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Abstract What is the bulk Hilbert space of quantum gravity? In this paper, we resolve this problem in 2d JT gravity, both with and without matter, providing an explicit definition of a non-perturbative Hilbert space specified in terms of metric variables. The states are wavefunctions of the length and matter state, but with a non-trivial and highly degenerate inner product. We explicitly identify the null states, and discuss their importance for defining operators non-perturbatively. To highlight the power of the formalism we developed, we study the non-perturbative effects for two bulk linear operators that may serve as proxies for the experience of an observer falling into a two-sided black hole: one captures the length of an Einstein-Rosen bridge and the other captures the center-of-mass collision energy between two particles falling from opposite sides. We track the behavior of these operators up to times of order e S BH $$ {e}^{S_{\textrm{BH}}} $$ , at which point the wavefunction spreads to the complete set of eigenstates of these operators. If these observables are indeed good proxies for the experience of an infalling observer, our results indicate an O(1) probability of detecting a firewall at late times that is self-averaging and universal.

Abstract Obsessive-compulsive disorder is a psychiatric disorder characterized by intrusive thoughts and repetitive behaviors. There are two prominent features: Harm Avoidance (HA) and Incompleteness (INC). Previous resting-state studies reported abnormally elevated connectivity between prefrontal cortical (PFC) and subcortical regions (thalamus, striatum) in OCD participants. Yet, little is known about the white matter (WM) structural abnormalities in these connections. Using brain parcellation and segmentation, whole brain tractography, and Neurite Orientation Dispersion and Density Imaging (NODDI), we aimed to characterize WM structural abnormalities in OCD vs. healthy controls and determine the extent to which NODDI indices of these connections were associated with subthreshold-threshold HA, INC and overall OCD symptom severity across all participants. Four PFC regions were segmented: ventral medial (vmPFC), ventrolateral (vlPFC), dorsomedial (dmPFC), and dorsolateral (dlPFC). NODDI Neurite Density (NDI) and Orientation Dispersion (ODI) indices of WM structure were extracted from connections between these PFC regions and the thalamus (42 OCD, 44 healthy controls, mean age[SD] = 23.65[4.25]y, 63.9% female) and striatum (38 OCD, 41 healthy controls, mean age[SD] = 23.59[4.27]y, 64.5% female). Multivariate analyses of covariance revealed no between-group differences in these indices. Multivariate regression models revealed that greater NDI in vmPFC-thalamus, greater NDI and ODI in vmPFC-striatum, and greater NDI in dmPFC-thalamus connections were associated with greater INC severity (Q ≤ 0.032). These findings highlight the utility of NODDI in the examination of WM structure in OCD, provide valuable insights into specific WM alterations underlying dimensional INC, and can facilitate the development of customized treatments for OCD individuals with treatment-resistant symptoms.

BackgroundFinancial incentives delivered via apps appear to be effective in encouraging physical activity. However, the literature on different incentive strategies is limited, and the question remains whether financial incentives offer a cost-effective intervention that could be funded at the population level. ObjectiveThis study aimed to explore patterns of tracked physical activity by users of an incentive-based app before and after a change in incentive strategy. A business decision to alter the incentives in a commercially available app offered a natural experiment to explore GPS-tracked data in a retrospective, quasi-experimental study. The purpose of this exploratory analysis was to inform the design of future controlled trials of incentives delivered via an app to optimize their usability and cost-effectiveness. MethodsWeekly minutes of tracked physical activity were explored among a sample of 1666 participants. A Friedman test was used to determine differences in physical activity before and after the change in incentive strategies. Post hoc Wilcoxon tests were used to assess minutes of physical activity in the 2 weeks before and after the change. A secondary analysis explored longitudinal patterns of physical activity by plotting the mean and median minutes of physical activity from 17 weeks before and 13 weeks after the change in incentive strategy. CIs were calculated using bias-corrected bootstraps. Demographics were also explored in this way. ResultsThere were significant differences in the weekly minutes of activity before and after the change in incentive strategy (Friedman χ22=42, P

Summary: We previously described that the KDM5B histone H3 lysine 4 demethylase is an oncogene in estrogen-receptor-positive breast cancer. Here, we report that KDM5A is amplified and overexpressed in basal breast tumors, and KDM5 inhibition (KDM5i) suppresses the growth of KDM5-amplified breast cancer cell lines. Using CRISPR knockout screens in a basal breast cancer cell line with or without KDM5i, we found that deletion of the ZBTB7A transcription factor and core SAGA complex sensitizes cells to KDM5i, whereas deletion of RHO-GTPases leads to resistance. Chromatin immunoprecipitation sequencing (ChIP-seq) and RNA sequencing (RNA-seq) revealed co-localization of ZBTB7A and KDM5A/B at promoters with high histone H3K4me3 and dependence of KDM5A chromatin binding on ZBTB7A. ZBTB7A knockout altered the transcriptional response to KDM5i at NF-κB targets and mitochondrion-related pathways. High expression of ZBTB7A in triple-negative breast cancer is significantly associated with poor response to neoadjuvant chemotherapy. Our work furthers the understanding of KDM5-mediated gene regulation and identifies mediators of sensitivity to KDM5i.

Abstract BackgroundType 1 diabetes (T1D) is a chronic condition in which the body produces too little insulin, a hormone needed to regulate blood glucose. Various factors such as carbohydrates, exercise, and hormones impact insulin needs. Beyond carbohydrates, most factors remain underexplored. Regulating insulin is a complex control task that can go wrong and cause blood glucose levels to fall outside a range that protects people from adverse health effects. Automated insulin delivery (AID) has been shown to maintain blood glucose levels within a narrow range. Beyond clinical outcomes, data from AID systems are little researched; such systems can provide data-driven insights to improve the understanding and treatment of T1D. ObjectiveThe aim is to discover unexpected temporal patterns in insulin needs and to analyze how frequently these occur. Unexpected patterns are situations where increased insulin does not result in lower glucose or where increased carbohydrate intake does not raise glucose levels. Such situations suggest that factors beyond carbohydrates influence insulin needs. MethodsWe analyzed time series data on insulin on board (IOB), carbohydrates on board (COB), and interstitial glucose (IG) from 29 participants using the OpenAPS AID system. Pattern frequency in hours, days (grouped via k-means clustering), weekdays, and months were determined by comparing the 95% CI of the mean differences between temporal units. Associations between pattern frequency and demographic variables were examined. Significant differences in IOB, COB, and IG across temporal dichotomies were assessed using Mann-Whitney U ResultsOn average, 13.5 participants had unexpected patterns and 9.9 had expected patterns. The patterns were more pronounced (ddτPdPdPd ConclusionsOur study shows that unexpected patterns in the insulin needs of people with T1D are as common as expected patterns. Unexpected patterns cannot be explained by carbohydrates alone. Our results highlight the complexity of glucose regulation and emphasize the need for personalized treatment approaches. Further research is needed to identify and quantify the factors that cause these patterns.

Purpose: To evaluate the impact anterior cruciate ligament reconstruction (ACLR) has on strike evasion rates, strike and landing rates, win percentage, and career longevity in Ultimate Fighting Championship (UFC) fighters. Methods: UFC fighters who underwent ACLR from 1993 to 2022 were matched 2:1 with uninjured controls. The percentage of each injured fighter’s career that occurred before ACLR was deemed the “index percentage.” Injured fighter performance pre-/post-ACLR was compared with control metrics pre-/postindex percentage. Results: Of the 82 patients with documented ACL injuries identified, 48 met the inclusion criteria. Of these, 27 returned for more than 2 fights and were paired with 54 controls. UFC fighters demonstrated return-to-sport rates of 81.25% and 56.25% for at least 1 and 2 fights, respectively. On average, it took 411.85 ± 174.73 (range, 165-879) days for fighters to return. All fighters had significantly lower evasion rates against total significant strikes, distance strikes, and head strikes, postindex (P < .05 for each). ACLR fighters had significantly lower submission attempts and evasion rates against clinch strikes, ground strikes, and total strikes, postindex (P < .05 for each). Controls had a significantly lower evasion rate against leg strikes, postindex. Both groups’ win percentages significantly declined (ACLR, P = .001; control, P = .012). No significant difference in total career fights was observed (P = .873). Conclusions: In this study, we found that most UFC fighters who undergo ACLR return to sport for at least 1 fight; however, just over half return for at least 2 fights. There was not a significant difference in career length between fighters who returned to sport following ACLR for at least 2 fights and their controls. Defensive performance, but not offensive performance, declined significantly following ACLR. All fighters demonstrated significant declines in their win percentage as their career progressed, irrespective of ACLR. Level of Evidence: Level III, retrospective comparative study.

Abstract Background There is an evaluation crisis in mobile health (mHealth). The majority of mHealth apps are released with little evidence base. While many agree on the need for comprehensive evaluations to assess the efficacy and effectiveness of mHealth apps, the field is some way from achieving that. This scoping review describes the current state of direct-to-consumer mHealth app evaluations so as to inform how the situation can be improved. Results Findings showed a predominance of wellness management apps, focusing on fitness, diet, mental health, or other lifestyle factors. Evaluations were conducted by companies at varied financing stages, with a mix of start-ups, scale-ups, and public companies. Most studies employed full-scale or pilot randomised controlled trial designs. Conclusions Participant demographics indicate a need for more inclusive recruitment strategies around ethnicity and gender so as to avoid worsening health inequalities. Measurement tools varied widely, highlighting the lack of standardisation in assessing mHealth apps. Promoting evidence-based practices in digital health should be a priority for organisations in this space.

IntroductionAdvances in spine surgery enable safe interventions in elderly patients, but perioperative neurocognitive disorders (pNCD), such as post-operative delirium (POD) and cognitive dysfunction (POCD), remain a serious concern. Pre-operative cognitive impairment is a major risk factor for pNCD. Comprehensive pre-operative cognitive assessments are not feasible in clinical practice, making effective screening methods desirable. This study investigates whether pre-operative cerebrovascular duplex sonography can assess subcortical (vascular) cognitive impairment and the risk for POD.MethodsThis prospective single-center study recruited patients aged ≥60 years scheduled for elective spine surgery at a German university hospital. Patients underwent pre-operative assessments including cognitive abilities (CERAD test battery), structural MRI, and cerebrovascular duplex sonography. POD screening was conducted three times daily for at least 3 days. The primary hypothesis, that the mean pulsatility index (PI) of both internal carotid arteries (ICA) predicts POD risk, was tested using logistic regression. Secondary analyses examined the association between POD risk and ICA flow (time-averaged peak velocities, TAPV) and correlations with cognitive profiles and MRI characteristics.ResultsPOD occurred in 22% of patients (n = 22/99) within three postoperative days. Patients with POD were significantly older (75.9 ± 5.4 vs. 70.0 ± 6.9 years, p

BackgroundA third of adults in Western countries have impaired sleep quality. A possible solution involves distributing sleep aids through smartphone apps, but most empirical studies are limited to small pilot trials in distinct populations (eg, soldiers) or individuals with clinical sleep disorders; therefore, general population data are required. Furthermore, recent research shows that sleep app users desire a personalized approach, offering an individually tailored choice of techniques. One such aid is Peak Sleep, a smartphone app based on scientifically validated principles for improving sleep quality, such as mindfulness meditation and cognitive behavioral therapy. ObjectiveWe aimed to test the impact of the smartphone app Peak Sleep on sleep quality and collect user experience data to allow for future app development. MethodsThis was a 2-arm pilot randomized controlled trial. Participants were general population adults in the United Kingdom (aged ≥18 years) who were interested in improving their sleep quality and were not undergoing clinical treatment for sleep disorder or using sleep medication ≥1 per week. Participants were individually randomized to receive the intervention (3 months of app use) versus a no-treatment control. The intervention involved free access to Peak Sleep, an app that offered a choice of behavioral techniques to support better sleep (mindfulness, cognitive behavioral therapy, and acceptance commitment therapy). The primary outcome was sleep quality assessed using the Insomnia Severity Index at baseline and 1-, 2-, and 3-month follow-ups. Assessments were remote using web-based questionnaires. Objective sleep data collection using the Oura Ring (Ōura Health Oy) was planned; however, because the COVID-19 pandemic lockdowns began just after recruitment started, this plan could not be realized. Participant engagement with the app was assessed using the Digital Behavior Change Intervention Engagement Scale and qualitative telephone interviews with a subsample. ResultsA total of 101 participants were enrolled in the trial, and 21 (21%) were qualitatively interviewed. Sleep quality improved in both groups over time, with Insomnia Severity Index scores of the intervention group improving by a mean of 2.5 and the control group by a mean of 1.6 (between-group mean difference 0.9, 95% CI –2.0 to 3.8), with was no significant effect of group (P=.91). App users’ engagement was mixed, with qualitative interviews supporting the view of a polarized sample who either strongly liked or disliked the app. ConclusionsIn this trial, self-reported sleep improved over time in both intervention and control arms, with no impact by group, suggesting no effect of the sleep app. Qualitative data suggested polarized views on liking or not liking the app, features that people engaged with, and areas for improvement. Future work could involve developing the app features and then testing the app using objective measures of sleep in a larger sample. Trial RegistrationClinicalTrials.gov NCT04487483; https://www.clinicaltrials.gov/study/NCT04487483

BackgroundPrevious systematic reviews of digital eating disorder interventions have demonstrated effectiveness at improving symptoms of eating disorders; however, our understanding of how these interventions work and what contributes to their effectiveness is limited. Understanding the behavior change techniques (BCTs) that are most commonly included within effective interventions may provide valuable information for researchers and developers. Establishing whether these techniques have been informed by theory will identify whether they target those mechanisms of action that have been identified as core to changing eating disorder behaviors. It will also evaluate the importance of a theoretical approach to digital intervention design. ObjectiveThis study aims to define the BCTs within digital self-management interventions or minimally guided self-help interventions for adults with eating disorders that have been evaluated within randomized controlled trials. It also assessed which of the digital interventions were grounded in theory and the range of modes of delivery included. MethodsA literature search identified randomized controlled trials of digital intervention for the treatment of adults with eating disorders with minimal therapist support. Each digital intervention was coded for BCTs using the established BCT Taxonomy v1; for the application of theory using an adapted version of the theory coding scheme (TCS); and for modes of delivery using the Mode of Delivery Ontology. A meta-analysis evaluated the evidence that any individual BCT moderated effect size or that other potential factors such as the application of theory or number of modes of delivery had an effect on eating disorder outcomes. ResultsDigital interventions included an average of 14 (SD 2.6; range 9-18) BCTs. Self-monitoring of behavior was included in all effective interventions, with Problem-solving, Information about antecedents, Feedback on behavior, Self-monitoring of outcomes of behavior, and Action planning identified in >75% (13/17) of effective interventions. Social support and Information about health consequences were more evident in effective interventions at follow-up compared with postintervention measurement. The mean number of modes of delivery was 4 (SD 1.6; range 2-7) out of 12 possible modes, with most interventions (15/17, 88%) being web based. Digital interventions that had a higher score on the TCS had a greater effect size than those with a lower TCS score (subgroup differences: χ21=9.7; P=.002; I²=89.7%) within the meta-analysis. No other subgroup analyses had statistically significant results. ConclusionsThere was a high level of consistency in terms of the most common BCTs within effective interventions; however, there was no evidence that any specific BCT contributed to intervention efficacy. The interventions that were more strongly informed by theory demonstrated greater improvements in eating disorder outcomes compared to waitlist or treatment-as-usual controls. These results can be used to inform the development of future digital eating disorder interventions. Trial RegistrationPROSPERO CRD42023410060; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=410060

In Singapore, especially in our healthcare institution, the use of strong opioids for the treatment of chronic non-cancer pain is relatively rare.1 Contrastingly, weak opioids such as tramadol are frequently prescribed for this condition, partly stemming from the widespread belief that tramadol has a better safety profile with a lower addiction risk than strong opioids.2 However, there appears to be a change in this opinion recently.3 In this study, we aimed to determine the prevalence of tramadol misuse in our healthcare institution, and to identify the associated risk factors.

Abstract The mechanistic link between neural circuit activity and behavior remains unclear. While manipulating cortical activity can bias certain behaviors and elicit artificial percepts, some tasks can still be solved when cortex is silenced or removed. Here, mice were trained to perform a visual detection task during which we selectively targeted groups of visually responsive and co-tuned neurons in L2/3 of primary visual cortex (V1) for two-photon photostimulation. The influence of photostimulation was conditional on two key factors: the behavioral state of the animal and the contrast of the visual stimulus. The detection of low-contrast stimuli was enhanced by photostimulation, while the detection of high-contrast stimuli was suppressed, but crucially, only when mice were highly engaged in the task. When mice were less engaged, our manipulations of cortical activity had no effect on behavior. The behavioral changes were linked to specific changes in neuronal activity. The responses of non-photostimulated neurons in the local network were also conditional on two factors: their functional similarity to the photostimulated neurons and the contrast of the visual stimulus. Functionally similar neurons were increasingly suppressed by photostimulation with increasing visual stimulus contrast, correlating with the change in behavior. Our results show that the influence of cortical activity on perception is not fixed, but dynamically and contextually modulated by behavioral state, ongoing activity and the routing of information through specific circuits.

Abstract The purpose of this study was to assess the risks of hyperthyroidism and hypothyroidism related to gynecological cancers. Population-based retrospective cohort study. We conducted a cohort study using the Taiwan National Health Insurance Research Database to explore hyperthyroidism and hypothyroidism associated with site-specific gynecologic cancers in women from January 1, 2000 to December 31, 2018. The examined gynecologic cancers included endometrial (EC), uterine corpus cancer (UC), and ovarian cancer (OC). The incidence and hazard ratios were quantified using Cox proportional hazards models. The incidence of developing gynecological (Gyn) cancers in the hyperthyroid and hypothyroid women was 0.29 and 0.44 per 1000 person-years, which was 0.86 fold lower and 1.13 fold higher than that in the comparison cohort (p 65 years: aHR = 0.94; for hypothyroid, adjusted hazard ratio (aHR) = 1.26; > 65 years: aHR = 1.38). Compared with the non-hypothyroid women and non-hyperthyroid women beyond 6 years of follow-up, hypothyroid and hyperthyroid women showed decreased risk of Gyn cancers. Medication treatment for hyperthyroid and hypothyroid disease did not showed significant association in subgroup analyses (aHR = 0.99 and 0.80, respectively). Our results show that women with hyperthyroidism have a significantly reduced risk of gynecological cancers, whereas women with hypothyroidism have a slightly increased risk of gynecological cancers suggesting an association between thyroid function level and risk of gynecological cancers.

Abstract The need to develop and provide integrated observation systems to better understand and manage global and regional environmental change is one of the major challenges facing Earth system science today. In 2008, the German Helmholtz Association took up this challenge and launched the German research infrastructure TERrestrial ENvironmental Observatories (TERENO). The aim of TERENO is the establishment and maintenance of a network of observatories as a basis for an interdisciplinary and long‐term research program to investigate the effects of global environmental change on terrestrial ecosystems and their socio‐economic consequences. State‐of‐the‐art methods from the field of environmental monitoring, geophysics, remote sensing, and modeling are used to record and analyze states and fluxes in different environmental disciplines from groundwater through the vadose zone, surface water, and biosphere, up to the lower atmosphere. Over the past 15 years we have collectively gained experience in operating a long‐term observing network, thereby overcoming unexpected operational and institutional challenges, exceeding expectations, and facilitating new research. Today, the TERENO network is a key pillar for environmental modeling and forecasting in Germany, an information hub for practitioners and policy stakeholders in agriculture, forestry, and water management at regional to national levels, a nucleus for international collaboration, academic training and scientific outreach, an important anchor for large‐scale experiments, and a trigger for methodological innovation and technological progress. This article describes TERENO's key services and functions, presents the main lessons learned from this 15‐year effort, and emphasizes the need to continue long‐term integrated environmental monitoring programmes in the future.

Abstract A feature the N $$ \mathcal{N} $$ = 2 supersymmetric Sachdev-Ye-Kitaev (SYK) model shares with extremal black holes is an exponentially large number of ground states that preserve supersymmetry. In fact, the dimension of the ground state subsector is a finite fraction of the total dimension of the SYK Hilbert space. This fraction has a remarkably simple bulk interpretation as the probability that the zero-temperature wormhole — a supersymmetric Einstein-Rosen bridge — has vanishing length. Using chord techniques, we compute the zero-temperature Hartle-Hawking wavefunction; the results reproduce the ground state count obtained from boundary index computations, including non-perturbative corrections. Along the way, we improve the construction [1] of the super-chord Hilbert space and show that the transfer matrix of the empty wormhole enjoys an enhanced N $$ \mathcal{N} $$ = 4 supersymmetry. We also obtain expressions for various two point functions at zero temperature. Finally, we find the expressions for the supercharges acting on more general wormholes with matter and present the superchord algebra.

Abstract Traumatic brain injury (TBI) results in activated microglia. Activated microglia can be measured in vivo by using positron emission topography (PET) ligand peripheral benzodiazepine receptor standardized uptake values (PBR28suv). Cell based therapies have utilized autologous bone marrow mononuclear cells (BMMNCs) to attenuate activated microglia after TBI. This study aims to utilize in vivo PBR28suv to assess the efficacy of BMMNCs therapy after TBI. Seventy-two hours after CCI injury, BMMNCs were harvested from the tibia and injected via tail-vein at 74 h after injury at a concentration of 2 million cells per kilogram of body weight. There were three groups of rats: Sham, CCI-alone and CCI-BMMNCs (AUTO). One hundred twenty days after injury, rodents were imaged with PBR28 and their cognitive behavior assessed utilizing the Morris Water Maze. Subsequent ex vivo analysis included brain volume and immunohistochemistry. BMMNCs therapy attenuated PBR28suv in comparison to CCI alone and it improved spatial learning as measured by the Morris Water Maze. Ex vivo analysis demonstrated preservation of brain volume, a decrease in amoeboid-shaped microglia in the dentate gyrus and an increase in the ratio of ramified to amoeboid microglia in the thalamus. PBR28suv is a viable option to measure efficacy of BMMNCs therapy after TBI.

Subarachnoid hemorrhage (SAH) is a type of hemorrhagic stroke resulting from the rupture of an arterial vessel within the brain. Unlike other stroke types, SAH affects both young adults (mid-40s) and the geriatric population. Patients with SAH often experience significant neurological deficits, leading to a substantial societal burden in terms of lost potential years of life. This review provides a comprehensive overview of SAH, examining its development across different stages (early, intermediate, and late) and highlighting the pathophysiological and pathohistological processes specific to each phase. The clinical management of SAH is also explored, focusing on tailored treatments and interventions to address the unique pathological changes that occur during each stage. Additionally, the paper reviews current treatment modalities and pharmacological interventions based on the evolving guidelines provided by the American Heart Association (AHA). Recent advances in our understanding of SAH will facilitate clinicians’ improved management of SAH to reduce the incidence of delayed cerebral ischemia in patients.

Abstract Introduction Increased moderate to vigorous physical activity (MVPA) can improve clinical and psychosocial outcomes for people living with and beyond cancer (LWBC). This study aimed to assess the feasibility and acceptability of trial procedures in a pilot randomised controlled trial (RCT) of a theory‐driven app‐based intervention with behavioural support focused on promoting brisk walking (a form of MVPA) in people LWBC (APPROACH). Methods Participants diagnosed with breast, prostate or colorectal cancer were recruited from a single UK hospital site. Assessments at baseline and 3 months included online questionnaires, device‐measured brisk walking (activPAL accelerometer) and self‐reported weight and height. Participants were randomised to intervention or control (care as usual). The intervention comprised a non‐cancer‐specific app to promote brisk walking (National Health Service ‘Active 10’) augmented with print information about habit formation, a walking planner and two behavioural support telephone calls. Feasibility and acceptability of trial procedures were explored. Initial estimates for physical activity informed a power calculation for a phase III RCT. A preliminary health economics analysis was conducted. Results Of those medically eligible, 369/577 (64%) were willing to answer further eligibility questions and 90/148 (61%) of those eligible were enrolled. Feasibility outcomes, including retention (97%), assessment completion rates (>86%) and app download rates in the intervention group (96%), suggest that the trial procedures are acceptable and that the intervention is feasible. The phase III RCT will require 472 participants to be randomised. As expected, the preliminary health economic analyses indicate a high level of uncertainty around the cost‐effectiveness of the intervention. Conclusions This pilot study demonstrates that a large trial of the brisk walking intervention with behavioural support is both feasible and acceptable to people LWBC. The results support progression onto a confirmatory phase III trial to determine the efficacy and cost‐effectiveness of the intervention.

BackgroundPortal vein tumor thrombus (PVTT) is a common complication and an obstacle to treatment, with a high recurrence rate and poor prognosis. There is still no global consensus or standard guidelines on the management of hepatocellular carcinoma (HCC) with PVTT. Increasing evidence suggests that more aggressive treatment modalities, including transarterial chemoembolization, radiotherapy, targeted therapy, and various combination therapies, may improve the prognosis and prolong the survival of advanced hepatocellular carcinoma (aHCC) patients with PVTT. We aim to comprehensively review and compare the efficacy and safety of these advanced options for aHCC with PVTT.MethodsA comprehensive literature search was conducted on PubMed and EMBASE for phase II or III randomized controlled trials (RCTs) investigating multimodality treatments for aHCC with PVTT. Kaplan–Meier curves for overall survival (OS) and progression-free survival were constructed to retrieve individual patient-level data to strengthen the comparison of the benefits of all multimodality treatments of interest. Each study was pooled in a fixed-effects network meta-analysis (NMA). We also conducted subgroup analyses using risk ratios extracted from each study, including viral etiology, Barcelona Clinic Liver Cancer (BCLC) staging, alpha-fetoprotein (AFP) levels, macrovascular invasion or portal vein tumor thrombosis, and extrahepatic spread. Multimodality treatments were ranked using SUCRA scores.ResultsWe identified 15 randomized controlled trials with 16 multimodality regimens that met the inclusion criteria. Among them, 5,236 patients with OS results and 5,160 patients with PFS results were included in the analysis. The hepatic arterial infusion chemotherapy of fluorouracil, leucovorin, and oxaliplatin (HAIC-FO) showed OS and PFS benefits over all the other therapies. In terms of OS, HAIC-FO, nivolumab, and TACE+Len were superior to sorafenib, lenvatinib, and donatinib monotherapies, as well as HAIC-FO+Sor. In terms of PFS, TACE+Len showed better benefits than lenvatinib, donatinib, and tremelimumab+durvalumab. A low heterogeneity (I2 < 50%) and consistency were observed. The SUCRA score for OS ranked HAIC-FO+sorafenib as the best treatment option among all multimodality treatments in hepatitis B, MVI, or PVTT with EHS and AFP 400 μg/L subgroups.ConclusionHAIC-FO and HAIC-FO+sorafenib are statistically better options for unresectable hepatocellular carcinoma with PVTT among the multimodality treatments, and their effective and safe implementation may provide the best outcomes for HCC-PVTT patients.

Summary: Legumes establish a symbiotic relationship with nitrogen-fixing rhizobia by developing nodules. Nodules are modified lateral roots that undergo changes in their cellular development in response to bacteria, but the transcriptional reprogramming that occurs in these root cells remains largely uncharacterized. Here, we describe the cell-type-specific transcriptome response of Medicago truncatula roots to rhizobia during early nodule development in the wild-type genotype Jemalong A17, complemented with a hypernodulating mutant (sunn-4) to expand the cell population responding to infection and subsequent biological inferences. The analysis identifies epidermal root hair and stele sub-cell types associated with a symbiotic response to infection and regulation of nodule proliferation. Trajectory inference shows cortex-derived cell lineages differentiating to form the nodule primordia and, posteriorly, its meristem, while modulating the regulation of phytohormone-related genes. Gene regulatory analysis of the cell transcriptomes identifies new regulators of nodulation, including STYLISH 4, for which the function is validated.

Abstract We derive simple bootstrap bounds on correlation functions of the BFSS matrix theory/D0-brane quantum mechanics. The result strengthens and extends Polchinski’s virial theorem bound to finite energies and gives the first non-trivial bound on ⟨Tr X 2⟩. Despite their simplicity, the bounds hint at some features of the dual black hole geometry. Our best lower bounds are already a factor of ∼ 2 from existing Monte Carlo results.

IntroductionComputational models play an increasingly important role in describing variation in neural activation in human neuroimaging experiments, including evaluating individual differences in the context of psychiatric neuroimaging. In particular, reinforcement learning (RL) techniques have been widely adopted to examine neural responses to reward prediction errors and stimulus or action values, and how these might vary as a function of clinical status. However, there is a lack of consensus around the importance of the precision of free parameter estimation for these methods, particularly with regard to the learning rate. In the present study, I introduce a novel technique which may be used within a general linear model (GLM) to model the effect of mis-estimation of the learning rate on reward prediction error (RPE)-related neural responses.MethodsSimulations employed a simple RL algorithm, which was used to generate hypothetical neural activations that would be expected to be observed in functional magnetic resonance imaging (fMRI) studies of RL. Similar RL models were incorporated within a GLM-based analysis method including derivatives, with individual differences in the resulting GLM-derived beta parameters being evaluated with respect to the free parameters of the RL model or being submitted to other validation analyses.ResultsInitial simulations demonstrated that the conventional approach to fitting RL models to RPE responses is more likely to reflect individual differences in a reinforcement efficacy construct (lambda) rather than learning rate (alpha). The proposed method, adding a derivative regressor to the GLM, provides a second regressor which reflects the learning rate. Validation analyses were performed including examining another comparable method which yielded highly similar results, and a demonstration of sensitivity of the method in presence of fMRI-like noise.ConclusionOverall, the findings underscore the importance of the lambda parameter for interpreting individual differences in RPE-coupled neural activity, and validate a novel neural metric of the modulation of such activity by individual differences in the learning rate. The method is expected to find application in understanding aberrant reinforcement learning across different psychiatric patient groups including major depression and substance use disorder.

Summary: Triple-negative breast cancer (TNBC) is a heterogeneous disease with limited treatment options. To characterize TNBC heterogeneity, we defined transcriptional, epigenetic, and metabolic subtypes and subtype-driving super-enhancers and transcription factors by combining functional and molecular profiling with computational analyses. Single-cell RNA sequencing revealed relative homogeneity of the major transcriptional subtypes (luminal, basal, and mesenchymal) within samples. We found that mesenchymal TNBCs share features with mesenchymal neuroblastoma and rhabdoid tumors and that the PRRX1 transcription factor is a key driver of these tumors. PRRX1 is sufficient for inducing mesenchymal features in basal but not in luminal TNBC cells via reprogramming super-enhancer landscapes, but it is not required for mesenchymal state maintenance or for cellular viability. Our comprehensive, large-scale, multiplatform, multiomics study of both experimental and clinical TNBC is an important resource for the scientific and clinical research communities and opens venues for future investigation.

Visible light (VL) has been shown to promote genotoxicity through free radical generation and structural protein degradation. These stressful events promote cellular vulnerability, which manifests clinically as erythema, hyperpigmentation, and photoaging. Having established biologic impacts of VL, development of photoprotection strategies against this part of the solar spectra are warranted. This invited review presents advances in the VL literature and discusses available and potential means of VL photoprotection.

Here, the authors provide a longitudinal genetic surveillance of the antimicrobial resistance potential of the human oral microbiome in the first decade of life, revealing a dynamic environment altered by tooth decay with the increasing potential to mobilize genes as children grow.

Abstract The emergence of the bulk Hilbert space is a mysterious concept in holography. In [1], the SYK model was solved in the double scaling limit by summing chord diagrams. Here, we explicitly construct the bulk Hilbert space of double scaled SYK by slicing open these chord diagrams; this Hilbert space resembles that of a lattice field theory where the length of the lattice is dynamical and determined by the chord number. Under a calculable bulk-to-boundary map, states of fixed chord number map to particular entangled 2-sided states with a corresponding size. This bulk reconstruction is well-defined even when quantum gravity effects are important. Acting on the double scaled Hilbert space is a Type II1 algebra of observables, which includes the Hamiltonian and matter operators. In the appropriate quantum Schwarzian limit, we also identify the JT gravitational algebra including the physical SL(2, ℝ) symmetry generators, and obtain explicit representations of the algebra using chord diagram techniques.

Abstract Background Symbiotic associations between bacteria and leguminous plants lead to the formation of root nodules that fix nitrogen needed for sustainable agricultural systems. Symbiosis triggers extensive genome and transcriptome remodeling in the plant, yet an integrated understanding of the extent of chromatin changes and transcriptional networks that functionally regulate gene expression associated with symbiosis remains poorly understood. In particular, analyses of early temporal events driving this symbiosis have only captured correlative relationships between regulators and targets at mRNA level. Here, we characterize changes in transcriptome and chromatin accessibility in the model legume Medicago truncatula, in response to rhizobial signals that trigger the formation of root nodules. Results We profiled the temporal chromatin accessibility (ATAC-seq) and transcriptome (RNA-seq) dynamics of M. truncatula roots treated with bacterial small molecules called lipo-chitooligosaccharides that trigger host symbiotic pathways of nodule development. Using a novel approach, dynamic regulatory module networks, we integrated ATAC-seq and RNA-seq time courses to predict cis-regulatory elements and transcription factors that most significantly contribute to transcriptomic changes associated with symbiosis. Regulators involved in auxin (IAA4-5, SHY2), ethylene (EIN3, ERF1), and abscisic acid (ABI5) hormone response, as well as histone and DNA methylation (IBM1), emerged among those most predictive of transcriptome dynamics. RNAi-based knockdown of EIN3 and ERF1 reduced nodule number in M. truncatula validating the role of these predicted regulators in symbiosis between legumes and rhizobia. Conclusions Our transcriptomic and chromatin accessibility datasets provide a valuable resource to understand the gene regulatory programs controlling the early stages of the dynamic process of symbiosis. The regulators identified provide potential targets for future experimental validation, and the engineering of nodulation in species is unable to establish that symbiosis naturally.

Abstract Background The purpose of this study was to assess the effectiveness of training residents in an orthodontic program in the placement of miniscrews by using cone beam computed tomography (CBCT) images. A total of 90 miniscrews were placed in 15 pig mandibles over a 3-year period by 15 first-year orthodontic residents. Miniscrews were divided into three groups (Control group: no radiographs; 2D group: placement with 2D radiographs; CBCT group: placement with CBCT). Proximity of the miniscrew to the neighboring root was measured. The miniscrew success rate was examined in the graduate clinic from 2015 to 2021. Results The percentage of root contact for each group was: 36.7% (11/30), 20.0% (6/30), 0% (0/30), for the Control, 2D, and CBCT groups, respectively. The CBCT group was significantly different from the Control and 2D groups (p

Objectives Patient experiences are critical when determining the acceptability of novel interventional pharmaceuticals. Here, we report the development and validation of a product acceptability questionnaire (SPRAY PAL) assessing feasibility, acceptability and tolerability of an intranasal Q-Griffithsin (Q-GRFT) drug product designed for COVID-19 prophylaxis.Design SPRAY PAL validation was undertaken as part of an ongoing phase 1 clinical trial designed to test the safety, pharmacokinetics and tolerability of intranasally administered Q-GRFT for the prevention of SARS-CoV-2 infection.Setting The phase 1 clinical trial took place at a University Outpatient Clinical Trials Unit from November 2021 to September 2023.Participants The initial SPRAY PAL questionnaire was piloted among healthy volunteers ages 25 to 55 in phase 1a of the clinical trial (N=18) and revised for administration in phase 1b for participants ages 24–59 (N=22).Results Spearman correlations tested convergent and discriminant validity. Internal consistency was assessed using Cronbach’s alpha, and test–retest reliability was assessed using intraclass correlation coefficients of responses collected from three repeated questionnaire administrations. The initial version demonstrated excellent internal consistency. The revised version demonstrated very good internal consistency after removal of one item (alpha=0.739). Excellent test–retest reliability (intraclass coefficient=0.927) and adequate convergent (r’s=0.208–0.774) and discriminant (r’s=0.123–0.392) validity were achieved. Subscales adequately distinguished between the constructs of acceptability, feasibility and tolerability.Conclusions The SPRAY PAL product acceptability questionnaire is a valid and reliable patient-reported outcomes measure that can be considered a credible tool for assessing patient-reported information about product acceptability, feasibility of use, tolerability of product and side effects and cost of product for novel intranasal drug formulations. The SPRAY PAL is generalisable, and items may be readily adapted to assess other intranasal formulations.Trial registration numbers NCT05122260 and NCT05437029.

Pansclerotic morphea (PSM) is a rare, devastating disease characterized by extensive soft tissue fibrosis, secondary contractions, and significant morbidity. PSM pathogenesis is unknown, and aggressive immunosuppressive treatments rarely slow disease progression. We aimed to characterize molecular mechanisms driving PSM and to identify therapeutically targetable pathways by performing single-cell and spatial RNA-Seq on 7 healthy controls and on lesional and nonlesional skin biopsies of a patient with PSM 12 months apart. We then validated our findings using immunostaining and in vitro approaches. Fibrotic skin was characterized by prominent type II IFN response, accompanied by infiltrating myeloid cells, B cells, and T cells, which were the main IFN-γ source. We identified unique CXCL9+ fibroblasts enriched in PSM, characterized by increased chemokine expression, including CXCL9, CXCL10, and CCL2. CXCL9+ fibroblasts were related to profibrotic COL8A1+ myofibroblasts, which had enriched TGF-β response. In vitro, TGF-β and IFN-γ synergistically increased CXCL9 and CXCL10 expression, contributing to the perpetuation of IFN-γ responses. Furthermore, cell-to-cell interaction analyses revealed cDC2B DCs as a key communication hub between CXCL9+ fibroblasts and COL8A1+ myofibroblasts. These results define PSM as an inflammation-driven condition centered on type II IFN responses. This work identified key pathogenic circuits between T cells, cDC2Bs, and myofibroblasts, and it suggests that JAK1/2 inhibition is a potential therapeutic option in PSM.

A pair-instability supernova (PISN) prevents black hole (BH) formation from stellar collapse within the approximate mass range M ∈ [65, 130] M _⊙ . However, such BHs may form hierarchically through merging ancestral BHs, whose properties determine those of the “child” one: mass, spin, and recoil velocity. Crucially, the child will leave its host environment if its birth recoil exceeds the corresponding escape velocity, preventing further mergers. We exploit relations between the final recoil and spin of quasi-circular BH mergers to obtain posterior probability distributions for the hypothetical ancestral masses, spins, and birth recoils of the component BHs of GW190521. To this, we present a Bayesian framework applicable to existing estimates for the components of BH merger observations. We consider both the quasi-circular (generically spinning) analysis performed by the LIGO–Virgo–KAGRA collaboration and the eccentric (aligned-spin) one performed by Romero-Shaw et al. We evaluate the probability p _2 _g that the GW190521 components inferred by these analyses formed from the merger of stellar-origin BHs and were retained by their environment. For the primary component, which populates the PISN gap, such scenario is strongly suppressed if GW190521 happened in a globular cluster with p _2 _g ∼ 10 ^−3 unless it was quasi circular and its ancestors had aligned spins, uncharacteristic of hierarchical formation channels, or small spins, which yields p _2 _g ≃ 10 ^−2 . If GW190521 was eccentric, we obtain p _2 _g ≃ 0.1 for any host other than an active galactic nucleus, and zero for a globular cluster. If GW190521 was quasi circular, a nuclear star cluster origin is possible with p _2 _g ∈ (∼0.4, ∼0.8).

Background: Much attention has been paid to advocate proper oral care/hygiene provision by healthcare providers in long-term care institutions (LTCIs). This study aimed to evaluate the effects of an oral health education (OHE) programme (intervention) on knowledge, attitudes, and practice (KAP) of healthcare providers in providing oral care/hygiene to older residents in LTCIs. Methods: A case control study was conducted at two LTCIs, with one assigned as the intervention group and the other as the control group. A KAP survey was administered before and after the intervention, and oral status was assessed by standardized clinical photographs taken before and after oral hygiene provision on three older residents. Results: A total of 40 healthcare providers (20 in intervention and 20 in control groups) participated, with the attitudes and overall KAP significantly improved in the intervention group after the OHE programme. Interestingly, the knowledge of those in the control LTCI was significantly declined at re-evaluation (mean scores were from 17.25 to 14.30), indicating inadequate oral health and care training despite having more experience in taking care of older people. Significant differences in practice were observed between the two groups after the OHE programme (p = 0.006). The three older residents exhibited poor oral health and multiple oral problems. Conclusions: This study revealed that the OHE programme effectively improved attitudes of the healthcare providers and provided a sustaining effect on attitude towards oral health and oral care. However, there were still inadequacies in oral hygiene provision by some healthcare providers, possibly due to unattended oral diseases and hygiene needs, as well as personal and environmental barriers that merit further investigation. Regular evaluation and enforcement of oral care/hygiene provision in LTCIs are necessary to maintain oral health and prevent dental and gum diseases in older residents. Immediate referral for dental treatment is recommended for older people with signs of dental/oral disease(s).

Abstract Background Bananas (Musa spp.) are a globally significant crop and are severely afflicted by diseases for which there are no effective chemical controls. Banana microbiomes may provide novel solutions to these constraints but are difficult to manage due to their high diversity and variability between locations. Hence ‘common core’ taxa, which are a subset of the microbiome that frequent all, or most, individuals of a host species, represent logical targets for the development of microbiome management approaches. Here, we first performed a pot experiment to characterise the effects of two factors that are likely to differ between farms (viz. edaphic conditions and host genotype) on bacterial diversity in bulk soil and seven plant compartments. From this experiment, we created shortlisted core ‘candidates’ that were then refined using a survey of 52 field-grown Musa spp. We confirmed the importance of the core through network analysis and by comparing the sequences of our core taxa with those reported in 22 previous studies. Results Diversity was found to differ between plant compartments and soils, but not genotypes. Therefore, we identified populations that were frequent across most plants irrespective of the soil in which they were grown. This led to the selection of 36 ‘common core’ bacteria, that represented 65–95% of the dominant taxa in field-grown plants and were identified as highly interconnected ‘hubs’ using network analysis – a characteristic shown to be indicative of microbes that influence host fitness in studies of other plants. Lastly, we demonstrated that the core taxa are closely related to banana-associated bacteria observed on five other continents. Conclusions Our study provides a robust list of common core bacterial taxa for Musa spp. Further research may now focus on how changes in the frequencies and activities of these most persistent taxa influence host fitness. Notably, for several of our core taxa, highly similar populations have already been isolated in previous studies and may be amenable to such experimentation. This contribution should help to accelerate the development of effective Musa spp. microbiome management practices.

Abstract The black hole interior is a mysterious region of spacetime where non-perturbative effects are sometimes important. These non-perturbative effects are believed to be highly theory-dependent. We sharpen these statements by considering a setup where the state of the black hole is in a superposition of states corresponding to boundary theories with different couplings, entangled with a reference which keeps track of those couplings. The entanglement wedge of the reference can then be interpreted as the bulk region most sensitive to the values of the couplings. In simple bulk models, e.g., JT gravity + a matter BCFT, the QES formula implies that the reference contains the black hole interior at late times. We also analyze the Renyi-2 entropy tr ρ 2 of the reference, which can be viewed as a diagnostic of chaos via the Loschmidt echo. We find explicitly the replica wormhole that diagnoses the island and restores unitarity. Numerical and analytical evidence of these statements in the SYK model is presented. Similar considerations are expected to apply in higher dimensional AdS/CFT, for marginal and even irrelevant couplings.

Social experiences influence future decision making. The authors here establish a method for quantifying this phenomenon in mice and identify an amygdalo-frontal-striatal circuit controlling how social context shapes decisions.

BackgroundDrink Less is a behavior change app to help higher-risk drinkers in the United Kingdom reduce their alcohol consumption. The app includes a daily notification asking users to “Please complete your drinks and mood diary,” yet we did not understand the causal effect of the notification on engagement nor how to improve this component of Drink Less. We developed a new bank of 30 new messages to increase users’ reflective motivation to engage with Drink Less. This study aimed to determine how standard and new notifications affect engagement. ObjectiveOur objective was to estimate the causal effect of the notification on near-term engagement, to explore whether this effect changed over time, and to create an evidence base to further inform the optimization of the notification policy. MethodsWe conducted a micro-randomized trial (MRT) with 2 additional parallel arms. Inclusion criteria were Drink Less users who consented to participate in the trial, self-reported a baseline Alcohol Use Disorders Identification Test score of ≥8, resided in the United Kingdom, were aged ≥18 years, and reported interest in drinking less alcohol. Our MRT randomized 350 new users to test whether receiving a notification, compared with receiving no notification, increased the probability of opening the app in the subsequent hour, over the first 30 days since downloading Drink Less. Each day at 8 PM, users were randomized with a 30% probability of receiving the standard message, a 30% probability of receiving a new message, or a 40% probability of receiving no message. We additionally explored time to disengagement, with the allocation of 60% of eligible users randomized to the MRT (n=350) and 40% of eligible users randomized in equal number to the 2 parallel arms, either receiving the no notification policy (n=98) or the standard notification policy (n=121). Ancillary analyses explored effect moderation by recent states of habituation and engagement. ResultsReceiving a notification, compared with not receiving a notification, increased the probability of opening the app in the next hour by 3.5-fold (95% CI 2.91-4.25). Both types of messages were similarly effective. The effect of the notification did not change significantly over time. A user being in a state of already engaged lowered the new notification effect by 0.80 (95% CI 0.55-1.16), although not significantly. Across the 3 arms, time to disengagement was not significantly different. ConclusionsWe found a strong near-term effect of engagement on the notification, but no overall difference in time to disengagement between users receiving the standard fixed notification, no notification at all, or the random sequence of notifications within the MRT. The strong near-term effect of the notification presents an opportunity to target notifications to increase “in-the-moment” engagement. Further optimization is required to improve the long-term engagement. International Registered Report Identifier (IRRID)RR2-10.2196/18690

Summary: Successfully navigating dynamic environments requires organisms to learn the consequences of their actions. The prelimbic prefrontal cortex (PL) formulates action-consequence memories and is modulated by addictive drugs like cocaine. We trained mice to obtain food rewards and then unexpectedly withheld reinforcement, triggering new action-consequence memory. New memory was disrupted by cocaine when delivered immediately following non-reinforcement, but not when delayed, suggesting that cocaine disrupted memory consolidation. Cocaine also rapidly inactivated cofilin, a primary regulator of the neuronal actin cytoskeleton. This observation led to the discovery that cocaine also within the time of memory consolidation elevated dendritic spine elimination and blunted spine formation rates on excitatory PL neurons, culminating in thin-type spine attrition. Training drug-naive mice to utilize inflexible response strategies also eliminated thin-type dendritic spines. Thus, cocaine may disrupt action-consequence memory, at least in part, by recapitulating neurobiological sequalae occurring in the formation of inflexible habits.

“Abejas nativas sin aguijón” se encuentran en bosques secos de la Reserva de Biosfera del Noroeste Amotapes Manglares, Tumbes, Perú, y poblaciones rurales cercanas. Estas abejas cumplen un rol importante como polinizadoras de cultivos agrícolas, forestales y como proveedoras de miel y polen", siendo Melipona mimética la especie más importante. Los objetivos del estudio fueron: la identificación molecular usando tres locis genéticos distintos (Citocromo c oxidasa, 28S ribosomal RNA y gen 16S rRNA), la Reacción en Cadena de la Polimerasa (PCR) y análisis bioinformático, identificándose a los géneros: Cephalotrigona sp., Geotrigona sp., Lestrimelitta sp., Melipona sp., Nannotrigona sp., Oxytrigona sp., Plebeia sp., Scaptotrigona, sp., Trigona sp. y Trigonisca sp. Y haciendo uso de Metagenómica y secuencias cortas del gen 16s DNAr, comprobado en NCBI, se encontró a especies bacterianas en: huevos 139, larvas 31, pupas 154 y adultos 39, siendo las más importantes Clostridium spp., Lactobacillus camelliae, Lactobacillus fermentum, Lactobacillus manihotivorans, Lactobacillus paracollinoides, Lactobacillus plantarum, Lactobacillus pontis, Lactobacillus reuteri, Lactobacillus sakei, Lactobacillus suebicus, Lactobacillus vaccinostercus, Lactobacillus vaginalis, Pediococcus acidilactici, y a través de técnicas dependiente e independiente de medios de cultivo a: Bacillus subtilis subsp subtilis en larva, Paenibacillus xylanilyticus en pupa y adulto: Humibacter sp., Acinetobacter sp., Acinetobacter nectaris y Fructobacillus sp. La identificación genómica y comunidad bacteriana es relevante, por tratarse del primer estudio de estas especies en Perú.

Abstract Social mixing contributes to the transmission of SARS-CoV-2. We developed a composite measure for risky social mixing, investigating changes during the pandemic and factors associated with risky mixing. Forty-five waves of online cross-sectional surveys were used (n = 78,917 responses; 14 September 2020 to 13 April 2022). We investigated socio-demographic, contextual and psychological factors associated with engaging in highest risk social mixing in England at seven timepoints. Patterns of social mixing varied over time, broadly in line with changes in restrictions. Engaging in highest risk social mixing was associated with being younger, less worried about COVID-19, perceiving a lower risk of COVID-19, perceiving COVID-19 to be a less severe illness, thinking the risks of COVID-19 were being exaggerated, not agreeing that one’s personal behaviour had an impact on how COVID-19 spreads, and not agreeing that information from the UK Government about COVID-19 can be trusted. Our composite measure for risky social mixing varied in line with restrictions in place at the time of data collection, providing some validation of the measure. While messages targeting psychological factors may reduce higher risk social mixing, achieving a large change in risky social mixing in a short space of time may necessitate a reimposition of restrictions.

The role of MYC in transcriptional reprogramming in prostate cancer remains poorly characterized. Here, MYC overexpression antagonizes the canonical AR transcriptional program leading to prostate tumor initiation and progression by disrupting transcriptional pause release at AR-regulated genes.

Abstract Traumatic brain injury (TBI) results in a cascade of cellular responses, which produce neuroinflammation, partly due to the activation of microglia. Accurate identification of microglial populations is key to understanding therapeutic approaches that modify microglial responses to TBI and improve long-term outcome measures. Notably, previous studies often utilized an outdated convention to describe microglial phenotypes. We conducted a temporal analysis of the response to controlled cortical impact (CCI) in rat microglia between ipsilateral and contralateral hemispheres across seven time points, identified microglia through expression of activation markers including CD45, CD11b/c, and p2y12 receptor and evaluated their activation state using additional markers of CD32, CD86, RT1B, CD200R, and CD163. We identified unique sub-populations of microglial cells that express individual or combination of activation markers across time points. We further portrayed how the size of these sub-populations changes through time, corresponding to stages in TBI response. We described longitudinal changes in microglial population after CCI in two different locations using activation markers, showing clear separation into cellular sub-populations that feature different temporal patterns of markers after injury. These changes may aid in understanding the symptomatic progression following TBI and help define microglial subpopulations beyond the outdated M1/M2 paradigm.

The double-scaled limit of the Sachdev-Ye-Kitaev (SYK) model takes the number of fermions and their interaction number to infinity in a coordinated way. In this limit, two entangled copies of the SYK model have a bulk description of sorts known as the "chord Hilbert space". We analyze a symmetry algebra acting on this Hilbert space, generated by the two Hamiltonians together with a two-sided operator known as the chord number. This algebra is a deformation of the JT gravitational algebra, and it contains a subalgebra that is a deformation of the $\mathfrak{sl}_2$ near-horizon symmetries. The subalgebra has finite-dimensional unitary representations corresponding to matter moving around in a discrete Einstein-Rosen bridge. In a semiclassical limit the discreteness disappears and the subalgebra simplifies to $\mathfrak{sl}_2$, but with a non-standard action on the boundary time coordinate. One can make the action of $\mathfrak{sl}_2$ algebra more standard at the cost of extending the boundary circle to include some "fake" portions. Such fake portions also accommodate certain subtle states that survive the semi-classical limit, despite oscillating on the scale of discreteness. We discuss applications of this algebra, including sub-maximal chaos, the traversable wormhole protocol, and a two-sided OPE.

Abstract Background Behaviour is key to suppressing the COVID-19 pandemic. Maintaining behaviour change can be difficult. We investigated engagement with hand cleaning, reducing the number of outings, and wearing a face covering over the course of the pandemic. Methods We used a series of 64 cross-sectional surveys between 10 February 2020 and 20 January 2022 (n ≈ 2000 per wave). Surveys investigated uptake of hand cleaning behaviours, out of home activity (England only, n ≈ 1700 per wave) and wearing a face covering (England only, restricted to those who reported going out shopping in the last week, n ≈ 1400 per wave). Results Reported hand cleaning has been high throughout the pandemic period (85 to 90% of participants consistently reporting washing their hands thoroughly and regularly with soap and water frequently or very frequently). Out of home activity has mirrored the easing and re-introduction of restrictive measures. Total number of outings were higher in the second national lockdown than in the first and third lockdowns. Wearing a face covering increased steadily between April to August 2020, plateauing until the end of measurement in May 2021, with approximately 80% of those who had been out shopping in the previous week reporting wearing a face covering frequently or very frequently. Conclusions Engagement with protective behaviours increased at the start of the pandemic and has remained high since. The greatest variations in behaviour reflected changes to Government rules. Despite the duration of restrictions, people have continued to adopt personal protective behaviours that were intended to prevent the spread of COVID-19.

HER2+ breast cancer often develop brain metastases (BCBMs) that are difficult to treat. Here, the authors show that p16INK4A loss in BCBMs from HER2+ breast tumors results in resistance to the HER2 inhibitor Tucatinib, and that CDK4/6 inhibition can restore sensitivity to this drug.

Abstract Background Morphea is an autoimmune, sclerosing skin disorder. Despite the recent emphasis on immune dysregulation in morphea, the role of autoantibodies in morphea pathogenesis or utility as biomarkers are poorly defined. Methods Autoantigen microarray was used to profile autoantibodies from the serum of participants from the Morphea in Adults and Children (MAC) cohort. Clinical and demographic features of morphea patients with myelin basic protein (MBP) autoantibodies were compared to those without. MBP immunohistochemistry staining was subsequently performed in morphea skin to assess for perineural inflammation in areas of staining. Immunofluorescence staining on mouse brain tissue was also performed using patient sera and mouse anti-myelin basic protein antibody to confirm the presence of MBP antibodies in patient sera. Results Myelin basic protein autoantibodies were found in greater frequency in morphea (n = 50, 71.4%) compared to systemic sclerosis (n = 2, 6.7%) and healthy controls (n = 7, 20%). Patients with MBP antibodies reported pain at higher frequencies. Morphea skin biopsies, highlighted by immunohistochemistry, demonstrated increased perineural inflammation in areas of MBP expression. Immunofluorescence staining revealed an increased fluorescence signal in myelinated areas of mouse brain tissue (i.e. axons) when incubated with sera from MBP antibody-positive morphea patients compared to sera from MBP antibody-negative morphea patients. Epitope mapping revealed target epitopes for MBP autoantibodies in morphea are distinct from those reported in MS, and included fragments 11–30, 41–60, 51–70, and 91–110. Conclusions A molecular classification of morphea based on distinct autoantibody biosignatures may be used to differentially classify morphea. We have identified anti-MBP as a potential antibody associated with morphea due to its increased expression in morphea compared to healthy controls and systemic sclerosis patients.

Here, we report a metabarcoding (ITS2) study to define the common core fungal microbiome (mycobiome) of healthy Musa spp. (bananas and plantains). To identify a list of 21 core fungal taxa, we first characterised the effects of edaphic conditions and host genotype – two factors that are likely to differ between farms – on the diversity of fungal communities in bulk soil and seven plant compartments. This experiment facilitated shortlisting of core ‘candidates’, which were then elevated to full core status if also found to frequent a wide-range of field-grown Musa spp. and exhibit hub-like characteristics in network analyses. Subsequently, we conducted a meta-analysis of eleven publicly available datasets of Musa spp. associated fungi demonstrating that the core fungi identified in our study have close relatives in other countries. The diversity and composition of mycobiomes differed between plant compartments and soils, but not genotypes. The core mycobiome included Fusarium oxysporum and its relatives, which dominated all plant compartments, as well as members of the Sordariomycetes, Dothideomycetes, and Mortierellomycota. Our study provides a robust list of common core fungal taxa for Musa spp. Further studies may consider how changes in the frequencies and activities of these taxa influence host fitness and whether they can be managed to improve banana production.

Zetomipzomib (KZR-616) is a selective inhibitor of the immunoproteasome currently undergoing clinical investigation in autoimmune disorders. Here, we characterized KZR-616 in vitro and in vivo using multiplexed cytokine analysis, lymphocyte activation and differentiation, and differential gene expression analysis. KZR-616 blocked production of >30 pro-inflammatory cytokines in human peripheral blood mononuclear cells (PBMCs), polarization of T helper (Th) cells, and formation of plasmablasts. In the NZB/W F1 mouse model of lupus nephritis (LN), KZR-616 treatment resulted in complete resolution of proteinuria that was maintained at least 8 weeks after the cessation of dosing and was mediated in part by alterations in T and B cell activation, including reduced numbers of short and long-lived plasma cells. Gene expression analysis of human PBMCs and tissues from diseased mice revealed a consistent and broad response focused on inhibition of T, B, and plasma cell function and the Type I interferon pathway and promotion of hematopoietic cell lineages and tissue remodeling. In healthy volunteers, KZR-616 administration resulted in selective inhibition of the immunoproteasome and blockade of cytokine production following ex vivo stimulation. These data support the ongoing development of KZR-616 in autoimmune disorders such as systemic lupus erythematosus (SLE)/LN.

Decorrido um triênio, completa-se no presente volume, IX de sua série, a lista d' "Os Peixes de água doce do Brasil" de H. W, Fowler, cuja primeira parte, dividida em três entregas sucessivas, constituiu matéria do volume VI dos Arquivos de Zoologia do Estado de São Paulo, São de ontem as nossas palavras de justificativa da edição. Desnecessário pois é repeti-las, bem como os louvores tecidos ao trabalho, que, sejam quais forem as falhas de que porventura se ressinta, constituirá durante muito tempo guia precioso para os estudos ulteirores no campo por ele abrangido. Considerando o limitado curso do idioma para o qual houve necessidade de passar os manuscritos, estamparam-se intactas, no final do volume, à guisa de "abstract", aquelas partes do original que, encerrando matéria de capital importância, se mostram ao mesmo tempo de inteligência mais difícil aos pouco conhecedores de nossa língua. Com isso pensamos contornar os inconvenientes de que se poderia arguir uma obra destinada, por sua natureza, a ser entendida e utilizada pelos que, nos quatro cantos do mundo, se interessam especialmente pela ictiologia brasileira.