LAMBADA: Backward Chaining for Automated Reasoning in Natural Language

Remarkable progress has been made on automated reasoning with knowledge specified as unstructured, natural text, by using the power of large language models (LMs) coupled with methods such as Chain-of-Thought prompting and Selection-Inference. These techniques search for proofs in the forward direction from axioms to the conclusion, which suffers from a combinatorial explosion of the search space, and thus high failure rates for problems requiring longer chains of reasoning. The classical automated reasoning literature has shown that reasoning in the backward direction (i.e. from the intended conclusion to the set of axioms that support it) is significantly more efficient at proof-finding problems. We import this intuition into the LM setting and develop a Backward Chaining algorithm, which we call LAMBADA, that decomposes reasoning into four sub-modules, each of which can be simply implemented by few-shot prompted LM inference. We show that LAMBADA achieves massive accuracy boosts over state-of-the-art forward reasoning methods on two challenging logical reasoning datasets, particularly when deep and accurate proof chains are required.Comment: 16 page

M. tuberculosis Sliding β-Clamp Does Not Interact Directly with the NAD+ -Dependent DNA Ligase

The sliding β-clamp, an important component of the DNA replication and repair machinery, is drawing increasing attention as a therapeutic target. We report the crystal structure of the M. tuberculosis β-clamp (Mtbβ-clamp) to 3.0 Å resolution. The protein crystallized in the space group C2221 with cell-dimensions a = 72.7, b = 234.9 & c = 125.1 Å respectively. Mtbβ-clamp is a dimer, and exhibits head-to-tail association similar to other bacterial clamps. Each monomer folds into three domains with similar structures respectively and associates with its dimeric partner through 6 salt-bridges and about 21 polar interactions. Affinity experiments involving a blunt DNA duplex, primed-DNA and nicked DNA respectively show that Mtbβ-clamp binds specifically to primed DNA about 1.8 times stronger compared to the other two substrates and with an apparent Kd of 300 nM. In bacteria like E. coli, the β-clamp is known to interact with subunits of the clamp loader, NAD+ -dependent DNA ligase (LigA) and other partners. We tested the interactions of the Mtbβ-clamp with MtbLigA and the γ-clamp loader subunit through radioactive gel shift assays, size exclusion chromatography, yeast-two hybrid experiments and also functionally. Intriguingly while Mtbβ-clamp interacts in vitro with the γ-clamp loader, it does not interact with MtbLigA unlike in bacteria like E. coli where it does. Modeling studies involving earlier peptide complexes reveal that the peptide-binding site is largely conserved despite lower sequence identity between bacterial clamps. Overall the results suggest that other as-yet-unidentified factors may mediate interactions between the clamp, LigA and DNA in mycobacteria

A big-data approach to understanding metabolic rate and response to obesity in laboratory mice [preprint]

Maintaining a healthy body weight requires an exquisite balance between energy intake and energy expenditure. In humans and in laboratory mice these factors are experimentally measured by powerful and sensitive indirect calorimetry devices. To understand the genetic and environmental factors that contribute to the regulation of body weight, an important first step is to establish the normal range of metabolic values and primary sources contributing to variability in results. Here we examine indirect calorimetry results from two experimental mouse projects, the Mouse Metabolic Phenotyping Centers and International Mouse Phenotyping Consortium to develop insights into large-scale trends in mammalian metabolism. Analysis of nearly 10,000 wildtype mice revealed that the largest experimental variances are consequences of institutional site. This institutional effect on variation eclipsed those of housing temperature, body mass, locomotor activity, sex, or season. We do not find support for the claim that female mice have greater metabolic variation than male mice. An analysis of these factors shows a normal distribution for energy expenditure in the phenotypic analysis of 2,246 knockout strains and establishes a reference for the magnitude of metabolic changes. Using this framework, we examine knockout strains with known metabolic phenotypes. We compare these effects with common environmental challenges including age, and exercise. We further examine the distribution of metabolic phenotypes exhibited by knockout strains of genes corresponding to GWAS obesity susceptibility loci. Based on these findings, we provide suggestions for how best to design and conduct energy balance experiments in rodents, as well as how to analyze and report data from these studies. These recommendations will move us closer to the goal of a centralized physiological repository to foster transparency, rigor and reproducibility in metabolic physiology experimentation

Impact of Rare and Common Genetic Variants on Diabetes Diagnosis by Hemoglobin A1c in Multi-Ancestry Cohorts: The Trans-Omics for Precision Medicine Program

Hemoglobin A1c (HbA1c) is widely used to diagnose diabetes and assess glycemic control in individuals with diabetes. However, nonglycemic determinants, including genetic variation, may influence how accurately HbA1c reflects underlying glycemia. Analyzing the NHLBI Trans-Omics for Precision Medicine (TOPMed) sequence data in 10,338 individuals from five studies and four ancestries (6,158 Europeans, 3,123 African-Americans, 650 Hispanics, and 407 East Asians), we confirmed five regions associated with HbA1c (GCK in Europeans and African-Americans, HK1 in Europeans and Hispanics, FN3K and/or FN3KRP in Europeans, and G6PD in African-Americans and Hispanics) and we identified an African-ancestry-specific low-frequency variant (rs1039215 in HBG2 and HBE1, minor allele frequency (MAF) = 0.03). The most associated G6PD variant (rs1050828-T, p.Val98Met, MAF = 12% in African-Americans, MAF = 2% in Hispanics) lowered HbA1c (−0.88% in hemizygous males, −0.34% in heterozygous females) and explained 23% of HbA1c variance in African-Americans and 4% in Hispanics. Additionally, we identified a rare distinct G6PD coding variant (rs76723693, p.Leu353Pro, MAF = 0.5%; −0.98% in hemizygous males, −0.46% in heterozygous females) and detected significant association with HbA1c when aggregating rare missense variants in G6PD. We observed similar magnitude and direction of effects for rs1039215 (HBG2) and rs76723693 (G6PD) in the two largest TOPMed African American cohorts, and we replicated the rs76723693 association in the UK Biobank African-ancestry participants. These variants in G6PD and HBG2 were monomorphic in the European and Asian samples. African or Hispanic ancestry individuals carrying G6PD variants may be underdiagnosed for diabetes when screened with HbA1c. Thus, assessment of these variants should be considered for incorporation into precision medicine approaches for diabetes diagnosis

Genetic determinants of telomere length from 109,122 ancestrally diverse whole-genome sequences in TOPMed

Genetic studies on telomere length are important for understanding age-related diseases. Prior GWAS for leukocyte TL have been limited to European and Asian populations. Here, we report the first sequencing-based association study for TL across ancestrally-diverse individuals (European, African, Asian and Hispanic/Latino) from the NHLBI Trans-Omics for Precision Medicine (TOPMed) program. We used whole genome sequencing (WGS) of whole blood for variant genotype calling and the bioinformatic estimation of telomere length in n=109,122 individuals. We identified 59 sentinel variants (p-value OBFC1indicated the independent signals colocalized with cell-type specific eQTLs for OBFC1 (STN1). Using a multi-variant gene-based approach, we identified two genes newly implicated in telomere length, DCLRE1B (SNM1B) and PARN. In PheWAS, we demonstrated our TL polygenic trait scores (PTS) were associated with increased risk of cancer-related phenotypes

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Modulating Enterocyte Metabolism Affects Whole Body Glucose Homeostasis in Mice

Obesity and its comorbidities are a growing concern in today’s world. Obesity and overweight increase the risk of developing several life threatening diseases, the risks of which are decreased significantly even with a moderate weight loss. The most common comorbidity of obesity is type-2 diabetes which involves a severe dysfunction in glycemic control. Several studies suggest that gut metabolism plays an important role in whole body energy metabolism. Data from peripheral administration of drugs that reduced food intake in rodents showed that the inhibition of eating was associated with increased fatty acid oxidation (FAO) and ketogenesis in the small intestine, but not in the liver. Gastric bypass studies in humans and rodents indicate that the restructuring of the small intestine leads to morphological and metabolic changes in the gut. These changes are associated with the almost immediate reversal of the diabetic phenotype seen post-surgery, which is absent or less pronounced in surgeries like gastric banding that do not involve these dramatic changes in the small intestine. The intestinal mucosa, or rather the epithelial cells in the small intestine, are the main cells that absorb nutrients from the diet, and redistribute them for storage or to immediately fuel metabolism in the rest of the body. Enteroendocrine cells in the gut epithelium respond to different nutritional and metabolic cues and release gut hormones that also control eating behavior and regulate glucose homeostasis. All these factors led us to hypothesize that modulating enterocyte metabolism by upregulating FAO in these cells might affect the development of diet-induced obesity (DIO) and impaired glucose homeostasis. To test this we developed two different transgenic mouse models to upregulate enterocyte FAO. Using the cre-loxP system, we overexpressed the mitochondrial protein Sirtuin 3 (SIRT3) or expressed a mutant 11 form of the mitochondrial protein carnitine palmitoyltransferase-1 (CPT1mt) in the enterocytes of mice. We phenotyped these mice under conditions of low-fat control diet (CD) or high-fat diet (HFD) feeding. Our results show that constitutive (over)expression of SIRT3 or CPT1mt in mouse enterocytes had no effects on body weight gain and the development of DIO. Also, enterocyte SIRT3 expression did not affect glycemic control in CD-fed mice, but improved insulin sensitivity and glucose tolerance in HFD-fed mice, despite the development of DIO. Conversely, enterocyte specific CPT1mt expression led to impaired glucose homeostasis in CD-fed mice, but improved it in HFD-fed mice with DIO. Together our results indicate that modulating enterocyte metabolism can affect whole body glucose homeostasis differentially independent of body weight, but dependent on the nutritional content of the diet. --> Obesity and its comorbidities are a growing concern in today’s world. Obesity and overweight increase the risk of developing several life threatening diseases, the risks of which are decreased significantly even with a moderate weight loss. The most common comorbidity of obesity is type-2 diabetes which involves a severe dysfunction in glycemic control.Several studies suggest that gut metabolism plays an important role in whole body energy metabolism. Data from peripheral administration of drugs that reduced food intake in rodents showed that the inhibition of eating was associated with increased fatty acid oxidation (FAO) and ketogenesis in the small intestine, but not in the liver. Gastric bypass studies in humans and rodents indicate that the restructuring of the small intestine leads to morphological and metabolic changes in the gut. These changes are associated with the almost immediate reversal of the diabetic phenotype seen post-surgery, which is absent or less pronounced in surgeries like gastric banding that do not involve these dramatic changes in the small intestine. The intestinal mucosa, or rather the epithelial cells in the small intestine, are the main cells that absorb nutrients from the diet, and redistribute them for storage or to immediately fuel metabolism in the rest of the body. Enteroendocrine cells in the gut epithelium respond to different nutritional and metabolic cues and release gut hormones that also control eating behavior and regulate glucose homeostasis.All these factors led us to hypothesize that modulating enterocyte metabolism by upregulating FAO in these cells might affect the development of diet-induced obesity (DIO) and impaired glucose homeostasis. To test this we developed two different transgenic mouse models to upregulate enterocyte FAO. Using the cre-loxP system, we overexpressed the mitochondrial protein Sirtuin 3 (SIRT3) or expressed a mutant form of the mitochondrial protein carnitine palmitoyltransferase-1 (CPT1mt) in the enterocytes of mice. We phenotyped these mice under conditions of low-fat control diet (CD) or high-fat diet (HFD) feeding.Our results show that constitutive (over)expression of SIRT3 or CPT1mt in mouse enterocytes had no effects on body weight gain and the development of DIO. Also, enterocyte SIRT3 expression did not affect glycemic control in CD-fed mice, but improved insulin sensitivity and glucose tolerance in HFD-fed mice, despite the development of DIO. Conversely, enterocyte specific CPT1mt expression led to impaired glucose homeostasis in CD-fed mice, but improved it in HFD-fed mice with DIO. Together our results indicate that modulating enterocyte metabolism can affect whole body glucose homeostasis differentially independent of body weight, but dependent on the nutritional content of the diet

Metabolic Adaptation of the Small Intestine to Short- and Medium-Term High-Fat Diet Exposure

ISSN:0021-9541ISSN:1097-465