Shifts in attention drive context-dependent subspace encoding in anterior cingulate cortex in mice during decision making.

Attention supports decision making by selecting the features that are relevant for decisions. Selective enhancement of the relevant features and inhibition of distractors has been proposed as potential neural mechanisms driving this selection process. Yet, how attention operates when relevance cannot be directly determined, and the attention signal needs to be internally constructed is less understood. Here we recorded from populations of neurons in the anterior cingulate cortex (ACC) of mice in an attention-shifting task where relevance of stimulus modalities changed across blocks of trials. In contrast with V1 recordings, decoding of the irrelevant modality gradually declined in ACC after an initial transient. Our analytical proof and a recurrent neural network model of the task revealed mutually inhibiting connections that produced context-gated suppression as observed in mice. Using this RNN model we predicted a correlation between contextual modulation of individual neurons and their stimulus drive, which we confirmed in ACC but not in V1.

FRONTAL WHITE MATTER CHANGES INDICATE RECOVERY WITH INPATIENT TREATMENT IN HEROIN ADDICTION.

Importance: Amidst an unprecedented opioid epidemic, identifying neurobiological correlates of change with medication-assisted treatment of heroin use disorder is imperative. Distributed white matter (WM) impairments in individuals with heroin use disorder (iHUD) have been associated with increased drug craving, a reliable predictor of treatment outcomes. However, little is known about the extent of whole-brain structural connectivity changes with inpatient treatment and abstinence in iHUD. Objective: To assess WM microstructure and associations with drug craving changes with inpatient treatment in iHUD (effects of time/re-scan compared to controls; CTL). Design: Longitudinal cohort study (12/2020-09/2022) where iHUD and CTL underwent baseline magnetic resonance imaging (MRI#1) and follow-up (MRI#2) scans, (mean interval of 13.9 weeks in all participants combined). Setting: The iHUD and CTL were recruited from urban inpatient treatment facilities and surrounding communities, respectively. Participants: Thirty-four iHUD (42.1yo; 7 women), 25 age-/sex-matched CTL (40.5yo; 9 women). Intervention: Between scans, inpatient iHUD continued their medically-assisted treatment and related clinical interventions. CTL participants were scanned at similar time intervals. Main Outcomes and Measures: Changes in white matter diffusion metrics [fractional anisotropy (FA), mean (MD), axial (AD), and radial diffusivities (RD)] in addition to baseline and cue-induced drug craving, and other clinical outcome variables (mood, sleep, affect, perceived stress, and therapy attendance). Results: Main findings showed HUD-specific WM microstructure changes encompassing mostly frontal major callosal, projection, and association tracts, characterized by increased FA (.949<1- p<.986) and decreased MD (.949<1-p<.997) and RD (.949<1-p<.999). The increased FA (r=- 0.72, p<.00001) and decreased MD (r=0.69, p<.00001) and RD (r=0.67, p<.0001) in the genu and body of the corpus callosum and the left anterior corona radiata in iHUD were correlated with a reduction in baseline craving (.949<1-p<.999). No other WM correlations with outcome variables reached significance. Conclusions and Relevance: Our findings suggest whole-brain normalization of structural connectivity with inpatient medically-assisted treatment in iHUD encompassing recovery in frontal WM pathways implicated in emotional regulation and top-down executive control. The association with decreases in baseline craving further supports the relevance of these WM markers to a major symptom in drug addiction, with implications for monitoring clinical outcomes. Key points: Question: Does white matter (WM) microstructure change with medication-assisted treatment in individuals with heroin use disorder (iHUD)?Findings: In this longitudinal cohort study, diffusion MRI was acquired in 34 inpatient iHUD and 25 healthy controls (CTL) twice, separated by a mean of 13.9 weeks. We found HUD- specific WM microstructure changes with time, characterized by increased anisotropy and decreased diffusivity in fronto-striatal WM pathways. These changes were correlated with decreased baseline drug craving with treatment.Meaning: Frontal WM changes and associated drug craving decreases suggest brain-behavior recovery with inpatient treatment in iHUD, potentially contributing to reduced drug use and sustained abstinence.

Measurement of Natriuretic Peptides in Patients with Suspected Heart Failure to Prevent Overuse of Echocardiography - a Pilot Study.

BACKGROUND: European Society of Cardiology (ESC) guidelines recommend measuring natriuretic peptides (BNP or NT-proBNP) in patients with suspected heart failure (HF) as a first-line tool. HF should be ruled-out if concen-trations of NT-proBNP are below 300 ng/L and 125 ng/L for acute HF and chronic HF, respectively. METHODS: Patients with suspected HF referred for transthoracic echocardiography (TTE) were enrolled; NT-pro-BNP concentrations were obtained from medical charts (measurement < 48 hours) or prospectively measured on the day of TTE. RESULTS: Out of 109 patients, NT-proBNP was measured by the referring department before TTE in 40 patients (36.7%), and 37.5% of these patients had NT-proBNP concentration below the rule-out threshold. NT-proBNP was measured in additional 38 patients on the day of TTE. Overall, 38.5% of the patients had a NT-proBNP concentration below the threshold value. CONCLUSIONS: Natriuretic peptides are not routinely measured in patients with suspected HF; systematic measurement would reduce unnecessary TTE by at least 38.5%.

Dengue Virus dependence on glucokinase activity and glycolysis Confers Sensitivity to NAD(H) biosynthesis inhibitors.

Viruses have developed sophisticated strategies to control metabolic activity of infected cells in order to supply replication machinery with energy and metabolites. Dengue virus (DENV), a mosquito-borne flavivirus responsible for dengue fever, is no exception. Previous reports have documented DENV interactions with metabolic pathways and shown in particular that glycolysis is increased in DENV-infected cells. However, underlying molecular mechanisms are still poorly characterized and dependence of DENV on this pathway has not been investigated in details yet. Here, we identified an interaction between the non-structural protein 3 (NS3) of DENV and glucokinase regulator protein (GCKR), a host protein that inhibits the liver-specific hexokinase GCK. NS3 expression was found to increase glucose consumption and lactate secretion in hepatic cell line expressing GCK. Interestingly, we observed that GCKR interaction with GCK decreases DENV replication, indicating the dependence of DENV to GCK activity and supporting the role of NS3 as an inhibitor of GCKR function. Accordingly, in the same cells, DENV replication both induces and depends on glycolysis. By targeting NAD(H) biosynthesis with the antimetabolite 6-Amino-Nicotinamide (6-AN), we decreased cellular glycolytic activity and inhibited DENV replication in hepatic cells. Infection of primary organotypic liver cultures (OLiC) from hamsters was also inhibited by 6-AN. Altogether, our results show that DENV has evolved strategies to control glycolysis in the liver, which could account for hepatic dysfunctions associated to infection. Besides, our findings suggest that lowering intracellular availability of NAD(H) could be a valuable therapeutic strategy to control glycolysis and inhibit DENV replication in the liver.

Multi-center study on sellar reconstruction after endoscopic transsphenoidal pituitary surgery.

INTRODUCTION: Surgical techniques for sellar reconstruction include no reconstruction, use of synthetic materials, autologous grafts, and/or vascularized flaps. The aim of this study was to conduct a multi-center study comparing the efficacy and postoperative morbidity associated with different sellar reconstruction techniques. METHODS: A retrospective chart review of patients who underwent endoscopic transsphenoidal surgery for pituitary tumors from five participating sites between January 2021 and March 2023 was performed. The variables included demographics, tumor characteristics, reconstruction technique, postoperative cerebrospinal fluid leak (CSF) leak, and 22-item Sino-Nasal Outcome Test (SNOT-22) scores. Comparisons of postoperative complications, SNOT-22 scores, and duration of surgery by type of onlay reconstruction were evaluated using Fisher's exact test, analysis of variance, and Kruskal‒Wallis test. RESULTS: Five hundred and one patients were identified. The median tumor size was 2.1 cm, and 64% were non-functioning. Intraoperative CSF leak was identified in 38% of patients. A total of 89% of patients underwent onlay reconstruction: 49% were reconstructed with mucosal grafts, 35% with nasoseptal flaps, and 5% with other onlay techniques. Nasoseptal flaps were utilized more frequently in the setting of giant pituitary adenomas (>3 cm), medial cavernous sinus wall resection, and high-flow intraoperative CSF leaks. Cases who utilized mucosal grafts had an overall shorter operating time (median: 183 min vs. 240 min; p < 0.001). Five postoperative CSF leaks were identified, and therefore, statistical analysis could not be performed for this complication. CONCLUSION: The effectiveness and morbidity of different sellar reconstruction techniques are comparable. Vascularized flaps were utilized more frequently in the setting of larger tumors and high-flow intraoperative CSF leaks.

Direct tumoral puncture embolization of onyx before endoscopic endonasal resection of a massive juvenile angiofibroma for a patient with Von Willebrand disease - A case report and review of literature.

INTRODUCTION: Standard treatment of a juvenile angiofibroma (JNA) is surgical resection, usually with an endoscopic endonasal surgery and a preoperative embolization. However, standard intra-arterial embolization may fail to completely devascularize tumors. A novel technique of direct intranasal intratumoral onyx embolization has been described. The aim of this study is to demonstrate the safety and the usefulness of this embolization technique on a pediatric case of JNA and to compare our results to previously reported cases. PRESENTATION OF CASE: A twelve-year-old patient suffering from Von Willebrand disease presented with a voluminous JNA with intracranial extension. Internal carotid artery (ICA) branches partially vascularized the tumor. The patient had two previous incomplete surgical resections, which were preceded by a standard embolization, due to massive perioperative bleeding. DISCUSSION: A direct intratumoral embolization of onyx safely allowed complete tumoral devascularization. Tumoral resection was then completed by an endonasal endoscopic approach. Surgery time was decreased (4,5 h versus 5,5 and 6,5 h) and blood loss were minimized (300 ml versus 1 l and 1,3 l). No complication occurred. Twelve articles previously reported this embolization technique. We present the first reported case of onyx embolization being used for a pediatric patient with a coagulation disorder and a voluminous tumor. CONCLUSION: A direct intratumoral onyx embolization allowed complete resection of a massive JNA, for a patient with Von Willebrand disease. Our data suggest that this technique is safe and may be instrumental for a JNA's resection, even if little vascularization comes from ICA branches.

Tethering of hexokinase 2 to mitochondria promotes resistance of liver cancer cells to natural killer cell cytotoxicity.

Hexokinases (HKs) control the first step of glucose catabolism. A switch of expression from liver HK (glucokinase, GCK) to the tumor isoenzyme HK2 is observed in hepatocellular carcinoma progression. Our prior work revealed that HK isoenzyme switch in hepatocytes not only regulates hepatic metabolic functions but also modulates innate immunity and sensitivity to Natural Killer (NK) cell cytotoxicity. This study investigates the impact of HK2 expression and its mitochondrial binding on the resistance of human liver cancer cells to NK-cell-induced cytolysis. We have shown that HK2 expression induces resistance to NK cell cytotoxicity in a process requiring mitochondrial binding of HK2. Neither HK2 nor GCK expression affects target cells' ability to activate NK cells. In contrast, mitochondrial binding of HK2 reduces effector caspase 3/7 activity both at baseline and upon NK-cell activation. Furthermore, HK2 tethering to mitochondria enhances their resistance to cytochrome c release triggered by tBID. These findings indicate that HK2 mitochondrial binding in liver cancer cells is an intrinsic resistance factor to cytolysis and an escape mechanism from immune surveillance.

A high internal heat flux and large core in a warm Neptune exoplanet.

Interactions between exoplanetary atmospheres and internal properties have long been proposed to be drivers of the inflation mechanisms of gaseous planets and apparent atmospheric chemical disequilibrium conditions1. However, transmission spectra of exoplanets have been limited in their ability to observationally confirm these theories owing to the limited wavelength coverage of the Hubble Space Telescope (HST) and inferences of single molecules, mostly H2O (ref. 2). In this work, we present the panchromatic transmission spectrum of the approximately 750 K, low-density, Neptune-sized exoplanet WASP-107b using a combination of HST Wide Field Camera 3 (WFC3) and JWST Near-Infrared Camera (NIRCam) and Mid-Infrared Instrument (MIRI). From this spectrum, we detect spectroscopic features resulting from H2O (21σ), CH4 (5σ), CO (7σ), CO2 (29σ), SO2 (9σ) and NH3 (6σ). The presence of these molecules enables constraints on the atmospheric metal enrichment (M/H is 10-18× solar3), vertical mixing strength (log10Kzz = 8.4-9.0 cm2 s-1) and internal temperature (>345 K). The high internal temperature is suggestive of tidally driven inflation4 acting on a Neptune-like internal structure, which can naturally explain the large radius and low density of the planet. These findings suggest that eccentricity-driven tidal heating is a critical process governing atmospheric chemistry and interior-structure inferences for most of the cool (<1,000 K) super-Earth-to-Saturn-mass exoplanet population.

Spousal bereavement and four-year trajectories of medication use: A nationwide register-based study in Swedish older adults.

BACKGROUND: Medication use around widowhood has been poorly described for most medication classes. Medication use patterns can reflect health consequences of spousal loss, as previously shown for psychotropic drugs. METHODS: We used data from nationwide health registers (2008-2020) to describe the patterns of use of dispensed medications in all widowed Swedes aged ≥65 years followed between 2 years before and 2 years after spousal death. All prescription drugs used by at least 5% of the cohort were considered according to their therapeutic subgroups (Anatomical Therapeutic Chemical [ATC] classification system 2nd level). We used group-based trajectory models to cluster widowed individuals into up to 4 distinct longitudinal patterns of monthly medication use. We ranked the therapeutic subgroups with similar patterns according to their plausibility to reflect potential health effects of spousal loss, compared to those of psycholeptics (mainly anxiolytics, hypnotics) and psychoanaleptics (mainly antidepressants) as the references. RESULTS: From 212,111 widowed adults included (68% female and 70% aged ≥75 years), we observed a significant increasing trend in medication use, especially after spousal death, for 21 out of the 39 different therapeutic subgroups that were used by at least 5% (most represented pharmacological groups: cardiovascular system, nervous system, and alimentary tract and metabolism). This increasing trend often concerned only a small proportion of individuals, with varying magnitude and speed of change in medication use across therapeutic subgroups. The patterns of use of antiepileptics, laxatives, skin emollients/protectives, analgesics, and drugs for anemia, constipation, or peptic ulcers, were the closest to those of references, displaying the largest changes in use, and were therefore ranked as the most likely to reflect health effects of spousal loss. CONCLUSION: Our results confirmed the increase in psychotropic medications' use in widowed older adults and identified several potential physical health effects of spousal loss that warrant further research.

Emerging Approaches to Profile Accessible Chromatin from Formalin-Fixed Paraffin-Embedded Sections.

Nucleosomes are non-uniformly distributed across eukaryotic genomes, with stretches of 'open' chromatin strongly associated with transcriptionally active promoters and enhancers. Understanding chromatin accessibility patterns in normal tissue and how they are altered in pathologies can provide critical insights to development and disease. With the advent of high-throughput sequencing, a variety of strategies have been devised to identify open regions across the genome, including DNase-seq, MNase-seq, FAIRE-seq, ATAC-seq, and NicE-seq. However, the broad application of such methods to FFPE (formalin-fixed paraffin-embedded) tissues has been curtailed by the major technical challenges imposed by highly fixed and often damaged genomic material. Here, we review the most common approaches for mapping open chromatin regions, recent optimizations to overcome the challenges of working with FFPE tissue, and a brief overview of a typical data pipeline with analysis considerations.

Social interactions generate complex selection patterns in virtual worlds.

Understanding the influence of social interactions on individual fitness is key to improving our predictions of phenotypic evolution. However, we often overlook the different components of selection regimes arising from interactions among organisms, including social, correlational, and indirect selection. This is due to the challenging sampling efforts required in natural populations to measure phenotypes expressed during interactions and individual fitness. Furthermore, behaviours are crucial in mediating social interactions, yet few studies have explicitly quantified these selection components on behavioural traits. In this study, we capitalize on an online multiplayer videogame as a source of extensive data recording direct social interactions among prey, where prey collaborate to escape a predator in realistic ecological settings. We estimate natural and social selection and their contribution to total selection on behavioural traits mediating competition, cooperation, and predator-prey interactions. Behaviours of other prey in a group impact an individual's survival, and thus are under social selection. Depending on whether selection pressures on behaviours are synergistic or conflicting, social interactions enhance or mitigate the strength of natural selection, although natural selection remains the main driving force. Indirect selection through correlations among traits also contributed to the total selection. Thus, failing to account for the effects of social interactions and indirect selection would lead to a misestimation of the total selection acting on traits. Dissecting the contribution of each component to the total selection differential allowed us to investigate the causal mechanisms relating behaviour to fitness and quantify the importance of the behaviours of conspecifics as agents of selection. Our study emphasizes that social interactions generate complex selective regimes even in a relatively simple ecological environment.

The Canadian VirusSeq Data Portal & Duotang: open resources for SARS-CoV-2 viral sequences and genomic epidemiology.

The COVID-19 pandemic led to a large global effort to sequence SARS-CoV-2 genomes from patient samples to track viral evolution and inform public health response. Millions of SARS-CoV-2 genome sequences have been deposited in global public repositories. The Canadian COVID-19 Genomics Network (CanCOGeN - VirusSeq), a consortium tasked with coordinating expanded sequencing of SARS-CoV-2 genomes across Canada early in the pandemic, created the Canadian VirusSeq Data Portal, with associated data pipelines and procedures, to support these efforts. The goal of VirusSeq was to allow open access to Canadian SARS-CoV-2 genomic sequences and enhanced, standardized contextual data that were unavailable in other repositories and that meet FAIR standards (Findable, Accessible, Interoperable and Reusable). In addition, the Portal data submission pipeline contains data quality checking procedures and appropriate acknowledgement of data generators that encourages collaboration. From inception to execution, the portal was developed with a conscientious focus on strong data governance principles and practices. Extensive efforts ensured a commitment to Canadian privacy laws, data security standards, and organizational processes. This Portal has been coupled with other resources like Viral AI and was further leveraged by the Coronavirus Variants Rapid Response Network (CoVaRR-Net) to produce a suite of continually updated analytical tools and notebooks. Here we highlight this Portal, including its contextual data not available elsewhere, and the 'Duotang', a web platform that presents key genomic epidemiology and modeling analyses on circulating and emerging SARS-CoV-2 variants in Canada. Duotang presents dynamic changes in variant composition of SARS-CoV-2 in Canada and by province, estimates variant growth, and displays complementary interactive visualizations, with a text overview of the current situation. The VirusSeq Data Portal and Duotang resources, alongside additional analyses and resources computed from the Portal (COVID-MVP, CoVizu), are all open-source and freely available. Together, they provide an updated picture of SARS-CoV-2 evolution to spur scientific discussions, inform public discourse, and support communication with and within public health authorities. They also serve as a framework for other jurisdictions interested in open, collaborative sequence data sharing and analyses.

A Screening Study Identified Decitabine as an Inhibitor of Equid Herpesvirus 4 That Enhances the Innate Antiviral Response.

Equid herpesvirus 4 (EHV-4) is a common respiratory pathogen in horses. It sporadically induces abortion or neonatal death. Although its contribution in neurological disorders is not clearly demonstrated, there is a strong suspicion of its involvement. Despite preventive treatments using vaccines against EHV-1/EHV-4, the resurgence of alpha-EHV infection still constitutes an important threat to the horse industry. Yet very few studies have been conducted on the search for antiviral molecules against EHV-4. A screening of 42 antiviral compounds was performed in vitro on equine fibroblast cells infected with the EHV-4 405/76 reference strain (VR2230). The formation of cytopathic effects was monitored by real-time cell analysis (RTCA), and the viral load was quantified by quantitative PCR. Aciclovir, the most widely used antiviral against alpha-herpesviruses in vivo, does not appear to be effective against EHV-4 in vitro. Potential antiviral activities were confirmed for eight molecules (idoxuridine, vidarabine, pritelivir, cidofovir, valganciclovir, ganciclovir, aphidicolin, and decitabine). Decitabine demonstrates the highest efficacy against EHV-4 in vitro. Transcriptomic analysis revealed the up-regulation of various genes implicated in interferon (IFN) response, suggesting that decitabine triggers the immune antiviral pathway.

Serum cytokine and inflammatory markers in individuals with heroin use disorder: potential biomarkers for diagnosis and disease severity.

Opioid use disorders cause major morbidity and mortality, and there is a pressing need for novel mechanistic targets and biomarkers for diagnosis and prognosis. Exposure to mu-opioid receptor (MOR) agonists causes changes in cytokine and inflammatory protein networks in peripheral blood, and also in brain glia and neurons. Individuals with heroin use disorder (iHUD) show dysregulated levels of several cytokines in blood. However, there is limited data on a comprehensive panel of such markers in iHUD versus healthy controls (HC), especially as a multi-target biomarker. We used a validated proximity extension assay for relative quantification of 92 cytokines and inflammatory proteins in serum of iHUD on medication assisted therapy (MAT; n=21), versus HC (n=24). Twenty-nine targets showed significant group differences (primarily iHUD>HC), surviving multiple comparison correction (p=0.05). This included 19 members of canonical cytokine families, including specific chemokines, interleukins, growth factors, and tumor necrosis factor (TNF)-related proteins. For dimensionality reduction, data from these 19 cytokines were entered into a principal component (PC) analysis, and PC1 scores were iHUD>HC (p<0.0001). A receiver-operating characteristic (ROC) curve analysis yielded an AUROC=91.7% (p<0.0001). This PC1 score remained a positive predictor of being in the HUD group in a multivariable logistic regression, which included demographic/clinical variables. Overall, this study shows a panel of cytokines that differ significantly between iHUD and HC, and provides a multi-target "cytokine biomarker score" for potential diagnostic purposes, and examination of disease severity.

Prescriptions of generic antiretroviral drugs in three healthcare centers in the Paris area, France.

In a retrospective study conducted in three hospitals in Paris, generic antiretroviral accounted for 30.2% of all prescriptions. Tenofovir disoproxil/emtricitabine (TDF/FTC) was the most prescribed generic ART (82.3% of generic prescriptions). Generic ART (gART) was more likely to be prescribed to women, to patients less than 50 years, and with recent HIV diagnosis less than 3 years. Physicians prescribed more gART if they were men, older than 55 years or worked at a university teaching hospital.

Low cabotegravir trough concentrations without oral lead-in in patients with HIV-1 switching to long-acting cabotegravir and rilpivirine.

In a cohort of 72 consecutive virologically-suppressed patients with HIV-1 switching to long-acting cabotegravir and rilpivirine, we observed low cabotegravir trough concentrations 1 and 3 months after the first injection, with a significant association with no oral lead-in at 1 month [odds ratio (OR) = 6.3 [95% confidence interval (CI) 1.7-29.5], P = 0.01] and three months (OR = 5.6 [95% CI 1.3-29.7], P = 0.03), and with high BMI at 1 month (OR = 1.3 [95% CI 1.1-1.6], P = 0.007).

Asymptomatic Bacteriuria and Urological Surgery: Risk Factor or Not? Results From the National and Multicenter TOCUS Database.

PURPOSE: Current guidelines recommend screening and treatment of asymptomatic bacteriuria prior to all urological surgeries breaching the mucosa. But little evidence supports this recommendation. At the least, risk stratification for postoperative UTI to support this strategy is lacking. The aim of this study was to define the associated factors for postoperative febrile infectious complications (UTI or surgical site infection) in urological surgery. MATERIALS AND METHODS: We conducted a retrospective, multicentric study including all consecutive patients undergoing any urological surgery with preoperative urine culture. The primary outcome was the occurrence of a UTI or surgical site infection occurring within 30 days after surgery. RESULTS: From 2016 to 2023, in 10 centers, 2389 patients were included with 838 (35%) positive urine cultures (mono-/bi-/polymicrobial). Postoperative infections occurred in 106 cases (4.4%), of which 44 had negative urine cultures (41%), 42 had positive mono-/bimicrobial urine cultures (40%), and 20 had polymicrobial urine cultures (19%). In multivariable analysis, UTI during the previous 12 months of surgery (odds ratio [OR] 3.43; 95% CI 2.07-5.66; P < .001), monomicrobial/bimicrobial preoperative urine culture (OR 3.68; 95% CI 1.57-8.42; P = .02), polymicrobial preoperative urine culture (OR 2.85; 95% CI 1.52-5.14; P < .001), and operative time (OR 1.09; 95% CI 1.04-1.15; P < .001) were independent associated factors for postoperative febrile infections. CONCLUSIONS: Positive urine culture, including preoperative polymicrobial urine culture, prior to urological surgery was associated with postoperative infection. Additionally, patients experiencing infectious complications also had a higher incidence of other complications. The effectiveness of systematic preventive antibiotic therapy for a positive urine culture has not been conclusively established.

A hemizygous supergene controls homomorphic and heteromorphic self-incompatibility systems in Oleaceae.

Self-incompatibility (SI) has evolved independently multiple times and prevents self-fertilization in hermaphrodite angiosperms. Several groups of Oleaceae such as jasmines exhibit distylous flowers, with two compatibility groups each associated with a specific floral morph.1 Other Oleaceae species in the olive tribe have two compatibility groups without associated morphological variation.2,3,4,5 The genetic basis of both homomorphic and dimorphic SI systems in Oleaceae is unknown. By comparing genomic sequences of three olive subspecies (Olea europaea) belonging to the two compatibility groups, we first locate the genetic determinants of SI within a 700-kb hemizygous region present only in one compatibility group. We then demonstrate that the homologous hemizygous region also controls distyly in jasmine. Phylogenetic analyses support a common origin of both systems, following a segmental genomic duplication in a common ancestor. Examination of the gene content of the hemizygous region in different jasmine and olive species suggests that the mechanisms determining compatibility groups and floral phenotypes (whether homomorphic or dimorphic) in Oleaceae rely on the presence/absence of two genes involved in gibberellin and brassinosteroid regulation.

Absorbed Dose-Response Relationship in Patients with Gastroenteropancreatic Neuroendocrine Tumors Treated with [177Lu]Lu-DOTATATE: One Step Closer to Personalized Medicine.

[177Lu]Lu-DOTATATE has been approved for progressive and inoperable gastroenteropancreatic neuroendocrine tumors (GEP-NETs) that overexpress somatostatin receptors. The absorbed doses by limiting organs and tumors can be quantified by serial postinfusion scintigraphy measurements of the γ-emissions from 177Lu. The objective of this work was to explore how postinfusion [177Lu]Lu-DOTATATE dosimetry could influence clinical management by predicting treatment efficacy (tumor shrinkage and survival) and toxicity. Methods: Patients with GEP-NETs treated with [177Lu]Lu-DOTATATE between 2016 and 2022 and who underwent dosimetry were included. Absorbed doses were calculated for healthy organs (liver, kidneys, bone marrow, and spleen) and tumors using PLANET Dose and the local energy deposition method based on serial posttreatment SPECT/CT. Up to 5 lesions per site were selected and measured on images collected at baseline and 3 mo after treatment end (measurement masked to the somatostatin receptor imaging uptake). For toxicity assessment, laboratory parameters were regularly monitored. Clinical data, including time to death or progression, were collected from the patients' health records. Correlations between absorbed doses by organs and toxicity and between absorbed doses by lesions and tumor volume variation were studied using regression models. Results: In total, 35 dosimetric studies were performed in patients with mostly grade 2 (77%) tumors and metastases in liver (89%), lymph nodes (77%), and bone (34%), and 146 lesions were analyzed: 1-9 lesions per patient, mostly liver metastases (65%) and lymph nodes (25%). The median total absorbed dose by tumors was 94.4 Gy. The absorbed doses by tumors significantly decreased between cycles. The absorbed dose by tumors was significantly associated with tumor volume variation (P < 0.001) 3 mo after treatment end, and it was a significant prognostic factor for survival. Toxicity analysis showed a correlation between the decrease of hematologic parameters such as lymphocytes or platelet concentrations and the absorbed doses by the spleen or bone marrow. The mean absorbed dose by the kidneys was not correlated with nephrotoxicity during the studied period. Conclusion: In patients treated with [177Lu]Lu-DOTATATE for GEP-NETs, tumor and healthy organ dosimetry can predict survival and toxicities, thus influencing clinical management.