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The most common complication in older surgical patients is postoperative delirium (POD). POD is associated with preoperative cognitive impairment and longer durations of intraoperative burst suppression (BSup) – electroencephalography (EEG) with repeated periods of suppression (very low-voltage brain activity). However, BSup has modest sensitivity for predicting POD. We hypothesized that a brain state of lowered EEG power immediately precedes BSup, which we have termed “pre-burst suppression” (preBSup). Further, we hypothesized that even patients without BSup experience these preBSup transient reductions in EEG power, and that preBSup (like BSup) would be associated with preoperative cognitive function and delirium risk. Data included 83 32-channel intraoperative EEG recordings of the first hour of surgery from 2 prospective cohort studies of patients ≥age 60 scheduled for ≥2-h non-cardiac, non-neurologic surgery under general anesthesia (maintained with a potent inhaled anesthetic or a propofol infusion). Among patients with BSup, we defined preBSup as the difference in 3–35 Hz power (dB) during the 1-s preceding BSup relative to the average 3–35 Hz power of their intraoperative EEG recording. We then recorded the percentage of time that each patient spent in preBSup, including those without BSup. Next, we characterized the association between percentage of time in preBSup and (1) percentage of time in BSup, (2) preoperative cognitive function, and (3) POD incidence. The percentage of time in preBSup and BSup were correlated (Spearman’s ρ [95% CI]: 0.52 [0.34, 0.66], p < 0.001). The percentage of time in BSup, preBSup, or their combination were each inversely associated with preoperative cognitive function (β [95% CI]: −0.10 [−0.19, −0.01], p = 0.024; −0.04 [−0.06, −0.01], p = 0.009; −0.04 [−0.06, −0.01], p = 0.003, respectively). Consistent with prior literature, BSup was significantly associated with POD (odds ratio [95% CI]: 1.34 [1.01, 1.78], p = 0.043), though this association did not hold for preBSup (odds ratio [95% CI]: 1.04 [0.95, 1.14], p = 0.421). While all patients had ≥1 preBSup instance, only 20.5% of patients had ≥1 BSup instance. These exploratory findings suggest that future studies are warranted to further study the extent to which preBSup, even in the absence of BSup, can identify patients with impaired preoperative cognition and/or POD risk.

Background. Burnout during registrar training is high, especially in resource-limited settings where stressors are intensified. Burnout leads to decreased quality of life for doctors, poor job and patient satisfaction, and difficulty retaining doctors.Objectives. Primary: to measure burnout among registrars working at Princess Marina Hospital in Gaborone, Botswana. Secondary: to determine factors contributing to burnout and identify potential wellness interventions.Methods. The validated Maslach Burnout Inventory was used to measure the degree of emotional exhaustion, depersonalisation and personal accomplishment. Work-related difficulties and potential wellness interventions were explored through multiple-choice and open-ended questions.Results. Of 40 eligible registrars, 20 (50%) completed the survey. High levels of burnout were reported for emotional exhaustion in 65% (13/20), depersonalisation in 45% (9/20), and personal accomplishment in 35% (7/20) of registrars. A high degree of burnout was reported by 75% (15/20) of registrars in one or more domains. In the previous 7 days, registrars worked an average of 77 hours, took 1.5 overnight calls, slept 5.7 hours per night, and 53% (10/19) had ≥1 of their patients die. Five (25%) registrars considered leaving Botswana to work in another country, which correlated with those with the highest degree of burnout. The most common frustrations included insufficient salary and limited medical resources. Suggested interventions included improved mentorship and wellness lectures.Conclusions. There is a high degree of burnout, especially emotional exhaustion, among registrars. Encouragingly, most registrars have a desire to work in Botswana after training. Future research on improving registrar wellness in low-resource settings is urgently needed.

The recent appearance of generative artificial intelligence (AI) platforms has been seen by many as disruptive for education. In this paper I attempt to locate the source of tension between educational goals and new information technologies including AI. I argue that this tension arises from new conceptions of epistemic agency that are incompatible with educational aims. I describe three competing theories of epistemic agency which I refer to as Makers, Managers, and Inforgs. I contend that educators are correct in maintaining the first of these, which is rooted in the educational theories of Locke and Dewey, as their main educational purpose. Competing theories do not serve the goals of learners, even as they must prepare for life in a very different epistemic environment.

BACKGROUND: Prediction scores for pretest probability of pulmonary embolism (PE) validated in outpatient settings are occasionally used in the intensive care unit (ICU).

This paper presents the results of an analysis of the 2021 piano and voice syllabuses of four Australian music examination boards investigating the percentage of included repertoire by Australian and female composers. The study aimed to address a gap in the research into examination boards within the Australian music education landscape, specifically questioning how they may perpetuate the exclusion of female and Australian composers from the repertoire studied by students. The research looked at trends between piano and voice, examination boards, difficulty levels, and between contemporary and classical syllabuses. Overall, the study found that works by Australian and female composers made up approximately 10% of all works available for study, with less than 4% of the available works by Australian female composers. There was also significant variance between boards, instruments, and syllabuses. Suggestions are made in this paper for improving the representation of Australian and female composers on examination board repertoire, since these boards are uniquely positioned to influence the repertoire taught in the private studio, and by extension, repertoire studied in schools, tertiary institutions, and performed in concert halls.

A retrospective case-series study of pedal- and motor-cyclists presenting to a major metropolitan trauma centre over an 18 month period was undertaken. The injury data were coded according to a number of outcome variables, including intracranial injury of AIS severity ≥ 2. Helmet use was coded. After stratification by rider type, data were analysed to examine the relationships between helmet use and injury using logistic regression. A total of 220 injured motorcycle riders and 137 injured pedal cyclists met the study’s inclusion criteria, with 195 motorcycle riders and passengers (88.6%) and 87 pedal cyclists (63.5%) wearing helmets. Helmets were associated with a significant reduction (p

The response of soil carbon represents one of the key uncertainties in future climate change. The ability of Earth system models (ESMs) to simulate present-day soil carbon is therefore vital for reliably estimating global carbon budgets required for Paris Agreement targets. In this study CMIP6 ESMs are evaluated against empirical datasets to assess the ability of each model to simulate soil carbon and related controls: net primary productivity (NPP) and soil carbon turnover time (τs). Comparing CMIP6 with the previous generation of models (CMIP5), a lack of consistency in modelled soil carbon remains, particularly the underestimation of northern high-latitude soil carbon stocks. There is a robust improvement in the simulation of NPP in CMIP6 compared with CMIP5; however, an unrealistically high correlation with soil carbon stocks remains, suggesting the potential for an overestimation of the long-term terrestrial carbon sink. Additionally, the same improvements are not seen in the simulation of τs. These results suggest that much of the uncertainty associated with modelled soil carbon stocks can be attributed to the simulation of below-ground processes, and greater emphasis is required on improving the representation of below-ground soil processes in future developments of models. These improvements would help to reduce the uncertainty in projected carbon release from global soils under climate change and to increase confidence in the carbon budgets associated with different levels of global warming.

Abstract Background The intervertebral disc is a known back pain generator and is frequently the focus of spinal manipulative therapy evaluation and treatment. The majority of our current knowledge regarding intradiscal pressure (IDP) changes related to spinal manual therapy involves cadaveric studies with their inherent limitations. Additional in vivo animal models are needed to investigate intervertebral disc physiological and molecular mechanisms related to spinal manipulation and spinal mobilization treatment for low back disorders. Methods Miniature pressure catheters (Millar SPR-1000) were inserted into either the L4-L5 or L5-L6 intervertebral disc of 3 deeply anesthetized adult cats (Oct 2012-May 2013). Changes in IDP were recorded during delivery of instrument-assisted spinal manipulation (Activator V® and Pulstar®) and motorized spinal flexion with/without manual spinous process contact. Results Motorized flexion of 30° without spinous contact decreased IDP of the L4-L5 disc by ~ 2.9 kPa, while physical contact of the L4 spinous process decreased IDP an additional ~ 1.4 kPa. Motorized flexion of 25° with L5 physical contact in a separate animal decreased IDP of the L5-L6 disc by ~ 1.0 kPa. Pulstar® impulses (setting 1–3) increased IDP of L4-L5 and L5-L6 intervertebral discs by ~ 2.5 to 3.0 kPa. Activator V® (setting 1–4) impulses increased L4-L5 IDP to a similar degree. Net changes in IDP amplitudes remained fairly consistent across settings on both devices regardless of device setting suggesting that viscoelastic properties of in vivo spinal tissues greatly dampen superficially applied manipulative forces prior to reaching deep back structures such as the intervertebral disc. Conclusions This study marks the first time that feline in vivo changes in IDP have been reported using clinically available instrument-assisted spinal manipulation devices and/or spinal mobilization procedures. The results of this pilot study indicate that a feline model can be used to investigate IDP changes related to spinal manual therapy mechanisms as well as the diminution of these spinal manipulative forces due to viscoelastic properties of the surrounding spinal tissues. Additional investigation of IDP changes is warranted in this and/or other in vivo animal models to provide better insights into the physiological effects and mechanisms of spinal manual therapy at the intervertebral disc level.

Strongly correlated changes between the amplitude of the seasonal cycle in temperature and the annual mean evaporative fraction indicate long-term drying in the Amazon, according to climate reanalyses and Earth System Model projections.

Background: We designed a prospective feasibility study to assess the 5x-multiplier (5x) calculation (eg, 3 pills in last 24 hours × 5 = 15) to standardize discharge opioid prescriptions compared to usual care. Methods: Faculty-based surgical teams volunteered for either 5x or usual care arms. Patients undergoing inpatient (≥48 hours) surgery and discharged by surgical teams were included. The primary end point was discharge oral morphine equivalents. Secondary end points were opioid-free discharges and 30-day refill rates. Results: Median last 24-hour oral morphine equivalents was similar between arms (7.5 mg 5x vs 10 mg usual care, P = .830). Median discharge oral morphine equivalents were less in the 5x arm (50 mg 5x vs 75 mg usual care, P

Cigarette craving contributes substantially to the maintenance of tobacco use disorder. Behavioral strategies to regulate craving may facilitate smoking cessation but remain underexplored. We adapted an emotion-regulation strategy, using proximal/distal self-positioning, to the context of cigarette craving to examine craving regulation in 42, daily smokers (18-25 years old). After overnight abstinence from smoking, before and after smoking their first cigarette of the day, participants viewed videos of natural scenes presenting young adults who were either smoking cigarettes ("smoke") or not ("non-smoke"). Before each video, participants were instructed to imagine themselves either immersed in the scene ("close") or distanced from it ("far"). They rated their craving after each video. Task-based fMRI data are presented for a subsample of participants (N = 21). We found main effects of smoking, instruction, and video type on craving-lower ratings after smoking than before, following the "far" vs. "close" instructions, and when viewing non-smoke vs. smoke videos. Before smoking, "smoke" vs. "non-smoke" videos elicited activation in, orbitofrontal cortex, anterior cingulate, lateral parietal cortex, mid-occipital cortex, ventral striatum, dorsal caudate, and midbrain. Smoking reduced activation in anterior cingulate, left inferior frontal gyrus, and bilateral temporal poles. Activation was reduced in the ventral striatum and medial prefrontal cortex after the "far" vs. the "close" instruction, suggesting less engagement with the stimuli during distancing. The results indicate that proximal/distal regulation strategies impact cue-elicited craving, potentially via downregulation of the ventral striatum and medial prefrontal cortex, and that smoking during abstinence may increase cognitive control capacity during craving regulation.

Abstract Background The link between mental health difficulties and terrorist behaviour has been the subject of debate for the last 50 years. Studies that report prevalence rates of mental health difficulties in terrorist samples or compare rates for those involved and not involved in terrorism, can inform this debate and the work of those responsible for countering violent extremism. Objectives To synthesise the prevalence rates of mental health difficulties in terrorist samples (Objective 1—Prevalence) and prevalence of mental health disorders pre‐dating involvement in terrorism (Objective 2—Temporality). The review also synthesises the extent to which mental health difficulties are associated with terrorist involvement compared to non‐terrorist samples (Objective 3—Risk Factor). Search Methods Searches were conducted between April and June 2022, capturing research until December 2021. We contacted expert networks, hand‐searched specialist journals, harvested records from published reviews, and examined references lists for included papers to identify additional studies. Selection Criteria Studies needed to empirically examine mental health difficulties and terrorism. To be included under Objective 1 (Prevalence) and Objective 2 (Temporality), studies had to adopt cross‐sectional, cohort, or case‐control design and report prevalence rates of mental health difficulties in terrorist samples, with studies under Objective 2 also needing to report prevalence of difficulties before detection or involvement in terrorism. For Objective 3 (Risk Factor) studies where there was variability in terrorist behaviour (involved vs. not involved) were included. Data Collection and Analysis Captured records were screened in DisillterSR by two authors. Risk of bias was assessed using Joanna Briggs Institute checklists, and random‐effects meta‐analysis conducted in Comprehensive Meta‐Analysis software. Results Fifty‐six papers reporting on 73 different terrorist samples (i.e., studies) (n = 13,648) were identified. All were eligible for Objective 1. Of the 73 studies, 10 were eligible for Objective 2 (Temporality) and nine were eligible for Objective 3 (Risk Factor). For Objective 1, the life‐time prevalence rate of diagnosed mental disorder in terrorist samples (k = 18) was 17.4% [95% confidence interval (CI) = 11.1%–26.3%]. When collapsing all studies reporting psychological problems, disorder, and suspected disorder into one meta‐analyses (k = 37), the pooled prevalence rate was 25.5% (95% CI = 20.2%–31.6%). When isolating studies reporting data for any mental health difficulty that emerged before either engagement in terrorism or detection for terrorist offences (Objective 2: Temporality), the life‐time prevalence rate was 27.8% (95% CI = 20.9%–35.9%). For Objective 3 (Risk Factor), it was not appropriate to calculate a pooled effect size due the differences in comparison samples. Odds ratios for these studies ranged from 0.68 (95% CI = 0.38–1.22) to 3.13 (95% CI = 1.87–5.23). All studies were assessed as having high‐risk of bias which, in part, reflects challenges conducting terrorism research. Author's Conclusions This review does not support the assertion that terrorist samples are characterised by higher rates of mental health difficulties than would be expected in the general population. Findings have implications for future research in terms of design and reporting. There are also implications for practice with regards the inclusion of mental health difficulties as indicators of risk.

The articles published as part of the Frontiers in Public Health research topic, “Investigating exposures and respiratory health in coffee workers” present research findings that better characterize exposures to diacetyl and 2,3-pentanedione and inform our understanding of the health risks posed by these exposures. Although various research groups and organizations have conducted risk assessments to derive occupational exposure limits (OELs) for diacetyl, differences in the data used and assumptions made in these efforts have resulted in a wide range of recommended OELs designed to protect human health. The primary drivers of these differences include the decision to use data from human or animal studies in conducting a quantitative risk assessment, and the application of uncertainty factors (UF) to derive an OEL. This Perspectives paper will discuss the practical implications of these decisions, and present additional commentary on the potential role that the recent investigation of human exposures to relatively low concentrations of α-diketones, specifically diacetyl and 2,3-pentanedione, may play in supporting qualitative or quantitative human health risk assessments.

Purpose: This study aimed to assess the optimal tumor diameter for predicting lymphatic metastasis and to determine intraoperatively the need for lymph node dissection in patients with endometrioid endometrial cancer. Methods: Military beneficiaries diagnosed with stage I–III endometrioid endometrial cancer during 2003–2016 who had at least 7 pelvic and/or paraaortic lymph nodes removed during the time of hysterectomy were studied. Tumor diameter was compared against the presence of positive nodes, using the prior models of 20 mm (ie, Mayo model) and 50 mm (ie, Milwaukee model), to determine the false-negative rate of each threshold. A separate analysis was completed to determine the optimal diameter for our population. Receiver operating characteristic curve analysis models of tumor diameter were evaluated for model fit and predictive power of lymph node involvement. Results: Of the 1224 patients with endometrioid endometrial cancer included, 13% (n = 160) had positive lymph node involvement. Tumor sizes ranged from 1 mm to 100 mm. In contrast to Mayo and Milwaukee models (ie, Mayo, Milwaukee), the optimal tumor diameter independent of myometrial invasion and grade of tumor to predict lymph node metastasis was found to be 35 mm. Conclusions: Endometrioid endometrial cancer tumor diameter of 35 mm was found to be the optimal threshold for lymphadenectomy when the operating surgeon has no knowledge of tumor invasion.

This essay is concerned with conceptualising digital socialism in two ways. First, this essay typifies digital socialism as a real utopian project bringing together the utopian potential of “full automation” as tied to socio-economic imperatives indicative of socialist aims. Second, in recognition of a critical gap between full automation and an emerging technological autonomy, this essay argues for a human-machine autonomy that situates autonomy as a shared condition among humans and machines. By conceiving of humans and automated technologies as autonomous subject aligned against capital, pursuing the aims of digital socialism can anticipate and avoid capitalist ideologies that hinders possibilities for autonomous pursuit of digital socialism.

Genome maintenance is an essential process in all cells. In prokaryotes, the RadD protein is important for survival under conditions that include DNA-damaging radiation. Precisely how RadD participates in genome maintenance remains unclear. Here we present a high-resolution X-ray crystal structure of ADP-bound Escherichia coli RadD, revealing a zinc-ribbon element that was not modelled in a previous RadD crystal structure. Insights into the mode of nucleotide binding and additional structure refinement afforded by the new RadD model will help to drive investigations into the activity of RadD as a genome stability and repair factor.

Deletion of the entire gene encoding the RarA protein of Escherichia coli results in a growth defect and additional deficiencies that were initially ascribed to a lack of RarA function. Further work revealed that most of the effects reflected the presence of sequences in the rarA gene that affect expression of the downstream gene, serS. The serS gene encodes the seryl aminoacyl-tRNA synthetase. Decreases in the expression of serS can trigger the stringent response. The sequences that affect serS expression are located in the last 15 nucleotides of the rarA gene.

The First International Satellite Land Surface Climatology Project (ISLSCP) Field Experiment (FIFE), Kansas, US, 1987–1989, made important contributions to the understanding of energy and CO2 exchanges between the land surface and the atmosphere, which heavily influenced the development of numerical land-surface modelling. Now, 30 years on, we demonstrate how the wealth of data collected during FIFE and its subsequent in-depth analysis in the literature continue to be a valuable resource for the current generation of land-surface models. To illustrate, we use the FIFE dataset to evaluate the representation of water stress on tallgrass prairie vegetation in the Joint UK Land Environment Simulator (JULES) and highlight areas for future development. We show that, while JULES is able to simulate a decrease in net carbon assimilation and evapotranspiration during a dry spell, the shape of the diurnal cycle is not well captured. Evaluating the model parameters and results against this dataset provides a case study on the assumptions in calibrating “unstressed” vegetation parameters and thresholds for water stress. In particular, the responses to low water availability and high temperatures are calibrated separately. We also illustrate the effect of inherent uncertainties in key observables, such as leaf area index, soil moisture and soil properties. Given these valuable lessons, simulations for this site will be a key addition to a compilation of simulations covering a wide range of vegetation types and climate regimes, which will be used to improve the way that water stress is represented within JULES.

Indoor dampness and mold are prevalent, and the exposure has been associated with various illnesses such as the exacerbation of existing asthma, asthma development, current asthma, ever-diagnosed asthma, bronchitis, respiratory infection, allergic rhinitis, dyspnea, wheezing, cough, upper respiratory symptoms, and eczema. However, assessing exposures or environments in damp and moldy buildings/rooms, especially by collecting and analyzing environmental samples for microbial agents, is complicated. Nonetheless, observational assessment (visual and olfactory inspection) has been demonstrated as an effective method for evaluating indoor dampness and mold. The National Institute for Occupational Safety and Health developed an observational assessment method called the Dampness and Mold Assessment Tool (DMAT). The DMAT uses a semi-quantitative approach to score the level of dampness and mold-related damage (mold odor, water damage/stains, visible mold, and wetness/dampness) by intensity or size for each of the room components (ceiling, walls, windows, floor, furnishings, ventilation system, pipes, and supplies and materials). Total or average room scores and factor-or component-specific scores can be calculated for data analysis. Because the DMAT uses a semi-quantitative scoring method, it better differentiates the level of damage compared to the binary (presence or absence of damage) approach. Thus, our DMAT provides useful information on identifying dampness and mold, tracking and comparing past and present damage by the scores, and prioritizing remediation to avoid potential adverse health effects in occupants. This protocol-type article describes the DMAT and demonstrates how to apply it to effectively manage indoor dampness and mold-related damage.

Reactive oxygen species (ROS) cause damage to DNA and proteins. Here, we report that the RecA recombinase is itself oxidized by ROS. Genetic and biochemical analyses revealed that oxidation of RecA altered its DNA repair and DNA recombination activities. Mass spectrometry analysis showed that exposure to ROS converted four out of nine Met residues of RecA to methionine sulfoxide. Mimicking oxidation of Met35 by changing it for Gln caused complete loss of function, whereas mimicking oxidation of Met164 resulted in constitutive SOS activation and loss of recombination activity. Yet, all ROS-induced alterations of RecA activity were suppressed by methionine sulfoxide reductases MsrA and MsrB. These findings indicate that under oxidative stress MsrA/B is needed for RecA homeostasis control. The implication is that, besides damaging DNA structure directly, ROS prevent repair of DNA damage by hampering RecA activity.

Ciliary motility is driven by axonemal dyneins that are assembled in the cytoplasm before deployment to cilia. Motile ciliopathy can result from defects in the dyneins themselves or from defects in factors required for their cytoplasmic pre-assembly. Recent work demonstrates that axonemal dyneins, their specific assembly factors, and broadly-acting chaperones are concentrated in liquid-like organelles in the cytoplasm called DynAPs (Dynein Axonemal Particles). Here, we use in vivo imaging in Xenopus to show that inner dynein arm (IDA) and outer dynein arm (ODA) subunits are partitioned into non-overlapping sub-regions within DynAPs. Using affinity- purification mass-spectrometry of in vivo interaction partners, we also identify novel partners for inner and outer dynein arms. Among these, we identify C16orf71/Daap1 as a novel axonemal dynein regulator. Daap1 interacts with ODA subunits, localizes specifically to the cytoplasm, is enriched in DynAPs, and is required for the deployment of ODAs to axonemes. Our work reveals a new complexity in the structure and function of a cell-type specific liquid-like organelle that is directly relevant to human genetic disease.

Ionizing radiation (IR) is lethal to most organisms at high doses, damaging every cellular macromolecule via induction of reactive oxygen species (ROS). Utilizing experimental evolution and continuing previous work, we have generated the most IR-resistant Escherichia coli populations developed to date. After 100 cycles of selection, the dose required to kill 99% the four replicate populations (IR9-100, IR10-100, IR11-100, and IR12-100) has increased from 750 Gy to approximately 3,000 Gy. Fitness trade-offs, specialization, and clonal interference are evident. Long-lived competing sub-populations are present in three of the four lineages. In IR9, one lineage accumulates the heme precursor, porphyrin, leading to generation of yellow-brown colonies. Major genomic alterations are present. IR9 and IR10 exhibit major deletions and/or duplications proximal to the chromosome replication terminus. Contributions to IR resistance have expanded beyond the alterations in DNA repair systems documented previously. Variants of proteins involved in ATP synthesis (AtpA), iron-sulfur cluster biogenesis (SufD) and cadaverine synthesis (CadA) each contribute to IR resistance in IR9-100. Major genomic and physiological changes are emerging. An isolate from IR10 exhibits protein protection from ROS similar to the extremely radiation resistant bacterium Deinococcus radiodurans, without evident changes in cellular metal homeostasis. Selection is continuing with no limit to IR resistance in evidence as our E. coli populations approach levels of IR resistance typical of D. radiodurans.

The brain is the physical organ of the mind but efforts to understand mental illness within a neurobiological context have hitherto been unavailing. Mental disorders (anxiety, depression, bipolar disorder, and schizophrenia) affect about one fifth of the population and present an almost endless societal challenge at the frontier of human sciences. Prodigious technological advances in functional neuroimaging and large-scale genetics have not yet delivered the prospect of refined molecular understanding of mental illness beyond early anatomical descriptions of brain metabolism. However, intensive clinical phenotyping and quantitative metabolic studies using sophisticated radio-ligands in positron-emission tomography, persistently favor the neurobiological approach. This Perspective pursues a familiar maxim in Medicine, aptly summarized in the words of Arthur Koestler: “Nature is generous in her senseless experiments on mankind.” Hitherto, studies in neuropsychiatry have largely ignored rare genetic disorders but derangements of specific components within the cerebral laboratory offer rich opportunities for mechanistic exploration. Aberrant psychic behavior is characteristic of many inborn errors of metabolism and although each disorder represents a universe of its own, we are at a threshold for understanding, since contemporary genetics and cell biology furnish abundant materials to take on the perturbing enigma of mental derangement. A further development relates to orphan drugs with actions on defined molecular targets: these represent new ways to study the pathogenesis of psychiatric phenomena associated with rare diseases and in a manner not formerly possible. Here we introduce the frontier of schizophrenia and its strong association with late-onset Tay-Sachs disease as a paradigm to explore.

Dopamine (DA) neurons are thought to encode reward prediction error (RPE), in addition to other signals, such as salience. While RPE is known to support learning, the role of salience in learning remains less clear. To address this, we recorded and manipulated VTA DA neurons in mice during fear extinction. We applied deep learning to classify mouse freezing behavior, eliminating the need for human scoring. Our fiber photometry recordings showed DA neurons in medial and lateral VTA have distinct activity profiles during fear extinction: medial VTA activity more closely reflected RPE, while lateral VTA activity more closely reflected a salience-like signal. Optogenetic inhibition of DA neurons in either region slowed fear extinction, with the relevant time period for inhibition differing across regions. Our results indicate salience-like signals can have similar downstream consequences to RPE-like signals, although with different temporal dependencies.

The concentration–carbon feedback (β), also called the CO2 fertilization effect, is a key unknown in climate–carbon-cycle projections. A better understanding of model mechanisms that govern terrestrial ecosystem responses to elevated CO2 is urgently needed to enable a more accurate prediction of future terrestrial carbon sink. We conducted C-only, carbon–nitrogen (C–N) and carbon–nitrogen–phosphorus (C–N–P) simulations of the Community Atmosphere Biosphere Land Exchange model (CABLE) from 1901 to 2100 with fixed climate to identify the most critical model process that causes divergence in β. We calculated CO2 fertilization effects at various hierarchical levels from leaf biochemical reaction and leaf photosynthesis to canopy gross primary production (GPP), net primary production (NPP), and ecosystem carbon storage (cpool) for seven C3 plant functional types (PFTs) in response to increasing CO2 under the RCP 8.5 scenario. Our results show that β values at biochemical and leaf photosynthesis levels vary little across the seven PFTs, but greatly diverge at canopy and ecosystem levels in all simulations. The low variation of the leaf-level β is consistent with a theoretical analysis that leaf photosynthetic sensitivity to increasing CO2 concentration is almost an invariant function. In the CABLE model, the major jump in variation of β values from leaf levels to canopy and ecosystem levels results from divergence in modeled leaf area index (LAI) within and among PFTs. The correlation of βGPP, βNPP, or βcpool each with βLAI is very high in all simulations. Overall, our results indicate that modeled LAI is a key factor causing the divergence in β in the CABLE model. It is therefore urgent to constrain processes that regulate LAI dynamics in order to better represent the response of ecosystem productivity to increasing CO2 in Earth system models.

Abstract Background Propionic acid (PA) is used as a food preservative and increasingly, as a precursor for the synthesis of monomers. PA is produced mainly through hydrocarboxylation of ethylene, also known as the ‘oxo-process’; however, Propionibacterium species are promising biological PA producers natively producing PA as their main fermentation product. However, for fermentation to be competitive, a PA yield of at least 0.6 g/g is required. Results A new strain able to reach the required yield was obtained using genome shuffling. To gain insight into the changes leading to the improved phenotype, the genome of the new strain was sequenced, and metabolomics and transcriptomics data were obtained. In combination, the data revealed three key mutations: (i) a mutation in the promoter region of a sugar transporter which enables an increase in the uptake rate of sucrose; (ii) a mutation in a polar amino acid transporter which improves consumption of amino acids and acid tolerance; and (iii) a mutation in a gene annotated as a cytochrome C biogenesis gene, which is likely responsible for the coupling of the Wood–Werkman cycle to ATP production were responsible for the phenotype. The bioprocess was further enhanced with a feeding strategy that achieved 70 g/L of product. The proposed bioprocess is expected to outperform the economics of the current ‘oxo-process’ by 2020. Conclusions In this study, using genome shuffling, we obtained a strain capable of producing PA exceeding the commercial needs. The multiomics comparison between the novel strain and the wild type revealed overexpression of amino acid pathways, changes in sucrose transporters and an increased activity in the methylglyoxal and the glucuronate interconversion pathways. The analysis also suggests that a mutation in the cytochrome C biogenesis gene, coupled with ATP production through the Wood–Werkman cycle, may be responsible for the increased PA production.