An implantable piezoelectric ultrasound stimulator (ImPULS) for deep brain activation.

Precise neurostimulation can revolutionize therapies for neurological disorders. Electrode-based stimulation devices face challenges in achieving precise and consistent targeting due to the immune response and the limited penetration of electrical fields. Ultrasound can aid in energy propagation, but transcranial ultrasound stimulation in the deep brain has limited spatial resolution caused by bone and tissue scattering. Here, we report an implantable piezoelectric ultrasound stimulator (ImPULS) that generates an ultrasonic focal pressure of 100 kPa to modulate the activity of neurons. ImPULS is a fully-encapsulated, flexible piezoelectric micromachined ultrasound transducer that incorporates a biocompatible piezoceramic, potassium sodium niobate [(K,Na)NbO3]. The absence of electrochemically active elements poses a new strategy for achieving long-term stability. We demonstrated that ImPULS can i) excite neurons in a mouse hippocampal slice ex vivo, ii) activate cells in the hippocampus of an anesthetized mouse to induce expression of activity-dependent gene c-Fos, and iii) stimulate dopaminergic neurons in the substantia nigra pars compacta to elicit time-locked modulation of nigrostriatal dopamine release. This work introduces a non-genetic ultrasound platform for spatially-localized neural stimulation and exploration of basic functions in the deep brain.

The transcription factor ZNF469 regulates collagen production in liver fibrosis.

Non-alcoholic fatty liver disease (NAFLD) - characterized by excess accumulation of fat in the liver - now affects one third of the world's population. As NAFLD progresses, extracellular matrix components including collagen accumulate in the liver causing tissue fibrosis, a major determinant of disease severity and mortality. To identify transcriptional regulators of fibrosis, we computationally inferred the activity of transcription factors (TFs) relevant to fibrosis by profiling the matched transcriptomes and epigenomes of 108 human liver biopsies from a deeply-characterized cohort of patients spanning the full histopathologic spectrum of NAFLD. CRISPR-based genetic knockout of the top 100 TFs identified ZNF469 as a regulator of collagen expression in primary human hepatic stellate cells (HSCs). Gain- and loss-of-function studies established that ZNF469 regulates collagen genes and genes involved in matrix homeostasis through direct binding to gene bodies and regulatory elements. By integrating multiomic large-scale profiling of human biopsies with extensive experimental validation we demonstrate that ZNF469 is a transcriptional regulator of collagen in HSCs. Overall, these data nominate ZNF469 as a previously unrecognized determinant of NAFLD-associated liver fibrosis.

In-Space Fabrication of Janus Base Nano-Matrix for Improved Assembly and Bioactivities.

In-space manufacturing of nanomaterials is a promising concept while having limited successful examples. DNA-inspired Janus base nanomaterials (JBNs), used for therapeutics delivery and tissue regeneration, are fabricated via a controlled self-assembly process in water at ambient temperature, making them highly suitable for in-space manufacturing. For the first time, we designed and accomplished the production of JBNs on orbit during the Axiom-2 (Ax-2) mission demonstrating great promising and benefits of in-space manufacturing of nanomaterials.

Cardiometabolic Improvements After Metabolic Surgery and Related Presurgery Factors.

Context: Metabolic surgery remains the most effective and durable treatment for severe obesity and related metabolic diseases. Objective: We examined cardiometabolic improvements after metabolic surgery and associated presurgery demographic and clinical factors in a large multiracial cohort. Methods: Included were 7804 patients (20-79 years) undergoing first-time metabolic surgery at Vanderbilt University Medical Center from 1999 to 2022. Pre- and 1-year postsurgery cardiometabolic profiles were extracted from medical records, including body mass index (BMI), blood pressure, blood lipids, glucose, and hemoglobin A1c. The 10-year atherosclerotic cardiovascular disease (ASCVD) risk was estimated per American College of Cardiology/American Heart Association equations. Pre- to postsurgery cardiometabolic profiles were compared by paired t-test, and associated factors were identified by multivariable linear and logistic regression. Results: Among 7804 patients, most were women and White, while 1618 were men and 1271 were Black; median age and BMI were 45 years [interquartile range (IQR): 37-53] and 46.4 kg/m2 (IQR: 42.1-52.4). At 1-year postsurgery, patients showed significant decreases in systolic blood pressure (10.5 [95% confidence interval: 10.1, 10.9] mmHg), total cholesterol (13.5 [10.3, 16.7] mg/dL), glucose (13.6 [12.9, 14.4] mg/dL), hemoglobin A1c (1.13% [1.06, 1.20]), and 10-year ASCVD risk (absolute reduction: 1.58% [1.22, 1.94]; relative reduction: 34.4% [29.4, 39.3]); all P < .0001. Older, male, or Black patients showed less reduction in 10-year ASCVD risk and lower odds of diabetes/hypertension/dyslipidemia remission than younger, female, or White patients. Patients with a history of diabetes, hypertension, dyslipidemia, or cardiovascular disease showed less cardiometabolic improvements than those without. Results were similar with or without further adjusting for weight loss and largely sustained at 2-year postsurgery. Conclusion: Metabolic surgery results in significant cardiometabolic improvements, particularly among younger, female, or White patients and those without comorbidities.

Testing prescribed burning to shift an agronomic grass community to a diverse native plant community.

Prescribed burning can be an effective land management tool. Here, we study changes in plant diversity and composition following experimental fire disturbance in microcosm units extracted from a twenty-five-year-old historically reclaimed grassland located at Highland Valley Copper mine in British Columbia (B.C.), Canada. Experimental microcosm units were dominated by agronomic grass species Elymus lanceolatus, Thinopyrum intermedium and Bromus inermis. The disturbance treatment was fire intensity, represented by three levels (light, moderate, and heavy), replicated six times per treatment. Fire intensity was controlled by modifying the weight of dried litter applied to each microcosm unit (50 g,150 g, 200g), along with the time each grass turf was burned (10 s, 15 s, 20 s). One day after the fire treatment was applied, microcosm units were seeded with a native species mix consisting of six grassland species common to southern B.C. to examine effectiveness of plant establishment postburn. Disturbance treatments resulted in higher overall alpha diversity, richness, evenness, and beta diversity. Plant community changes included colonization of seeded native forbs, grasses, and legumes in response to disturbance. Aboveground net primary productivity (ANPP) was net neutral within the light and moderate burning disturbance treatments but resulted in increased ANPP with heavy disturbance. Litter mass reduced plant diversity and ANPP, indicating that litter was a major factor in plant community dynamics. These results suggest disturbance by burning leads to short term positive plant community response towards increasing diversity of semi-arid grasslands, and aids in shifting plant communities to higher diversity composed of an increase in native plant species. Our results also suggest that without active management the gains observed in native species establishment might quickly be out shadowed and restricted by the previously dominant agronomic plant community.

Enhanced Patient Portal Engagement Associated with Improved Weight Loss Outcomes in Post-Bariatric Surgery Patients.

Background: Bariatric surgery is an effective intervention for obesity, but it requires comprehensive postoperative self-management to achieve optimal outcomes. While patient portals are generally seen as beneficial in engaging patients in health management, the link between their use and post-bariatric surgery weight loss remains unclear. Objective: This study investigated the association between patient portal engagement and postoperative body mass index (BMI) reduction among bariatric surgery patients. Methods: This retrospective longitudinal study included patients who underwent Roux-en-Y gastric bypass (RYGB) or sleeve gastrectomy (SG) at Vanderbilt University Medical Center (VUMC) between January 2018 and March 2021. Using generalized estimating equations, we estimated the association between active days of postoperative patient portal use and the reduction of BMI percentage (%BMI) at 3, 6, and 12 months post-surgery. Covariates included duration since surgery, the patient's age at the time of surgery, gender, race and ethnicity, type of bariatric surgery, severity of comorbid conditions, and socioeconomic disadvantage. Results: The study included 1,415 patients, mostly female (80.9%), with diverse racial and ethnic backgrounds. 805 (56.9%) patients underwent RYGB and 610 (43.1%) underwent SG. By one-year post-surgery, the mean (SD) %BMI reduction was 31.1% (8.3%), and the mean (SD) number of patient portal active days was 61.0 (41.2). A significantly positive association was observed between patient portal engagement and %BMI reduction, with variations revealed over time. Each 10-day increment of active portal use was associated with a 0.57% ([95% CI: 0.42- 0.72], P < .001) and 0.35% ([95% CI: 0.22- 0.49], P < .001) %BMI reduction at 3 and 6 months postoperatively. The association was not statistically significant at 12 months postoperatively (ß=-0.07, [95% CI: -0.24- 0.09], P = .54). Various portal functions, including messaging, visits, my record, medical tools, billing, resources, and others, were positively associated with %BMI reduction at 3- and 6-months follow-ups. Conclusions: Greater patient portal engagement, which may represent stronger adherence to postoperative instructions, better self-management of health, and enhanced communication with care teams, was associated with improved postoperative weight loss. Future investigations are needed to identify important portal features that contribute to the long-term success of weight loss management.

Non-Operative Approach to Contained Perforated Marginal Ulcers: A Systematic Review and Case Series.

BACKGROUND: Perforated marginal ulcers (PMUs) are a rare but known complication of bariatric surgery. Management typically involves prompt surgical intervention, but limited data exists on non-operative approaches. This study reviews published data on non-operative management of PMUs and presents a case series of patients who were managed non-operatively. Our hypothesis is that certain patients with signs of perforation can be successfully managed non-operatively with close observation. METHODS: We completed a systematic review searching PubMed, Embase, Web of Science, Cochrane, and clinicaltrials.gov. Ultimately 3 studies described the presentation and non-operative management of 5 patients. Additionally, we prospectively collected data from our institution on all patients who presented between Dec. 2022 and Dec. 2023 with PMUs confirmed on imaging and managed non-operatively. RESULTS: In our literature review, three patients had Roux-en-Y gastric bypass (RYGB), while two had one anastomosis gastric bypass. One patient required surgery two days after admission. Another underwent elective conversion surgery weeks later for a non-healing ulcer. Two received endoscopic interventions. One patient recovered with nil-per-os (NPO) status, and intravenous proton pump inhibitor (PPI) treatment. The patients in our case series presented with normal vital signs, an average of 30 months after RYGB, and with CT scan signs of perforation. None of these patients required surgical or endoscopic intervention. CONCLUSION: In conclusion, while perforated marginal ulcers have traditionally been considered a surgical emergency, some patients can be successfully treated with non-operative management. More research is needed to identify the clinical presentation features, comorbidities, and imaging findings of this group.

Assessing neuroprotective effects of diroximel fumarate and siponimod via modulation of pacemaker channels in an experimental model of remyelination.

Cuprizone (CPZ)-induced alterations in axonal myelination are associated with a period of neuronal hyperexcitability and increased activity of hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels in the thalamocortical (TC) system. Substances used for the treatment of multiple sclerosis (MS) have been shown to normalize neuronal excitability in CPZ-treated mice. Therefore, we aimed to examine the effects of diroximel fumarate (DRF) and the sphingosine 1-phospate receptor (S1PR) modulator siponimod on action potential firing and the inward current (Ih) carried by HCN ion channels in naive conditions and during different stages of de- and remyelination. Here, DRF application reduced Ih current density in ex vivo patch clamp recordings from TC neurons of the ventrobasal thalamic complex (VB), thereby counteracting the increase of Ih during early remyelination. Siponimod reduced Ih in VB neurons under control conditions but had no effect in neurons of the auditory cortex (AU). Furthermore, siponimod increased and decreased AP firing properties of neurons in VB and AU, respectively. Computational modeling revealed that both DRF and siponimod influenced thalamic bursting during early remyelination by delaying the onset and decreasing the interburst frequency. Thus, substances used in MS treatment normalize excitability in the TC system by influencing AP firing and Ih.

Biodegradable Microspheres and Hydrogel Drug Delivery System of Tumor Necrosis Factor (TNF) Inhibitor and Growth Differentiation Factor 5 (GDF5) Reduces Disk Inflammation in the Rabbit Model.

STUDY DESIGN: Preclinical study. OBJECTIVE: Develop and test a drug delivery system (DDS) composed of anti-inflammatories and growth factors in the rabbit disk injury model. SUMMARY OF BACKGROUND DATA: Biological therapies that inhibit inflammation or enhance cell proliferation can alter intervertebral disk (IVD) homeostasis to favor regeneration. As biological molecules have short half-lives and one molecule may not cover multiple disease pathways, effective treatments may require a combination of growth factors and anti-inflammatory agents delivered in a sustained manner. MATERIALS AND METHODS: Biodegradable microspheres were generated separately to encapsulate tumor necrosis factor alpha (TNFα) inhibitors [etanercept (ETN)] or growth differentiation factor 5 (GDF5) and were embedded into a thermoresponsive hydrogel. Release kinetics and activity of ETN and GDF5 were measured in vitro . For in vivo testing, New Zealand White rabbits (n=12) underwent surgery for disk puncture and treatment with blank-DDS, ETN-DDS, or ETN+GDF5-DDS at levels L34, L45, and L56. Radiographic and magnetic resonance images of the spines were obtained. The IVDs were isolated for histologic and gene expression analyses. RESULTS: ETN and GDF5 were encapsulated into poly (L-lactide-co-glycolide) microspheres and had average initial bursts of 2.4±0.1 and 11.2±0.7 µg from DDS, respectively. In vitro studies confirmed that ETN-DDS inhibited TNFα-induced cytokine release and GDF5-DDS induced protein phosphorylation. In vivo studies showed that rabbit IVDs treated with ETN+GDF5-DDS had better histologic outcomes, higher levels of extracellular, and lower levels of inflammatory gene expression than IVDs treated with blank-DDS or ETN-DDS. CONCLUSIONS: This pilot study demonstrated that DDS can be fabricated to deliver sustained and therapeutic dosages of ETN and GDF5. In addition, ETN+GDF5-DDS may have greater anti-inflammatory and regenerative effects than ETN-DDS alone. Thus, intradiscal injection of controlled release TNF-α inhibitors and growth factors may be a promising treatment to reduce disk inflammation and back pain.

Harmonization and standardization of nucleus pulposus cell extraction and culture methods.

Background: In vitro studies using nucleus pulposus (NP) cells are commonly used to investigate disc cell biology and pathogenesis, or to aid in the development of new therapies. However, lab-to-lab variability jeopardizes the much-needed progress in the field. Here, an international group of spine scientists collaborated to standardize extraction and expansion techniques for NP cells to reduce variability, improve comparability between labs and improve utilization of funding and resources. Methods: The most commonly applied methods for NP cell extraction, expansion, and re-differentiation were identified using a questionnaire to research groups worldwide. NP cell extraction methods from rat, rabbit, pig, dog, cow, and human NP tissue were experimentally assessed. Expansion and re-differentiation media and techniques were also investigated. Results: Recommended protocols are provided for extraction, expansion, and re-differentiation of NP cells from common species utilized for NP cell culture. Conclusions: This international, multilab and multispecies study identified cell extraction methods for greater cell yield and fewer gene expression changes by applying species-specific pronase usage, 60-100 U/ml collagenase for shorter durations. Recommendations for NP cell expansion, passage number, and many factors driving successful cell culture in different species are also addressed to support harmonization, rigor, and cross-lab comparisons on NP cells worldwide.

Effects of Axonal Demyelination, Inflammatory Cytokines and Divalent Cation Chelators on Thalamic HCN Channels and Oscillatory Bursting.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system that is characterized by the progressive loss of oligodendrocytes and myelin and is associated with thalamic dysfunction. Cuprizone (CPZ)-induced general demyelination in rodents is a valuable model for studying different aspects of MS pathology. CPZ feeding is associated with the altered distribution and expression of different ion channels along neuronal somata and axons. However, it is largely unknown whether the copper chelator CPZ directly influences ion channels. Therefore, we assessed the effects of different divalent cations (copper; zinc) and trace metal chelators (EDTA; Tricine; the water-soluble derivative of CPZ, BiMPi) on hyperpolarization-activated cyclic nucleotide-gated (HCN) channels that are major mediators of thalamic function and pathology. In addition, alterations of HCN channels induced by CPZ treatment and MS-related proinflammatory cytokines (IL-1ß; IL-6; INF-α; INF-ß) were characterized in C57Bl/6J mice. Thus, the hyperpolarization-activated inward current (Ih) was recorded in thalamocortical (TC) neurons and heterologous expression systems (mHCN2 expressing HEK cells; hHCN4 expressing oocytes). A number of electrophysiological characteristics of Ih (potential of half-maximal activation (V0.5); current density; activation kinetics) were unchanged following the extracellular application of trace metals and divalent cation chelators to native neurons, cell cultures or oocytes. Mice were fed a diet containing 0.2% CPZ for 35 days, resulting in general demyelination in the brain. Withdrawal of CPZ from the diet resulted in rapid remyelination, the effects of which were assessed at three time points after stopping CPZ feeding (Day1, Day7, Day25). In TC neurons, Ih was decreased on Day1 and Day25 and revealed a transient increased availability on Day7. In addition, we challenged naive TC neurons with INF-α and IL-1ß. It was found that Ih parameters were differentially altered by the application of the two cytokines to thalamic cells, while IL-1ß increased the availability of HCN channels (depolarized V0.5; increased current density) and the excitability of TC neurons (depolarized resting membrane potential (RMP); increased the number of action potentials (APs); produced a larger voltage sag; promoted higher input resistance; increased the number of burst spikes; hyperpolarized the AP threshold), INF-α mediated contrary effects. The effect of cytokine modulation on thalamic bursting was further assessed in horizontal slices and a computational model of slow thalamic oscillations. Here, IL-1ß and INF-α increased and reduced oscillatory bursting, respectively. We conclude that HCN channels are not directly modulated by trace metals and divalent cation chelators but are subject to modulation by different MS-related cytokines.

Using Implementation Science to Promote Integration and Sustainability of Community Health Workers in the HIV Workforce.

BACKGROUND: Community health worker (CHW) interventions are an evidence-based practice adopted by health care settings to increase retention in care and viral suppression for people living with HIV (PLWH) from racial/ethnic minority communities. However, disparate funding, unclear roles vis a vis other care team members, limited training and promotion opportunities, and a lack of standards for wages and tasks limit the ability to effectively use CHWs as part of the health care team. Guided by the Exploration, Preparation, Implementation, and Sustainment and Reach, Effectiveness, Adoption, Implementation, and Maintenance frameworks, this study describes the key determinants for CHW integration and sustainability at 3 agencies in Shelby County, TN, to improve viral suppression and reduce disparities among rural and urban people living with HIV. SETTING: Memphis Transitional Grant Area (TGA) which includes 8 rural and urban counties in west Tennessee, Arkansas, and Mississippi. METHODS: Seventeen key informants were identified using purposeful and snowball sampling techniques, including community and agency leadership staff, frontline staff, and faith leaders. RESULTS: Key determinants of CHW integration include establishing clear and standardized CHW roles within and across organizations, facilitating interorganizational networks, and leveraging funds for livable CHW wages and sustainable positions. Training strategies that strengthen the CHW workforce include content related to trauma-informed care, managing stress, and cultural humility. CONCLUSION: Several inner and outer settings and innovation and bridging factors affect CHW positions. Data collected will inform the implementation and sustainment of future policies and interventions intended to improve HIV care continuum outcomes and reduce disparities for PLWH.

Caloric Restriction and Weight Loss Are Primary Factors in the Early Tissue-Specific Metabolic Changes After Bariatric Surgery.

OBJECTIVE: To evaluate changes in insulin sensitivity, hormone secretion, and hepatic steatosis immediately after caloric restriction, vertical sleeve gastrectomy (VSG), and Roux-en-Y gastric bypass (RYGB). RESEARCH DESIGN AND METHODS: Obese subjects were assessed for 1) insulin sensitivity with hyperinsulinemic-euglycemic clamp with glucose tracer infusion, 2) adipokine concentrations with serum and subcutaneous adipose interstitial fluid sampling, and 3) hepatic fat content with MRI before and 7-10 days after VSG, RYGB, or supervised caloric restriction. RESULTS: Each group exhibited an ∼5% total body weight loss, accompanied by similar improvements in hepatic glucose production and hepatic, skeletal muscle, and adipose tissue insulin sensitivity. Leptin concentrations in plasma and adipose interstitial fluid were equally decreased, and reductions in hepatic fat were similar. CONCLUSIONS: The improvements in insulin sensitivity and adipokine secretion observed early after bariatric surgery are replicated by equivalent caloric restriction and weight loss.

Designing Actionable Solutions and Curriculum for Pain Disparities Education.

The Liaison Committee on Medical Education (LCME) require medical schools to teach their students how to recognize and work toward eliminating health disparities. However, time constraints and a dearth of guidance for educators in teaching pain disparities curricula pose significant challenges. Herein we describe successes and lessons learned after designing, implementing, and evaluating an innovative pain disparities curriculum that was embedded in a longitudinal health equity curriculum for third year medical school students at an academic institution. Although the curriculum was developed for medical school students, the concepts may be broadly applicable to other training settings such as residency and fellowship programs.

Novel Cyclic Lipopeptides Fusaricidin Analogs for Treating Wound Infections.

Both acute and chronic cutaneous wounds are often difficult to treat due to the high-risk for bacterial contamination. Once hospitalized, open wounds are at a high-risk for developing hospital-associated infections caused by multi drug-resistant bacteria such as Staphylococcus aureus and Pseudomonas aeruginosa. Treating these infections is challenging, not only because of antibiotic resistance, but also due to the production of biofilms. New treatment strategies are needed that will help in both stimulating the wound healing process, as well as preventing and eliminating bacterial wound infections. Fusaricidins are naturally occurring cyclic lipopeptides with antimicrobial properties that have shown to be effective against a variety of fungi and Gram-positive bacteria, with low toxicity. Continuing with our efforts toward the identification of novel cyclic lipopeptides Fusaricidin analogs, herein we report the synthesis and evaluation of the antimicrobial activity for two novel cyclic lipopeptides (CLP), CLP 2605-4 and CLP 2612-8.1 against methicillin resistant S. aureus and P. aeruginosa, respectively, in in vivo porcine full thickness wound model. Both CLPs were able to reduce bacterial counts by approximately 3 log CFU/g by the last assessment day. Peptide 2612-8.1 slightly enhanced the wound healing, however, wounds treated with peptide 2605-4, have shown higher levels of inflammation and impaired wound healing process. This study highlights the importance of identifying new antimicrobials that can combat bacterial infection while not impeding tissue repair.

Ending the HIV Epidemic: One Southern Community Speaks.

Memphis, Tennessee and its surrounding counties have been profoundly affected by the HIV epidemic. Using a participatory research approach this study identified from a community perspective: 1) the barriers and facilitators for providing support to achieve viral suppression to the most at-risk groups living with HIV in the Memphis Transitional Grant Area and 2) opportunities to strengthen the health care system through the use of community health workers (CHWs) to do outreach and engage with people living with HIV. Themes of barriers include intersectional stigma, HIV criminal laws, abstinence-only sex education, housing, transportation, and limited access to HIV case management and mental health services. Strategies to address these barriers included HIV education to youth in schools and community-wide campaigns, more testing sites, involving faith leaders, funding for housing options, innovative transportation services, rapid start of culturally appropriate HIV medical treatment, intensive case management services, and mental health counseling. Two opportunities to utilize CHWs to address the barriers identified in this geographic area are as policy advocates and as an integrated member of the HIV primary care team. The findings of this study can inform a strategy to build the CHW workforce which may have widespread implications for ending the HIV epidemic in this geographic area and across the United States.

Circulating mucosal-associated invariant T cells identify patients responding to anti-PD-1 therapy.

Immune checkpoint inhibitors are used for treating patients with metastatic melanoma. Since the response to treatment is variable, biomarkers are urgently needed to identify patients who may benefit from such therapy. Here, we combine single-cell RNA-sequencing and multiparameter flow cytometry to assess changes in circulating CD8+ T cells in 28 patients with metastatic melanoma starting anti-PD-1 therapy, followed for 6 months: 17 responded to therapy, whilst 11 did not. Proportions of activated and proliferating CD8+ T cells and of mucosal-associated invariant T (MAIT) cells are significantly higher in responders, prior to and throughout therapy duration. MAIT cells from responders express higher level of CXCR4 and produce more granzyme B. In silico analysis support MAIT presence in the tumor microenvironment. Finally, patients with >1.7% of MAIT among peripheral CD8+ population show a better response to treatment. Our results thus suggest that MAIT cells may be considered a biomarker for patients responding to anti-PD-1 therapy.

Getting to the root of grafting-induced traits.

Grafting is an ancient technique that involves the physical joining of genotypically distinct shoot and root systems, in order to achieve a desirable compound plant. This practice is widely used in modern agriculture to improve biotic and abiotic stress tolerance, modify plant architecture, induce precocious flowering and rejuvenate old perennial varieties, boost yield, and more. Beneficial new rootstock-scion combinations are currently identified through an inefficient trial and error process, which presents a significant bottleneck for the application of grafting to combat new environmental challenges. Identifying the mechanisms that underlie beneficial grafting-induced traits will facilitate rapid breeding and genetic engineering of new rootstock x scion combinations that exhibit superior performance across varying agricultural environments.

Chalcones bearing a 3,4,5-trimethoxyphenyl motif are capable of selectively inhibiting oncogenic K-Ras signaling.

Ras proteins are small GTPases which regulate cellular proliferation, differentiation, and apoptosis. Constitutively active mutant Ras are expressed in ~15-20% human cancers, and K-Ras mutations account for ~85% of all Ras mutations. Despite the significance of Ras proteins in refractory cancers, there is no anti-Ras drug available in clinic. Since K-Ras must interact with the plasma membrane (PM) for biological activity, inhibition of the K-Ras/PM interaction is a tractable approach to block oncogenic K-Ras activity. Here, we discovered chalcones 1 and 8 exhibit anti-K-Ras activity, and show that the compounds mislocalize K-Ras from the PM and block oncogenic K-Ras signal output. Also, 1 inhibits the growth of K-Ras-driven human cancer cells. Our data suggest that 1 could be a promising starting point for developing anti-K-Ras cancer drug.

Intra- and intermolecular Fe-catalyzed dicarbofunctionalization of vinyl cyclopropanes.

Design and implementation of the first (asymmetric) Fe-catalyzed intra- and intermolecular difunctionalization of vinyl cyclopropanes (VCPs) with alkyl halides and aryl Grignard reagents has been realized via a mechanistically driven approach. Mechanistic studies support the diffusion of alkyl radical intermediates out of the solvent cage to participate in an intra- or intermolecular radical cascade with a range of VCPs followed by re-entering the Fe radical cross-coupling cycle to undergo (stereo)selective C(sp2)-C(sp3) bond formation. This work provides a proof-of-concept of the use of vinyl cyclopropanes as synthetically useful 1,5-synthons in Fe-catalyzed conjunctive cross-couplings with alkyl halides and aryl/vinyl Grignard reagents. Overall, we provide new design principles for Fe-mediated radical processes and underscore the potential of using combined computations and experiments to accelerate the development of challenging transformations.