Risk Assessment of Displaced Sediment by an Extreme Event Cyclone in a Peri-Urban Zone Using Bioassays and Analytical Chemistry.

Hawke's Bay in New Zealand was impacted by Cyclone Gabrielle in 2023, experiencing intense weather conditions and rainfall. Rivers and streams surged beyond their banks, displacing large amounts of sediment. The sewage treatment plant and industries in the Waitangi catchment, south of the city of Napier, were heavily impacted, making them potential sources of contaminants. The aim of this study was to investigate the risk of displaced sediments deposited south of Napier City, using bioassays and chemical analysis methods. Sediment samples were collected across a gradient between the coastline and the Waitangi Stream. The toxicity of chemically extracted or elutriate samples was assessed by Microtox®, mussel embryo-larval development, and aryl hydrocarbon and constitutive androstane receptor yeast two-hybrid assays. Targeted chemical analysis and automated identification and quantification system (AIQS-GC) methods were used to identify contaminants. The elutriates showed low toxicity and the yeast assays showed levels of activity like those previously reported. Chemical methods confirmed historical contamination by DDT and its metabolites DDE and DDD, as well as by plant sterols. Overall, the toxicity and chemicals detected are what would be expected from a typical agricultural soil. The risk posed by the displaced sediment in the Waitangi catchment can be considered low. Combining chemical and bioanalytical methods was an effective approach to investigate the potential risks of post-disaster contamination.

Efficacy and safety of diclofenac suppository for postoperative pain relief after diagnostic hystero-laparoscopy and dye test: A double-blind, placebo-controlled, randomized trial.

Objective: To determine the efficacy and safety of rectal diclofenac for relieving postoperative pain following diagnostic hystero-laparoscopy and dye test (dHLD). Methods: A prospective, double-blind, placebo-controlled, randomized trial was conducted among women who underwent dHLD to evaluate fertility. The women received either rectal diclofenac with intramuscular pentazocine or intramuscular pentazocine with rectal placebo for postoperative analgesia. The median pain scores at different time points were assessed as the primary outcome measures using the Numerical Rating Scale for pain. The secondary outcome measures were analgesic consumption, time at which first analgesic was requested, satisfaction with pain relief and any adverse events. Results: In total, 108 participants were analysed (54 in each group, 1:1 ratio). The median score for postoperative pain was lower for the diclofenac group compared with the placebo group at 4 h (52.53 vs 56.47; p = 0.507), 6 h (50.48 vs 58.52; p = 0.174), 8 h (51.42 vs 57.65; p = 0.296), 10 h (51.35 vs 57.65; p = 0.285) and 12 h (52.45 vs 56.55; p = 0.485) post surgery, although the difference was not significant (p > 0.05). Seventeen participants required rescue analgesia with 30 mg of pentazocine: 11 at 4 h post surgery [5 (62.5 %) vs 6 (66.7 %)], three at 6 h post surgery [2 (25.0 %) vs 1 (11.1 %)], two at 8 h post surgery [1 (12.5 %) vs 1 (11.1 %)], and one at 12 h post surgery [0 vs 1 (11.1 %)] for the diclofenac and placebo groups respectively (p = 0.713). There were no significant differences in postoperative adverse effect profiles, overall patient satisfaction, and need for rescue analgesia between the two groups (p > 0.05). Conclusions: Postoperative use of rectal diclofenac and pentazocine is safe, but did not significantly improve pain scores, patient satisfaction and need for rescue analgesia following dHLD, compared with patients who received pentazocine and placebo. While a multi-modal approach to pain relief following dHLD does not appear to be significantly beneficial, a multi-centre study is needed to confirm or refute these findings.

Proteomic changes orchestrate metabolic acclimation of a unicellular diazotrophic cyanobacterium during light-dark cycle and nitrogen fixation states.

Cyanobacteria have developed an impressive array of proteins and pathways, each tailored for specific metabolic attributes, to execute photosynthesis and biological nitrogen (N2)-fixation. An understanding of these biologically incompatible processes provides important insights into how they can be optimized for renewable energy. To expand upon our current knowledge, we performed label-free quantitative proteomic analysis of the unicellular diazotrophic cyanobacterium Crocosphaera subtropica ATCC 51142 grown with and without nitrate under 12-hour light-dark cycles. Results showed significant shift in metabolic activities including photosynthesis, respiration, biological nitrogen fixation (BNF), and proteostasis to different growth conditions. We identified 14 nitrogenase enzymes which were among the most highly expressed proteins in the dark under nitrogen-fixing conditions, emphasizing their importance in BNF. Nitrogenase enzymes were not expressed under non nitrogen fixing conditions, suggesting a regulatory mechanism based on nitrogen availability. The synthesis of key respiratory enzymes and uptake hydrogenase (HupSL) synchronized with the synthesis of nitrogenase indicating a coordinated regulation of processes involved in energy production and BNF. Data suggests alternative pathways that cells utilize, such as oxidative pentose phosphate (OPP) and 2-oxoglutarate (2-OG) pathways, to produce ATP and support bioenergetic BNF. Data also indicates the important role of uptake hydrogenase for the removal of O2 to support BNF. Overall, this study expands upon our knowledge regarding molecular responses of Crocosphaera 51142 to nitrogen and light-dark phases, shedding light on potential applications and optimization for renewable energy.

Cold snare polypectomy: A closer look at the efficacy and limitations for polyps 10-20 mm in size.

Current guidelines recommend cold snare polypectomy for polyps less than 10 mm in size. Conversely, endoscopic mucosal resection is still the preferred technique for larger polyps. Concerns regarding cold snare polypectomy for larger polyps revolve around the difficulty in conducting en-bloc resection (resulting in piecemeal removal), and the potential for local residual polyp tissue and a high rate of recurrence. On the other hand, cold snare technique has the advantages of shortening procedure time, reducing delayed bleeding risks and lowering cost of treatment. Numerous ongoing and recent studies are focused on evaluating the risks and benefits of this technique for polyps larger than 10 mm, with the goal of providing clear guidelines in the near future. The aim of this editorial is to provide our readers with an overview regarding this subject and the latest developments surrounding it.

Siblings at home: Moderating influence of sibling presence and composition on the relation between problem behaviors and theory of mind in early childhood.

Despite the prevalence of internalizing and externalizing difficulties in children, the impact of these problem behaviors on the development of important social cognitive skills, such as Theory of Mind (ToM), is not well-understood. Indeed, many studies that have explored relations between problem behaviors and ToM report inconsistent findings. A possible reason for these disparities may be a lack of accounting for social protective factors within the home, such as the presence and number of siblings. Here, we explored the moderating influence of sibling presence and number on the relation between problem behaviors (i.e., internalizing and externalizing) and ToM. A total of 184 children (88 boys; Mage = 64.6 months, SD = 10.39) completed six well-validated ToM tasks while mothers reported on their children's externalizing and internalizing behaviors. Children who had siblings living in the same home exhibited higher ToM than children without siblings. In addition, both sibling presence and number of siblings moderated the relation between children's externalizing behaviors and ToM, such that in children without siblings externalizing behaviors were negatively associated with ToM. In contrast, children with siblings had similar ToM regardless of externalizing behaviors. As well, children with relatively fewer siblings and higher externalizing behaviors displayed lower ToM than children with relatively more siblings and higher externalizing behaviors. We did not detect a moderating effect of sibling presence or number on the relation between internalizing behaviors and ToM. These findings provide support for siblings' protective utility within the context of children's social cognition.

Protocol for the generation of cultured cortical brain organoid slices.

Three-dimensional brain organoids from human pluripotent stem cells are a powerful tool for studying human neural networks. Here, we present a protocol for generating cortical brain organoid slices (cBOS) derived from regionalized cortical organoids and grown at the air-liquid interphase. We provide steps for slicing organoids and maintaining them in long-term culture. We then detail approaches for quality control including the evaluation of cell death and cellular identity. Finally, we describe procedures for the expression of a genetically encoded nanosensor for ATP. For complete details on the use and execution of this protocol, please refer to Petersilie et al.1.

Kinetics of Calcite Nucleation onto Sulfated Chitosan Derivatives and Implications for Water-Polysaccharide Interactions during Crystallization of Sparingly Soluble Salts.

Anionic macromolecules are found at sites of CaCO3 biomineralization in diverse organisms, but their roles in crystallization are not well-understood. We prepared a series of sulfated chitosan derivatives with varied positions and degrees of sulfation, DS(SO3 -), and measured calcite nucleation rate onto these materials. Fitting the classical nucleation theory model to the kinetic data reveals the interfacial free energy of the calcite-polysaccharide-solution system, γnet, is lowest for nonsulfated controls and increases with DS(SO3 -). The kinetic prefactor also increases with DS(SO3 -). Simulations of Ca2+-H2O-chitosan systems show greater water structuring around sulfate groups compared to uncharged substituents, independent of sulfate location. Ca2+-SO3 - interactions are solvent-separated by distances that are inversely correlated with DS(SO3 -) of the polysaccharide. The simulations also predict SO3 - and NH3 + groups affect the solvation waters and HCO3 - ions associated with Ca2+. Integrating the experimental and computational evidence suggests sulfate groups influence nucleation by increasing the difficulty of displacing near-surface water, thereby increasing γnet. By correlating γnet and net charge per monosaccharide for diverse polysaccharides, we suggest the solvent-separated interactions of functional groups with Ca2+ influence thermodynamic and kinetic components to crystallization by similar solvent-dominated processes. The findings reiterate the importance of establishing water structure and properties at macromolecule-solution interfaces.

A dyadic investigation of shy children's behavioral and affective responses to delivering a speech.

Shyness is typically associated with avoidant social behavior and restricted affect in new social situations. However, we know considerably less about how one child's shyness influences another child's behavior and affect in new social situations. Children's shyness was parent-reported when children were age 3 (N = 105, 52 girls, Mage = 3.50 years), and children were tested approximately 1 year later (Mage = 4.76 years) in same-gender dyads where they were asked to give an impromptu speech about their most recent birthday in front of an experimenter and the other member of the dyad. We examined whether children's shyness and speech order influenced their own and their social partner's observed behavior and affect during the speech. Regardless of speech order, children's own shyness was positively associated with their own avoidant social behavior and gaze aversion. Regardless of shyness, children who gave their speech second averted their gaze more than children who gave their speech first. We also found that children who gave their speech second displayed less positive affect if their social partner who they watched give the speech first was shyer. We speculate that some 4-year-old children may be sensitive to the avoidant behaviors of their shy peers and, in turn, respond with less animation when it is their turn to participate in the same activity. RESEARCH HIGHLIGHTS: We examined whether preschool children's shyness and speech order influenced their own and their social partner's observed behavior and affect during a dyadic speech task Children's own shyness was positively associated with their own avoidant social behavior and gaze aversion Children who gave their speech second averted their gaze more than children who gave their speech first. Children who gave their speech second displayed less positive affect if their social partner who they watched give a speech first was shyer These findings suggest that preschool-aged children are sensitive to learning about their environment indirectly through social observation.

Dotatate PET/CT and 225Ac-Dotatate Therapy for Somatostatin Receptor-expressing Metastatic Breast Cancer.

Background Somatostatin receptors, and specifically somatostatin receptor type 2 (SSTR2), have primarily been associated with neuroendocrine tumors and have revolutionized the imaging and therapy of patients with these tumors. SSTR2 is expressed on other tumors at lower prevalence. Purpose To evaluate the potential of SSTR2-targeted imaging and therapy in patients with breast cancer. Materials and Methods In a preclinical experiment, SSTR2 expression was assessed in tissue microarrays of breast cancer samples using H-score analysis. H-scores higher than 50 (0-300 scale) were considered positive. Then, a prospective phase 2 clinical trial of SSTR2-targeted tetraazacyclododecane tetraacetic acid octreotate (Dotatate) PET/CT was performed in participants with biopsy-proven estrogen receptor (ER)-positive breast cancer from January to August 2023. A positive Dotatate PET/CT scan was defined as tumors with a Krenning score of 3 (avidity greater than liver) or 4 (avidity greater than spleen). The proportion of positive scans and the 95% CI were calculated. One participant with metastatic ER-positive breast cancer and a Krenning 4 Dotatate PET/CT result underwent treatment with SSTR2-targeted actinium 225 (225Ac) Dotatate. Results Preclinical microarrays demonstrated that 63 of 123 ER-positive breast cancer tissue samples (51% [95% CI: 42, 60]) but only 22 of 121 ER-negative breast cancer tissue samples (18% [95% CI: 12, 26]) were enriched for SSTR2 (P < .001). Thirty female participants (mean age, 66 years ± 15) with metastatic ER-positive breast cancer were accrued to the phase 2 SSTR2-targeted imaging trial and underwent Dotatate PET/CT. Dotatate PET/CT demonstrated that nine of 30 participants (30% [95% CI: 15, 49]) had tumors with Krenning scores of 3 or 4, indicating strong SSTR2 expression. SSTR2-targeted therapy with alpha-emitting 225Ac-Dotatate resulted in a near complete response in a heavily pretreated participant with metastatic ER-positive breast cancer and a Krenning 4 Dotatate PET result. Conclusion Molecular imaging targeting SSTR2 and radioligand therapy with SSTR2-targeted 225Ac-Dotatate enables a new therapeutic option for patients with metastatic breast cancer. Clinical trial registration no. NCT05880394 © RSNA, 2024 See also the editorial by Lin and Choyke in this issue.

Behavioral and neural responses to social exclusion in women: the role of facial attractiveness and friendliness.

The behavioral and neural responses to social exclusion were examined in women randomized to four conditions, varying in levels of attractiveness and friendliness. Informed by evolutionary theory, we predicted that being socially excluded by attractive unfriendly women would be more distressing than being excluded by unattractive women, irrespective of their friendliness level. Our results contradicted most of our predictions but provide important insights into women's responses to interpersonal conflict. Accounting for rejection sensitivity, P300 event-related potential amplitudes were largest when women were excluded by unattractive unfriendly women. This may be due to an expectancy violation or an annoyance with being excluded by women low on social desirability. An examination of anger rumination rates by condition suggests the latter. Only attractive women's attractiveness ratings were lowered in the unfriendly condition, indicating they were specifically punished for their exclusionary behavior. Women were more likely to select attractive women to compete against with one exception-they selected the Black attractive opponent less often than the White attractive opponent when presented as unfriendly. Finally, consistent with studies on retaliation in relation to social exclusion, women tended to rate competitors who rejected them as being more rude, more competitive, less attractive, less nice, and less happy than non-competitors. The ubiquity of social exclusion and its pointed emotional and physiological impact on women demands more research on this topic.

Mapping deterioration in electrospun zein nonwoven nanostructures encapsulating corn oil.

Electrospun nonwovens of biopolymers are gaining popularity in filtration, coatings, encapsulation, and packaging materials. However, their applications are hindered by limited stability, particularly when loaded with lipids. This research aimed to apply a multiscale approach to gain insights into deteriorative processes, e.g., oxidation, limiting the shelf life of these complex materials, using corn oil-loaded electrospun zein nonwovens as a model system. Oil-doped zein electrospun nonwovens were stored in the dark at 23 °C and 33% relative humidity for 28 days and tested at selected intervals to monitor their morphology and mechanical properties. Lipid oxidation was assessed using the thiobarbituric acid reactive species (TBARS) assay. The photophysical properties of intrinsic, i.e., tyrosine (Tyr), and extrinsic, i.e., boron-dipyrromethene undecanoic acid 581/591 (BODIPY C11), lumiphores were also monitored to evaluate changes in local molecular rigidity, and oxidation, respectively. The protein secondary structure was determined with Fourier transform infrared spectroscopy (FTIR). Scanning electron microscopy (SEM) analysis of the oil-loaded electrospun nonwovens revealed that the diameter of the ribbon-like fiber significantly decreased during storage from 701 ± 23 nm to 620 ± 44 nm. Breakage of the electrospun fibers was observed and correlated with increased brittleness and molecular rigidity of the nonwoven material, reflected by an increase in Tyr emission intensity and phosphorescence lifetime. Changes in tensile strength, brittleness and matrix rigidity also correlated with a zein secondary structure transition from unordered to ordered ß-sheets. Raman and luminescence micrographs showed oil migration during storage, thereby increasing lipid oxidation. The correlation between local rigidity and lipid distribution/oxidation suggests that reorganizing protein structures increased material brittleness and displaced encapsulated oils within the electrospun fiber. Understanding deteriorative mechanisms aids in developing innovative strategies to improve the stability of these novel food-grade materials.

Relative decline in density of Northern Hemisphere tree species in warm and arid regions of their climate niches.

Although climate change is expected to drive tree species toward colder and wetter regions of their distribution, broadscale empirical evidence is lacking. One possibility is that past and present human activities in forests obscure or alter the effects of climate. Here, using data from more than two million monitored trees from 73 widely distributed species, we quantify changes in tree species density within their climatic niches across Northern Hemisphere forests. We observe a reduction in mean density across species, coupled with a tendency toward increasing tree size. However, the direction and magnitude of changes in density exhibit considerable variability between species, influenced by stand development that results from previous stand-level disturbances. Remarkably, when accounting for stand development, our findings show a significant change in density toward cold and wet climatic conditions for 43% of the species, compared to only 14% of species significantly changing their density toward warm and arid conditions in both early- and late-development stands. The observed changes in climate-driven density showed no clear association with species traits related to drought tolerance, recruitment and dispersal capacity, or resource use, nor with the temperature or aridity affiliation of the species, leaving the underlying mechanism uncertain. Forest conservation policies and associated management strategies might want to consider anticipated long-term species range shifts alongside the integration of contemporary within-distribution density changes.

Sociability across Eastern-Western cultures: Is it the same underlying construct?

In this study, we examined cross-cultural differences in sociability, a core personality facet of the higher order extraversion trait, which has been reported at lower levels in Eastern versus Western cultures several decades ago. Up until now, however, East-West cultural comparisons on the Western-defined construct of sociability have been limited, despite the extensive research published on extraversion indicating that this personality dimension is globally relevant across cultures. Following current practices, we first assessed for measurement invariance (MI) on the Cheek and Buss sociability scale between Chinese (n = 816, 47.2% male, M = 18.51 years, SD = 1.26 years) and Canadian (n = 995, 30.8% male, M = 19.62 years, SD = 1.25 years) young adult samples to ensure any comparisons would be valid and meaningful. Results from a multigroup confirmatory factor analysis (exact invariance) showed that there was measurement non-invariance at the scalar level in the sociability construct across country and country by sex, and the newer alignment method (approximate invariance) confirmed these results, suggesting that mean level comparisons of sociability were biased and noninformative. Our findings indicated that although a few of the higher-level personality dimensions such as extraversion are considered universal, the facets underlying their meaning, like sociability, are not as clearly delineated between cultures. Alongside the present-day pursuit of understanding personality across cultures through an indigenous measurement lens in tandem with the notion of universality, researchers should also consider narrowing their focus onto lower-level facets, each of which is likely to be uniquely embedded into a cultural context.

The Scalding Truth: Geospatial Analysis Identifies Communities at Risk for Pediatric Scald Burns.

INTRODUCTION: Pediatric scald burns account for 12% of all U.S. burn center admissions and are the most common type of burn in children. We hypothesized that geospatial analysis of burn registry data could identify specific geographic areas and risk factors to focus injury prevention efforts. METHODS: The burn registry of a U.S. regional burn center was used to retrospectively identify pediatric scald burn patients ages 0-17, from January 2018 to June 2023. Geocoding of patient home addresses with census tract data was performed. Area Deprivation Index (ADI) was assigned to patients at the census block group level. Burn incident hot spot analysis to identify statistically significant burn incident clusters was done using the Getis Ord Gi∗ statistic. RESULTS: There were 950 pediatric scald burn patients meeting study criteria. The cohort was 52% male and 36% White, with median age of 3 y and median total body surface area of 1.5%; 23.8% required hospital admission. On multivariable logistic regression, increased child poverty levels (P = 0.004) and children living in single-parent households (P = 0.009) were associated with increased scald burn incidence. Geospatial analysis identified burn hot spots, which were associated with higher ADI (P < 0.001). Black patients were more likely to undergo admission compared to White patients. CONCLUSIONS: Geospatial analysis of burn registry data identified geographic areas at high risk of pediatric scald burn. ADI, poverty, and children in single-parent households were the greatest predictors of injury. Addressing these inequalities requires targeted injury prevention education, enhanced outpatient support systems and more robust community resources.

Fostering student authorship skills in synthetic biology.

Women and racial minorities are underrepresented in the synthetic biology community. Developing a scholarly identity by engaging in a scientific community through writing and communication is an important component for STEM retention, particularly for underrepresented individuals. Several excellent pedagogical tools have been developed to teach scientific literacy and to measure competency in reading and interpreting scientific literature. However, fewer tools exist to measure learning gains with respect to writing, or that teach the more abstract processes of peer review and scientific publishing, which are essential for developing scholarly identity and publication currency. Here we describe our approach to teaching scientific writing and publishing to undergraduate students within a synthetic biology course. Using gold standard practices in project-based learning, we created a writing project in which students became experts in a specific application area of synthetic biology with relevance to an important global problem or challenge. To measure learning gains associated with our learning outcomes, we adapted and expanded the Student Attitudes, Abilities, and Beliefs (SAAB) concept inventory to include additional questions about the process of scientific writing, authorship, and peer review. Our results suggest the project-based approach was effective in achieving the learning objectives with respect to writing and peer reviewed publication, and resulted in high student satisfaction and student self-reported learning gains. We propose that these educational practices could contribute directly to the development of scientific identity of undergraduate students as synthetic biologists, and will be useful in creating a more diverse synthetic biology research enterprise.

Characterization of the transcriptional effects of the plastic additive dibutyl phthalate alone and in combination with microplastic on the green-lipped mussel Perna canaliculus.

The presence and persistence of microplastics (MPs) in diverse aquatic environments are of global concern. Microplastics can impact marine organisms via direct physical interaction and the release of potentially harmful chemical additives incorporated into the plastic. These chemicals are physically bound to the plastic matrix and can leach out. The hazards associated with chemical additives to exposed organisms is not well characterized. We investigated the hazards of plastic additives leaching from plastic. We used the common plasticizer dibutyl phthalate (DBP) as a chemical additive proxy and the New Zealand green-lipped mussel (Perna canaliculus) as a model. We used early-adult P. canaliculus exposed to combinations of virgin and DBP-spiked polyvinyl chloride (PVC), MPs, and DBP alone for 7 days. Whole transcriptome sequencing (RNA-seq) was conducted to assess whether leaching of DBP from MPs poses a hazard. The differences between groups were evaluated using pairwise permutational multivariate analysis of variance (PERMANOVA), and all treatments were significantly different from controls. In addition, a significant difference was seen between DBP and PVC MP treatment. Transcriptome analysis revealed that mussels exposed to DBP alone had the most differentially expressed genes (914), followed by PVC MP + DBP (448), and PVC MP (250). Gene ontology functional analysis revealed that the most enriched pathway types were in cellular metabolism, immune response, and endocrine disruption. Microplastic treatments enriched numerous pathways related to cellular metabolism and immune response. The combined exposure of PVC MP + DBP appears to cause combined effects, suggesting that DBP is bioavailable to the exposed mussels in the PVC MP + DBP treatment. Our results support the hypothesis that chemical additives are potentially an important driver of MP toxicity. Environ Toxicol Chem 2024;43:1604-1614. © 2024 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Interventional probability of causation (IPoC) with epidemiological and partial mechanistic evidence: benzene vs. formaldehyde and acute myeloid leukemia (AML).

INTRODUCTION: Causal epidemiology for regulatory risk analysis seeks to evaluate how removing or reducing exposures would change disease occurrence rates. We define interventional probability of causation (IPoC) as the change in probability of a disease (or other harm) occurring over a lifetime or other specified time interval that would be caused by a specified change in exposure, as predicted by a fully specified causal model. We define the closely related concept of causal assigned share (CAS) as the predicted fraction of disease risk that would be removed or prevented by a specified reduction in exposure, holding other variables fixed. Traditional approaches used to evaluate the preventable risk implications of epidemiological associations, including population attributable fraction (PAF) and the Bradford Hill considerations, cannot reveal whether removing a risk factor would reduce disease incidence. We argue that modern formal causal models coupled with causal artificial intelligence (CAI) and realistically partial and imperfect knowledge of underlying disease mechanisms, show great promise for determining and quantifying IPoC and CAS for exposures and diseases of practical interest. METHODS: We briefly review key CAI concepts and terms and then apply them to define IPoC and CAS. We present steps to quantify IPoC using a fully specified causal Bayesian network (BN) model. Useful bounds for quantitative IPoC and CAS calculations are derived for a two-stage clonal expansion (TSCE) model for carcinogenesis and illustrated by applying them to benzene and formaldehyde based on available epidemiological and partial mechanistic evidence. RESULTS: Causal BN models for benzene and risk of acute myeloid leukemia (AML) incorporating mechanistic, toxicological and epidemiological findings show that prolonged high-intensity exposure to benzene can increase risk of AML (IPoC of up to 7e-5, CAS of up to 54%). By contrast, no causal pathway leading from formaldehyde exposure to increased risk of AML was identified, consistent with much previous mechanistic, toxicological and epidemiological evidence; therefore, the IPoC and CAS for formaldehyde-induced AML are likely to be zero. CONCLUSION: We conclude that the IPoC approach can differentiate between likely and unlikely causal factors and can provide useful upper bounds for IPoC and CAS for some exposures and diseases of practical importance. For causal factors, IPoC can help to estimate the quantitative impacts on health risks of reducing exposures, even in situations where mechanistic evidence is realistically incomplete and individual-level exposure-response parameters are uncertain. This illustrates the strength that can be gained for causal inference by using causal models to generate testable hypotheses and then obtaining toxicological data to test the hypotheses implied by the models-and, where necessary, refine the models. This virtuous cycle provides additional insight into causal determinations that may not be available from weight-of-evidence considerations alone.

Naming fMRI-guided white matter language tract volumes influence naming decline after temporal lobe resection.

OBJECTIVE: The aim of this study was to explore the relation of language functional MRI (fMRI)-guided tractography with postsurgical naming decline in people with temporal lobe epilepsy (TLE). METHODS: Twenty patients with unilateral TLE (9 left) were studied with auditory and picture naming functional MRI tasks. Activation maxima in the left posterobasal temporal lobe were used as seed regions for whole-brain fibre tractography. Clinical naming performance was assessed preoperatively, 4 months, and 12 months following temporal lobe resection. Volumes of white matter language tracts in both hemispheres as well as tract volume laterality indices were explored as moderators of postoperative naming decline using Pearson correlations and multiple linear regression with other clinical variables. RESULTS: Larger volumes of white matter language tracts derived from auditory and picture naming maxima in the hemisphere of subsequent surgery as well as stronger lateralization of picture naming tract volumes to the side of surgery correlated with greater language decline, which was independent of fMRI lateralization status. Multiple regression for picture naming tract volumes was associated with a significant decline of naming function with 100% sensitivity and 93% specificity at both short-term and long-term follow-up. INTERPRETATION: Naming fMRI-guided white matter language tract volumes relate to postoperative naming decline after temporal lobe resection in people with TLE. This can assist stratification of surgical outcome and minimize risk of postoperative language deficits in TLE.

Connectome-driven neural inventory of a complete visual system.

Vision provides animals with detailed information about their surroundings, conveying diverse features such as color, form, and movement across the visual scene. Computing these parallel spatial features requires a large and diverse network of neurons, such that in animals as distant as flies and humans, visual regions comprise half the brain's volume. These visual brain regions often reveal remarkable structure-function relationships, with neurons organized along spatial maps with shapes that directly relate to their roles in visual processing. To unravel the stunning diversity of a complex visual system, a careful mapping of the neural architecture matched to tools for targeted exploration of that circuitry is essential. Here, we report a new connectome of the right optic lobe from a male Drosophila central nervous system FIB-SEM volume and a comprehensive inventory of the fly's visual neurons. We developed a computational framework to quantify the anatomy of visual neurons, establishing a basis for interpreting how their shapes relate to spatial vision. By integrating this analysis with connectivity information, neurotransmitter identity, and expert curation, we classified the ~53,000 neurons into 727 types, about half of which are systematically described and named for the first time. Finally, we share an extensive collection of split-GAL4 lines matched to our neuron type catalog. Together, this comprehensive set of tools and data unlock new possibilities for systematic investigations of vision in Drosophila, a foundation for a deeper understanding of sensory processing.

Genetic and pharmacological reduction of CDK14 mitigates synucleinopathy.

Parkinson's disease (PD) is a debilitating neurodegenerative disease characterized by the loss of midbrain dopaminergic neurons (DaNs) and the abnormal accumulation of α-Synuclein (α-Syn) protein. Currently, no treatment can slow nor halt the progression of PD. Multiplications and mutations of the α-Syn gene (SNCA) cause PD-associated syndromes and animal models that overexpress α-Syn replicate several features of PD. Decreasing total α-Syn levels, therefore, is an attractive approach to slow down neurodegeneration in patients with synucleinopathy. We previously performed a genetic screen for modifiers of α-Syn levels and identified CDK14, a kinase of largely unknown function as a regulator of α-Syn. To test the potential therapeutic effects of CDK14 reduction in PD, we ablated Cdk14 in the α-Syn preformed fibrils (PFF)-induced PD mouse model. We found that loss of Cdk14 mitigates the grip strength deficit of PFF-treated mice and ameliorates PFF-induced cortical α-Syn pathology, indicated by reduced numbers of pS129 α-Syn-containing cells. In primary neurons, we found that Cdk14 depletion protects against the propagation of toxic α-Syn species. We further validated these findings on pS129 α-Syn levels in PD patient neurons. Finally, we leveraged the recent discovery of a covalent inhibitor of CDK14 to determine whether this target is pharmacologically tractable in vitro and in vivo. We found that CDK14 inhibition decreases total and pathologically aggregated α-Syn in human neurons, in PFF-challenged rat neurons and in the brains of α-Syn-humanized mice. In summary, we suggest that CDK14 represents a novel therapeutic target for PD-associated synucleinopathy.