Insufficient pollinator visitation often limits yield in crop systems worldwide.

Declining pollinator populations could threaten global food production, especially if current crop yields are limited by insufficient pollinator visitation to flowers, in a phenomenon referred to as 'pollinator limitation'. Here, we assess the global prevalence of pollinator limitation, explore the risk factors, such as crop type or geographic region, that predict where pollinator limitation is more likely and ask by how much increases in pollinator visitation could improve crop yields. We address these questions using 198,360 plant-pollinator interactions and 2,083 yield measurements from 32 crop species grown in 120 study systems. We find that 28-61% of global crop systems are pollinator limited and that this limitation most frequently occurs in blueberry, coffee and apple crops. For a few datasets, we note that the probability of pollinator limitation decreases with greater forest land cover surrounding a crop field at 1 km, although average effect sizes are small. Finally, we estimate that for those crops we identify as pollinator limited, increasing pollinator visitation at all farms to existing levels observed in the 90th percentile of each study system would close 63% of yield gaps between high- and low-yielding fields. Our findings show variations in sensitivity to pollinator limitation across diverse crop systems and indicate that realistic increases in pollinator visitation could mitigate crop yield shortfalls attributable to pollinator limitation.

Evidence from comprehensive independent validation studies for smooth pursuit dysfunction as a sensorimotor biomarker for psychosis.

Smooth pursuit eye movements are considered a well-established and quantifiable biomarker of sensorimotor function in psychosis research. Identifying psychotic syndromes on an individual level based on neurobiological markers is limited by heterogeneity and requires comprehensive external validation to avoid overestimation of prediction models. Here, we studied quantifiable sensorimotor measures derived from smooth pursuit eye movements in a large sample of psychosis probands (N = 674) and healthy controls (N = 305) using multivariate pattern analysis. Balanced accuracies of 64% for the prediction of psychosis status are in line with recent results from other large heterogenous psychiatric samples. They are confirmed by external validation in independent large samples including probands with (1) psychosis (N = 727) versus healthy controls (N = 292), (2) psychotic (N = 49) and non-psychotic bipolar disorder (N = 36), and (3) non-psychotic affective disorders (N = 119) and psychosis (N = 51) yielding accuracies of 65%, 66% and 58%, respectively, albeit slightly different psychosis syndromes. Our findings make a significant contribution to the identification of biologically defined profiles of heterogeneous psychosis syndromes on an individual level underlining the impact of sensorimotor dysfunction in psychosis.

Benefits of subthalamic nucleus deep brain stimulation on visually-guided saccades depend on stimulation side and classic paradigm in Parkinson's disease.

OBJECTIVE: We aimed to gain further insight into previously reported beneficial effects of subthalamic nucleus deep brain stimulation (STN-DBS) on visually-guided saccades by examining the effects of unilateral compared to bilateral stimulation, paradigm, and target eccentricity on saccades in individuals with Parkinson's disease (PD). METHODS: Eleven participants with PD and STN-DBS completed the visually-guided saccade paradigms with OFF, RIGHT, LEFT, and BOTH stimulation. Rightward saccade performance was evaluated for three paradigms and two target eccentricities. RESULTS: First, we found that BOTH and LEFT increased gain, peak velocity, and duration compared to OFF stimulation. Second, we found that BOTH and LEFT stimulation decreased latency during the gap and step paradigms but had no effect on latency during the overlap paradigm. Third, we found that RIGHT was not different compared to OFF at benefiting rightward saccade performance. CONCLUSIONS: Left unilateral and bilateral stimulation both improve the motor outcomes of rightward visually-guided saccades. Additionally, both improve latency, a cognitive-motor outcome, but only in paradigms when attention does not require disengagement from a present stimulus. SIGNIFICANCE: STN-DBS primarily benefits motor and cognitive-motor aspects of visually-guided saccades related to reflexive attentional shifting, with the latter only evident when the fixation-related attentional system is not engaged.

Neurocognitive change over the course of a multiday external lumbar drain trial in patients with suspected normal pressure hydrocephalus.

Objective: To characterize neurocognitive response to cerebrospinal fluid (CSF) diversion during a multiday external lumbar drainage (ELD) trial in patients with suspected normal pressure hydrocephalus (NPH). Methods: Inpatients (N = 70) undergoing an ELD trial as part of NPH evaluation participated. Cognition and balance were assessed using standardized measures before and after a three-day ELD trial. Cognitive change pre- to post-ELD trial was assessed in relation to change in balance, baseline neuroimaging findings, NPH symptoms, demographics, and other disease-relevant clinical parameters. Results: Multiday ELD resulted in significant cognitive improvement (particularly on measures of memory and language). This improvement was independent of demographics, test-retest interval, number of medical and psychiatric comorbidities, NPH symptom duration, estimated premorbid intelligence, baseline level of cognitive impairment, cerebrovascular disease burden, degree of ventriculomegaly, or other NPH-related morphological brain alterations. Balance scores evidenced a greater magnitude of improvement than cognitive scores and were weakly, but positively correlated with cognitive change scores. Conclusions: Findings suggest that cognitive improvement associated with a multiday ELD trial can be sufficiently captured with bedside neurocognitive testing. These findings support the utility of neuropsychological consultation, along with balance assessment, in informing clinical decision-making regarding responsiveness to temporary CSF diversion for patients undergoing elective NPH evaluation. Implications for the understanding of neuroanatomical and cognitive underpinnings of NPH are discussed.

Explainable deep learning-based survival prediction for non-small cell lung cancer patients undergoing radical radiotherapy.

BACKGROUND AND PURPOSE: Survival is frequently assessed using Cox proportional hazards (CPH) regression; however, CPH may be too simplistic as it assumes a linear relationship between covariables and the outcome. Alternative, non-linear machine learning (ML)-based approaches, such as random survival forests (RSFs) and, more recently, deep learning (DL) have been proposed; however, these techniques are largely black-box in nature, limiting explainability. We compared CPH, RSF and DL to predict overall survival (OS) of non-small cell lung cancer (NSCLC) patients receiving radiotherapy using pre-treatment covariables. We employed explainable techniques to provide insights into the contribution of each covariable on OS prediction. MATERIALS AND METHODS: The dataset contained 471 stage I-IV NSCLC patients treated with radiotherapy. We built CPH, RSF and DL OS prediction models using several baseline covariable combinations. 10-fold Monte-Carlo cross-validation was employed with a split of 70%:10%:20% for training, validation and testing, respectively. We primarily evaluated performance using the concordance index (C-index) and integrated Brier score (IBS). Local interpretable model-agnostic explanation (LIME) values, adapted for use in survival analysis, were computed for each model. RESULTS: The DL method exhibited a significantly improved C-index of 0.670 compared to the CPH and a significantly improved IBS of 0.121 compared to the CPH and RSF approaches. LIME values suggested that, for the DL method, the three most important covariables in OS prediction were stage, administration of chemotherapy and oesophageal mean radiation dose. CONCLUSION: We show that, using pre-treatment covariables, a DL approach demonstrates superior performance over CPH and RSF for OS prediction and use explainable techniques to provide transparency and interpretability.

Breaking Down Silos Between Medical Education and Health Systems: Creating an Integrated Multilevel Data Model to Advance the Systems-Based Practice Competency.

ABSTRACT: The complexity of improving health in the United States and the rising call for outcomes-based physician training present unique challenges and opportunities for both graduate medical education (GME) and health systems. GME programs have been particularly challenged to implement systems-based practice (SBP) as a core physician competency and educational outcome. Disparate definitions and educational approaches to SBP, as well as limited understanding of the complex interactions between GME trainees, programs, and their health system settings, contribute to current suboptimal educational outcomes elated to SBP. To advance SBP competence at individual, program, and institutional levels, the authors present the rationale for an integrated multilevel systems approach to assess and evaluate SBP, propose a conceptual multilevel data model that integrates health system and educational SBP performance, and explore the opportunities and challenges of using multilevel data to promote an empirically driven approach to residency education. The development, study, and adoption of multilevel analytic approaches to GME are imperative to the successful operationalization of SBP and thereby imperative to GME's social accountability in meeting societal needs for improved health. The authors call for the continued collaboration of national leaders toward producing integrated and multilevel datasets that link health systems and their GME-sponsoring institutions to evolve SBP.

Protection of p-Coumaric acid against chronic stress-induced neurobehavioral deficits in mice via activating the PKA-CREB-BDNF pathway.

There is a body of evidence to suggest that chronic stress modulates neurochemical homeostasis, alters neuronal structure, inhibits neurogenesis and contributes to development of mental disorders. Chronic stress-associated mental disorders present common symptoms of cognitive impairment and depression with complex disease mechanisms. P-coumaric acid (p-CA), a natural phenolic compound, is widely distributed in vegetables, cereals and fruits. p-CA exhibits a wide range of health-related effects, including anti-oxidative-stress, anti-mutagenesis, anti-inflammation and anti-cancer activities. The current study aims to evaluate the therapeutic potential of p-CA against stress-associated mental disorders. We assessed the effect of p-CA on cognitive deficits and depression-like behavior in mice exposed to chronic restraint stress (CRS); we used network pharmacology, biochemical and molecular biological approaches to elucidate the underlying molecular mechanisms. CRS exposure caused memory impairments and depression-like behavior in mice; p-CA administration attenuated these CRS-induced memory deficits and depression-like behavior. Network pharmacology analysis demonstrated that p-CA was possibly involved in multiple targets and a variety of signaling pathways. Among them, the protein kinase A (PKA) - cAMP-response element binding protein (CREB) - brain derived neurotrophic factor (BDNF) signaling pathway was predominant and further characterized. The levels of PKA, phosphorylated CREB (pCREB) and BDNF were significantly lowered in the hippocampus of CRS mice, suggesting disruption of the PKA-CREB-BDNF signaling pathway; p-CA treatment restored the signaling pathway. Furthermore, CRS upregulated expression of proinflammatory cytokines in hippocampus, while p-CA reversed the CRS-induced effects. Our findings suggest that p-CA will offer therapeutic benefit to patients with stress-associated mental disorders.

Urocanic acid facilitates acquisition of object recognition memory in mice.

Trans-urocanic acid (UCA), an isomer of cis-UCA that is mainly located in the skin, has recently been reported to have a role in short-term working memory and in the consolidation, reconsolidation and retrieval of long-term memory. However, its effect on memory acquisition remains unclear. In the present study, the effect of UCA on short-term and long-term memory acquisition in mice was investigated using novel object recognition (NOR) and object location recognition (OLR) protocols that each involved three stages: habituation, sampling and testing. UCA was intraperitoneally injected 0.5 h pre-sampling, and the discrimination index during subsequent testing was determined in NOR and OLR tasks. The results showed that 10 mg/kg UCA significantly facilitated short-term and long-term memory acquisition in both types of tasks. Furthermore, 30 mg/kg UCA significantly facilitated long-term memory acquisition in the NOR task and tended to facilitate long-term memory acquisition in the OLR tasks but did not facilitate short-term memory acquisition in either task. Additionally, the enhancing role of UCA on memory acquisition was not dependent on changes of nonspecific responses, e.g. exploratory behavior and locomotor activity. The current study suggests that UCA facilitates short-term and long-term recognition memory acquisition, which further extends the functional role of UCA in the brain function.

Common Pediatric Otolaryngology Procedures: Ergonomic Considerations.

Background Otolaryngologists in high-volume children's hospitals developed their operating room workflow practices based on the factors of safety, efficiency, and surgeon preference. Recent data show important benefits and potential reduced risks of proper ergonomic positioning for surgeons to prevent injury. These data suggest that the current operating room workflow practices, in addition to prior training, should be monitored and hopefully improved for surgeons' health. Surprisingly, recent studies have suggested the benefits of standing versus sitting on cognitive function. Objective This study reports the workflow norms for seven operating procedures in pediatric otolaryngology. We seek to identify 1) surgeon preferences, 2) when practices become norms, and 3) whether procedure positions are associated with surgeon discomfort or injury. Methods The Otolaryngology Section of the American Academy of Pediatrics was queried employing a 23-question survey. We included demographic information, reasons for preferences, and surgeon-reported pain. We focused on three workflow issues: 1) length of procedures, 2) site selection (operating room bed vs. transport stretcher), and 3) position of the surgeon (sitting vs. standing). Results Sixty-nine American Academy of Pediatrics members completed the survey. The length of the procedure had minimal effect, with 90% sitting for short procedures such as bilateral myringotomy with tubes, myringoplasty, tonsillectomy, and adenoidectomy. All sit for direct laryngoscopy and bronchoscopy. Most stand for the removal of nasal foreign bodies, drainage of neck abscess procedures, and thyroglossal duct cyst excision. Residency training (75%) and personal comfort (81%) were the more frequently cited reasons for preference. Fewer than one in five (16%) reported preexisting neck or back pain, but this doubled (35%) throughout their otolaryngology practice. Conditional distributions of pain showed reports of pain were greater for individuals in practice for over 20 years. Conclusions Pediatric otolaryngologists develop their operating room preferences early during residency training. High rates of neck and back pain (35%) may develop during a surgeon's career. We suggest improved understanding of ergonomics in concert with operating room workflow should be considered during otolaryngology residency training since recent data suggest potential benefits of standing on cognitive function.

Peripheral inflammation is associated with impairments of inhibitory behavioral control and visual sensorimotor function in psychotic disorders.

Elevated markers of peripheral inflammation are common in psychosis spectrum disorders and have been associated with brain anatomy, pathology, and physiology as well as clinical outcomes. Preliminary evidence suggests a link between inflammatory cytokines and C-reactive protein (CRP) with generalized cognitive impairments in a subgroup of individuals with psychosis. Whether these patients with elevated peripheral inflammation demonstrate deficits in specific cognitive domains remains unclear. To examine this, seventeen neuropsychological and sensorimotor tasks and thirteen peripheral inflammatory and microvascular markers were quantified in a subset of B-SNIP consortium participants (129 psychosis, 55 healthy controls). Principal component analysis was conducted across the inflammatory markers, resulting in five inflammation factors. Three discrete latent cognitive domains (Visual Sensorimotor, General Cognitive Ability, and Inhibitory Behavioral Control) were characterized based on the neurobehavioral battery and examined in association with inflammation factors. Hierarchical clustering analysis identified cognition-sensitive high/low inflammation subgroups. Among persons with psychotic disorders but not healthy controls, higher inflammation scores had significant associations with impairments of Inhibitory Control (R2 = 0.100, p-value = 2.69e-4, q-value = 0.004) and suggestive associations with Visual Sensorimotor function (R2 = 0.039, p-value = 0.024, q-value = 0.180), but not with General Cognitive Ability (R2 = 0.015, p-value = 0.162). Greater deficits in Inhibitory Control were observed in the high inflammation patient subgroup, which represented 30.2 % of persons with psychotic disorders, as compared to the low inflammation psychosis subgroup. These findings indicate that inflammation dysregulation may differentially impact specific neurobehavioral domains across psychotic disorders, particularly performance on tasks requiring ongoing behavioral monitoring and control.

Tracking auditory mismatch negativity responses during full conscious state and coma.

The mismatch negativity (MMN) is considered the electrophysiological change-detection response of the brain, and therefore a valuable clinical tool for monitoring functional changes associated with return to consciousness after severe brain injury. Using an auditory multi-deviant oddball paradigm, we tracked auditory MMN responses in seventeen healthy controls over a 12-h period, and in three comatose patients assessed over 24 h at two time points. We investigated whether the MMN responses show fluctuations in detectability over time in full conscious awareness, or whether such fluctuations are rather a feature of coma. Three methods of analysis were utilized to determine whether the MMN and subsequent event-related potential (ERP) components could be identified: traditional visual analysis, permutation t-test, and Bayesian analysis. The results showed that the MMN responses elicited to the duration deviant-stimuli are elicited and reliably detected over the course of several hours in healthy controls, at both group and single-subject levels. Preliminary findings in three comatose patients provide further evidence that the MMN is often present in coma, varying within a single patient from easily detectable to undetectable at different times. This highlights the fact that regular and repeated assessments are extremely important when using MMN as a neurophysiological predictor of coma emergence.

Non-Specific Signal Peptidase Processing of Extracellular Proteins in Staphylococcus aureus N315.

Staphylococcus aureus is one of the major community-acquired human pathogens, with growing multidrug-resistance, leading to a major threat of more prevalent infections to humans. A variety of virulence factors and toxic proteins are secreted during infection via the general secretory (Sec) pathway, which requires an N-terminal signal peptide to be cleaved from the N-terminus of the protein. This N-terminal signal peptide is recognized and processed by a type I signal peptidase (SPase). SPase-mediated signal peptide processing is the crucial step in the pathogenicity of S. aureus. In the present study, the SPase-mediated N-terminal protein processing and their cleavage specificity were evaluated using a combination of N-terminal amidination bottom-up and top-down proteomics-based mass spectrometry approaches. Secretory proteins were found to be cleaved by SPase, specifically and non-specifically, on both sides of the normal SPase cleavage site. The non-specific cleavages occur at the relatively smaller residues that are present next to the -1, +1, and +2 locations from the original SPase cleavage site to a lesser extent. Additional random cleavages at the middle and near the C-terminus of some protein sequences were also observed. This additional processing could be a part of some stress conditions and unknown signal peptidase mechanisms.

Gray matter volume drives the brain age gap in schizophrenia: a SHAP study.

Neuroimaging-based brain age is a biomarker that is generated by machine learning (ML) predictions. The brain age gap (BAG) is typically defined as the difference between the predicted brain age and chronological age. Studies have consistently reported a positive BAG in individuals with schizophrenia (SCZ). However, there is little understanding of which specific factors drive the ML-based brain age predictions, leading to limited biological interpretations of the BAG. We gathered data from three publicly available databases - COBRE, MCIC, and UCLA - and an additional dataset (TOPSY) of early-stage schizophrenia (82.5% untreated first-episode sample) and calculated brain age with pre-trained gradient-boosted trees. Then, we applied SHapley Additive Explanations (SHAP) to identify which brain features influence brain age predictions. We investigated the interaction between the SHAP score for each feature and group as a function of the BAG. These analyses identified total gray matter volume (group × SHAP interaction term ß = 1.71 [0.53; 3.23]; pcorr < 0.03) as the feature that influences the BAG observed in SCZ among the brain features that are most predictive of brain age. Other brain features also presented differences in SHAP values between SCZ and HC, but they were not significantly associated with the BAG. We compared the findings with a non-psychotic depression dataset (CAN-BIND), where the interaction was not significant. This study has important implications for the understanding of brain age prediction models and the BAG in SCZ and, potentially, in other psychiatric disorders.

Rare and declining bee species are key to consistent pollination of wildflowers and crops across large spatial scales.

Biodiversity promotes ecosystem function (EF) in experiments, but it remains uncertain how biodiversity loss affects function in larger-scale natural ecosystems. In these natural ecosystems, rare and declining species are more likely to be lost, and function needs to be maintained across space and time. Here, we explore the importance of rare and declining bee species to the pollination of three wildflowers and three crops using large-scale (72 sites across 5000 km2 ), multi-year datasets. Half of the sampled bee species (82/164) were rare or declining, but these species provided only ~15% of overall pollination. To determine the number of species important to EF, we used two methods of "scaling up," both of which have previously been used for biodiversity-function analysis. First, we summed bee species' contributions to pollination across space and time and then found the minimum set of species needed to provide a threshold level of function across all sites; according to this method, effectively no rare and declining bee species were important to pollination. Second, we account for the "insurance value" of biodiversity by finding the minimum set of bee species needed to simultaneously provide a threshold level of function at each site in each year. The second method leads to the conclusion that 25 rare and eight declining bee species (36% and 53% of all rare and declining bee species, respectively) are included in the minimum set. Our findings provide some of the strongest evidence yet that rare and declining species are key to meeting threshold levels of EF, thereby providing a more direct link between real-world biodiversity loss and EF.

Profile of Embedded Validity Indicators in Criminal Defendants with Verified Valid Neuropsychological Test Performance.

OBJECTIVE: Few studies have examined the use of embedded validity indicators (EVIs) in criminal-forensic practice settings, where judgements regarding performance validity can carry severe consequences for the individual and society. This study sought to examine how various EVIs perform in criminal defendant populations, and determine relationships between EVI scores and intrapersonal variables thought to influence performance validity. METHOD: Performance on 16 empirically established EVI cutoffs were examined in a sample of 164 criminal defendants with valid performance who were referred for forensic neuropsychological evaluation. Subsequent analyses examined the relationship between EVI scores and intrapersonal variables in 83 of these defendants. RESULTS: Half of the EVIs (within the Wechsler Adult Intelligence Scale Digit Span Total, Conners' Continuous Performance Test Commissions, Wechsler Memory Scale Logical Memory I and II, Controlled Oral Word Association Test, Trail Making Test Part B, and Stroop Word and Color) performed as intended in this sample. The EVIs that did not perform as intended were significantly influenced by relevant intrapersonal variables, including below-average intellectual functioning and history of moderate-severe traumatic brain injury and neurodevelopmental disorder. CONCLUSIONS: This study identifies multiple EVIs appropriate for use in criminal-forensic settings. However, based on these findings, practitioners may wish to be selective in choosing and interpreting EVIs for forensic evaluations of criminal court defendants.

The anatomy of the head muscles in caecilians (Amphibia: Gymnophiona): Variation in relation to phylogeny and ecology?

In limbless fossorial vertebrates such as caecilians (Gymnophiona), head-first burrowing imposes severe constraints on the morphology and overall size of the head. As such, caecilians developed a unique jaw-closing system involving the large and well-developed m. interhyoideus posterior, which is positioned in such a way that it does not significantly increase head diameter. Caecilians also possess unique muscles among amphibians. Understanding the diversity in the architecture and size of the cranial muscles may provide insights into how a typical amphibian system was adapted for a head-first burrowing lifestyle. In this study, we use dissection and non-destructive contrast-enhanced micro-computed tomography (µCT) scanning to describe and compare the cranial musculature of 13 species of caecilians. Our results show that the general organization of the head musculature is rather constant across extant caecilians. However, the early-diverging Rhinatrema bivittatum mainly relies on the 'ancestral' amphibian jaw-closing mechanism dominated by the m. adductores mandibulae, whereas other caecilians switched to the use of the derived dual jaw-closing mechanism involving the additional recruitment of the m. interhyoideus posterior. Additionally, the aquatic Typhlonectes show a greater investment in hyoid musculature than terrestrial caecilians, which is likely related to greater demands for ventilating their large lungs, and perhaps also an increased use of suction feeding. In addition to three-dimensional interactive models, our study provides the required quantitative data to permit the generation of accurate biomechanical models allowing the testing of further functional hypotheses.

Dihydromyricetin Attenuates Depressive-like Behaviors in Mice by Inhibiting the AGE-RAGE Signaling Pathway.

Depression is a complex mental disorder, affecting approximately 280 million individuals globally. The pathobiology of depression is not fully understood, and the development of new treatments is urgently needed. Dihydromyricetin (DHM) is a natural flavanone, mainly distributed in Ampelopsis grossedentata. DHM has demonstrated a protective role against cardiovascular disease, diabetes, liver disease, cancer, kidney injury and neurodegenerative disorders. In the present study, we examined the protective effect of DHM against depression in a chronic depression mouse model induced by corticosterone (CORT). Animals exposed to CORT displayed depressive-like behaviors; DHM treatment reversed these behaviors. Network pharmacology analyses showed that DHM's function against depression involved a wide range of targets and signaling pathways, among which the inflammation-linked targets and signaling pathways were critical. Western blotting showed that CORT-treated animals had significantly increased levels of the advanced glycation end product (AGE) and receptor of AGE (RAGE) in the hippocampus, implicating activation of the AGE-RAGE signaling pathway. Furthermore, enzyme-linked immunosorbent assay (ELISA) detected a marked increase in the production of proinflammatory cytokines, interleukin-1 beta (IL-1ß), IL-6 and tumor necrosis factor-alpha (TNFα) in the hippocampus of CORT-treated mice. DHM administration significantly counteracted these CORT-induced changes. These findings suggest that protection against depression by DHM is mediated by suppression of neuroinflammation, predominantly via the AGE-RAGE signaling pathway.

Tulp1 deficiency causes early-onset retinal degeneration through affecting ciliogenesis and activating ferroptosis in zebrafish.

Mutations in TUB-like protein 1 (TULP1) are associated with severe early-onset retinal degeneration in humans. However, the pathogenesis remains largely unknown. There are two homologous genes of TULP1 in zebrafish, namely tulp1a and tulp1b. Here, we generated the single knockout (tulp1a-/- and tulp1b-/-) and double knockout (tulp1-dKO) models in zebrafish. Knockout of tulp1a resulted in the mislocalization of UV cone opsins and the degeneration of UV cones specifically, while knockout of tulp1b resulted in mislocalization of rod opsins and rod-cone degeneration. In the tulp1-dKO zebrafish, mislocalization of opsins was present in all types of photoreceptors, and severe degeneration was observed at a very early age, mimicking the clinical manifestations of TULP1 patients. Photoreceptor cilium length was significantly reduced in the tulp1-dKO retinas. RNA-seq analysis showed that the expression of tektin2 (tekt2), a ciliary and flagellar microtubule structural component, was downregulated in the tulp1-dKO zebrafish. Dual-luciferase reporter assay suggested that Tulp1a and Tulp1b transcriptionally activate the promoter of tekt2. In addition, ferroptosis might be activated in the tulp1-dKO zebrafish, as suggested by the up-regulation of genes related to the ferroptosis pathway, the shrinkage of mitochondria, reduction or disappearance of mitochondria cristae, and the iron and lipid droplet deposition in the retina of tulp1-dKO zebrafish. In conclusion, our study establishes an appropriate zebrafish model for TULP1-associated retinal degeneration and proposes that loss of TULP1 causes defects in cilia structure and opsin trafficking through the downregulation of tekt2, which further increases the death of photoreceptors via ferroptosis. These findings offer insight into the pathogenesis and clinical treatment of early-onset retinal degeneration.

Reduced task-evoked pupillary response in preparation for an executive cognitive control response among individuals across the psychosis spectrum.

Task-evoked pupillary response (TEPR) is a measure of physiological arousal modulated by cognitive demand. Healthy individuals demonstrate greater TEPR prior to correct versus error antisaccade trials and correct antisaccade versus visually guided saccade (VGS) trials. The relationship between TEPR and antisaccade performance in individuals with psychotic disorders and their relatives has not been investigated. Probands with schizophrenia, schizoaffective disorder, psychotic bipolar disorder, their first-degree relatives, and controls from the B-SNIP study completed antisaccade and VGS tasks. TEPR prior to execution of responses on these tasks was evaluated among controls compared to probands and relatives according to diagnostic groups and neurobiologically defined subgroups (biotypes). Controls demonstrated greater TEPR on antisaccade correct versus error versus VGS trials. TEPR was not differentiated between antisaccade correct versus error trials in bipolar or schizophrenia probands, though was greater on antisaccade compared to prosaccade trials. There was no modulation of TEPR in schizoaffective probands. Relatives of schizophrenia and schizoaffective probands and those with elevated psychosis spectrum traits failed to demonstrate differential TEPR on antisaccade correct versus error trials. No proband or relative biotypes demonstrated differential TEPR on antisaccade correct versus error trials, and only proband biotype 3 and relative biotypes 3 and 2 demonstrated greater TEPR on antisaccade versus VGS trials. Our findings suggest that aberrant modulation of preparatory activity prior to saccade execution contributes to impaired executive cognitive control across the psychosis spectrum, including nonpsychotic relatives with elevated clinical risk. Reduced pupillary modulation under cognitive challenge may thus be a biomarker for the psychosis phenotype.