Prediction of drug-target binding affinity based on multi-scale feature fusion.

Accurate prediction of drug-target binding affinity (DTA) plays a pivotal role in drug discovery and repositioning. Although deep learning methods are widely used in DTA prediction, two significant challenges persist: (i) how to effectively represent the complex structural information of proteins and drugs; (ii) how to precisely model the mutual interactions between protein binding sites and key drug substructures. To address these challenges, we propose a MSFFDTA (Multi-scale feature fusion for predicting drug target affinity) model, in which multi-scale encoders effectively capture multi-level structural information of drugs and proteins are designed. And then a Selective Cross Attention (SCA) mechanism is developed to filter out the trivial interactions between drug-protein substructure pairs and retain the important ones, which will make the proposed model better focusing on these key interactions and offering insights into their underlying mechanism. Experimental results on two benchmark datasets demonstrate that MSFFDTA is superior to several state-of-the-art methods across almost all comparison metrics. Finally, we provide the ablation and case studies with visualizations to verify the effectiveness and the interpretability of MSFFDTA. The source code is freely available at https://github.com/whitehat32/MSFF-DTA/.

PNPO-PLP axis senses prolonged hypoxia in macrophages by regulating lysosomal activity.

Oxygen is critical for all metazoan organisms on the earth and impacts various biological processes in physiological and pathological conditions. While oxygen-sensing systems inducing acute hypoxic responses, including the hypoxia-inducible factor pathway, have been identified, those operating in prolonged hypoxia remain to be elucidated. Here we show that pyridoxine 5'-phosphate oxidase (PNPO), which catalyses bioactivation of vitamin B6, serves as an oxygen sensor and regulates lysosomal activity in macrophages. Decreased PNPO activity under prolonged hypoxia reduced an active form of vitamin B6, pyridoxal 5'-phosphate (PLP), and inhibited lysosomal acidification, which in macrophages led to iron dysregulation, TET2 protein loss and delayed resolution of the inflammatory response. Among PLP-dependent metabolism, supersulfide synthesis was suppressed in prolonged hypoxia, resulting in the lysosomal inhibition and consequent proinflammatory phenotypes of macrophages. The PNPO-PLP axis creates a distinct layer of oxygen sensing that gradually shuts down PLP-dependent metabolism in response to prolonged oxygen deprivation.

The effect of preoperative different dexamethasone regimens on postoperative glycemic control in patients with type 2 diabetes mellitus undergoing total joint arthroplasty: a retrospective cohort study.

BACKGROUND: Concerns have been raised regarding the impact of preoperative intravenous dexamethasone on postoperative glycemic control in diabetic patients undergoing total joint arthroplasty (TJA). This study aimed to determine relationships between preoperative different dexamethasone regimens and postoperative fasting blood glucose (FBG), as well as to identify risk factors for postoperative FBG ≥ 200 mg/dl in diabetic patients undergoing TJA. METHODS: This retrospective study included 1216 diabetic patients undergoing TJA and categorized into group A (dexamethasone = 0 mg), group B (dexamethasone = 5 mg), and group C (dexamethasone = 10 mg). All dexamethasone was administered before skin incision. FBG levels were monitored until postoperative day (POD) 3. Analyses were conducted for periprosthetic joint infection (PJI) and wound complications during 90 days postoperatively. And the risk factors for postoperative FBG ≥ 200 mg/dl were identified. RESULTS: Preoperative dexamethasone administration resulted in a transiently higher FBG on POD 0 and POD 1 (all P < 0.001). However, no differences were observed on POD 2 (P = 0.583) and POD 3 (P = 0.131) among three groups. While preoperative dexamethasone led to an increase in postoperative mean FBG and postoperative maximum FBG (all P < 0.001), no differences were found in wound complications (P = 0.548) and PJI (P = 1.000). Increased HbA1c and preoperative high FBG, but not preoperative dexamethasone, were identified as risk factors for postoperative FBG ≥ 200 mg/dl. Preoperative HbA1c level of ≥ 7.15% was associated with an elevated risk of postoperative FBG ≥ 200 mg/dl. CONCLUSIONS: Although preoperative intravenous administration of 5 mg or 10 mg dexamethasone in diabetic patients showed transient effects on postoperative FBG after TJA, no differences were found in the rates of PJI and wound complications during 90 days postoperatively. Notably, patients with a preoperative HbA1c level of ≥ 7.15% and elevated preoperative FBG may encountered postoperative FBG ≥ 200 mg/dl.

Bone wax reduces blood loss after total hip arthroplasty: a prospective, randomized controlled study.

Background: Previous studies have demonstrated the efficacy of bone wax in reducing blood loss in various orthopedic surgeries. However, the effect of bone wax on total hip arthroplasty (THA) remains unclear. The objective of this study was to assess the efficacy of bone wax in THA. Methods: We enrolled 104 patients in this randomized controlled trial. These patients were randomized (1:1) to either the bone wax or control group. The primary outcome was total blood loss after THA. The secondary outcomes included serum hemoglobin (Hb) level, change in Hb level, lower limb diameters on the first and third postoperative day (POD), range of motion at discharge, length of postoperative hospital stay, and adverse events. Results: Patients in the bone wax group had significantly lower total blood loss on PODs 1 and 3 (p < 0.05). Moreover, patients in the bone wax group performed better in terms of postoperative serum Hb level, change in Hb level on PODs 1 and 3, and length of postoperative hospital stay (all p < 0.05). Patients in the bone wax group did not experience any bone wax-related adverse events. Conclusion: Bone wax administration in THA significantly reduced perioperative blood loss. Therefore, bone wax is promising for optimizing blood-conserving management protocols in THA. Clinical trial registration: [https://clinicaltrials.gov/], identifier [ChiCTR2100043868].

Shrimp community structure and influence of environmental variables in the East China Sea and Yellow Sea in spring.

Based on data collected from research vessel cruises performed in May 2020 off the East China Sea (ECS) and the southern Yellow Sea (YS) (26°30'-35°00' N, 120°30'-127°00' E), we analyzed the shrimp community and its relationships with environmental variables by using index of relative importance, biodiversity indices, and multivariate techniques. A total of 29 species were recorded, belonging to 11 families and 19 genera. The dominant species were Metapenaeopsis longirostris, Leptochela gracilis, Solenocera melantho, Crangon hakodatei, Parapenaeus fissuroides, Plesionika izumiae, and Trachypenaeus curvirostris, which together accounted for 82.9% of the total biomass and 90.8% of the total abundance of shrimps. Results of Cluster and NMDS analyses showed that three groups were identified for the shrimp community in the ECS and YS in spring, including group A (inshore of northern ECS and YS group), group B (offshore of northern ECS group) and group C (southern ECS group). ANOSIM and SIMPER analysis showed significant differences between group A and B, gourp A and C, and group B and C, with the dissimilarity of 92.2%, 95.8% and 91.6%, respectively. The typical species were T. curvirostris, C. hakodatei, L. gracilis and Palaemon gravieri in group A, and S. melantho in group B, and M. longirostris, P. fissuroides, P. izumiae and Solenocera alticarinata in group C. Significant differences were also detected in biomass, diversity index, species richness index and evenness index among groups, with significantly greater values in group C than those in A and B. Environmental variables and the substrate also displayed significant differences among groups. Results of canonical correspondence analysis showed that bottom temperature, bottom salinity, depth, and the substrate were the main environmental variables affecting spatial structure of shrimp community. Water mass characteristics and substrate type had important influences on the distribution of shrimp community in the ECS and YS in spring.

Spatial evolution of global petrochemical risk and the influence by industrialization.

The petrochemical industry is an integral contributor to the global economy and plays a critical role in improving the lives of people worldwide. However, its development has also led to frequent accidents, and the evolution and global impact of these risks have not been adequately assessed. This study is aimed at quantitatively analyzing the current state of petrochemical risk and its impact on industrial development in 58 coastal countries (regions) worldwide by identifying petrochemical risk impact indicators and constructing threshold regression models. We showed that the global petrochemical risk has been unevenly decreasing in recent years. In some countries (regions), the petrochemical risk remains unchanged or is increasing; in particular, coastal provinces of China need to address this issue. Moreover, when industrialization and economic development levels are < 53.6 and 34,918.4 USD/person, respectively, petrochemical accidents negatively affect industrial development; however, above these thresholds, they do not impact industrial development. Coastal areas of China and some developing countries are far below these thresholds. Therefore, the risk from petrochemicals remains a critical factor affecting industrial development in countries with low industrialization levels.

Sulfur metabolic response in macrophage limits excessive inflammatory response by creating a negative feedback loop.

The excessive inflammatory response of macrophages plays a vital role in the pathogenesis of various diseases. The dynamic metabolic alterations in macrophages, including amino acid metabolism, are known to orchestrate their inflammatory phenotype. To explore a new metabolic pathway that regulates the inflammatory response, we examined metabolome changes in mouse peritoneal macrophages (PMs) in response to lipopolysaccharide (LPS) and found a coordinated increase of cysteine and its related metabolites, suggesting an enhanced demand for cysteine during the inflammatory response. Because Slc7a11, which encodes a cystine transporter xCT, was remarkably upregulated upon the pro-inflammatory challenge and found to serve as a major channel of cysteine supply, we examined the inflammatory behavior of Slc7a11 knockout PMs (xCT-KO PMs) to clarify an impact of the increased cysteine demand on inflammation. The xCT-KO PMs exhibited a prolonged upregulation of pro-inflammatory genes, which was recapitulated by cystine depletion in the culture media of wild-type PMs, suggesting that cysteine facilitates the resolution of inflammation. Detailed analysis of the sulfur metabolome revealed that supersulfides, such as cysteine persulfide, were increased in PMs in response to LPS, which was abolished in xCT-KO PMs. Supplementation of N-acetylcysteine tetrasulfide (NAC-S2), a supersulfide donor, attenuated the pro-inflammatory gene expression in xCT-KO PMs. Thus, activated macrophages increase cystine uptake via xCT and produce supersulfides, creating a negative feedback loop to limit excessive inflammation. Our study highlights the finely tuned regulation of macrophage inflammatory response by sulfur metabolism.

Ti4+-dopamine/sodium alginate multicomponent complex derived N-doped TiO2@carbon nanocomposites for efficient removal of methylene blue.

A one-pot route for the preparation of TiO2@carbon nanocomposite from Ti4+/polysaccharide coordination complex has been developed and shown advantages in operation, cost, environment, etc. However, the photodegradation rate of methylene blue (MB) needs to be improved. N-doping has been proven as an efficient means to enhance photodegradation performance. Thus, the present study upgraded the TiO2@carbon nanocomposite to N-doped TiO2@carbon nanocomposite (N-TiO2@C) from Ti4+-dopamine/sodium alginate multicomponent complex. The composites were characterized by FT-IR, XRD, XPS, UV-vis DRS, TG-DTA, and SEM-EDS. The obtained TiO2 was a typical rutile phase, and the carboxyl groups existed on N-TiO2@C. The photocatalyst consequently showed high removal efficiency of MB. The cycling experiment additionally indicated the high stability of N-TiO2@C. The present work provided a novel route for preparing N-TiO2@C. Moreover, it can be extended to prepare N-doped polyvalent metal oxides@carbon composites from all water-soluble polysaccharides such as cellulose derivatives, starch, and guar gum.

Lineage-specific differences and regulatory networks governing human chondrocyte development.

To address large gaps in our understanding of the molecular regulation of articular and growth plate cartilage development in humans, we used our directed differentiation approach to generate these distinct cartilage tissues from human embryonic stem cells. The resulting transcriptomic profiles of hESC-derived articular and growth plate chondrocytes were similar to fetal epiphyseal and growth plate chondrocytes, with respect to genes both known and previously unknown to cartilage biology. With the goal to characterize the regulatory landscapes accompanying these respective transcriptomes, we mapped chromatin accessibility in hESC-derived chondrocyte lineages, and mouse embryonic chondrocytes, using ATAC-sequencing. Integration of the expression dataset with the differentially accessible genomic regions revealed lineage-specific gene regulatory networks. We validated functional interactions of two transcription factors (TFs) (RUNX2 in growth plate chondrocytes and RELA in articular chondrocytes) with their predicted genomic targets. The maps we provide thus represent a framework for probing regulatory interactions governing chondrocyte differentiation. This work constitutes a substantial step towards comprehensive and comparative molecular characterizations of distinct chondrogenic lineages and sheds new light on human cartilage development and biology.

A Review of Strategies Associated with Surgical Decompression in Traumatic Spinal Cord Injury.

Traumatic spinal cord injury (TSCI) is frequent. Timely diagnosis and treatment have reduced the mortality, but the long-term recovery of neurologic functions remains ominous. After TSCI, tissue bleeding, edema, and adhesions lead to an increase in the intraspinal pressure, further causing the pathophysiologic processes of ischemia and hypoxia and eventually accelerating the cascade of secondary spinal cord injury. Timely surgery with appropriate decompression strategies can reduce that secondary injury. However, disagreement about the safety and effectiveness of decompression surgery and the timing of surgery still exists. The level and severity of spinal cord injury do have an impact on the timing of surgery; therefore, TSCI subpopulations may benefit from early surgery. Early surgery perhaps has little effect on recovery from complete TSCI but might be of benefit in patients with incomplete injury. Early decompression should be considered in patients with incomplete cervical TSCI. Patient age should not be used as an exclusion criterion for early surgery. The best time point for early surgery is although influenced by the shortest duration to thoroughly examine the patient's condition and stabilize the patient's state. After the patient's condition is fully evaluated, we can perform the surgical modality of emergency myelotomy and decompression. Therefore, a number of conditions should be considered, such as standardized decompression methods, indications and operation timing to ensure the effectiveness and safety of early surgical intervention, and promotion of the functional recovery of residual nerve tissue.

Predict multi-type drug-drug interactions in cold start scenario.

BACKGROUND: Prediction of drug-drug interactions (DDIs) can reveal potential adverse pharmacological reactions between drugs in co-medication. Various methods have been proposed to address this issue. Most of them focus on the traditional link prediction between drugs, however, they ignore the cold-start scenario, which requires the prediction between known drugs having approved DDIs and new drugs having no DDI. Moreover, they're restricted to infer whether DDIs occur, but are not able to deduce diverse DDI types, which are important in clinics. RESULTS: In this paper, we propose a cold start prediction model for both single-type and multiple-type drug-drug interactions, referred to as CSMDDI. CSMDDI predict not only whether two drugs trigger pharmacological reactions but also what reaction types they induce in the cold start scenario. We implement several embedding methods in CSMDDI, including SVD, GAE, TransE, RESCAL and compare it with the state-of-the-art multi-type DDI prediction method DeepDDI and DDIMDL to verify the performance. The comparison shows that CSMDDI achieves a good performance of DDI prediction in the case of both the occurrence prediction and the multi-type reaction prediction in cold start scenario. CONCLUSIONS: Our approach is able to predict not only conventional binary DDIs but also what reaction types they induce in the cold start scenario. More importantly, it learns a mapping function who can bridge the drugs attributes to their network embeddings to predict DDIs. The main contribution of CSMDDI contains the development of a generalized framework to predict the single-type and multi-type of DDIs in the cold start scenario, as well as the implementations of several embedding models for both single-type and multi-type of DDIs. The dataset and source code can be accessed at https://github.com/itsosy/csmddi .

Measurement and Evolution of High-quality Development Level of Marine Fishery in China.

High-quality development of marine fisheries provides an important advantage for China to build itself into a maritime power and implement the Blue Granary Plan effectively. Based on the concepts of 'new development', 'food security', and the six dimensions of 'openness, innovation, coordination, green, sharing, and security', in this study, we established an evaluation index system for the high-quality development of China's marine fishery sector. We applied the entropy method to evaluate the high-quality development level of China's marine fishery sector from 2000 to 2016 and explored its spatial and temporal evolution rules. Our results indicated that: 1) from 2000 to 2016, China's marine fishery sector was in the primary stage of high-quality development; 2) spatially, the highquality development of marine fisheries showed an upward trend in all provinces, autonomous regions, and municipalities in the country (not including Hong Kong, Macao and Taiwan of China), and with time, the distribution pattern changed from single to multi-polarization; 3) temporally, the development level of high-quality marine fisheries fluctuated during the study period. From 2000 to 2010, the growth rate in openness was relatively slow, but after 2010, it increased rapidly. Notably, innovation is the driving force for high-quality development. The green and security factors provide a solid guarantee for high-quality development. In the high-quality development of a region, economic development is better coordinated, and the distribution of benefits is more inclusive. This study provides a theoretical basis to formulate effective marine fishery policies for the high-quality development of the marine fishery sector in China. Exploring the high-quality development and evolution process of marine fishery is conducive to promoting the sustainable development of marine fishery industry, ensuring marine fishery food security, and alleviating global food crisis.

Drug-drug interaction prediction with learnable size-adaptive molecular substructures.

Drug-drug interactions (DDIs) are interactions with adverse effects on the body, manifested when two or more incompatible drugs are taken together. They can be caused by the chemical compositions of the drugs involved. We introduce gated message passing neural network (GMPNN), a message passing neural network which learns chemical substructures with different sizes and shapes from the molecular graph representations of drugs for DDI prediction between a pair of drugs. In GMPNN, edges are considered as gates which control the flow of message passing, and therefore delimiting the substructures in a learnable way. The final DDI prediction between a drug pair is based on the interactions between pairs of their (learned) substructures, each pair weighted by a relevance score to the final DDI prediction output. Our proposed method GMPNN-CS (i.e. GMPNN + prediction module) is evaluated on two real-world datasets, with competitive results on one, and improved performance on the other compared with previous methods. Source code is freely available at https://github.com/kanz76/GMPNN-CS.

Stage-specific influence of temperature on the growth rate of Japanese Spanish mackerel (Scomberomorus niphonius) in early life.

Since 1850, each successive decade has been warmer than any preceding one. Warming could make a major contribution to the growth of fish larvae. To evaluate the influence of water temperature on the growth of larvae who spawned in later spring and early summer, we selected Scomberomorus niphonius, which has important ecological and economic value as a sample fish species. We conducted high-resolution spatiotemporal surveys during the 2015 spawning season at an important spawning ground in China. We found that the temperature required for larval survival was stricter than that for spawning. Within the appropriate temperature range, a rapid rise in water temperature was favourable for larval hatching, but S. niphonius hatched at relatively low temperature exhibited a faster growth rate in the yolk-sac and pre-flexion stages. The accumulated temperature and hatching temperature significantly affected the growth rate of S. niphonius larvae. The model that considered developmental stages provided a better explanation of the data than the model that only considered the temperature effect. The model improvement in terms of variance explained was higher for the early developmental stages than for the later developmental stages, suggesting that stage-specific temperature influences were prominent in the earlier stages, like the yolk-sac stage, and then reduced. Our results implied that water temperature anomalies could be hazardous to fish larvae, especially for fish spawning in late spring and early summer. Given that early-life stage fish are highly sensitive to water temperature, it is imperative to incorporate the potential effects of climate change into fisheries management.

A Comparison Between Unstemmed and Stemmed Constrained Condylar Knee Prostheses in Primary Total Knee Arthroplasty: A Propensity Score-Matched Analysis.

OBJECTIVE: To compare and analyze the clinical outcomes between unstemmed and stemmed constrained condylar knees (CCK) in complex primary total knee arthroplasty (TKA) in terms of implant survivorship, change in outcome evaluations, and complications. METHODS: We reviewed 156 consecutive patients who received primary TKA using PFC®SIGMA®TC3 (TC3) of constrained condylar design between January 2009 and January 2017 at our institution. After removing patients who met exclusion criteria, 25 patients were identified as unstemmed TC3 cases and 81 as stemmed TC3 cases. Propensity score matching was used to select 25 stemmed cases as a control group for the unstemmed group with comparable preoperative conditions including preoperative demographics, preoperative diagnosis, preoperative range of motion, main reason to use TC3, ASA score (American Society of Anesthesiologists), and follow-up duration. Preoperative and postoperative clinical evaluations including Knee Society Score (KSS), Hospital for Special Surgery (HSS) score, the 12-Item Short-Form Health Survey (SF-12), and the range of motion (ROM) were obtained and compared. The instability, periprosthetic fracture, radiolucent lines, polyethylene wear, and heterotrophic ossification were assessed according to the anteroposterior and lateral radiographs of the knee. The complications and implant survivorship between the two groups were also recorded and compared. RESULTS: 3After the index surgery, both groups showed substantial improvement in KSS (knee and function), HSS score, SF-12, and ROM compared with baseline. There was no significant difference in the mean KSS scores (knee and function), HSS score, SF-12, and ROM between the unstemmed and stemmed group postoperatively. No statistically significant difference was found in the overall complication rate between the two groups. The overall Kaplan-Meier survivorship was 98.0% (95% confidence interval 94.1%-100.0%) at 7 years. No significant difference was found in the survival rate between the unstemmed group (100.0%) and the stemmed group (96.0%) at 7 years (log rank, P = 0.317). The mean duration of follow-up was 7.0 years for unstemmed group and 7.7 years for stemmed group. CONCLUSIONS: In patients with adequate bone stock receiving complex primary TKA, unstemmed CCK could achieve similar clinical outcomes at mid-term follow-up as stemmed CCK.

Relationships between Diatom Abundances in Rat Organs and in Environmental Waters.

OBJECTIVE: A diagnosis of drowning remains one of the most challenging issues in forensic science, especially for decomposed bodies. Diatom analysis is considered as an encouraging method for diagnosing drowning. In this study, we developed a drowned rat model using different diatom densities in water. METHODS: A total of 120 adult Sprague-Dawley rats were used and divided into six groups, wherein experimental groups 1-5 were drowned rats (group A) and postmortem submersion rats (group B) that were submerged in water with five different Cyclotella sp. diatom densities, while the remaining group was used as a blank control. The combination of microwave digestion and vacuum filtration method was used to accomplish efficient tissue digestion and ascertain higher accuracy of diatom determinations within organs. RESULTS: The abundances of diatoms in the lungs, livers, and kidneys were significantly different. The diatom abundances in the lungs, livers, and kidneys were directly proportional to the water diatom densities, and specific quantitative relationships could be approximated by separate regression equations for each organ type. However, the trends associated with the diatom increases among organs slightly differed. In addition, the diatom abundances in the lungs, livers, and kidneys were all positively correlated. Diatoms were not observed in the postmortem submersion groups nor in the blank control groups. CONCLUSION: The results of this study provide valuable information for establishing a quantitative diatom framework for informing future forensic medicine efforts.

Nomogram to predict collapse-free survival after core decompression of nontraumatic osteonecrosis of the femoral head.

BACKGROUND: Nontraumatic osteonecrosis of the femoral head (NONFH) is a devastating disease, and the risk factors associated with progression into collapse after core decompression (CD) remain poorly defined. Therefore, we aim to define risk factors associated with collapse-free survival (CFS) after CD of precollapse NONFH and to propose a nomogram for individual risk prediction. METHODS: According to the baseline characteristics, clinical information, radiographic evaluations, and laboratory examination, a nomogram was developed using a single institutional cohort of patients who received multiple drilling for precollapse NONFH between January 2007 and December 2019 to predict CFS after CD of precollapse NONFH. Furthermore, we used C statistics, calibration plot, and Kaplan-Meier curve to test the discriminative ability and calibration of the nomogram to predict CFS. RESULTS: One hundred and seventy-three patients who underwent CD for precollapse NONFH were retrospectively screened and included in the present study. Using a multiple Cox regression to identify relevant risk factors, the following risk factors were incorporated in the prediction of CFS: acute onset of symptom (HR, 2.78; 95% CI, 1.03-7.48; P = 0.043), necrotic location of Japanese Investigation Committee (JIC) C1 and C2 (HR, 3.67; 95% CI, 1.20-11.27; P = 0.023), necrotic angle in the range of 250-299°(HR, 5.08; 95% CI, 1.73-14.93; P = 0.003) and > 299° (HR, 9.96; 95% CI, 3.23-30.70; P < 0.001), and bone marrow edema (BME) before CD (HR, 2.03; 95% CI, 1.02-4.02; P = 0.042). The C statistics was 0.82 for CFS which revealed good discriminative ability and calibration of the nomogram. CONCLUSIONS: Independent predictors of progression into collapse after CD for precollapse NONFH were identified to develop a nomogram predicting CFS. In addition, the nomogram could divide precollapse NONFH patients into prognosis groups and performed well in internal validation.

Joint disease-specificity at the regulatory base-pair level.

Given the pleiotropic nature of coding sequences and that many loci exhibit multiple disease associations, it is within non-coding sequence that disease-specificity likely exists. Here, we focus on joint disorders, finding among replicated loci, that GDF5 exhibits over twenty distinct associations, and we identify causal variants for two of its strongest associations, hip dysplasia and knee osteoarthritis. By mapping regulatory regions in joint chondrocytes, we pinpoint two variants (rs4911178; rs6060369), on the same risk haplotype, which reside in anatomical site-specific enhancers. We show that both variants have clinical relevance, impacting disease by altering morphology. By modeling each variant in humanized mice, we observe joint-specific response, correlating with GDF5 expression. Thus, we uncouple separate regulatory variants on a common risk haplotype that cause joint-specific disease. By broadening our perspective, we finally find that patterns of modularity at GDF5 are also found at over three-quarters of loci with multiple GWAS disease associations.