measurements.MethodsICU specialists with a qualification in advanced echocardiography reviewed 2D echo clips from critically ill patients on mechanical ventilation with PaO2:FiO(2) <300. Subjective assessments of RV size and function were made independently using a three-class categorical scale. Agreement (B-score) and bias (p value) were analysed using objective echo measurements. RV size assessment included RV end-diastolic area (EDA) and diameters. RV function assessment included fractional area change, S, TAPSE and RV free wall strain. Binary and ordinal analysis was performed.ResultsFifty-two clinicians reviewed 2D images from 80 patients. Fair agreement was seen with objective measures vs binary assessment of RV size (RV EDA 0.26 [p<0.001], RV dimensions 0.29 [p=0.06]) and function (RV free wall strain 0.27 [p<0.001], TAPSE 0.27 [p<0.001], S 0.29 [p<0.001], FAC 0.31 [p=0.16]). However, ordinal data analysis showed poor agreement with RV dimensions (0.11 [p=0.06]) and RV free wall strain (0.14 [p=0.16]). If one-step disagreement was allowed, agreement was good (RV dimensions 0.6 [p=0.06], RV free wall strain 0.6 [p=0.16]). Significant overestimation of severity of abnormalities was seen with subjective assessment vs RV EDA, TAPSE, S and fractional area change.ConclusionSubjective (visual) assessment of RV size and function, by ICU specialists trained in advanced echo, can be fairly reliable for the initial exclusion of significant RV pathology. It seems prudent to avoid subjective RV assessment in isolation

Potent Inhibitors of Hepatitis C Virus NS3 Protease: Employment of a Difluoromethyl Group as a Hydrogen-Bond Donor

The design and synthesis of potent, tripeptidic acylsulfonamide inhibitors of HCV NS3 protease that contain a difluoromethyl cyclopropyl amino acid at P1 are described. A cocrystal structure of <b>18</b> with a NS3/4A protease complex suggests the presence of a H-bond between the polarized C–H of the CHF₂ moiety and the backbone carbonyl of Leu135 of the enzyme. Structure–activity relationship studies indicate that this H-bond enhances enzyme inhibitory potency by 13- and 17-fold compared to the CH₃ and CF₃ analogues, respectively, providing insight into the deployment of this unique amino acid