Regulatory T Cell Insufficiency in Autoimmune Diabetes Is Driven by Selective Loss of Neuropilin-1 on Intraislet Regulatory T Cells.

Approaches to reverse or limit regulatory T cell (Treg) insufficiency are of great interest for development of immunotherapeutic treatments for autoimmune patients, including type 1 diabetes. Treg insufficiency is heavily implicated in the progression of autoimmune diabetes in the NOD mouse model and is characterized by defects in Treg numbers, development, and/or function. Utilizing a Treg-centric screen, we show that intraislet Tregs have a uniquely dysfunctional phenotype, hallmarked by an almost complete lack of neuropilin-1 (Nrp1), a cell surface receptor required to maintain Treg stability. Intraislet Nrp1- Tregs exhibit hallmark features of fragility, including reduced suppressive capacity, decreased CD73 and Helios, and increased Rorγt and Tbet. Intraislet Nrp1- Tregs also exhibit decreased Foxp3 expression on a per cell basis, suggesting that Nrp1 may also be required for long-term Treg stability. Mechanistically, Treg-restricted augmentation of Nrp1 expression limited the onset of autoimmune diabetes in NOD mice suggesting that Nrp1 critically impacts intraislet Treg function. Transcriptional analysis showed that Nrp1 restoration led to an increase in markers and pathways of TCR signaling, survival, and suppression, and when Nrp1 protein expression is examined by cellular indexing of transcriptomes and epitopes by sequencing, significant differences were observed between Nrp1+ and Nrp1- Tregs in all tissues, particularly in markers of Treg fragility. This translated into substantive differences between Nrp1+ and Nrp1- Tregs that afforded the former with a competitive advantage in the islets. Taken together, these data suggest that maintenance of Nrp1 expression and signaling on Tregs limits diabetes onset and may serve as a strategy to combat Treg insufficiency in autoimmune disease.

Quality of Video Content Related to Deep Inferior Epigastric Perforator Flap Breast Reconstruction: Social Media Platforms Versus Large Language Models.

INTRODUCTION: The deep inferior epigastric perforator (DIEP) flap is currently one of the main options in breast reconstruction. The information about this surgery is critical for the patient, in order to choose the breast reconstruction method. Our study aims to analyze and compare the quality and accuracy of the information related to the DIEP flap reconstruction method provided by social media platforms (SMPs) and the new large language models (LLMs). MATERIALS AND METHODS: A total of 50 videos in English and Spanish were selected from the main SMPs (YouTube, Instagram, and Facebook) using the keywords "DIEP flap" and "colgajo DIEP." The duration, number of likes, dislikes, number of visits, upload date, author, and the video category (institutional video, media, patient experience, academic, and surgery) were analyzed. 3 specific questions were asked to 2 new LLMs (ChatGPT and Google Bard). The quality of information in SMPs and LLMs was analyzed and compared by 2 independent board-certified plastic surgeons using the Journal of American Medical Association and DISCERN scales. RESULTS: LLMs showed a statistically significant higher quality of information when compared with SMPs based on the DISCERN scores. The average DISCERN scores for answers given by ChatGPT and Google Bard were 54 ± 6.841 and 61.17 ± 6.306, respectively (good quality). In SMPs, the average scores were 2.31 ± 0.67 (insufficient quality) and 32.87 ± 9.62 (low quality) for the Journal of American Medical Association and DISCERN scales respectively. Thirty-eight percent of the videos in SMPs were performed by nonmedical authors. CONCLUSIONS: The quality of information for breast reconstruction using DIEP flaps from LLMs was considered good and significantly better than in SMPs. The information found in SMPs was insufficient and of low quality. Academic plastic surgeons have an opportunity to provide quality content on this type of reconstruction in LLM and SMPs.

Physicochemical characterization of pectin and mango peel (Mangifera indica L.) from Mexican cultivars.

In Mexico, about 40 % of the mango harvest is lost due to marketing problems. Moreover, the mango industry generates peel and seed waste that ranges from 35 to 60 % of the total weight of processed fruits. This unexploited mango biomass represents a potential resource for producing value-added by-products. A market alternative is exploiting the mango peel as a source of biofunctional compounds, such as pectin. This hydrocolloid has applications in the pharmaceutical, cosmetic, and food industries. This study quantified the peel components of the Ataulfo, Panameño, Manila, and Haden cultivars. The mango peel showed a considerable input of dietary fiber (37-45 % DM), minerals (1018-2156 mg/100 g DM), phenols (2123-4851 mg gallic acid equivalent/100 g DM), flavonoids (0.74-2.7 mg quercetin equivalent/g DM) and antioxidant capacity (375-937 µM Trolox equivalent/g DM). The four cultivars presented high methoxyl pectins (66-71 %). The molecular weight of the pectins analyzed was from 957 to 4859 kDa. The Panameño cultivar showed the highest amount of pectin and viscosity concerning the peel of the other cultivars and a higher content of glucomannans (≈28.21 %). The pectin of the Haden cultivar was the only one with arabinoxylans since xylose was not detected in the pectin of the other cultivars. The chemical characteristics of the studied mango peels are promising for their industrialization.

Superficial Branch of the Radial Nerve Versus Sural Nerve Grafting After Traumatic Adult Brachial Plexus Injury.

The purpose of this study was to compare two sources of nerve graft for brachial plexus reconstruction: the denervated superficial branch of the radial nerve (SBRN) and the sural nerve. Ninety-seven patients who underwent brachial plexus reconstruction with denervated SBRN nerve (24 patients with 24 grafts) or with sural nerve grafting (73 patients with 83 nerve grafts) were included. The two groups were compared with respect to postoperative muscle reinnervation, disabilities of the arm, shoulder, and hand (DASH) scores. In the SBRN group, only four (17%) of the nerve grafts provided grade III or higher muscle function. In the sural nerve group, 31 (37%) of the nerve grafts provided grade III or higher muscle function. Smoking had a negative impact on muscle recovery. Denervated SBRN grafts are associated with inferior outcomes when compared with sural nerve grafts in the treatment of traumatic adult brachial plexus injuries. (Journal of Surgical Orthopaedic Advances 33(2):080-083, 2024).

Using OR Black Box Technology to Determine Quality Improvement Outcomes for In-situ Timeout and Debrief Simulation.

OBJECTIVE: The purpose of this study was to determine quality improvement outcomes following the pilot implementation of an in-situ simulation designed to enhance surgical safety checklist performance. BACKGROUND: OR Black Box (ORBB) technology allows near real-time assessment for surgical safety checklist performance. Before our study, timeout quality was 73.3%, compliance was 99.9%, and engagement was 89.7% (n=1993 cases); Debrief Quality was 76.0%, compliance was 66.9%, and engagement was 66.7% (n=1842 cases). METHODS: This IRB-approved study used prospective convergent multi-methods. During 2 months, a 15-minute in-situ simulation, incorporating rapid cycle deliberate practice, was implemented for OR teams. ORBB analytics generated Timeout and Debrief scores for actual operations performed by surgeons who participated in simulation (Sim-group) versus those who did not (No-sim group) over 6 months, including 2 months pre-intervention, during-intervention, and post-intervention. Inductive content analysis was performed based on simulation discussions to determine team member perspectives. RESULTS: Thirty simulations with 163 interprofessional participants were conducted. ORBB data from 1570 cases were analyzed. Scores were significantly better for the Sim-group compared with the No-sim group for debrief quality (84% vs. 79% P<0.001, during-intervention), compliance (73% vs. 66%, P<0.001, post-intervention), and engagement (80% vs. 73%, P=0.012, during-intervention). There were no between-group differences for Timeout scores. Thematic analysis identified 2 primary categories: "culture of safety" and "policy." CONCLUSIONS: This simulation-based QI intervention created a psychologically safe training environment for OR teams. The novel use of ORBB technology facilitated outcome analysis and showed significantly better Debrief scores for simulation-trained surgeons compared with nontrained surgeons.

Development of a tibial intraneural ganglion cyst after surgery on a peroneal intraneural ganglion in a pediatric patient: further support for the articular origin of intraneural ganglion cysts. Illustrative case.

BACKGROUND: The articular origin of intraneural cysts has been previously described and well supported. Intraneural ganglion cysts most commonly occur in adults and in the common peroneal nerve arising from the anterior aspect of the superior tibiofibular joint (STFJ). OBSERVATIONS: The authors report a pediatric patient who developed a tibial intraneural cyst arising from the posterior aspect of the STFJ within months after surgical treatment of a peroneal intraneural cyst from the anterior aspect of the same joint. Surgery consisted of disconnecting the articular branch of the peroneal nerve and decompression of the cyst. Three-month postoperative magnetic resonance imaging showed resolution of the peroneal intraneural cyst and anterior compartment denervation but demonstrated a clinically occult small tibial intraneural ganglion cyst arising from the STFJ with popliteus muscle atrophy. LESSONS: This case underscores the importance of addressing the underlying etiology (articular synovitis) or the communication pathways (articular branches) whenever feasible to mitigate intraneural cyst recurrence. Furthermore, this report reinforces the validity of the articular theory. https://thejns.org/doi/10.3171/CASE24277.

Long-term outcomes following the Ross procedure in neonates and infants: A multi-institutional analysis.

OBJECTIVES: For neonates and infants with aortic valve pathology, the Ross procedure historically has been associated with high rates of morbidity and mortality. Data regarding long-term durability are lacking. METHODS: The international, multi-institutional Ross Collaborative included 6 tertiary care centers. Infants who underwent a Ross operation between 1996 and 2016 (allowing a minimum 5 years of follow-up) were retrospectively identified. Serial echocardiograms were examined to study evolution in neoaortic size and function. RESULTS: Primary diagnoses for the 133 patients (n = 30 neonates) included isolated aortic stenosis (14%, n = 19), Shone complex (14%, n = 19), and aortic stenosis plus other (excluding Shone complex; n = 95, 71%), including arch obstruction (n = 55), left ventricular hypoplasia (n = 9), and mitral disease (moderate or greater stenosis or regurgitation, n = 31). At the time of the Ross procedure, median age was 96 days (interquartile range, 36-186), and median weight was 4.4 kg (3.6-6.5). In-hospital mortality occurred in 13 of 133 patients (10%) (4/30 [13%] neonates). Postdischarge mortality occurred in 10 of 120 patients (8%) at a median of 298 days post-Ross. Post-Ross neoaortic dilatation occurred, peaking at 4 to 5 SDs above normal at 2 to 3 years before returning to near-baseline z-score at a median follow-up of 11.5 [6.4-17.4] years. Autograft/left ventricular outflow tract reintervention was required in 5 of 120 patients (4%) at a median of 10.3 [4.1-12.8] years. Freedom from moderate or greater neoaortic regurgitation was 86% at 15 years. CONCLUSIONS: Neonates and infants experience excellent postdischarge survival and long-term freedom from autograft reintervention and aortic regurgitation after the Ross. Neoaortic dilatation normalizes in this population in the long-term. Increased consideration should be given to Ross in neonates and infants with aortic valve disease.

Autoantibodies Neutralizing GM-CSF in HIV-Negative Colombian Patients Infected with Cryptococcus gattii and C. neoformans.

BACKGROUND: Cryptococcosis is a life-threatening disease caused by Cryptococcus neoformans or C. gattii. Neutralizing autoantibodies (auto-Abs) against granulocyte-macrophage colony-stimulating factor (GM-CSF) in otherwise healthy adults with cryptococcal meningitis have been described since 2013. We searched for neutralizing auto-Abs in sera collected from Colombian patients with non-HIV-associated cryptococcosis in a retrospective national cohort from 1997 to 2016. METHODS: We reviewed clinical and laboratory records and assessed the presence of neutralizing auto-Abs against GM-CSF in 30 HIV negative adults with cryptococcosis (13 caused by C. gattii and 17 caused by C. neoformans). RESULTS: We detected neutralizing auto-Abs against GM-CSF in the sera of 10 out of 13 (77%) patients infected with C. gattii and one out of 17 (6%) patients infected with C. neoformans. CONCLUSIONS: We report eleven Colombian patients diagnosed with cryptococcosis who had auto-Abs that neutralize GM-CSF. Among these patients, ten were infected with C. gattii and only one with C. neoformans.

Extended Realities for Sensorially Diverse Children.

Learning space for children with different sensory needs, nowadays, can be interactive, multisensory experiences, designed collaboratively by 1) specialists in special-needs learning, 2) extended realities (XR) technologists, and 3) sensorial diverse children, to provide the motivation, challenge, and development of key skills. While traditional audio and visual sensors in XR are challenging for XR applications to meet the needs of visually and hearing impaired sensorial-diverse children, our research goes a step ahead by integrating sensory technologies including haptic, tactile, kinaesthetic, and olfactory feedback that was well received by the children. Our research also demonstrates the protocols for 1) development of a suite of XR-applications; 2) methods for experiments and evaluation; and 3) tangible improvements in XR learning experience. Our research considered and is in compliance with the ethical and social implications and has the necessary approval for accessibility, user safety, and privacy.

From the simulation lab to the operating room: simulation performance predicts intraoperative performance in robotic gastrojejunostomy.

BACKGROUND: Simulation and video-based assessment (VBA) offer residents the opportunity to develop operative skills while ensuring patient safety. This study aims to determine whether simulation training can predict residents' operative performance, focusing on the gastrojejunal (GJ) anastomosis during robotic pancreatoduodenectomy. METHODS: Twenty-seven general surgery residents completed simulated robotic GJ drills and subsequently performed GJs in the operating room (OR). Both simulated and intraoperative performances were video recorded and retrospectively assessed by two blinded graders using the Objective Structural Assessment of Technical Skills (OSATS) scale, time to completion, and occurrence of errors. Intraoperative GJ OSATS scores were compared in cases with and without Clinically Relevant Delayed Gastric Emptying (CRDGE). Statistical analysis was performed using Spearman's rho, Chi-square, and Kruskal-Wallis tests. RESULTS: For simulated GJs, the median OSATS score was 29 (IQR 27-33), time to completion was 30 min (IQR 27-35), and 11 cases had at least one error. Intraoperative GJs had a median OSATS of 30 (IQR 27-31), time to completion of 41 min (IQR 36-51), and errors occurred in nine cases. The OSATS score on the simulated GJs demonstrated a significant positive correlation to the OSATS score on the operative GJs (r = 0.74; p < 0.001) and less time to completion (r = - 0.68; p < 0.001). A shorter simulated GJ completion time significantly correlated with a higher intraoperative OSATS score (r = - 0.52; p < 0.01). Residents with at least one error in the simulated GJs had lower OSATS scores and higher times intraoperatively. Those cases with CRDGE had significantly lower intraoperative OSATS scores than those without CRDGE. CONCLUSION: Performance on a simulated robotic GJ environment is a robust predictor of OR GJ performance, demonstrating predictive validity. VBA of residents' operative GJ performance is associated with the presentation of CRDGE. Simulation-based training may be crucial to optimizing surgical outcomes before operating on patients.

Yerba Mate (Ilex paraguariensis) Reduces Colitis Severity by Promoting Anti-Inflammatory Macrophage Polarization.

Yerba Mate (YM) (Ilex paraguariensis) is a natural herbal supplement with a well-described anti-inflammatory capacity and beneficial effects in different inflammatory contexts such as insulin resistance or obesity. However, whether YM could improve other inflammatory conditions such as colitis or the immune cell population that can be modulated by this plant remains elusive. Here, by using 61 male and female C57BL/6/J wild-type (WT) mice and the dextran sodium sulfate (DSS)-induced acute colitis model, we evaluated the effect of YM on colitis symptoms and macrophage polarization. Our results showed that the oral administration of YM reduces colitis symptoms and improves animal survival. Increasing infiltration of anti-inflammatory M2 macrophage was observed in the colon of the mice treated with YM. Accordingly, YM promoted M2 macrophage differentiation in vivo. However, the direct administration of YM to bone marrow-derived macrophages did not increase anti-inflammatory polarization, suggesting that YM, through an indirect mechanism, is able to skew the M1/M2 ratio. Moreover, YM consumption reduced the Eubacterium rectale/Clostridium coccoides and Enterobacteriaceae groups and increased the Lactobacillus/Lactococcus group in the gut microbiota. In summary, we show that YM promotes an immunosuppressive environment by enhancing anti-inflammatory M2 macrophage differentiation, reducing colitis symptoms, and suggesting that YM consumption may be a good cost-effective treatment for ulcerative colitis.

Dentoalveolar, periodontal and skeletal effects of maxillary expansion techniques assisted by temporary anchorage devices compared with conventional protocols in growing patients with transverse maxillary deficiency: A systematic review and meta-analysis.

OBJECTIVES: To synthesise the dentoalveolar, periodontal and skeletal changes that occur when using maxillary expansion techniques assisted by temporary anchorage devices compared to conventional protocols. METHODS: Five databases and grey literature were consulted, up to December 2023, focusing on intervention designs and excluding other type of studies. The quality assessment was conducted by using the adaptation for orthodontics of the CONSORT statement, the guidelines for reporting non-randomised studies, the RoB-2 tool, and the ROBINS-I tool. A descriptive summary and meta-analysis using RevMan 5.4 were performed. RESULTS: Nine clinical trials were included (n=377 patients, mean age 13.2±0.6) with a diagnosis of transverse maxillary deficiency. The analysed studies showed qualitative dentoalveolar and periodontal changes after expansion, which were greater on the maxillary first premolars in tooth-borne appliances. Meta-analyses for some effects were included from two studies (n=64); patients who used tooth-borne appliances had greater effects of buccal intercoronal width between the premolars with statistically significant differences (Std Mean difference 2.34; 95% CI: 0.04-4.65 p=0.05). Conversely, those patients who used bone-borne or hybrid appliances had greater effects of buccal intercoronal width between molars with statistically significant differences (Std Mean difference -0.64; 95% CI: -1.38-0.10; p=0.09). CONCLUSIONS: According to the studies analysed, all measurements increased in the intervention groups after expansion. Quantitative analyses show different findings at dentoalveolar level when tooth-borne, bone-borne or hybrid appliances are considered. Nevertheless, the results should be taken with caution due to the heterogeneity of the studies. The protocol was registered at PROSPERO (CRD42021283170), with no funding to report.

Enhancing Readability of Online Patient-Facing Content: The Role of AI Chatbots in Improving Cancer Information Accessibility.

BACKGROUND: Internet-based health education is increasingly vital in patient care. However, the readability of online information often exceeds the average reading level of the US population, limiting accessibility and comprehension. This study investigates the use of chatbot artificial intelligence to improve the readability of cancer-related patient-facing content. METHODS: We used ChatGPT 4.0 to rewrite content about breast, colon, lung, prostate, and pancreas cancer across 34 websites associated with NCCN Member Institutions. Readability was analyzed using Fry Readability Score, Flesch-Kincaid Grade Level, Gunning Fog Index, and Simple Measure of Gobbledygook. The primary outcome was the mean readability score for the original and artificial intelligence (AI)-generated content. As secondary outcomes, we assessed the accuracy, similarity, and quality using F1 scores, cosine similarity scores, and section 2 of the DISCERN instrument, respectively. RESULTS: The mean readability level across the 34 websites was equivalent to a university freshman level (grade 13±1.5). However, after ChatGPT's intervention, the AI-generated outputs had a mean readability score equivalent to a high school freshman education level (grade 9±0.8). The overall F1 score for the rewritten content was 0.87, the precision score was 0.934, and the recall score was 0.814. Compared with their original counterparts, the AI-rewritten content had a cosine similarity score of 0.915 (95% CI, 0.908-0.922). The improved readability was attributed to simpler words and shorter sentences. The mean DISCERN score of the random sample of AI-generated content was equivalent to "good" (28.5±5), with no significant differences compared with their original counterparts. CONCLUSIONS: Our study demonstrates the potential of AI chatbots to improve the readability of patient-facing content while maintaining content quality. The decrease in requisite literacy after AI revision emphasizes the potential of this technology to reduce health care disparities caused by a mismatch between educational resources available to a patient and their health literacy.

Social determinants of health in post-treatment cancer survivors: Scoping review.

PURPOSE: To identify, analyze and describe the available scientific evidence about the influence of social determinants of health on cancer survivors. METHODS: A scoping review was outlined according to the steps described by the Joanna Brigs Institute Reviewer's Manual: selection of studies, data mapping, and results grouping, synthesis and report, was conducted. PubMed, CINAHL, Scopus and LILACS databases were searched from 2011 to 2023. RESULTS: Out of a total of 1783 papers initially screened, only 19 studies met the inclusion criteria for the scoping review, focusing on the primary social determinants impacting the health of cancer survivors. These studies were categorized into six main themes: a) employment (challenges in work reintegration and work-place difficulties); b) variations among different ethnic groups; c) disparities based on sex; d) barriers and facilitators in accessing health and social security services; e) the role of support networks and social environments; and f) socioeconomic lever (influence of income and socioeconomic status). CONCLUSIONS: Understanding the impact of social determinants on the post-treatment quality of life for cancer survivors is crucial. Comprehensive survivorship care should address not just medical needs but also holistic aspects like social support, education, overall well-being, and improvements in physical and social environments. This multifaceted approach ensures the well-rounded support needed for optimal survivorship outcomes.

Neuromuscular choristoma-associated desmoid-type fibromatosis of the brachial plexus: Additional evidence to support a nerve-driven mechanism.

BACKGROUND: We have recently described circumferential nerve involvement of neuromuscular choristoma associated with desmoid-type fibromatosis (NMC-DTF) in cases involving the sciatic nerve, supporting a nerve-derived mechanism for the DTF. We wondered whether a similar growth pattern occurs in cases involving the brachial plexus (BP). METHODS: We reviewed all available magnetic resonance (MR) imaging in patients diagnosed at our institution with NMC or NMC-DTF of the BP. We also performed a literature search of patients with NMC or NMC-DTF of the BP. RESULTS: In our clinical records, four patients with NMC of the BP were identified, and three developed NMC-DTF. All three patients had MR imaging evidence of circumferential encasement of the BP. In the literature, we identified 15 cases of NMC of the BP, of which 12 had identified NMC-DTF. Four published cases included MR images, and only two were of sufficient quality for review. The single provided image in both cases demonstrated a similar pattern of circumferential encasement of the BP by the NMC-DTF. One additional case report was published without MR images but described circumferential involvement in the surgical findings. One unpublished case of NMC-DTF of the BP from an international radiology meeting also had this circumferential pattern pattern on MRI. CONCLUSIONS: The MRI findings of circumferential nerve involvement in patients with NMC-DTF of the BP are similar to our previously reported data in patients with NMC-DTF of the sciatic nerve, providing further imaging-based support of a nerve-driven mechanism. Clinical implications are presented based on the proposed pathogenetic mechanism.

[The FECYT seal of quality, a recognition and a stimulus for Archivos]. / El sello de calidad FECYT, un reconocimiento y un estímulo para Archivos.

Un año más, mediante esta nota editorial, damos cuenta de las estadísticas y los principales avances de nuestra revista. En cuanto a las estadísticas editoriales, que se detallan en los apartados posteriores, podemos afirmar que son las de una revista consolidada: flujo nutrido y constante de trabajos recibidos/publicados, tasas de aceptación y rechazo proporcionadas, tiempos de gestión razonables y diversidad en las autorías. El logro más destacable del 2023 fue superar con éxito el proceso de evaluación de la Octava edición de Evaluación de la calidad editorial y científica de las revistas científicas españolas, comúnmente conocido como 'Sello FECYT'….

Optimizing donor fascicle selection in Oberlin's procedure: A retrospective review of anatomical variability using intraoperative neuromonitoring.

BACKGROUND: Transfer of the fascicle carrying the flexor carpi ulnaris (FCU) branch of the ulnar nerve (UN) to the biceps/brachialis muscle branch of the musculocutaneous nerve (Oberlin's procedure), is a mainstay technique for elbow flexion restoration in patients with upper brachial plexus injury. Despite its widespread use, there are few studies regarding the anatomic location of the donor fascicle for Oberlin's procedure. Our report aims to analyze the anatomical variability of this fascicle within the UN, while obtaining quantifiable, objective data with intraoperative neuromonitoring (IONM) for donor fascicle selection. METHODS: We performed a retrospective review of patients at our institution who underwent an Oberlin's procedure from September 2019 to July 2023. We used IONM for donor fascicle selection (greatest FCU muscle and least intrinsic hand muscle activation). We prospectively obtained demographic and electrophysiological data, as well as anatomical location of donor fascicles and post-surgical morbidities. Surgeon's perception of FCU/intrinsic muscle contraction was compared to objective muscle amplitude during IONM. RESULTS: Eight patients were included, with a mean age of 30.5 years and an injury-to-surgery interval of 4 months. Donor fascicle was located anterior in two cases, posterior in two, radial in two and ulnar in two patients. Correlation between surgeon's perception and IONM findings were consistent in six (75%) cases. No long term motor or sensory deficits were registered. CONCLUSIONS: Fascicle anatomy within the UN at the proximal arm is highly variable. The use of IONM can aid in optimizing donor fascicle selection for Oberlin's procedure.

HIF1α-dependent uncoupling of glycolysis suppresses tumor cell proliferation.

Hypoxia-inducible factor-1α (HIF1α) attenuates mitochondrial activity while promoting glycolysis. However, lower glycolysis is compromised in human clear cell renal cell carcinomas, in which HIF1α acts as a tumor suppressor by inhibiting cell-autonomous proliferation. Here, we find that, unexpectedly, HIF1α suppresses lower glycolysis after the glyceraldehyde 3-phosphate dehydrogenase (GAPDH) step, leading to reduced lactate secretion in different tumor cell types when cells encounter a limited pyruvate supply such as that typically found in the tumor microenvironment in vivo. This is because HIF1α-dependent attenuation of mitochondrial oxygen consumption increases the NADH/NAD+ ratio that suppresses the activity of the NADH-sensitive GAPDH glycolytic enzyme. This is manifested when pyruvate supply is limited, since pyruvate acts as an electron acceptor that prevents the increment of the NADH/NAD+ ratio. Furthermore, this anti-glycolytic function provides a molecular basis to explain how HIF1α can suppress tumor cell proliferation by increasing the NADH/NAD+ ratio.

Photoredox Nucleophilic (Radio)fluorination of Alkoxyamines.

Herein, we report a photoredox nucleophilic (radio)fluorination using TEMPO-derived alkoxyamines, a class of substrates accessible in a single step from a diversity of readily available carboxylic acids, halides, alkenes, alcohols, aldehydes, boron reagents, and C-H bonds. This mild and versatile one-electron pathway affords radiolabeled aliphatic fluorides that are typically inaccessible applying conventional nucleophilic substitution technologies due to insufficient reactivity and competitive elimination. Automation of this photoredox process is also demonstrated with a user-friendly and commercially available photoredox flow reactor and radiosynthetic platform, therefore expediting access to labeled aliphatic fluorides in high molar activity (Am) for (pre)clinical evaluation.