An all-atom protein generative model.

Proteins mediate their functions through chemical interactions; modeling these interactions, which are typically through sidechains, is an important need in protein design. However, constructing an all-atom generative model requires an appropriate scheme for managing the jointly continuous and discrete nature of proteins encoded in the structure and sequence. We describe an all-atom diffusion model of protein structure, Protpardelle, which represents all sidechain states at once as a "superposition" state; superpositions defining a protein are collapsed into individual residue types and conformations during sample generation. When combined with sequence design methods, our model is able to codesign all-atom protein structure and sequence. Generated proteins are of good quality under the typical quality, diversity, and novelty metrics, and sidechains reproduce the chemical features and behavior of natural proteins. Finally, we explore the potential of our model to conduct all-atom protein design and scaffold functional motifs in a backbone- and rotamer-free way.

A preparative small-molecule mimic of liver CYP450 enzymes in the aliphatic C-H oxidation of carbocyclic N-heterocycles.

An emerging trend in small-molecule pharmaceuticals, generally composed of nitrogen heterocycles (N-heterocycles), is the incorporation of aliphatic fragments. Derivatization of the aliphatic fragments to improve drug properties or identify metabolites often requires lengthy de novo syntheses. Cytochrome P450 (CYP450) enzymes are capable of direct site- and chemo-selective oxidation of a broad range of substrates but are not preparative. A chemoinformatic analysis underscored limited structural diversity of N-heterocyclic substrates oxidized using chemical methods relative to pharmaceutical chemical space. Here, we describe a preparative chemical method for direct aliphatic oxidation that tolerates a wide range of nitrogen functionality (chemoselective) and matches the site of oxidation (site-selective) of liver CYP450 enzymes. Commercial small-molecule catalyst Mn(CF3-PDP) selectively effects direct methylene oxidation in compounds bearing 25 distinct heterocycles including 14 out of 27 of the most frequent N-heterocycles found in U.S. Food and Drug Administration (FDA)-approved drugs. Mn(CF3-PDP) oxidations of carbocyclic bioisostere drug candidates (for example, HCV NS5B and COX-2 inhibitors including valdecoxib and celecoxib derivatives) and precursors of antipsychotic drugs blonanserin, buspirone, and tiospirone and the fungicide penconazole are demonstrated to match the major site of aliphatic metabolism obtained with liver microsomes. Oxidations are demonstrated at low Mn(CF3-PDP) loadings (2.5 to 5 mol%) on gram scales of substrate to furnish preparative amounts of oxidized products. A chemoinformatic analysis supports that Mn(CF3-PDP) significantly expands the pharmaceutical chemical space accessible to small-molecule C-H oxidation catalysis.

expHRD: an individualized, transcriptome-based prediction model for homologous recombination deficiency assessment in cancer.

BACKGROUND: Homologous recombination deficiency (HRD) stands as a clinical indicator for discerning responsive outcomes to platinum-based chemotherapy and poly ADP-ribose polymerase (PARP) inhibitors. One of the conventional approaches to HRD prognostication has generally centered on identifying deleterious mutations within the BRCA1/2 genes, along with quantifying the genomic scars, such as Genomic Instability Score (GIS) estimation with scarHRD. However, the scarHRD method has limitations in scenarios involving tumors bereft of corresponding germline data. Although several RNA-seq-based HRD prediction algorithms have been developed, they mainly support cohort-wise classification, thereby yielding HRD status without furnishing an analogous quantitative metric akin to scarHRD. This study introduces the expHRD method, which operates as a novel transcriptome-based framework tailored to n-of-1-style HRD scoring. RESULTS: The prediction model has been established using the elastic net regression method in the Cancer Genome Atlas (TCGA) pan-cancer training set. The bootstrap technique derived the HRD geneset for applying the expHRD calculation. The expHRD demonstrated a notable correlation with scarHRD and superior performance in predicting HRD-high samples. We also performed intra- and extra-cohort evaluations for clinical feasibility in the TCGA-OV and the Genomic Data Commons (GDC) ovarian cancer cohort, respectively. The innovative web service designed for ease of use is poised to extend the realms of HRD prediction across diverse malignancies, with ovarian cancer standing as an emblematic example. CONCLUSIONS: Our novel approach leverages the transcriptome data, enabling the prediction of HRD status with remarkable precision. This innovative method addresses the challenges associated with limited available data, opening new avenues for utilizing transcriptomics to inform clinical decisions.

High Performance Proprioceptive Fiber Actuators Based on Ag Nanoparticles-Incorporated Hybrid Twisted and Coiled System.

Thermally driven fiber actuators are emerging as promising tools for a range of robotic applications, encompassing soft and wearable robots, muscle function restoration, assistive systems, and physical augmentation. Yet, to realize their full potential in practical applications, several challenges, such as a high operational temperature, incorporation of intrinsic self-sensing capabilities for closed-loop feedback control, and reliance on bulky, intricate actuation systems, must be addressed. Here, an Ag nanoparticles-based twisted and coiled fiber actuator that achieves a high contractile actuation of ≈36% is reported at a considerably low operational temperature of ≈83 °C based on a synergistic effect of constituent fiber elements with low glass transition temperatures. The fiber actuator can monitor its contractile actuation in real-time based on the piezoresistive properties inherent to its Ag-based conductive region, demonstrating its proprioceptive sensing capability. By exploiting this capability, the proprioceptive fiber actuator adeptly maintains its intended contractile behavior, even when faced with unplanned external disturbances. To demonstrate the capabilities of the fiber actuator, this study integrates it into a closed-loop feedback-controlled bionic arm as an artificial muscle, offering fresh perspectives on the future development of intelligent wearable devices and soft robotic systems.

Genome-scale and pathway engineering for the sustainable aviation fuel precursor isoprenol production in Pseudomonas putida.

Sustainable aviation fuel (SAF) will significantly impact global warming in the aviation sector, and important SAF targets are emerging. Isoprenol is a precursor for a promising SAF compound DMCO (1,4-dimethylcyclooctane) and has been produced in several engineered microorganisms. Recently, Pseudomonas putida has gained interest as a future host for isoprenol bioproduction as it can utilize carbon sources from inexpensive plant biomass. Here, we engineer metabolically versatile host P. putida for isoprenol production. We employ two computational modeling approaches (Bilevel optimization and Constrained Minimal Cut Sets) to predict gene knockout targets and optimize the "IPP-bypass" pathway in P. putida to maximize isoprenol production. Altogether, the highest isoprenol production titer from P. putida was achieved at 3.5 g/L under fed-batch conditions. This combination of computational modeling and strain engineering on P. putida for an advanced biofuels production has vital significance in enabling a bioproduction process that can use renewable carbon streams.

Xenogeneic cross-circulation for physiological support and recovery of ex vivo human livers.

BACKGROUND AND AIMS: The scarcity of suitable donor livers highlights a continuing need for innovation to recover organs with reversible injuries in liver transplantation. APPROACH AND RESULTS: Explanted human donor livers (n = 5) declined for transplantation were supported using xenogeneic cross-circulation of whole blood between livers and xeno-support swine. Livers and swine were assessed over 24 hours of xeno-support. Livers maintained normal global appearance, uniform perfusion, and preservation of histologic and subcellular architecture. Oxygen consumption increased by 75% ( p = 0.16). Lactate clearance increased from -0.4 ± 15.5% to 31.4 ± 19.0% ( p = 0.02). Blinded histopathologic assessment demonstrated improved injury scores at 24 hours compared with 12 hours. Vascular integrity and vasoconstrictive function were preserved. Bile volume and cholangiocellular viability markers improved for all livers. Biliary structural integrity was maintained. CONCLUSIONS: Xenogeneic cross-circulation provided multisystem physiological regulation of ex vivo human livers that enabled functional rehabilitation, histopathologic recovery, and improvement of viability markers. We envision xenogeneic cross-circulation as a complementary technique to other organ-preservation technologies in the recovery of marginal donor livers or as a research tool in the development of advanced bioengineering and pharmacologic strategies for organ recovery and rehabilitation.

Mn-Catalyzed Aerobic Oxidative α-Cyanation of Tertiary Amines Using Azo/Hydrazide Redox.

Azo compounds such as diethyl azodicarboxylate have been used in oxidative coupling reactions to generate iminium ions from tertiary amines. However, the requirement of stoichiometric amounts of azo compounds limits their large-scale applications. Herein, we present an aerobic oxidative α-cyanation of tertiary amines using catalytic amounts of an azo compound or hydrazine. The developed protocol provides a practical and ecofriendly route for α-cyanated tertiary amines, using molecular oxygen as the terminal oxidant.

Polygenic and socioeconomic contributions to nicotine use and cardiometabolic health in early mid-life.

INTRODUCTION: Early mid-life is marked by accumulating risks for cardiometabolic illness linked to health-risk behaviors like nicotine use. Identifying polygenic indices (PGI) has enriched scientific understanding of the cumulative genetic contributions to behavioral and cardiometabolic health, though few studies have assessed these associations alongside socioeconomic (SES) and lifestyle factors. METHODS: Drawing on data from 2,337 individuals from the United States participating in the National Longitudinal Study of Adolescent to Adult Health, the current study assesses the fraction of variance in five related outcomes - use of conventional and electronic cigarettes, body mass index (BMI), waist circumference, and glycosylated hemoglobin (A1c) - explained by PGI, SES, and lifestyle. RESULTS: Regression models on African ancestry (AA) and European ancestry (EA) subsamples reveal that the fraction of variance explained by PGI ranges across outcomes. While adjusting for sex and age, PGI explained 3.5%, 2.2%, and 0% in the AA subsample of variability in BMI, waist circumference, and A1c, respectively (in the EA subsample these figures were 7.7%, 9.4%, and 1.3%). The proportion of variance explained by PGI in nicotine-use outcomes is also variable. Results further indicate that PGI and SES are generally complementary, accounting for more variance in the outcomes when modeled together versus separately. CONCLUSIONS: PGI are gaining attention in population health surveillance, but polygenic variability might not align clearly with health differences in populations or surpass SES as a fundamental cause of health disparities. We discuss future steps in integrating PGI and SES to refine population health prediction rules. IMPLICATIONS: Study findings point to the complementary relationship of polygenic indices (PGI) and socioeconomic indicators in explaining population variance in nicotine outcomes and cardiometabolic wellness. Population health surveillance and prediction rules would benefit from the combination of information from both polygenic and socioeconomic risks. Additionally, the risk for electronic cigarette use among users of conventional cigarettes may have a genetic component tied to the cumulative genetic propensity for heavy smoking. Further research on PGI for vaping is needed.

A longitudinal study of learning difficulties in adolescence and biomarkers of cardiometabolic risk in adulthood: A gendered pathways approach.

OBJECTIVES: Little is known about the relationship between learning difficulties (LD) in adolescence and physical health in adulthood. This study investigates the gender-specific pathways through which LD is longitudinally associated with cardiometabolic risk in adulthood. STUDY DESIGN: We used data from the National Longitudinal Study of Adolescent to Adult Health (N = 11,342). To assess cardiometabolic risk, 11 biomarkers related to cardiovascular functioning, glucose metabolism, lipid metabolism, and inflammation were utilized. METHODS: We first estimated the association between LD in adolescence and cardiometabolic risk in adulthood. Then, we examined whether this association is mediated by educational attainment and body mass index (BMI). Finally, we employed a moderated mediation model to determine whether gender moderates these mediation patterns. RESULTS: LD in adolescence was positively associated with cardiometabolic risk in adulthood (b = 0.165, p < 0.001). LD also predicted lower educational attainment (b = -0.724, p < 0.001) and higher BMI (b = 0.589, p < 0.05). Educational attainment and BMI explained 18 and 25 percent of the positive association between LD and cardiometabolic risk, respectively. A moderated mediation model revealed that indirect effects of LD on cardiometabolic risk via educational attainment and BMI were more pronounced among women than men. CONCLUSION: LD in adolescence is a significant predictor of cardiometabolic risk in adulthood. Interventions focusing on the academic and health behaviors of girls with LD may be effective in improving their adult physical health.

Children's bullying victimization and the acculturative stress of immigrant mothers in Korea: Exploring heterogeneity by mother's country of origin.

OBJECTIVES: Over the past three decades, the number of multicultural families in Korea, defined as a family consisting of a native Korean and a marriage immigrant, has increased significantly. Although bullying victimization among multicultural family youth is rightfully a growing concern, less is known about the effects bullying has on immigrant mothers of children who have been bullying victims. METHOD: Using data from the Multicultural Adolescents Panel Study, this study investigates whether children's bullying victimization is associated with immigrant mothers' acculturative stress and whether this association differs depending on mothers' country of origin (China, Japan, and Southeast Asian countries). RESULTS: Fixed effects estimates revealed that children's bullying victimization is positively associated with their immigrant mother's acculturative stress, and this association is robust to controlling for unobserved time-constant individual-level heterogeneity. When stratified by mother's country of origin, the association was larger and statistically significant only among Southeast Asian mothers. No associations were observed among Japanese and Chinese mothers. CONCLUSIONS: Our findings suggest that interventions aiming to support bullied children should be expanded to also support their immigrant mothers. Policymakers may wish to consider the specific backgrounds and contexts of immigrant mothers, with special attention to Southeast Asian women. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Genetically Stable and Scalable Nanoengineering of Human Primary T Cells via Cell Mechanoporation.

Effective tumor regression has been observed with chimeric antigen receptor (CAR) T cells; however, the development of an affordable, safe, and effective CAR-T cell treatment remains a challenge. One of the major obstacles is that the suboptimal genetic modification of T cells reduces their yield and antitumor activity, necessitating the development of a next-generation T cell engineering approach. In this study, we developed a nonviral T cell nanoengineering system that allows highly efficient delivery of diverse functional nanomaterials into primary human T cells in a genetically stable and scalable manner. Our platform leverages the unique cell deformation and restoration process induced by the intrinsic inertial flow in a microchannel to create nanopores in the cellular membrane for macromolecule internalization, leading to effective transfection with high scalability and viability. The proposed approach demonstrates considerable potential as a practical alternative technique for improving the current CAR-T cell manufacturing process.

Thoughts and emotions evoked by thinking about own death: American versus Japanese undergraduates.

The prompts "What emotions does the thought of your own death arouse in you?" and "What will happen to you when your body dies?" have been used to induce anxiety in Terror Management Theory. The current study investigated how the responses to these prompts may reveal cross-national differences by using a text-mining approach. Undergraduates in the US (n = 298) and Japan (n = 212) participated in the study. Across both groups, anxiety was the most common emotion. Cross-national differences also emerged, such that students in the US were more likely to mention sadness, funeral, and religiosity for the first prompt, and acceptance, spiritual change, and religiosity for the second prompt. Students in Japan were more likely to mention regret for the first, and sadness, emptiness, and funeral for the second prompt. Results revealed differences and similarities in thoughts and emotions people associate with when thinking about own death.

Exploring quantitative traits-associated copy number deletions through reanalysis of UK10K consortium whole genome sequencing cohorts.

OBJECTIVES: We performed comprehensive association analyses of common high-confidence gnomAD-reported copy number deletions (CNDs) with 60 quantitative traits from UK10K consortium WGS data. METHODS: The study made use of data generated by the UK10K Consortium. UK10K consortium WGS data consist of TwinsUK (n = 1754, middle-aged females) and ALSPAC (n = 1867, birth to adolescence) cohorts. UK10K consortium called 18,739 CNDs (hg19) with GenomeSTRiP software. After filtering out variants with minor allele frequency < 0.05 or HWE P < 1.0 × 10- 6, 1222 (TwinsUK) and 1211 (ALSPAC) CNDs remained for association analyses with 60 normalized quantitative traits. RESULTS: We identified 23 genome-wide significant associations at 13 loci, among which 2 associations reached experiment-wide significance. We found that two common deletions in chromosome 4, located between WDR1 and ZNF518B (23.3 kb, dbVar ID:nssv15888957, 4:10211262-10,234,569 and 9.8 kb, dbVar ID:nssv15888975, 4:10392422-10,402,191), were associated with uric acid levels (P = 5.23 × 10- 11 and 2.29 × 10- 8, respectively). We also discovered a novel deletion spanning chromosome 18 (823 bp, dbVar ID: nssv15841628, 8:74347187-74,348,010) associated with low HDL cholesterol levels (P = 4.15 × 10- 7). Additionally, we observed two red blood cell traits-associated loci with genome-wide significance, a 13.2 kb deletion in 7q22.1 (nssv15922542) and a 3.7 kb deletion in 12q24.12 (nssv15813226), both of which were located in regions previously reported to be associated with red blood cell traits. Two deletions in 11q11 (nssv15803200 and nssv15802240), where clusters of multiple olfactory receptor genes exist, and a deletion (nssv15929560) upstream to DOCK5 were associated with childhood obesity. Finally, when defining Trait-Associated copy number Deletions (TADs) as CNDs with phenotype associations at sub-threshold significance (P < 10- 3), we identified 157 (97.5%) out of 161 TADs in non-coding regions, with a mean size of 4 kb (range: 209 - 47,942 bp). CONCLUSION: We conducted a reanalysis of the UK10K Whole Genome Sequencing cohort, which led to the identification of multiple high confidence copy number deletions associated with quantitative traits. These deletions have standard dbVar IDs and replicate previous findings, as well as reveal novel loci that require further replication studies.

Integrative Magneto-Microfluidic Separation of Immune Cells Facilitates Clinical Functional Assays.

Accurately analyzing the functional activities of natural killer (NK) cells in clinical diagnosis remains challenging due to their coupling with other immune effectors. To address this, an integrated immune cell separator is required, which necessitates a streamlined sample preparation workflow including immunological cell isolation, removal of excess red blood cells (RBCs), and buffer exchange for downstream analysis. Here, a self-powered integrated magneto-microfluidic cell separation (SMS) chip is presented, which outputs high-purity target immune cells by simply inputting whole blood. The SMS chip intensifies the magnetic field gradient using an iron sphere-filled inlet reservoir for high-performance immuno-magnetic cell selection and separates target cells size-selectively using a microfluidic lattice for RBC removal and buffer exchange. In addition, the chip incorporates self-powered microfluidic pumping through a degassed polydimethylsiloxane chip, enabling the rapid isolation of NK cells at the place of blood collection within 40 min. This chip is used to isolate NK cells from whole blood samples of hepatocellular cancer patients and healthy volunteers and examined their functional activities to identify potential abnormalities in NK cell function. The SMS chip is simple to use, rapid to sort, and requires small blood volumes, thus facilitating the use of immune cell subtypes for cell-based diagnosis.

Transcriptomes of the tumor-adjacent normal tissues are more informative than tumors in predicting recurrence in colorectal cancer patients.

BACKGROUND: Previous investigations of transcriptomic signatures of cancer patient survival and post-therapy relapse have focused on tumor tissue. In contrast, here we show that in colorectal cancer (CRC) transcriptomes derived from normal tissues adjacent to tumors (NATs) are better predictors of relapse. RESULTS: Using the transcriptomes of paired tumor and NAT specimens from 80 Korean CRC patients retrospectively determined to be in recurrence or nonrecurrence states, we found that, when comparing recurrent with nonrecurrent samples, NATs exhibit a greater number of differentially expressed genes (DEGs) than tumors. Training two prognostic elastic net-based machine learning models-NAT-based and tumor-based in our Samsung Medical Center (SMC) cohort, we found that NAT-based model performed better in predicting the survival when the model was applied to the tumor-derived transcriptomes of an independent cohort of 450 COAD patients in TCGA. Furthermore, compositions of tumor-infiltrating immune cells in NATs were found to have better prognostic capability than in tumors. We also confirmed through Cox regression analysis that in both SMC-CRC as well as in TCGA-COAD cohorts, a greater proportion of genes exhibited significant hazard ratio when NAT-derived transcriptome was used compared to when tumor-derived transcriptome was used. CONCLUSIONS: Taken together, our results strongly suggest that NAT-derived transcriptomes and immune cell composition of CRC are better predictors of patient survival and tumor recurrence than the primary tumor.

Engineering Rhodosporidium toruloides for production of 3-hydroxypropionic acid from lignocellulosic hydrolysate.

Microbial production of valuable bioproducts is a promising route towards green and sustainable manufacturing. The oleaginous yeast, Rhodosporidium toruloides, has emerged as an attractive host for the production of biofuels and bioproducts from lignocellulosic hydrolysates. 3-hydroxypropionic acid (3HP) is an attractive platform molecule that can be used to produce a wide range of commodity chemicals. This study focuses on establishing and optimizing the production of 3HP in R. toruloides. As R. toruloides naturally has a high metabolic flux towards malonyl-CoA, we exploited this pathway to produce 3HP. Upon finding the yeast capable of catabolizing 3HP, we then implemented functional genomics and metabolomic analysis to identify the catabolic pathways. Deletion of a putative malonate semialdehyde dehydrogenase gene encoding an oxidative 3HP pathway was found to significantly reduce 3HP degradation. We further explored monocarboxylate transporters to promote 3HP transport and identified a novel 3HP transporter in Aspergillus pseudoterreus by RNA-seq and proteomics. Combining these engineering efforts with media optimization in a fed-batch fermentation resulted in 45.4 g/L 3HP production. This represents one of the highest 3HP titers reported in yeast from lignocellulosic feedstocks. This work establishes R. toruloides as a host for 3HP production from lignocellulosic hydrolysate at high titers, and paves the way for further strain and process optimization towards enabling industrial production of 3HP in the future.

Rapid quantification of alcohol production in microorganisms based on nanostructure-initiator mass spectrometry (NIMS).

We described a mass spectrometry-based assay to rapidly quantify the production of primary alcohols directly from cell cultures. This novel assay used the combination of TEMPO-based oxidation chemistry and oxime ligation, followed by product analysis based on Nanostructure-Initiator Mass Spectrometry. This assay enables quantitative monitor both C5 to C18 alcohols as well as glucose and gluconate in the growth medium to support strain characterization and optimization. We find that this assay yields similar results to gas chromatography for isoprenol production but required much less acquisition time per sample. We applied this assay to gain new insights into P. Putida's utilization of alcohols and find that this strain largely could not grow on heptanol and octanol.

Independent representations of self-motion and object location in barrel cortex output.

During active tactile exploration, the dynamic patterns of touch are transduced to electrical signals and transformed by the brain into a mental representation of the object under investigation. This transformation from sensation to perception is thought to be a major function of the mammalian cortex. In primary somatosensory cortex (S1) of mice, layer 5 (L5) pyramidal neurons are major outputs to downstream areas that influence perception, decision-making, and motor control. We investigated self-motion and touch representations in L5 of S1 with juxtacellular loose-seal patch recordings of optogenetically identified excitatory neurons. We found that during rhythmic whisker movement, 54 of 115 active neurons (47%) represented self-motion. This population was significantly more modulated by whisker angle than by phase. Upon active touch, a distinct pattern of activity was evoked across L5, which represented the whisker angle at the time of touch. Object location was decodable with submillimeter precision from the touch-evoked spike counts of a randomly sampled handful of these neurons. These representations of whisker angle during self-motion and touch were independent, both in the selection of which neurons were active and in the angle-tuning preference of coactive neurons. Thus, the output of S1 transiently shifts from a representation of self-motion to an independent representation of explored object location during active touch.

Biosynthesis of neuroprotective melatonin is dysregulated in Huntington's disease.

Huntington's disease (HD) is a progressive neurodegenerative brain disorder associated with uncontrolled body movements, cognitive decline, and reduced circulating melatonin levels. Melatonin is a potent antioxidant and exogenous melatonin treatment is neuroprotective in experimental HD models. In neurons, melatonin is exclusively synthesized in the mitochondrial matrix. Thus, we investigated the integrity of melatonin biosynthesis pathways in pineal and extrapineal brain areas in human HD brain samples, in the R6/2 mouse model of HD and in full-length mutant huntingtin knock-in cells. Aralkylamine N-acetyltransferase (AANAT) is the rate-limiting step enzyme in the melatonin biosynthetic pathway. We found that AANAT expression is significantly decreased in the pineal gland and the striatum of HD patients compared to normal controls. In the R6/2 mouse forebrain, AANAT protein expression was decreased in synaptosomal, but not nonsynaptosomal, mitochondria and was associated with decreased synaptosomal melatonin levels compared to wild type mice. We also demonstrate sequestration of AANAT in mutant-huntingtin protein aggregates likely resulting in decreased AANAT bioavailability. Paradoxically, AANAT mRNA expression is increased in tissues where AANAT protein expression is decreased, suggesting a potential feedback loop that is, ultimately unsuccessful. In conclusion, we demonstrate that pineal, extrapineal, and synaptosomal melatonin levels are compromised in the brains of HD patients and R6/2 mice due, at least in part, to protein aggregation.

Genome-wide association study of occupational attainment as a proxy for cognitive reserve.

Occupational attainment, which represents middle-age cognitive activities, is a known proxy marker of cognitive reserve for Alzheimer's disease. Previous genome-wide association studies have identified numerous genetic variants and revealed the genetic architecture of educational attainment, another marker of cognitive reserve. However, the genetic architecture and heritability for occupational attainment remain elusive. We performed a large-scale genome-wide association study of occupational attainment with 248 847 European individuals from the UK Biobank using the proportional odds logistic mixed model method. In this analysis, we defined occupational attainment using the classified job levels formulated in the UK Standard Occupational Classification system considering the individual professional skill and academic level. We identified 30 significant loci (P < 5 × 10-8); 12 were novel variants, not associated with other traits. Among them, four lead variants were associated with genes expressed in brain tissues by expression quantitative trait loci mapping from 10 brain regions: rs13002946, rs3741368, rs11654986 and rs1627527. The single nucleotide polymorphism-based heritability was estimated to be 8.5% (standard error of the mean = 0.004) and partitioned heritability was enriched in the CNS and brain tissues. Genetic correlation analysis showed shared genetic backgrounds between occupational attainment and multiple traits, including education, intelligence, leisure activities, life satisfaction and neuropsychiatric disorders. In two-sample Mendelian randomization analysis, we demonstrated that high occupation levels were associated with reduced risk for Alzheimer's disease [odds ratio (OR) = 0.78, 95% confidence interval (CI) = 0.65-0.92 in inverse variance weighted method; OR = 0.73, 95% CI = 0.57-0.92 in the weighted median method]. This causal relationship between occupational attainment and Alzheimer's disease was robust in additional sensitivity analysis that excluded potentially pleiotropic single nucleotide polymorphisms (OR = 0.72, 95% CI = 0.57-0.91 in the inverse variance weighted method; OR = 0.72, 95% CI = 0.53-0.97 in the weighted median method). Multivariable Mendelian randomization confirmed that occupational attainment had an independent effect on the risk for Alzheimer's disease even after taking educational attainment into account (OR = 0.72, 95% CI = 0.54-0.95 in the inverse variance weighted method; OR = 0.68, 95% CI = 0.48-0.97 in the weighted median method). Overall, our analyses provide insights into the genetic architecture of occupational attainment and demonstrate that occupational attainment is a potential causal protective factor for Alzheimer's disease as a proxy marker of cognitive reserve.