Explore the vast range of titles available.

The best-characterized members of the plant-specific SIAMESE-RELATED (SMR) family of cyclin-dependent kinase inhibitors regulate the transition from the mitotic cell cycle to endoreplication, also known as endoreduplication, an altered version of the cell cycle in which DNA is replicated without cell division. Some other family members are implicated in cell cycle responses to biotic and abiotic stresses. However, the functions of most SMRs remain unknown, and the specific cyclindependent kinase complexes inhibited by SMRs are unclear. Here, we demonstrate that a diverse group of SMRs, including an SMR from the bryophyte Physcomitrella patens, can complement an Arabidopsis thaliana siamese (sim) mutant and that both Arabidopsis SIM and P. patens SMR can inhibit CDK activity in vitro. Furthermore, we show that Arabidopsis SIM can bind to and inhibit both CDKA;1 and CDKB1;1. Finally, we show that SMR2 acts to restrict cell proliferation during leaf growth in Arabidopsis and that SIM, SMR1/LGO, and SMR2 play overlapping roles in controlling the transition from cell division to endoreplication during leaf development. These results indicate that differences in SMR function in plant growth and development are primarily due to differences in transcriptional and posttranscriptional regulation, rather than to differences in fundamental biochemical function.

Background Among the most widely predicted climate change-related impacts to biodiversity are geographic range shifts, whereby species shift their spatial distribution to track their climate niches. A series of commonly articulated hypotheses have emerged in the scientific literature suggesting species are expected to shift their distributions to higher latitudes, greater elevations, and deeper depths in response to rising temperatures associated with climate change. Yet, many species are not demonstrating range shifts consistent with these expectations. Here, we evaluate the impact of anthropogenic climate change (specifically, changes in temperature and precipitation) on species’ ranges, and assess whether expected range shifts are supported by the body of empirical evidence. Methods We conducted a Systematic Review, searching online databases and search engines in English. Studies were screened in a two-stage process (title/abstract review, followed by full-text review) to evaluate whether they met a list of eligibility criteria. Data coding, extraction, and study validity assessment was completed by a team of trained reviewers and each entry was validated by at least one secondary reviewer. We used logistic regression models to assess whether the direction of shift supported common range-shift expectations (i.e., shifts to higher latitudes and elevations, and deeper depths). We also estimated the magnitude of shifts for the subset of available range-shift data expressed in distance per time (i.e., km/decade). We accounted for methodological attributes at the study level as potential sources of variation. This allowed us to answer two questions: (1) are most species shifting in the direction we expect (i.e., each observation is assessed as support/fail to support our expectation); and (2) what is the average speed of range shifts? Review findings We found that less than half of all range-shift observations (46.60%) documented shifts towards higher latitudes, higher elevations, and greater marine depths, demonstrating significant variation in the empirical evidence for general range shift expectations. For the subset of studies looking at range shift rates, we found that species demonstrated significant average shifts towards higher latitudes (average = 11.8 km/dec) and higher elevations (average = 9 m/dec), although we failed to find significant evidence for shifts to greater marine depths. We found that methodological factors in individual range-shift studies had a significant impact on the reported direction and magnitude of shifts. Finally, we identified important variation across dimensions of range shifts (e.g., greater support for latitude and elevation shifts than depth), parameters (e.g., leading edge shifts faster than trailing edge for latitude), and taxonomic groups (e.g., faster latitudinal shifts for insects than plants). Conclusions Despite growing evidence that species are shifting their ranges in response to climate change, substantial variation exists in the extent to which definitively empirical observations confirm these expectations. Even though on average, rates of shift show significant movement to higher elevations and latitudes for many taxa, most species are not shifting in expected directions. Variation across dimensions and parameters of range shifts, as well as differences across taxonomic groups and variation driven by methodological factors, should be considered when assessing overall confidence in range-shift hypotheses. In order for managers to effectively plan for species redistribution, we need to better account for and predict which species will shift and by how much. The dataset produced for this analysis can be used for future research to explore additional hypotheses to better understand species range shifts.

Adding docetaxel to androgen deprivation therapy (ADT) improves survival in patients with metastatic, hormone-sensitive prostate cancer, but uncertainty remains about who benefits most. We therefore aimed to obtain up-to-date estimates of the overall effects of docetaxel and to assess whether these effects varied according to prespecified characteristics of the patients or their tumours. The STOPCAP M1 collaboration conducted a systematic review and meta-analysis of individual participant data. We searched MEDLINE (from database inception to March 31, 2022), Embase (from database inception to March 31, 2022), the Cochrane Central Register of Controlled Trials (from database inception to March 31, 2022), proceedings of relevant conferences (from Jan 1, 1990, to Dec 31, 2022), and ClinicalTrials.gov (from database inception to March 28, 2023) to identify eligible randomised trials that assessed docetaxel plus ADT compared with ADT alone in patients with metastatic, hormone-sensitive prostate cancer. Detailed and updated individual participant data were requested directly from study investigators or through relevant repositories. The primary outcome was overall survival. Secondary outcomes were progression-free survival and failure-free survival. Overall pooled effects were estimated using an adjusted, intention-to-treat, two-stage, fixed-effect meta-analysis, with one-stage and random-effects sensitivity analyses. Missing covariate values were imputed. Differences in effect by participant characteristics were estimated using adjusted two-stage, fixed-effect meta-analysis of within-trial interactions on the basis of progression-free survival to maximise power. Identified effect modifiers were also assessed on the basis of overall survival. To explore multiple subgroup interactions and derive subgroup-specific absolute treatment effects we used one-stage flexible parametric modelling and regression standardisation. We assessed the risk of bias using the Cochrane Risk of Bias 2 tool. This study is registered with PROSPERO, CRD42019140591. We obtained individual participant data from 2261 patients (98% of those randomised) from three eligible trials (GETUG-AFU15, CHAARTED, and STAMPEDE trials), with a median follow-up of 72 months (IQR 55–85). Individual participant data were not obtained from two additional small trials. Based on all included trials and patients, there were clear benefits of docetaxel on overall survival (hazard ratio [HR] 0·79, 95% CI 0·70 to 0·88; p<0·0001), progression-free survival (0·70, 0·63 to 0·77; p<0·0001), and failure-free survival (0·64, 0·58 to 0·71; p<0·0001), representing 5-year absolute improvements of around 9–11%. The overall risk of bias was assessed to be low, and there was no strong evidence of differences in effect between trials for all three main outcomes. The relative effect of docetaxel on progression-free survival appeared to be greater with increasing clinical T stage (pinteraction=0·0019), higher volume of metastases (pinteraction=0·020), and, to a lesser extent, synchronous diagnosis of metastatic disease (pinteraction=0·077). Taking into account the other interactions, the effect of docetaxel was independently modified by volume and clinical T stage, but not timing. There was no strong evidence that docetaxel improved absolute effects at 5 years for patients with low-volume, metachronous disease (–1%, 95% CI –15 to 12, for progression-free survival; 0%, –10 to 12, for overall survival). The largest absolute improvement at 5 years was observed for those with high-volume, clinical T stage 4 disease (27%, 95% CI 17 to 37, for progression-free survival; 35%, 24 to 47, for overall survival). The addition of docetaxel to hormone therapy is best suited to patients with poorer prognosis for metastatic, hormone-sensitive prostate cancer based on a high volume of disease and potentially the bulkiness of the primary tumour. There is no evidence of meaningful benefit for patients with metachronous, low-volume disease who should therefore be managed differently. These results will better characterise patients most and, importantly, least likely to gain benefit from docetaxel, potentially changing international practice, guiding clinical decision making, better informing treatment policy, and improving patient outcomes. UK Medical Research Council and Prostate Cancer UK.

Ketamine commonly and rapidly induces dissociative and other altered states of consciousness (ASCs) in humans. However, the neural mechanisms that contribute to these experiences remain unknown. We used functional neuroimaging to engage key regions of the brain’s affective circuits during acute ketamine-induced ASCs within a randomized, multi-modal, placebo-controlled design examining placebo, 0.05 mg/kg ketamine, and 0.5 mg/kg ketamine in nonclinical adult participants (NCT03475277). Licensed clinicians monitored infusions for safety. Linear mixed effects models, analysis of variance, t-tests, and mediation models were used for statistical analyses. Our design enabled us to test our pre-specified primary and secondary endpoints, which were met: effects of ketamine across dose conditions on (1) emotional task-evoked brain activity, and (2) sub-components of dissociation and other ASCs. With this design, we also could disentangle which ketamine-induced affective brain states are dependent upon specific aspects of ASCs. Differently valenced ketamine-induced ASCs mediated opposing effects on right anterior insula activity. Participants experiencing relatively higher depersonalization induced by 0.5 mg/kg of ketamine showed relief from negative brain states (reduced task-evoked right anterior insula activity, 0.39 SD). In contrast, participants experiencing dissociative amnesia showed an exacerbation of insula activity (0.32 SD). These results in nonclinical participants may shed light on the mechanisms by which specific dissociative states predict response to ketamine in depressed individuals. The neural mechanisms underlying ketamine-induced altered states of consciousness are not well understood. Here, the authors show that depersonalization and dissociative amnesia related to ketamine have opposing effects on the activity of the right anterior insula in response to social threat.

Background. Invasive candidiasis is an important cause of morbidity and mortality among patients with health care–associated infection. The echinocandins have potent fungicidal activity against most Candida species, but there are few data comparing the safety and efficacy of echinocandins in the treatment of invasive candidiasis. Methods. This was an international, randomized, double-blind trial comparing micafungin (100 mg daily) and micafungin (150 mg daily) with a standard dosage of caspofungin (70 mg followed by 50 mg daily) in adults with candidemia and other forms of invasive candidiasis. The primary end point was treatment success, defined as clinical and mycological success at the end of blinded intravenous therapy. Results. A total of 595 patients were randomized to one the treatment groups and received at least 1 dose of study drug. In the modified intent-to-treat population, 191 patients were assigned to the micafungin 100 mg group, 199 to the micafungin 150 mg group, and 188 to the caspofungin group. Demographic characteristics and underlying disorders were comparable across the groups. Approximately 85% of patients had candidemia; the remainder had noncandidemic invasive candidiasis. At the end of blinded intravenous therapy, treatment was considered successful for 76.4% of patients in the micafungin 100 mg group, 71.4% in the micafungin 150 mg group, and 72.3% in the caspofungin group. The median time to culture negativity was 2 days in the micafungin 100 mg group and the caspofungin group, compared with 3 days in the micafungin 150 mg groups. There were no significant differences in mortality, relapsing and emergent infections, or adverse events between the study arms. Conclusions. Dosages of micafungin 100 mg daily and 150 mg daily were noninferior to a standard dosage of caspofungin for the treatment of candidemia and other forms of invasive candidiasis.

Teleost fishes account for 96% of all fish species and exhibit a spectacular variety of body forms. Teleost lineages range from deep bodied to elongate (e.g., eels, needlefish), laterally compressed (e.g., ribbonfish) to globular (e.g., pufferfish), and include uniquely shaped lineages such as seahorses, flatfishes, and ocean sunfishes. Adaptive body shape convergence within fishes has long been hypothesized but the nature of the relationships between fish form and ecological and environmental variables remain largely unknown at the macroevolutionary scale. To facilitate the investigation of the interacting factors influencing teleost body shape evolution we measured eight functionally relevant linear traits on adult-sized specimens along with specimen mass. Linear measurements of standard length, maximum body depth, maximum fish width, lower jaw length, mouth width, head depth, minimum caudal peduncle depth, and minimum caudal peduncle width were taken in millimeters with calipers, or tape measures for oversized specimens. We measured these traits on a total of 16,523 specimens (1—3 specimens per species) at the Smithsonian National Museum of Natural History and took approximately 7000 person hours of data collection to complete. The data went through a three-step error-checking process to clean and validate the data and then species averages were calculated. We present the complete specimen data set, which encompasses approximately one-fifth of extant teleost species diversity, spanning ~90% of teleost families and ~96% of orders. The species and family names are compatible with the taxonomy used by FishBase and the order information with the phylogenetically informed taxonomy of Betancur-R and colleagues published in 2014. This dataset is licensed under Creative Commons CC0 1.0 Universal (CC0 1.0) but please cite this paper when using the data or a subset of it.

Super enhancers regulate oncogenes and other molecular targets in ependymomas, and identification of these genes provides potential therapeutic targets. Targeting brain tumours Ependymomas are chemotherapy-resistant brain tumours, which lack effective molecular targets for the development of therapeutics. Here, Jeremy Rich and colleagues map transcriptionally active regulatory regions in primary ependymomas to identify super-enhancer-associated genes and define distinct enhancer landscapes between molecular subgroups of ependymoma. They find putative oncogenes and other molecular targets that are regulated by these enhancers and confirm the importance of these genes for cancer cell growth by using RNAi knockdown or small-molecule inhibitor approaches. The study exemplifies how information about enhancer landscapes can be applied to dissect molecular differences between tumours and help guide future development of precision therapies. Genomic sequencing has driven precision-based oncology therapy; however, the genetic drivers of many malignancies remain unknown or non-targetable, so alternative approaches to the identification of therapeutic leads are necessary. Ependymomas are chemotherapy-resistant brain tumours, which, despite genomic sequencing, lack effective molecular targets. Intracranial ependymomas are segregated on the basis of anatomical location (supratentorial region or posterior fossa) and further divided into distinct molecular subgroups that reflect differences in the age of onset, gender predominance and response to therapy 1 , 2 , 3 . The most common and aggressive subgroup, posterior fossa ependymoma group A (PF-EPN-A), occurs in young children and appears to lack recurrent somatic mutations 2 . Conversely, posterior fossa ependymoma group B (PF-EPN-B) tumours display frequent large-scale copy number gains and losses but have favourable clinical outcomes 1 , 3 . More than 70% of supratentorial ependymomas are defined by highly recurrent gene fusions in the NF-κB subunit gene RELA (ST-EPN-RELA), and a smaller number involve fusion of the gene encoding the transcriptional activator YAP1 (ST-EPN-YAP1) 1 , 3 , 4 . Subependymomas, a distinct histologic variant, can also be found within the supratetorial and posterior fossa compartments, and account for the majority of tumours in the molecular subgroups ST-EPN-SE and PF-EPN-SE. Here we describe mapping of active chromatin landscapes in 42 primary ependymomas in two non-overlapping primary ependymoma cohorts, with the goal of identifying essential super-enhancer-associated genes on which tumour cells depend. Enhancer regions revealed putative oncogenes, molecular targets and pathways; inhibition of these targets with small molecule inhibitors or short hairpin RNA diminished the proliferation of patient-derived neurospheres and increased survival in mouse models of ependymomas. Through profiling of transcriptional enhancers, our study provides a framework for target and drug discovery in other cancers that lack known genetic drivers and are therefore difficult to treat.

The linear ubiquitination complex (LUBAC) is poorly understood in humans. Casanova and colleagues identify natural mutations in a component of human LUBAC and use this to dissect its function in vivo and in vitro . We report the clinical description and molecular dissection of a new fatal human inherited disorder characterized by chronic autoinflammation, invasive bacterial infections and muscular amylopectinosis. Patients from two kindreds carried biallelic loss-of-expression and loss-of-function mutations in HOIL1 ( RBCK1 ), a component of the linear ubiquitination chain assembly complex (LUBAC). These mutations resulted in impairment of LUBAC stability. NF-κB activation in response to interleukin 1β (IL-1β) was compromised in the patients' fibroblasts. By contrast, the patients' mononuclear leukocytes, particularly monocytes, were hyper-responsive to IL-1β. The consequences of human HOIL-1 and LUBAC deficiencies for IL-1β responses thus differed between cell types, consistent with the unique association of autoinflammation and immunodeficiency in these patients. These data suggest that LUBAC regulates NF-κB–dependent IL-1β responses differently in different cell types.

Background. Patients with candidemia frequently have a central venous catheter (CVC) in place, and its early removal is considered the standard of care. Methods. We performed a subgroup analysis of 2 phase III, multicenter, double-blind, randomized, controlled trials of candidemia to examine the effects of early CVC removal (within 24 or 48 h after treatment initiation) on the outcomes of 842 patients with candidemia. Inclusion criteria were candidemia, age >16 years, CVC at diagnosis, and receipt of ≥1 dose of the study drug. Six outcomes were evaluated: treatment success, rates of persistent and recurrent candidemia, time to mycological eradication, and survival at 28 and 42 days. Univariate and multivariate analyses were performed, controlling for potential confounders. Results. In univariate analysis, early CVC removal did not improve time to mycological eradication or rates of persistent or recurrent candidemia but was associated with better treatment success and survival. These benefits were lost in multivariate analysis, which failed to show any beneficial effect of early CVC removal on all 6 outcomes and identified Acute Physiology and Chronic Health Evaluation II score, older age, and persistent neutropenia as the most significant variables. Our findings were consistent across all outcomes and time points (removal within 24 or 48 h and survival at 28 and 42 days). The median time to eradication of candidemia was similar between the 2 study groups. Conclusions. In this cohort of 842 adults with candidemia followed up prospectively, early CVC removal was not associated with any clinical benefit. These findings suggest an evidence-based re-evaluation of current treatment recommendations.

Chronic Levodopa therapy, the gold-standard treatment for Parkinson’s Disease (PD), leads to the emergence of involuntary movements, called levodopa-induced dyskinesia (LID). Cerebellar stimulation has been shown to decrease LID severity in PD patients. Here, in order to determine how cerebellar stimulation induces LID alleviation, we performed daily short trains of optogenetic stimulations of Purkinje cells (PC) in freely moving LID mice. We demonstrated that these stimulations are sufficient to suppress LID or even prevent their development. This symptomatic relief is accompanied by the normalization of aberrant neuronal discharge in the cerebellar nuclei, the motor cortex and the parafascicular thalamus. Inhibition of the cerebello-parafascicular pathway counteracted the beneficial effects of cerebellar stimulation. Moreover, cerebellar stimulation reversed plasticity in D1 striatal neurons and normalized the overexpression of FosB, a transcription factor causally linked to LID. These findings demonstrate LID alleviation and prevention by daily PC stimulations, which restore the function of a wide motor network, and may be valuable for LID treatment. Here, the authors studied how cerebellar stimulation alleviates levodopa-induced dyskinesia (LID). They demonstrated that Purkinje cell opto-stimulation is sufficient to prevent LID development and can normalize brain activity in a wide motor network in mice.