Next Generation SICLOPPS Screening for the Identification of Inhibitors of the HIF-1α/HIF-1ß Protein-Protein Interaction.

Split-intein circular ligation of proteins and peptides (SICLOPPS) is a method for generating intracellular libraries of cyclic peptides that has yielded several first-in-class inhibitors. Here, we detail a revised high-content, high-throughput SICLOPPS screening protocol that utilizes next-generation sequencing, biopanning, and computational tools to identify hits against a given protein-protein interaction. We used this platform for the identification of inhibitors of the HIF-1α/HIF-1ß protein-protein interaction. The revised platform resulted in a significantly higher positive hit rate than that previously reported for SICLOPPS screens, and the identified cyclic peptides were more active in vitro and in cells than our previously reported inhibitors. The platform detailed here may be used for the identification of inhibitors of a wide range of other targets.

Resection versus biopsy in patients with glioblastoma (RESBIOP study): study protocol for an international multicentre prospective cohort study (ENCRAM 2202).

INTRODUCTION: There are no guidelines or prospective studies defining the optimal surgical treatment for glioblastomas in older patients (≥70 years), for those with a limited functioning performance at presentation (Karnofsky Performance Scale ≤70) or for those with tumours in certain locations (midline, multifocal). Therefore, the decision between resection and biopsy is varied, among neurosurgeons internationally and at times even within an institution. This study aims to compare the effects of maximal tumour resection versus tissue biopsy on survival, functional, neurological and quality of life outcomes in these patient subgroups. Furthermore, it evaluates which modality would maximise the potential to undergo adjuvant treatment. METHODS AND ANALYSIS: This study is an international, multicentre, prospective, two-arm cohort study of an observational nature. Consecutive patients with glioblastoma will be treated with resection or biopsy and matched with a 1:1 ratio. Primary endpoints are (1) overall survival and (2) proportion of patients that have received adjuvant treatment with chemotherapy and radiotherapy. Secondary endpoints are (1) proportion of patients with National Institute of Health Stroke Scale deterioration at 6 weeks, 3 months and 6 months after surgery; (2) progression-free survival (PFS); (3) quality of life at 6 weeks, 3 months and 6 months after surgery and (4) frequency and severity of serious adverse events. The total duration of the study is 5 years. Patient inclusion is 4 years; follow-up is 1 year. ETHICS AND DISSEMINATION: The study has been approved by the Medical Ethics Committee (METC Zuid-West Holland/Erasmus Medical Center; MEC-2020-0812). The results will be published in peer-reviewed academic journals and disseminated to patient organisations and media. TRIAL REGISTRATION NUMBER: NCT06146725.

Contrastive learning explains the emergence and function of visual category-selective regions.

Modular and distributed coding theories of category selectivity along the human ventral visual stream have long existed in tension. Here, we present a reconciling framework-contrastive coding-based on a series of analyses relating category selectivity within biological and artificial neural networks. We discover that, in models trained with contrastive self-supervised objectives over a rich natural image diet, category-selective tuning naturally emerges for faces, bodies, scenes, and words. Further, lesions of these model units lead to selective, dissociable recognition deficits, highlighting their distinct functional roles in information processing. Finally, these pre-identified units can predict neural responses in all corresponding face-, scene-, body-, and word-selective regions of human visual cortex, under a highly constrained sparse positive encoding procedure. The success of this single model indicates that brain-like functional specialization can emerge without category-specific learning pressures, as the system learns to untangle rich image content. Contrastive coding, therefore, provides a unifying account of object category emergence and representation in the human brain.

Glioblastoma induces the recruitment and differentiation of dendritic-like "hybrid" neutrophils from skull bone marrow.

Tumor-associated neutrophil (TAN) effects on glioblastoma (GBM) biology remain under-characterized. We show here that neutrophils with dendritic features-including morphological complexity, expression of antigen presentation genes, and the ability to process exogenous peptide and stimulate major histocompatibility complex (MHC)II-dependent T cell activation-accumulate intratumorally and suppress tumor growth in vivo. Trajectory analysis of patient TAN scRNA-seq identifies this "hybrid" dendritic-neutrophil phenotype as a polarization state that is distinct from canonical cytotoxic TANs, and which differentiates from local precursors. These hybrid-inducible immature neutrophils-which we identified in patient and murine glioblastomas-arise not from circulation, but from local skull marrow. Through labeled skull flap transplantation and targeted ablation, we characterize calvarial marrow as a contributor of antitumoral myeloid antigen-presenting cells (APCs), including TANs, which elicit T cell cytotoxicity and memory. As such, agents augmenting neutrophil egress from skull marrow-such as intracalvarial AMD3100, whose survival-prolonging effect in GBM we report-present therapeutic potential.

MerlinS13 phosphorylation regulates meningioma Wnt signaling and magnetic resonance imaging features.

Meningiomas are associated with inactivation of NF2/Merlin, but approximately one-third of meningiomas with favorable clinical outcomes retain Merlin expression. Biochemical mechanisms underlying Merlin-intact meningioma growth are incompletely understood, and non-invasive biomarkers that may be used to guide treatment de-escalation or imaging surveillance are lacking. Here, we use single-cell RNA sequencing, proximity-labeling proteomic mass spectrometry, mechanistic and functional approaches, and magnetic resonance imaging (MRI) across meningioma xenografts and patients to define biochemical mechanisms and an imaging biomarker that underlie Merlin-intact meningiomas. We find Merlin serine 13 (S13) dephosphorylation drives meningioma Wnt signaling and tumor growth by attenuating inhibitory interactions with ß-catenin and activating the Wnt pathway. MRI analyses show Merlin-intact meningiomas with S13 phosphorylation and favorable clinical outcomes are associated with high apparent diffusion coefficient (ADC). These results define mechanisms underlying a potential imaging biomarker that could be used to guide treatment de-escalation or imaging surveillance for patients with Merlin-intact meningiomas.

A systematic review of pre-injury anxiety disorder and post-concussion outcomes in youth and young adult athletes.

Pre-injury anxiety disorder may be a risk factor for poor outcomes following sportsrelated concussion. A systematic review was performed to characterize the relationship between pre-injury anxiety disorder and post-concussion symptom presentation and recovery time after sports-related concussions among children, adolescents, and young adults. A PRISMA-compliant literature search was conducted in Ovid MEDLINE, PsycINFO, EMBASE, and Scopus for articles published up to 25 January 2024. The initial query yielded 1358 unique articles. Articles that analyzed the relationship between pre-injury anxiety disorder and post-concussion symptoms and recovery time were included. A final cohort of 11 articles was extracted, comprising a total of 8390 study participants, of whom 921 had a history of pre-injury anxiety disorder. Pre-injury anxiety disorder was associated with prolonged time to return to sports activity and an increased incidence of physical, emotional, cognitive, and sleep-related symptoms. While the results of this review suggest an association between pre-injury anxiety disorder and post-concussion symptoms and recovery time, future studies should be more stringent regarding standardized anxiety disorder definitions, longitudinal assessment of post-concussion symptoms, anxiety disorder subtypes, and anxiety treatment history.

Endovascular Embolization of Aneurysmal Renal Arteriovenous Malformation.

Renal arteriovenous malformations (AVM) represent an uncommon vascular condition characterized by an abnormal direct communication between an intrarenal artery and vein. Though asymptomatic in many individuals, treatment is often indicated if the AVM causes flank pain, hematuria, or medically refractory hypertension, or if there is an associated renal artery aneurysm. We present a case of a large right renal AVM with associated renal artery aneurysm and large varix which was incidentally found on magnetic resonance imaging of the spine. Endovascular and open surgical options were considered, including ex-vivo renal vascular reconstruction and nephrectomy. The patient was successfully treated with endovascular embolization of the AVM with coil packing of the arterial aneurysm and inflow artery. The patient recovered uneventfully with well-maintained renal function and blood pressure control. We review and discuss the literature on the etiology and treatment options for renal AVM.

Feedstock variability impacts the bioconversion of sugar and lignin streams derived from corn stover by Clostridium tyrobutyricum and engineered Pseudomonas putida.

Feedstock variability represents a challenge in lignocellulosic biorefineries, as it can influence both lignocellulose deconstruction and microbial conversion processes for biofuels and biochemicals production. The impact of feedstock variability on microbial performance remains underexplored, and predictive tools for microbial behaviour are needed to mitigate risks in biorefinery scale-up. Here, twelve batches of corn stover were deconstructed via deacetylation, mechanical refining, and enzymatic hydrolysis to generate lignin-rich and sugar streams. These batches and their derived streams were characterised to identify their chemical components, and the streams were used as substrates for producing muconate and butyrate by engineered Pseudomonas putida and wildtype Clostridium tyrobutyricum, respectively. Bacterial performance (growth, product titers, yields, and productivities) differed among the batches, but no strong correlations were identified between feedstock composition and performance. To provide metabolic insights into the origin of these differences, we evaluated the effect of twenty-three isolated chemical components on these microbes, including three components in relevant bioprocess settings in bioreactors, and we found that growth-inhibitory concentrations were outside the ranges observed in the streams. Overall, this study generates a foundational dataset on P. putida and C. tyrobutyricum performance to enable future predictive models and underscores their resilience in effectively converting fluctuating lignocellulose-derived streams into bioproducts.

Impact of motor dysfunction on neuropsychiatric symptom profile in patients with autopsy-confirmed Alzheimer's disease.

Motor dysfunction, which includes changes in gait, balance, and/or functional mobility, is a lesser-known feature of Alzheimer's Disease (AD), especially as it relates to the development of neuropsychiatric symptoms (NPS). This study (1) compared rates of NPS between autopsy-confirmed AD patients with and without early-onset motor dysfunction and (2) compared rates of non-AD dementia autopsy pathology (Lewy Body disease, Frontotemporal Lobar degeneration) between these groups. This retrospective longitudinal cohort study utilized National Alzheimer's Coordinating Center (NACC) data. Participants (N = 856) were required to have moderate-to-severe autopsy-confirmed AD, Clinical Dementia Rating-Global scores of ≤1 at their index visit, and NPS and clinician-rated motor data. Early motor dysfunction was associated with significantly higher NPI-Q total scores (T = 4.48, p < .001) and higher odds of delusions (OR [95%CI]: 1.73 [1.02-2.96]), hallucinations (2.45 [1.35-4.56]), depression (1.51 [1.11-2.06]), irritability (1.50 [1.09-2.08]), apathy (1.70 [1.24-2.36]), anxiety (1.38 [1.01-1.90]), nighttime behaviors (1.98 [1.40-2.81]), and appetite/eating problems (1.56 [1.09-2.25]). Early motor dysfunction was also associated with higher Lewy Body disease pathology (1.41 [1.03-1.93]), but not Frontotemporal Lobar degeneration (1.10 [0.71-1.69]), on autopsy. Our results suggest that motor symptoms in early AD are associated with a higher number and severity of NPS, which may be partially explained by comorbid non-AD neuropathology.

Sleepiness in retired male boxers: daytime sleepiness and its relationship with impulsiveness and depression symptomatology in retired professional male boxers.

BACKGROUND: Boxing exposes fighters to head impacts and potential traumatic brain injury (TBI). Though research has explored the neuropsychiatric consequences of contact sports, there is limited research into Excessive Daytime Sleepiness (EDS) and its relationship to other outcomes, such as impulsiveness and depression. Therefore, this study aimed to describe EDS in retired boxers using the Epworth Sleepiness Scale (ESS) and to examine how boxing and sleepiness relate to impulsiveness and depression symptomatology. METHODS: 86 male retired professional boxers from the Professional Fighters Brain Health Study (PFBHS) met the inclusion criteria. Adjusted multivariable models analyzed relationships between professional boxing bouts, EDS (ESS), impulsiveness (Barratt Impulsiveness Scale Version 11 (BIS-11)), and/or depression (Patient Health Questionnaire-9 (PHQ-9)). A causal mediation analysis was performed to assess whether boxing bouts and ESS scores predicted BIS-11 and PHQ-9 scores. RESULTS: Mean age was ∼51 years, fighters averaged ∼36 professional bouts, and ESS mean(SD) was 7.5(5.3). ESS scores were significantly associated with raw BIS-11 (Beta = 1.26, 95%CI = 0.77-1.75, p < 0.001) and ordinal PHQ-9 (OR = 1.20, 95%CI = 1.11-1.31, p < 0.001) scores in adjusted models, and the significant relationship between boxing bouts and BIS-11/PHQ-9 was mediated by ESS. CONCLUSIONS: EDS in retired male professional boxers may be strongly associated with other neuropsychiatric sequelae of TBI (impulsiveness and depression).Sleepiness; sleep; boxing; contact sports; impulsiveness; impulsivity; depression; Epworth sleepiness scale box.

Asymmetric gas diffusion layers for improved water management in PGM-free electrodes.

Proton-exchange-membrane fuel cells (PEMFCs) offer a long-term, carbon-emission free solution to the energy needs of the transportation sector. However, high cost continues to limit PEMFC commercialization. Replacing expensive platinum group metal (PGM) catalysts with PGM-free catalysts could reduce cost, but the low active site density of PGM-free catalysts necessitates the use of thick electrodes that suffer from substantial mass transport losses. In these thick PGM-free electrodes, effective water management and oxygen transport are crucial to achieve high performance. In this work, we investigate the role of anode and cathode gas diffusion layer (GDL) configurations in controlling water management. Asymmetric GDL configurations, in which the anode GDL exhibits higher permeability than the cathode GDL, showed higher performance compared to conventional symmetric configurations. Computational modeling showed that the improved performance is mainly due to improved water management, resulting in lower liquid water saturation and faster oxygen transport in the cathode.

Sociodemographic and geographic factors impacting radiotherapy recommendation, initiation, and completion for patients with cancer.

BACKGROUND: More than half of patients with cancer receive radiotherapy, which often requires daily treatments for several weeks. The impact of geographic and sociodemographic factors on the odds of patients with cancer being recommended radiotherapy, starting radiotherapy, and completing radiotherapy is not well understood. METHODS: This was a retrospective patient cohort study that included patients diagnosed with one of the 10 most common solid cancers from January 1, 2018, to December 31, 2021, in the National Cancer Database. The primary predictor was radial distance from a patient's home to their cancer treatment hospital. Other covariates included baseline patient characteristics (age, sex, comorbidities, metastatic disease, cancer site), sociodemographic characteristics (race, ethnicity, median income quartile, insurance status), geographic region, and facility type. The three primary outcomes were being recommended radiotherapy, starting recommended radiotherapy, and completing radiotherapy. RESULTS: Of the 3,068,919 patients included, patients living >50 miles away had lower odds of being recommended radiotherapy than those living <10 miles away. Compared to White patients, Asian and Hispanic patients had lower odds of being recommended radiotherapy, and Black patients had lower odds of starting recommended radiotherapy. Uninsured patients, those with Medicaid or Medicare, and patients in lower median income quartiles had lower odds of starting or completing radiotherapy. CONCLUSIONS: Geographic and sociodemographic factors impact access to radiotherapy at different levels in cancer care and understanding these factors could aid policymakers and practices in identifying and supporting at-risk patients.

Craniometric determinants of the fitted filtration efficiency of disposable masks.

Introduction: Exposure to harmful aerosols is of increasing public health concern due to the SARS-CoV-2 pandemic and wildland fires. These events have prompted risk reduction behaviors, notably the use of disposable respiratory protection. This project investigated whether craniofacial morphology impacts the efficiency of disposable masks (N95, KN95, surgical masks, KF94) most often worn by the public to protect against toxic and infectious aerosols. This project was registered with ClinicaltTrials.gov (NCT05388201; registration May 18, 2022). Methods: One-hundred participants (50 men, 50 women) visited the Environmental Protection Agency's Human Studies Facility in Chapel Hill, NC between 2022-2023. Craniometrics and 3D scans were used to separate participants into four clusters. Boosting and elastic net regression yielded five measurements (bizygomatic breadth, nose length, bizygomatic nasal arc, neck circumference, ear breadth) that were the best predictors of filtration efficiency based on overall model fit. Fitted filtration efficiency was quantified for each mask at baseline and when tightened using an ear-loop clip. Results: The mean unmodified mask performance ranged from 55.3% (15.7%) in the large KF94 to 69.5% (12.3%) in the KN95. Modified performance ranged from 66.3% (9.4%) in the surgical to 80.7% (12.0%) in the KN95. Clusters with larger face width and neck circumference had higher unmodified mask efficiency. Larger nose gap area and nose length decreased modified mask performance. Discussion: We identify face width, nose size, nose shape, neck circumference, and ear breadth as specific features that modulate disposable mask fit in both unmodified and modified conditions. This information can optimize guidance on respiratory protection afforded by disposable ear-loop masks.

Frequency ratio of the 229mTh nuclear isomeric transition and the 87Sr atomic clock.

Optical atomic clocks1,2 use electronic energy levels to precisely keep track of time. A clock based on nuclear energy levels promises a next-generation platform for precision metrology and fundamental physics studies. Thorium-229 nuclei exhibit a uniquely low-energy nuclear transition within reach of state-of-the-art vacuum ultraviolet (VUV) laser light sources and have, therefore, been proposed for construction of a nuclear clock3,4. However, quantum-state-resolved spectroscopy of the 229mTh isomer to determine the underlying nuclear structure and establish a direct frequency connection with existing atomic clocks has yet to be performed. Here, we use a VUV frequency comb to directly excite the narrow 229Th nuclear clock transition in a solid-state CaF2 host material and determine the absolute transition frequency. We stabilize the fundamental frequency comb to the JILA 87Sr clock2 and coherently upconvert the fundamental to its seventh harmonic in the VUV range by using a femtosecond enhancement cavity. This VUV comb establishes a frequency link between nuclear and electronic energy levels and allows us to directly measure the frequency ratio of the 229Th nuclear clock transition and the 87Sr atomic clock. We also precisely measure the nuclear quadrupole splittings and extract intrinsic properties of the isomer. These results mark the start of nuclear-based solid-state optical clocks and demonstrate the first comparison, to our knowledge, of nuclear and atomic clocks for fundamental physics studies. This work represents a confluence of precision metrology, ultrafast strong-field physics, nuclear physics and fundamental physics.

Bow Hunter Phenomenon From Advanced Cerebrovascular Disease Treated With Subclavian Artery Stenting and Carotid Endarterectomy.

Bow Hunter syndrome (BHS) is a rare disorder characterized by mechanical occlusion of the vertebral artery (VA) during neck rotation, resulting in symptomatic, transient, and positional vertebrobasilar insufficiency. We describe a case of a 76-year-old female who presented with dizziness and right ear tinnitus triggered by right head rotation. Her symptoms would immediately resolve upon returning her head to the neutral position. CT angiogram showed 80% stenosis of the left subclavian artery origin, 50%-70% stenosis of the proximal right internal carotid artery (ICA), and near occlusive stenoses of the origins of the bilateral VAs. After failing conservative management, the patient was treated with left subclavian artery stenting, followed by a right carotid endarterectomy (CEA) 6 weeks later. Follow-up at 1 month showed resolution of paroxysmal symptoms and no neurological sequelae. To our knowledge, there have not yet been reported cases of patients with concurrent BHS, subclavian artery stenosis, and carotid artery stenosis. We suggest that global revascularization via subclavian artery stenting and CEA may be considered as treatment for patients with BHS complicated by other cerebrovascular disease secondary to stenoses of the ICA and subclavian artery. This approach obviates the need for more complex surgery or endovascular intervention of the VA.

Going Underground: Demographics, Services, and Best Practices Endorsed by Practitioners Providing Support for Naturalistic Psychedelic Use.

Psychedelic-assisted therapy (PAT) has shown preliminary efficacy for psychiatric and physical health conditions. Although some people report naturalistic psychedelic use with so-called "underground" practitioners, little is known about PAT that occurs outside of controlled clinical settings or perspectives of these practitioners. We conducted an anonymous online survey of individuals who reported providing psychedelic support services (e.g. trip sitting and/or preparatory/follow-up psychotherapy) in naturalistic settings. We investigated demographics, including education and licensing, details about services provided, and reported client outcomes. Among 107 participants, 40.2% held a full or in-progress license and 44.9% had not obtained a relevant graduate degree. Almost all participants reported pre-screening clients before treatment, offering preparation, integration, and trip-sitting services, and most employed a range of therapeutic modalities, centering primarily on non-directive approaches. Participants reported that clients most commonly consumed psilocybin, and treated numerous conditions, primarily aligning with indications targeted in psychedelic clinical research. Perceptions of clients' symptom changes were largely positive, although a small proportion reported worsened personality disorder symptoms. Further research delineating client and practitioner perspectives of naturalistic PAT services is warranted, and such work may shed light on the benefits and risks specific to naturalistic PAT as well as inform best practices for practitioners.

Electronic Structure and CO2 Reactivity of Group IV/V/VI Tetraperoxometalates.

Tetraperoxo metal complexes are a category of dioxygen compounds with novel properties. One of their underconsidered applications is in direct air capture (DAC) reactions, whose study is of great interest in order to slow the effects of climate change. Through computational modeling, the present work considers a family of tetraperoxometalate complexes of the form [M(O2)4]x- that capture atmospheric CO2 to produce [MO(O2)2(CO3)]x- and O2. This reaction was experimentally documented with vanadium and serves as a model for analogous reactions with Group IV (x = 4; M = Ti, Zr, Hf), Group V (x = 3; M = V, Nb, Ta), and Group VI (x = 2; M = Cr, Mo, W) metal centers. Descriptors from density functional theory (DFT) calculations, including optimized structures, partial charges, and frontier orbital interactions, provide rationalization for predicted differences in reactivity. Of the nine complexes studied, [Ti(O2)4]4- and [W(O2)4]2-, respectively, represent the most and least efficient DAC reagents from their differing abilities to stabilize a bidentate peroxycarbonate (κ2-CO42-) intermediate in the proposed reaction mechanism.

In Vivo Silencing of Intestinal DMT1 Mitigates Iron Loading in ß-thalassemia Intermedia (Hbbth3/+) Mice.

ß-thalassemia is an iron-loading anemia caused by homozygous mutation of the hemoglobin subunit ß (HBB) gene. In ß-thalassemia intermedia (ßTI), a non-transfusion-dependent form of the disease, iron overload is caused by excessive absorption of dietary iron due to inappropriately low production of the iron-regulatory hormone hepcidin. Low hepcidin stabilizes the iron exporter ferroportin (FPN) on the basolateral membrane of enterocytes. High FPN activity may deplete intracellular iron and enhance expression of the predominant iron importer divalent metal-ion transporter 1 (DMT1). In mice, DMT1 mediates normal iron absorption under physiological conditions and excessive iron absorption in pathological iron overload (e.g., hereditary hemochromatosis). Here, we hypothesized that DMT1 drives elevated iron absorption in ßTI. Accordingly, we crossed Hbbth3/+ mice, a pre-clinical model of ßTI, with intestine-specific DMT1 KO mice. Ablation of intestinal DMT1 in Hbbth3/+ mice caused a pathophysiological shift from iron overload to an iron-deficiency phenotype with exacerbated anemia. DMT1 is thus required for iron absorption and iron loading in Hbbth3/+ mice. Based upon these outcomes, we further logically postulated that in vivo knockdown of intestinal DMT1 would mitigate iron loading in Hbbth3/+ mice. Ginger-derived, lipid nanoparticles carrying DMT1-specific (or control) siRNAs were administered by oral, intragastric gavage to 4-week-old Hbbth3/+ mice daily for 16 days. siRNA treatment reduced DMT1 expression by >80% and blunted iron loading, as indicated by significant reductions in liver iron and serum ferritin (which reflect body iron stores). These notable experimental outcomes establish intestinal DMT1 as a plausible therapeutic target to mitigate iron overload in ßTI.