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The TIR1/AFB auxin co-receptors mediate diverse responses to the plant hormone auxin. The Arabidopsis genome encodes six TIR1/AFB proteins representing three of the four clades that were established prior to angiosperm radiation. To determine the role of these proteins in plant development we performed an extensive genetic analysis involving the generation and characterization of all possible multiply-mutant lines. We find that loss of all six TIR1/AFB proteins results in early embryo defects and eventually seed abortion, and yet a single wild-type allele of TIR1 or AFB2 is sufficient to support growth throughout development. Our analysis reveals extensive functional overlap between even the most distantly related TIR1/AFB genes except for AFB1. Surprisingly, AFB1 has a specialized function in rapid auxin-dependent inhibition of root growth and early phase of root gravitropism. This activity may be related to a difference in subcellular localization compared to the other members of the family.

Genetic variants affecting pancreatic islet enhancers are central to T2D risk, but the gene targets of islet enhancer activity are largely unknown. We generate a high-resolution map of islet chromatin loops using Hi-C assays in three islet samples and use loops to annotate target genes of islet enhancers defined using ATAC-seq and published ChIP-seq data. We identify candidate target genes for thousands of islet enhancers, and find that enhancer looping is correlated with islet-specific gene expression. We fine-map T2D risk variants affecting islet enhancers, and find that candidate target genes of these variants defined using chromatin looping and eQTL mapping are enriched in protein transport and secretion pathways. At IGF2BP2 , a fine-mapped T2D variant reduces islet enhancer activity and IGF2BP2 expression, and conditional inactivation of IGF2BP2 in mouse islets impairs glucose-stimulated insulin secretion. Our findings provide a resource for studying islet enhancer function and identifying genes involved in T2D risk. Risk loci for type 2 diabetes (T2D) reside in pancreatic islet enhancers. Here, the authors generate high-resolution maps of islet chromatin conformation using Hi-C which they combine with ATAC-seq and ChIP-seq data to annotate candidate target genes of enhancers and validate IGF2BP2 activity in mouse islets.

Strigolactones (SLs) are well known for their role in repressing shoot branching. In pea, increased transcript levels of SL biosynthesis genes are observed in stems of highly branched SL deficient (ramosus1 (rms1) and rms5) and SL response (rms3 and rms4) mutants indicative of negative feedback control. In contrast, the highly branched rms2 mutant has reduced transcript levels of SL biosynthesis genes. Grafting studies and hormone quantification led to a model where RMS2 mediates a shoot-to-root feedback signal that regulates both SL biosynthesis gene transcript levels and xylem sap levels of cytokinin exported from roots. Here we cloned RMS2 using synteny with Medicago truncatula and demonstrated that it encodes a putative auxin receptor of the AFB4/5 clade. Phenotypes similar to rms2 were found in Arabidopsis afb4/5 mutants, including increased shoot branching, low expression of SL biosynthesis genes and high auxin levels in stems. Moreover, afb4/5 and rms2 display a specific resistance to the herbicide picloram. Yeast-two-hybrid experiments supported the hypothesis that the RMS2 protein functions as an auxin receptor. SL root feeding using hydroponics repressed auxin levels in stems and down-regulated transcript levels of auxin biosynthesis genes within one hour. This auxin down-regulation was also observed in plants treated with the polar auxin transport inhibitor NPA. Together these data suggest a homeostatic feedback loop in which auxin up-regulates SL synthesis in an RMS2-dependent manner and SL down-regulates auxin synthesis in an RMS3 and RMS4-dependent manner.

Dysfunctional pancreatic islet beta cells are a hallmark of type 2 diabetes (T2D), but a comprehensive understanding of the underlying mechanisms, including gene dysregulation, is lacking. Here we integrate information from measurements of chromatin accessibility, gene expression and function in single beta cells with genetic association data to nominate disease-causal gene regulatory changes in T2D. Using machine learning on chromatin accessibility data from 34 nondiabetic, pre-T2D and T2D donors, we identify two transcriptionally and functionally distinct beta cell subtypes that undergo an abundance shift during T2D progression. Subtype-defining accessible chromatin is enriched for T2D risk variants, suggesting a causal contribution of subtype identity to T2D. Both beta cell subtypes exhibit activation of a stress-response transcriptional program and functional impairment in T2D, which is probably induced by the T2D-associated metabolic environment. Our findings demonstrate the power of multimodal single-cell measurements combined with machine learning for characterizing mechanisms of complex diseases. Single-cell multiomic and functional characterization of human pancreatic islets identifies two beta cell subtypes correlated with type 2 diabetes progression that exhibit distinct gene regulatory programs and electrophysiological phenotypes.

Robotic surgery has increased for common general surgery procedures. This study evaluates how robotic use affects the case distributions of herniorrhaphy and cholecystectomy for general surgery residents according to postgraduate year (PGY). We reviewed Accreditation Council for Graduate Medical Education (ACGME) biliary or hernia cases logged by surgical residents in the academic year 2017-2018. Operative reports were reviewed to compare approaches (robotic, laparoscopic, and open) by resident role and PGY level. Open cholecystectomies were excluded. Overall, 470 hernia and 657 cholecystectomy cases were logged. Hernia repairs were performed robotically in 15.9%, laparoscopically in 9.5%, and open in 74.7%. Cholecystectomies were performed robotically in 16.4% and laparoscopically in 83.6%. Residents were teaching assistants in 1.8% of hernia repairs and 1.5% of cholecystectomies. Distribution of cases by technique and PGY level was significantly different for both procedures, with chief residents performing the majority of robotic cholecystectomies (52.6%, P < .0001) and hernia repairs (59.7%, P < .0001). Migration of robotic cases to senior resident level and low percentage of teaching assistant roles held by residents suggest exposure to common operations may be delayed during general surgery residency training. Introduction of new technology in surgical training should be carefully reviewed and may benefit from a structured curriculum.

Background Social determinants of health challenge in at-risk patients seen in safety net facilities. Study design We performed a retrospective review of surgical oncology specialty clinic referrals at a safety net institution evaluating referral compliance and times to first appointment and initiation of definitive treatment. Main outcomes measured included completion of initial visit, initiation of definitive treatment, time from referral to first appointment, and time from first appointment to initiation of definitive treatment. Results Of 189 new referrals, English was not spoken by 52.4% and 69.4% were Hispanic. Patients presented without insurance in 39.2% of cases. Electronic patient portal was accessed by 31.6% of patients. Of all new referrals, 55.0% arrived for initial consultation and 53.4% initiated definitive treatment. Malignant diagnosis (P < .0001) and lack of insurance (P = .01) were associated with completing initial consultation. Initiation of definitive treatment was associated with not speaking English (P = .03), malignant diagnosis (P < .0001), and lack of insurance (P = .03). Times to first appointment and initiation of definitive treatment were not significantly affected by race/ethnicity, language, insurance, treatment recommended, or electronic patient portal access. Conclusion Access to surgical oncology care for at-risk patients at a safety net facility is not adversely affected by lack of insurance, primary spoken language, or race/ethnicity. However, a significant proportion of all patients fail to complete the initial consultation and definitive treatment. Lessons learned from safety net facilities may help to inform disparities in health care found elsewhere.

Ventral hernia repair (VHR) is one of the most common general surgery procedures; however, few studies with long-term follow-up of VHR outcomes exist.BACKGROUNDVentral hernia repair (VHR) is one of the most common general surgery procedures; however, few studies with long-term follow-up of VHR outcomes exist.We performed a retrospective review of VHRs performed from 2000 to 2009 at a single institution. Our primary outcome was recurrence, and secondary outcomes were reoperations and complications including seroma, hematomas, abdominal wall abscess, wound infections, and mesh infections.METHODSWe performed a retrospective review of VHRs performed from 2000 to 2009 at a single institution. Our primary outcome was recurrence, and secondary outcomes were reoperations and complications including seroma, hematomas, abdominal wall abscess, wound infections, and mesh infections.Our sample population (n=420; mean age 46.3±11.7 years) included 230 females (54.8%), and cases included laparoscopic (n=31; 7.5%), laparoscopic converted to open (n=7; 1.7%), and open (n=373, 90%). As compared to suture repairs, mesh repair was associated with lower rates of complications (25.7% vs 29.5%, p=0.10) and recurrence (12.8% vs 15.2%, p=0.67). Laparoscopic repairs had lower rates of complications than open repairs (25% vs 26.8%; p=0.70) but similar rates of recurrence (13.8% and 13.6%; p=0.53). After logistic regression, obesity, chronic obstructive pulmonary disease, component separation technique, and prolonged operating time (>75th percentile) were associated with increased complications.RESULTSOur sample population (n=420; mean age 46.3±11.7 years) included 230 females (54.8%), and cases included laparoscopic (n=31; 7.5%), laparoscopic converted to open (n=7; 1.7%), and open (n=373, 90%). As compared to suture repairs, mesh repair was associated with lower rates of complications (25.7% vs 29.5%, p=0.10) and recurrence (12.8% vs 15.2%, p=0.67). Laparoscopic repairs had lower rates of complications than open repairs (25% vs 26.8%; p=0.70) but similar rates of recurrence (13.8% and 13.6%; p=0.53). After logistic regression, obesity, chronic obstructive pulmonary disease, component separation technique, and prolonged operating time (>75th percentile) were associated with increased complications.Obesity is a modifiable risk factor and must be addressed in patients undergoing VHRs. Mesh repair does not increase the risk of adverse long-term outcomes and may be performed safely in patients undergoing VHR.CONCLUSIONObesity is a modifiable risk factor and must be addressed in patients undergoing VHRs. Mesh repair does not increase the risk of adverse long-term outcomes and may be performed safely in patients undergoing VHR.

To improve the quality of cancer operations, the American College of Surgeons published Operative Standards for Cancer Surgery, which has been incorporated into Commission on Cancer (CoC) accreditation requirements. We sought to determine if compliance with operative standards was associated with technical surgical outcomes. Oncologic operative reports from 2017 at a CoC and non-CoC institution were examined for documentation of Operative Standards essential steps. Lymph node (LN) yield for lung and colon cases and re-excision rates for breast cases were recorded. Correct documentation was poor for colon, breast, and lung cases with numerous elements documented in <10% of operative reports at both centers. For lung cases, there was no significant difference in meeting ≥10 LN benchmark or average LN yield between the 2 institutions. For colon cases, average lymph node yield was lower in the non-CoC facility, but there was no significant difference in meeting ≥12 LN benchmark. For breast cases, re-excision rates were similar in both programs. Many essential steps in Operative Standards were poorly documented in operative reports, regardless of CoC status. Achieving benchmark technical surgical outcomes was not associated with documented compliance with these standards. Whether improved documentation leads to better surgical outcomes requires further investigation.

Altered function and gene regulation of pancreatic islet beta cells is a hallmark of type 2 diabetes (T2D), but a comprehensive understanding of mechanisms driving T2D is still missing. Here we integrate information from measurements of chromatin activity, gene expression and function in single beta cells with genetic association data to identify disease-causal gene regulatory changes in T2D. Using machine learning on chromatin accessibility data from 34 non-diabetic, pre-T2D and T2D donors, we robustly identify two transcriptionally and functionally distinct beta cell subtypes that undergo an abundance shift in T2D. Subtype-defining active chromatin is enriched for T2D risk variants, suggesting a causal contribution of subtype identity to T2D. Both subtypes exhibit activation of a stress-response transcriptional program and functional impairment in T2D, which is likely induced by the T2D-associated metabolic environment. Our findings demonstrate the power of multimodal single-cell measurements combined with machine learning for identifying mechanisms of complex diseases.Competing Interest StatementK.J.G. does consulting for Genentech and holds stock in Vertex Pharmaceuticals. J.C. is employed by and holds stock in Pfizer Inc.

The role of shared genetic risk in the etiology of type 1 diabetes (T1D) and type 2 diabetes (T2D) and the mechanisms of these effects is unknown. In this study, we generated T1D association data of 15k samples imputed into the HRC reference panel which we compared to T2D association data of 159k samples imputed into 1000 Genomes. The effects of genetic variants on T1D and T2D risk at known loci and genome-wide were positively correlated, which we replicated using data from the UK Biobank and clinically-defined diabetes in the WTCCC. Increased risk of T1D and T2D was correlated with higher fasting insulin and fasting glucose level and decreased birth weight, among T1D- and T2D-specific correlations, and T1D and T2D associated variants were enriched in regulatory elements for pancreatic, insulin resistance (adipose, CD19+ B cell), and developmental (CD184+ endoderm) cell types. We fine-mapped causal variants at known T1D and T2D loci and found evidence for co-localization at five signals, four of which had same direction of effect, including CENPW and GLIS3. Shared risk variants at GLIS3 and other signals were associated with measures of islet function, while CENPW was associated with early growth, and we identified shared risk variants at GLIS3 in islet accessible chromatin with allelic effects on islet regulatory activity. Our findings support shared genetic risk involving variants affecting islet function as well as insulin resistance, growth and development in the etiology of T1D and T2D.