Search

Using population-level cancer diagnosis data, we compared cancer incidence in locations affected by smoke from a six week-long open cut coal mine fire in regional Victoria, Australia, up to seven years following the event. There was no detectable effect on cancer incidence overall. While several subgroups exhibited changes, these were more likely due to statistical chance rather than real effects. These findings may be limited by low statistical power and short duration of follow up. To confirm the influence of open cut coal mine fires on cancer incidence, further research and an extended follow-up duration are necessary., Competing Interests: Declaration of Competing Interest MJA holds investigator-initiated grants from Pfizer, Boehringer-Ingelheim, GSK and Sanofi for unrelated research. He has undertaken an unrelated consultancy for Sanofi. He has also received a speaker’s fee from GSK. All other authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: In 2014, the Hazelwood coalmine fire in regional Victoria, Australia shrouded nearby communities in smoke for six weeks. Prior investigations identified substantial adverse effects, including increases in the use of health services. In this study, we examined the effects on hospital and ambulance use in the eight years following the fire., Methods: Using Victorian hospital (Jan 2009-Jun 2022) and ambulance (Jan 2013-Dec 2021) data, we conducted an interrupted time series of changes to the rate of hospital admissions, emergency presentations, and ambulance attendances. A categorical exposure model compared two locations, most-exposed Morwell and less-exposed Latrobe Valley, to the rest of regional Victoria. A continuous exposure model used spatial estimates of fire-related PM 2.5 . Analyses were stratified by sex, age group (<65/65+ years), and condition (cardiovascular, respiratory, mental health, injury)., Results: There were small but significant increases in overall hospital admissions and emergency presentations across all analyses, but little evidence of change in overall ambulance attendances. Effects varied considerably by condition, with the biggest relative increases observed among hospital admissions for mental health conditions and injuries. While cardiovascular-related hospital admissions and emergency presentations increased post-fire, ambulance attendances decreased., Conclusions: Our findings suggest the Hazelwood coalmine fire likely increased hospital usage. However, it is unclear whether this was due to the direct effects of smoke exposure on health, or the disruptive socioeconomic and behavioural impacts of an environmental disaster that affected how communities engaged with various health services., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Michael J Abramson reports financial support was provided by Pfizer Inc. Michael J Abramson reports financial support was provided by Boehringer Ingelheim Corp USA. Michael J Abramson reports financial support was provided by Sanofi. Michael J Abramson reports financial support was provided by GlaxoSmithKline Inc. Rongbin Xu reports financial support was provided by VicHealth. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

We report time resolved observations of the crystallization from liquid hydrogen, supercooled to temperatures below the melting point, using 11.2 keV X-ray diffraction from the Linac Coherent Light Source (LCLS). Changes to the metastable solid and liquid structure factors have been dynamically measured. This allows for a direct determination of the lowest energy crystal polymorphs, the stacking probabilities, as well as the liquid and solid densities and temperatures. Such measurements provide experimental evidence of an Arrhenius-like growth kinetics along the stacking direction during supercooling., (© 2024. The Author(s).)

In 2014, a fire at an open cut coalmine in regional Victoria, Australia burned for 6 weeks. Residents of the nearby town of Morwell were exposed to smoke, which included high levels of fine particulate matter (PM 2.5 ). We investigated whether the long-term effects of PM 2.5 on respiratory health were moderated by diet quality. A cross-sectional analysis was conducted of data collected 8.5 years after the mine fire from 282 residents of Morwell and 166 residents from the nearby unexposed town of Sale. Primary outcomes were respiratory symptoms. Exposure was coalmine fire-related PM 2.5 and diet quality was assessed as Australian Recommended Food Score (ARFS) derived using the Australian Eating Survey (AES). The moderating effect of diet quality on respiratory outcomes associated with PM 2.5 was assessed using logistic regression models, adjusting for potential confounders. Diet quality was poor in this sample, with 60% in the lowest category of overall diet quality. Overall diet quality and fruit and vegetable quality significantly attenuated the association between PM 2.5 and prevalence of chronic cough and phlegm. Sauce/condiment intake was associated with a greater effect of PM 2.5 on COPD prevalence. No other moderating effects were significant. The moderating effects of overall diet quality and vegetable and fruit intake aligned with a priori hypotheses, suggesting potential protective benefits. While more evidence is needed to confirm these findings, improving diets, especially fruit and vegetable intake, may provide some protection against the effects of smoke exposure from fire events., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Thara Govindaraju, Matthew Carroll, Brigitte M. Borg, Catherine L. Smith, Caroline X. Gao, David Brown, David Poland, Shantelle Allgood, Jillian F. Skin, Michael J. Abrasion, Tyler J. Lane reports financial support was provided by Victoria Department of Health. Michael J. Abramson reports a relationship with Pfizer, Boehringer-Ingelheim, Sanofi, GSK that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Aim: There are few long-term studies of respiratory health effects of landscape fires, despite increasing frequency and intensity due to climate change. We investigated the association between exposure to coal mine fire PM 2.5 and fractional exhaled nitric oxide (FeNO) concentration 7.5 years later., Methods: Adult residents of Morwell, who were exposed to the 2014 Hazelwood mine fire over 6 weeks, and unexposed residents of Sale, participated in the Hazelwood Health Study Respiratory Stream in 2021, including measurements of FeNO concentration, a marker of eosinophilic airway inflammation. Individual exposure to coal mine fire PM 2.5 was modelled and mapped to time-location diaries. The effect of exposure to PM 2.5 on log-transformed FeNO in exhaled breath was investigated using multivariate linear regression models in the entire sample and stratified by potentially vulnerable subgroups., Results: A total of 326 adults (mean age: 57 years) had FeNO measured. The median FeNO level (interquartile range [IQR]) was 17.5 [15.0] ppb, and individual daily exposure to coal mine fire PM 2.5 was 7.2 [13.8] µg/m 3 . We did not identify evidence of association between coal mine fire PM 2.5 exposure and FeNO in the general adult sample, nor in various potentially vulnerable subgroups. The point estimates were consistently close to zero in the total sample and subgroups., Conclusion: Despite previous short-term impacts on FeNO and respiratory health outcomes in the medium term, we found no evidence that PM 2.5 from the Hazelwood coal mine fire was associated with any long-term impact on eosinophilic airway inflammation measured by FeNO levels., (© 2024. The Author(s).)

The main protease (M pro ) of SARS-CoV-2 is critical for viral function and a key drug target. M pro is only active when reduced; turnover ceases upon oxidation but is restored by re-reduction. This suggests the system has evolved to survive periods in an oxidative environment, but the mechanism of this protection has not been confirmed. Here, we report a crystal structure of oxidized M pro showing a disulfide bond between the active site cysteine, C145, and a distal cysteine, C117. Previous work proposed this disulfide provides the mechanism of protection from irreversible oxidation. M pro forms an obligate homodimer, and the C117-C145 structure shows disruption of interactions bridging the dimer interface, implying a correlation between oxidation and dimerization. We confirm dimer stability is weakened in solution upon oxidation. Finally, we observe the protein's crystallization behavior is linked to its redox state. Oxidized M pro spontaneously forms a distinct, more loosely packed lattice. Seeding with crystals of this lattice yields a structure with an oxidation pattern incorporating one cysteine-lysine-cysteine (SONOS) and two lysine-cysteine (NOS) bridges. These structures further our understanding of the oxidative regulation of M pro and the crystallization conditions necessary to study this structurally., (© 2024. The Author(s).)

Even when brain scans fail to detect a striate lesion, functional evidence for blindsight can be adduced. In the aftermath of an automobile accident, JK became blind. Results of ophthalmic exams indicated that the blindness must be cortical. Nevertheless, multiple MRI scans failed to detect structural damage to the striate cortex. Prior to the accident JK had been an athlete; after the accident he retained some athletic abilities, arousing suspicions that he might be engaged in fraud. His residual athletic abilities-e.g., hitting a handball or baseball, or catching a Frisbee-coupled with his experienced blindness, suggested blindsight. But due to the apparent absence of striate lesions, we designed a series of tasks for temporal and spatial dimensions in an attempt to detect functional evidence of his disability. Indeed, test results revealed compelling neural evidence that comport with his subjective reports. This spatiotemporal task-related method that includes contrasts with healthy controls, and detailed understanding of the patient's conscious experience, can be generalized for clinical, scientific and forensic investigations of blindsight., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Lane, Liou, Kung, Tseng and Wu.)

Background: In 2014, the Hazelwood coalmine fire shrouded the regional Australian town of Morwell in smoke and ash for 6 weeks. One of the fire's by-products, PM 2.5 , is associated with an increased risk of COVID-19 and severe disease. However, it is unclear whether the effect persisted for years after exposure. In this study, we surveyed a cohort established prior to the pandemic to determine whether PM 2.5 from the coalmine fire increased long-term vulnerability to COVID-19 and severe disease., Methods: From August to December 2022, 612 members of the Hazelwood Health Study's adult cohort, established in 2016/17, participated in a follow-up survey that included standardized items to capture COVID-19 cases, as well as questions about hospitalization and vaccinations. Associations were evaluated in crude and adjusted logistic regression models., Results: A total of 268 (44%) participants self-reported or met symptom criteria for having had COVID-19 at least once. All models found a positive association, with odds of COVID-19 increasing by between 4% and 30% for a 10 μg/m 3 increase in coalmine fire-related PM 2.5 exposure. However, the association was significant in only 2 of the 18 models. There were insufficient hospitalizations to examine severity (n = 7; 1%)., Conclusion: The findings are inconclusive on the effect of coalmine fire-related PM 2.5 exposure on long-term vulnerability to COVID-19. Given the positive association that was robust to modelling variations as well as evidence for a causal mechanism, it would be prudent to treat PM 2.5 from fire events as a long-term risk factor until more evidence accumulates., (© 2023 The Authors. Respirology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Respirology.)

Photolyase is an enzyme that uses light to catalyze DNA repair. To capture the reaction intermediates involved in the enzyme's catalytic cycle, we conducted a time-resolved crystallography experiment. We found that photolyase traps the excited state of the active cofactor, flavin adenine dinucleotide (FAD), in a highly bent geometry. This excited state performs electron transfer to damaged DNA, inducing repair. We show that the repair reaction, which involves the lysis of two covalent bonds, occurs through a single-bond intermediate. The transformation of the substrate into product crowds the active site and disrupts hydrogen bonds with the enzyme, resulting in stepwise product release, with the 3' thymine ejected first, followed by the 5' base.

Although highly related, mental illness may not fully determine perceived well-being, a distinction captured by dual-continuum models. Separating mental illness and well-being into related but separate constructs prompted investigation into potential buffers to reduce the impact of mental illness on perceived well-being. This study explored two such buffers in health literacy and psychological resilience among Australian men. Using the Ten to Men Australian Longitudinal Study on Male Health, this secondary data analysis of n = 8,408 men between 18 and 60 years of age assessed the moderating effect of three components of health literacy (feeling supported by health care providers, ability to find health information, and active engagement with health care providers) and psychological resilience on the relationship between mental illness and well-being. Mental illness symptoms were negatively associated with well-being, whereas psychological resilience, active engagement with health care, and health care provider support (β res = .65, β eng = .28, and β sup = .25) had positive significant relationships with the outcome (all p ≤ .001). Ability to find health information ( p = .25) and psychological resilience ( p = .43) were not significantly associated with well-being. Of the four interactions tested, health literacy relating to health care worker support was the only significant moderator between mental illness and well-being (β sup = .03). This study identified that meaningful support and understanding from health care providers for Australian men aged between 18 and 60 years may somewhat ameliorate the impact of mental illness on well-being. Further related investigation may reveal specific interventions that improve perceptions of support among men., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Neuroimaging and lesion studies suggested that the dorsolateral prefrontal and posterior parietal cortices mediate visual metacognitive awareness. The causal evidence provided by non-invasive brain stimulation, however, is inconsistent., Objective/hypothesis: Here we revisit a major figure discrimination experiment adding a new Kanizsa figure task trying to resolve whether bilateral continuous theta-burst transcranial magnetic stimulation (cTBS) over these regions affects perceptual metacognition. Specifically, we tested whether subjective visibility ratings and/or metacognitive efficiency are lower when cTBS is applied to these two regions in comparison to an active control region., Methods: A within-subjects design including three sessions spaced by one-week intervals was implemented. In each session, every participant was administered bilateral cTBS to either prefrontal, control or parietal cortices. Two concurrent tasks were performed, a real and an illusory figure task, stabilising objective performance with use of an adaptive staircase procedure., Results: When performing the replicated task, cTBS was found insufficient to disrupt neither visibility ratings nor metacognitive efficiency. However, with use of Kanizsa style illusory figures, cTBS over the dorsolateral prefrontal, but not over the posterior parietal cortex, was observed to significantly diminish metacognitive efficiency., Conclusion(s): Real and illusory figure tasks demonstrated different cTBS effects. A possible explanation is the involvement of the prefrontal cortex in the creation of expectations, which is necessary for efficient metacognition. Failure to replicate previous findings for the real figure task, however, cannot be said to support, conclusively, the notion that these brain regions have a causal role in metacognitive awareness. This inconsistent finding may result from certain limitations of our study, thereby suggesting the need for yet further investigation., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Many nations have established workers' compensation systems as a feature of their social protection system. These systems typically provide time-limited entitlements such as wage replacement benefits and funding for medical treatment. Entitlements may end for workers with long-term health conditions before they have returned to employment. We sought to determine the prevalence of transitions to alternative forms of social protection, specifically social security benefits, among injured workers with long-term disability, when workers' compensation benefits end. We linked Australian workers' compensation and social security data to examine receipt of social security payments one year before and after workers' compensation benefit cessation. Study groups included (1) injured workers whose workers' compensation benefits ceased due to reaching a 260-week limit introduced by legislative reform (N = 2761), (2) a control group of injured workers with at least 104 weeks workers compensation income support (N = 3890), and (3) a matched community control group (N = 10,114). Adjusted binary logistic regression examined the odds of transitions to social security in the injured worker groups relative to the community control group. Within 12 months of workers' compensation benefit cessation, 60% (N = 1669) of the exposed group received social security payments, of which 41% (N = 1120) received the unemployment allowance and 19% (N = 516) the disability pension. Among the work injured control group, 42% (N = 1676) received social security payments after workers compensation benefits ceased. Transitions to social security payments were significantly more common than community levels for both exposed (OR 25.0, 95%CI = 20.7, 30.1) and work injured control groups (OR 4.7, 95%CI = 4.2, 5.3). Many injured workers with long-term health problems transition to social security when their workers' compensation benefits cease. Transitions were more common among workers whose claims ended due to legislative reform which time-limited benefits. Design and implementation of system level policy reform should consider the social and economic impacts of transitions between separate social protection systems., Competing Interests: The authors declare that they have no competing interests.The authors declare that they have no competing interests., (© 2023 The Authors.)

Objective: In 2015, South Australia replaced its workers' compensation system with the aim of improving return to work rates. We examined whether this was achieved by focusing on the duration of time off work, as well as claim processing times and claim volumes to understand how this may have been achieved., Methods: The primary outcome was mean weeks of compensated disability duration. Secondary outcomes tested alternative mechanisms of a change in disability duration: (1) mean employer report and insurer decision times to evaluate whether there had been changes in claim processing and (2) claim volumes to determine whether the new system altered the cohort under investigation. Outcomes were aggregated into monthly units and analysed with an interrupted time series design. Three condition subgroups-injury, disease and mental health-were compared in separate analyses., Results: While disability duration steadily declined before the RTW Act came into effect, afterwards it flatlined. A similar effect was observed in insurer decision time. Claim volumes gradually increased. Employer report time gradually decreased. Condition subgroups mostly followed a similar pattern to overall claims, though the increase in insurer decision time appears largely driven by changes in injury claims., Conclusions: The increase in disability duration after the RTW Act took effect may be attributable to an increase in insurer decision time, which itself could be due to the disruption of overhauling a compensation system or the elimination of provisional liability entitlements that incentivised early decision making and provided early intervention., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Using data from n  = 194 nation-states, Kleck found that firearm availability was only associated with firearm suicide rates, but not total or non-firearm suicides. He thus concluded that while firearm availability influences how people commit suicide, it does not affect total numbers. However, the study contains numerous logical and methodological issues and is at odds with the evidence base. Therefore, I attempt to reproduce the original results., Method: I reproduce the original study's methods: ordinary least squares regression, weighted by the square root of the population, with log-transformed suicide rates and three separate firearm availability measures: global estimates from the Small Arms Survey , proportion of suicides committed with firearms, and a European Union survey of firearm ownership. I also test several methodological variations and include U.S. suicide data., Results: In contrast to Kleck, global analyses with Small Arms Survey data found a significant and positive association between firearm availability and total suicides, as did U.S. analyses. Analyses with other firearm availability measures comported with the original study, finding no association., Conclusion: The main result in Kleck failed to reproduce, finding instead a significant association between firearm availability and suicide rates, as did U.S. analyses. While reproductions of Kleck's other analyses continued to show no association, they were based on unreliable methods. I therefore reject Kleck's conclusion that that firearm availability does not influence suicide rates. HighlightsUsing data global data, I find firearm availability is positively associated with suicide rates.I identify serious flaws in the logic and methods of Kleck and an earlier review.For transparency, data and code have been archived on a public repository.

The phase transition between water and ice is ubiquitous and one of the most important phenomena in nature. Here, we performed time-resolved x-ray scattering experiments capturing the melting and recrystallization dynamics of ice. The ultrafast heating of ice I is induced by an IR laser pulse and probed with an intense x-ray pulse which provided us with direct structural information on different length scales. From the wide-angle x-ray scattering (WAXS) patterns, the molten fraction, as well as the corresponding temperature at each delay, were determined. The small-angle x-ray scattering (SAXS) patterns, together with the information extracted from the WAXS analysis, provided the time-dependent change of the size and the number of liquid domains. The results show partial melting (~13%) and superheating of ice occurring at around 20 ns. After 100 ns, the average size of the liquid domains grows from about 2.5 nm to 4.5 nm by the coalescence of approximately six adjacent domains. Subsequently, we capture the recrystallization of the liquid domains, which occurs on microsecond timescales due to the cooling by heat dissipation and results to a decrease of the average liquid domain size., (© 2023. The Author(s).)

The past century has witnessed an exponential increase in our atomic-level understanding of molecular and cellular mechanisms from a structural perspective, with multiple landmark achievements contributing to the field. This, coupled with recent and continuing breakthroughs in artificial intelligence methods such as AlphaFold2, and enhanced computational power, is enabling our understanding of protein structure and function at unprecedented levels of accuracy and predictivity. Here, we describe some of the major recent advances across these fields, and describe, as these technologies coalesce, the potential to utilise our enhanced knowledge of intricate cellular and molecular systems to discover novel therapeutics to alleviate human suffering., Competing Interests: Conflict of interest statement All authors are shareholders and employees of CHARM Therapeutics Ltd. and declare competing financial interests., (Copyright © 2023. Published by Elsevier Ltd.)

Background: In 2014, wildfires ignited a coal mine in Australia, burning for 6 weeks, releasing large amounts of fine particulate matter ≤2.5 μm in diameter (PM 2.5 ). We investigated the association between individual PM 2.5 exposure and emergency department presentations (EDPs) within 5 years post-fire., Methods: Survey and exposure data for 2725 residents from an exposed and unexposed town were linked with ED administrative data from 2009 to 2019. The association between individual PM 2.5 and EDPs was assessed using recurrent survival analysis., Results: A 10 μg/m 3 increase in PM 2.5 was associated with a 10% increase in respiratory EDPs (HR = 1.10; 95%CI:1.00-1.22) over 5 years post-fire. Increased risks of EDPs for ischaemic heart disease (HR = 1.39; 95%CI:1.12-1.73), atherothrombotic disease (HR = 1.27; 95%CI:1.08-1.50), and cardiovascular disease (HR = 1.10, 95%CI:0.99-1.22) were evident within 2.5 years., Conclusion: PM 2.5 exposure from a 6-week mine fire increased the 5-year risk of respiratory conditions. An increased risk of CVD within 2.5 years post-fire subsided after this time., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Michael Abramson reports a relationship with Pfizer that includes: funding grants. Michael Abramson reports a relationship with Boehringer-Ingelheim that includes: funding grants. Michael Abramson reports a relationship with Sanofi that includes: consulting or advisory and funding grants. Michael Abramson reports a relationship with GSK that includes: funding grants and speaking and lecture fees. Dion Stub reports a relationship with National Heart Foundation of Australia that includes: funding grants. Yuming Guo reports a relationship with Australian National Health and Medical Research Council that includes: funding grants., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The 2014 Hazelwood coal mine fire in the Latrobe Valley, Australia, distributed toxic smoke into surrounding communities over 45 days. This study investigated risk and protective factors associated with four trajectories of posttraumatic distress (resilient, recovery, delayed-onset, chronic) among exposed adults. Participants (N = 709) completed surveys in 2016-2017 and 2019-2020 assessing mine fire-related particulate matter (PM 2.5 ) exposure; sociodemographic, physical, and mental health variables; and exposure to other traumatic and recent stressful events. Mine fire-related posttraumatic distress was measured using the IES-R; trajectories were determined according to established clinical significance thresholds. Relative risk ratios (RRRs) were generated from multivariate multinomial regressions. The resilient trajectory was most common (77.0%). The chronic trajectory (8.5%) was associated with loneliness, RRR = 2.59, 95% CI [1.30, 5.16], and physical health diagnoses, RRR = 2.31, 95% CI [1.32, 4.02]. The delayed-onset trajectory (9.1%) was associated with multiple recent stressful events, RRR = 2.51, 95% CI [1.37, 4.59]; mental health diagnoses, RRR = 2.30, 95% CI [1.25, 4.24]; loneliness, RRR = 2.05, 95% CI [1.09, 3.88]; and male gender, RRR = 2.01, 95% CI [1.18, 3.44]. Socioeconomic advantage protected against chronic, RRR = 0.68, 95% CI [0.53, 0.86], and delayed-onset trajectory membership, RRR = 0.68, 95% CI [0.50, 0.94]; social support protected against chronic trajectory membership, RRR = 0.67, 95% CI [0.49, 0.92]. PM 2.5 exposure did not determine trajectory. These findings enhance understanding of longer-term posttraumatic responses to large-scale smoke events and can inform mental health initiatives within at-risk communities., (© 2023 The Authors. Journal of Traumatic Stress published by Wiley Periodicals LLC on behalf of International Society for Traumatic Stress Studies.)

Recent experiments continue to find evidence for a liquid-liquid phase transition (LLPT) in supercooled water, which would unify our understanding of the anomalous properties of liquid water and amorphous ice. These experiments are challenging because the proposed LLPT occurs under extreme metastable conditions where the liquid freezes to a crystal on a very short time scale. Here, we analyze models for the LLPT to show that coexistence of distinct high-density and low-density liquid phases may be observed by subjecting low-density amorphous (LDA) ice to ultrafast heating. We then describe experiments in which we heat LDA ice to near the predicted critical point of the LLPT by an ultrafast infrared laser pulse, following which we measure the structure factor using femtosecond x-ray laser pulses. Consistent with our predictions, we observe a LLPT occurring on a time scale < 100 ns and widely separated from ice formation, which begins at times >1 μs., (© 2023. The Author(s).)

Resting state networks comprise several brain regions that exhibit complex patterns of interaction. Switching from eyes closed (EC) to eyes open (EO) during the resting state modifies these patterns of connectivity, but precisely how these change remains unclear. Here we use functional magnetic resonance imaging to scan healthy participants in two resting conditions (viz., EC and EO). Seven resting state networks were chosen for this study: salience network (SN), default mode network (DMN), central executive network (CEN), dorsal attention network (DAN), visual network (VN), motor network (MN) and auditory network (AN). We performed functional connectivity (FC) analysis for each network, comparing the FC maps for both EC and EO. Our results show increased connectivity between most networks during EC relative to EO, thereby suggesting enhanced integration during EC and greater modularity or specialization during EO. Among these networks, SN is distinctive: during the transition from EO to EC it evinces increased connectivity with DMN and decreased connectivity with VN. This change might imply that SN functions in a manner analogous to a circuit switch, modulating resting state relations with DMN and VN, when transitioning between EO and EC.

Diffuse scattering has long been proposed to probe protein dynamics relevant for biological function, and more recently, as a tool to aid structure determination. Despite recent advances in measuring and modeling this signal, the field has not been able to routinely use experimental diffuse scattering for either application. A persistent challenge has been to devise models that are sophisticated enough to robustly reproduce experimental diffuse features but remain readily interpretable from the standpoint of structural biology. This chapter presents eryx, a suite of computational tools to evaluate the primary models of disorder that have been used to analyze protein diffuse scattering. By facilitating comparative modeling, eryx aims to provide insights into the physical origins of this signal and help identify the sources of disorder that are critical for reproducing experimental features. This framework also lays the groundwork for the development of more advanced models that integrate different types of disorder without loss of interpretability., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: Educators are exposed to several work-related hazards. Evidence suggests musculoskeletal pain, psychological distress, and student-inflicted violence-related injuries are common. However, there is little evidence on the burden of workplace injury among Australian educators., Aim: To compare incidence of injury claims and duration of compensated time off work between educators and non-educators, and associated factors., Methods: Retrospective cohort study of 1,559,676 Australian workers' compensation claims, including 84,915 educator claims, lodged between July 2009 to June 2015, from the National Dataset for Compensation-based Statistics. Cases were included if aged 18+ years and working in the education sector less than 100 h per week. Negative binomial regression models estimated the relative risk of making a compensation claim and survival analyses calculated disability duration within educators by sex, age, injury type and mechanism, socioeconomic area, remoteness, and jurisdiction., Results: Compared to non-educators, educators had lower rates of injury claims and shorter disability durations. However, educators had a higher rate of claims for mental health conditions and assault, with the highest risk being among those in special education and education aides. Among educators, injury claim rates were highest among special educators, education aides, and secondary educators., Discussion and Conclusion: Though surveys indicate Australians in the education sector have higher incidences of work-related injuries, this study found lower incidence of injury claims and shorter disability durations than others. Educators' injury-reporting and absenteeism behaviors may be constrained by ethical, social, and administrative attitudes. Educators had higher rates of claims for mental health and assault-related injury, particularly special educators, and education aides, which suggests a need for targeted prevention efforts., Competing Interests: Declaration of Competing Interest The Authors declare that there is no conflict of interest., (Copyright © 2022. Published by Elsevier Ltd.)

Previous research has suggested that bodily signals from internal organs are associated with diverse cortical and subcortical processes involved in sensory-motor functions, beyond homeostatic reflexes. For instance, a recent study demonstrated that the preparation and execution of voluntary actions, as well as its underlying neural activity, are coupled with the breathing cycle. In the current study, we investigated whether such breathing-action coupling is limited to voluntary motor action or whether it is also present for mental actions not involving any overt bodily movement. To answer this question, we recorded electroencephalography (EEG), electromyography (EMG), and respiratory signals while participants were conducting a voluntary action paradigm including self-initiated motor execution (ME), motor imagery (MI), and visual imagery (VI) tasks. We observed that the voluntary initiation of ME, MI, and VI are similarly coupled with the respiration phase. In addition, EEG analysis revealed the existence of readiness potential (RP) waveforms in all three tasks (i.e., ME, MI, VI), as well as a coupling between the RP amplitude and the respiratory phase. Our findings show that the voluntary initiation of both imagined and overt action is coupled with respiration, and further suggest that the breathing system is involved in preparatory processes of voluntary action by contributing to the temporal decision of when to initiate the action plan, regardless of whether this culminates in overt movements., Competing Interests: Declaration of Competing Interest H.D.P., O.A.K. and O.B. are inventors on a provisional patent application PCT/IB2020/050858 (Title: Method and system for determining the intention of performing a voluntary action) held by the Swiss Federal Institute (EPFL). O.B. is cofounder and shareholder of Metaphysiks Engineering SA. O.B. is member of the board and shareholder of Mindmaze SA., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

The concomitant motion of electrons and nuclei on the femtosecond time scale marks the fate of chemical and biological processes. Here we demonstrate the ability to initiate and track the ultrafast electron rearrangement and chemical bond breaking site-specifically in real time for the carbon monoxide diatomic molecule. We employ a local resonant x-ray pump at the oxygen atom and probe the chemical shifts of the carbon core-electron binding energy. We observe charge redistribution accompanying core-excitation followed by Auger decay, eventually leading to dissociation and hole trapping at one site of the molecule. The presented technique is general in nature with sensitivity to chemical environment changes including transient electronic excited state dynamics. This work provides a route to investigate energy and charge transport processes in more complex systems by tracking selective chemical bond changes on their natural timescale., (© 2022. The Author(s).)

Reversibly photoswitchable fluorescent proteins are essential markers for advanced biological imaging, and optimization of their photophysical properties underlies improved performance and novel applications. Here we establish a link between photoswitching contrast, one of the key parameters that dictate the achievable resolution in nanoscopy applications, and chromophore conformation in the non-fluorescent state of rsEGFP2, a widely employed label in REversible Saturable OpticaL Fluorescence Transitions (RESOLFT) microscopy. Upon illumination, the cis chromophore of rsEGFP2 isomerizes to two distinct off-state conformations, trans1 and trans2, located on either side of the V151 side chain. Reducing or enlarging the side chain at this position (V151A and V151L variants) leads to single off-state conformations that exhibit higher and lower switching contrast, respectively, compared to the rsEGFP2 parent. The combination of structural information obtained by serial femtosecond crystallography with high-level quantum chemical calculations and with spectroscopic and photophysical data determined in vitro suggests that the changes in switching contrast arise from blue- and red-shifts of the absorption bands associated to trans1 and trans2, respectively. Thus, due to elimination of trans2, the V151A variants of rsEGFP2 and its superfolding variant rsFolder2 display a more than two-fold higher switching contrast than their respective parent proteins, both in vitro and in E. coli cells. The application of the rsFolder2-V151A variant is demonstrated in RESOLFT nanoscopy. Our study rationalizes the connection between structural and photophysical chromophore properties and suggests a means to rationally improve fluorescent proteins for nanoscopy applications., (© 2022 The Authors. ChemPhysChem published by Wiley-VCH GmbH.)

This study investigated whether homicides increased after protested police-involved deaths, focusing on the period after Michael Brown's death in Ferguson in August 2014. It also tests for effects of legal cynicism by comparing effects in homicide and aggravated assault on the assumption that reporting of the latter is discretionary and police abuses may make communities reluctant to notify police. Using FBI data from 44 U.S. cities, homicide and assault rates from 2011 to 2019 were analyzed using an interrupted time series design and combined in a meta-analysis to calculate pooled effects. A meta-regression tested effect moderators including external investigations and city/county sociodemographic characteristics. With a conservative threshold of p ≤ .01, 21 of the 44 cities experienced a significant increase and one had a significant decrease. The pooled effect was a 26.1% increase in the homicide (99% CI: 15.3% to 36.8%). Aggravated assaults increased above baseline, though the effect was 15.2 percentage points smaller (99% CI: -26.7 to -3.6) than the effect in homicides. When outcomes were measured as percent change, there were no significant effect moderators, but when measured as absolute change, homicides increased to a greater extent when the death was subject to external investigation and in cities with higher Black populations, poverty rates, and baseline homicide rates. The findings suggest that protested police-involved deaths led to an increase in homicides and other violence due to the distrust fomented within the very communities whom police are meant to protect.

Objectives: The aims of the study are to determine the continuity of care (CoC) provided by primary care physicians among workers with low back pain, to identify factors associated with CoC, and to investigate whether CoC is associated with working time loss., Methods: Continuity of care was measured with the usual provider continuity metric. Ordinal logistic regression models examined factors associated with CoC. Quantile regression models examined the association between working time loss and CoC., Results: Complete CoC was observed in 33.8% of workers, high CoC among 37.7%, moderate CoC in 22.1%, and low CoC in 6.4%. In workers with more than 2-months time loss, those with complete CoC had less time off work., Conclusions: Higher CoC with a primary care physician is associated with less working time loss and this relationship is strongest in the subacute phase of low back pain., Competing Interests: Conflicts of Interest: The following organizations supplied data for use in this study: WorkCover Queensland, WorkSafe Victoria, and ReturnToWork South Australia. The study authors have received funding for unrelated research in the past 36 months from WorkSafe Victoria. The study authors have also received unrelated funding from Safe Work Australia, the Victorian Department of Health, Insurance and Care NSW, the State Insurance Regulatory Authority of NSW, and the Australian Government Department of Education. Alex Collie was supported by an Australian Research Council Future Fellowship (FT190100281)., (Copyright © 2022 American College of Occupational and Environmental Medicine.)

Serial femtosecond crystallography (SFX) has become one of the standard techniques at X-ray free-electron lasers (XFELs) to obtain high-resolution structural information from microcrystals of proteins. Nevertheless, reliable sample delivery is still often limiting data collection, as microcrystals can clog both field- and flow-focusing nozzles despite in-line filters. In this study, we developed acoustic 2D focusing of protein microcrystals in capillaries that enables real-time online characterization of crystal size and shape in the sample delivery line after the in-line filter. We used a piezoelectric actuator to create a standing wave perpendicular to the crystal flow, which focused lysozyme microcrystals into a single line inside a silica capillary so that they can be imaged using a high-speed camera. We characterized the acoustic contrast factor, focus size, and the coaxial flow lines and developed a splitting union that enables up-concentration to at least a factor of five. The focus size, flow rates, and geometry may enable an upper limit of up-concentration as high as 200 fold. The novel feedback and concentration control could be implemented for serial crystallography at synchrotrons with minor modifications. It will also aid the development of improved sample delivery systems that will increase SFX data collection rates at XFELs, with potential applications to many proteins that can only be purified and crystallized in small amounts.

SARS-CoV-2 papain-like protease (PLpro) covers multiple functions. Beside the cysteine-protease activity, facilitating cleavage of the viral polypeptide chain, PLpro has the additional and vital function of removing ubiquitin and ISG15 (Interferon-stimulated gene 15) from host-cell proteins to support coronaviruses in evading the host's innate immune responses. We identified three phenolic compounds bound to PLpro, preventing essential molecular interactions to ISG15 by screening a natural compound library. The compounds identified by X-ray screening and complexed to PLpro demonstrate clear inhibition of PLpro in a deISGylation activity assay. Two compounds exhibit distinct antiviral activity in Vero cell line assays and one inhibited a cytopathic effect in non-cytotoxic concentration ranges. In the context of increasing PLpro mutations in the evolving new variants of SARS-CoV-2, the natural compounds we identified may also reinstate the antiviral immune response processes of the host that are down-regulated in COVID-19 infections., (© 2022. The Author(s).)

Purpose To identify whether there were differences in work disability duration between injured workers employed by small, medium, large, and self-insured firms and whether these differences varied between workers' compensation jurisdictions in Canada and Australia. Methods Workers' compensation data were used to identify comparable lost-time, work-related injury and musculoskeletal disorder claims in five Canadian and five Australian jurisdictions between 2011 and 2015. Work disability duration was measured using cumulative disability days paid up to one-year post-injury. Jurisdiction-specific quantile regression models were used to estimate differences in cumulative disability days paid to claims from small (< 20 full-time equivalents (FTEs)) medium (20-199 FTEs), large (200 + FTEs) and self-insured firms at the 25th, 50th, and 70th percentiles in the disability distribution, adjusting for confounders. Results Compared to large firms, workers in small firms generally had longer work disability duration at each percentile, particularly in Saskatchewan and Alberta (Canada), Victoria and Australian Capital Territory (Australia), where an additional 31.1, 18.4, 58.5 and 37.0 days were paid at the 75th percentiles, respectively. The disability duration of workers from self-insured firms was longer than large firms in all Canadian jurisdictions but was shorter or no different in Australian jurisdictions. Smaller differences were observed between claims from large and medium-sized firms. Conclusions Workers in small firms had longer work disability duration than those in large firms in all but one of the study jurisdictions. Claims management processes need to be sensitive to the challenges that small firms face in accommodating and returning injured workers back to work., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose Time off work after workplace injury varies by compensation system. While often attributed to features of the compensation system, unaccounted regional factors may drive much of the effect. In this study, we compare disability durations by state and territory of residence within a single national workers' compensation system. Large differences would indicate that factors other than compensation system settings are responsible for system effects observed in previous studies. Methods We applied crude and adjusted Cox proportional hazards models to compare disability durations by state and territory of residence. Confounders included factors known to influence disability duration. Durations were left-censored at two weeks and right-censored at 104 weeks. Results We analysed N = 31,641 claims. In both crude and adjusted models, three of the seven states and territories significantly differed from the reference group, New South Wales. However, two of the three were different between crude and adjusted models. Regional effects were relatively small compared to other factors including insurer type, age, and type of injury. Conclusions Regional factors influence disability duration, which persist with adjustment for demographic, work, insurer type, and injury confounders. However, the effects are inconsistently significant and fairly small, especially when compared to the effect of confounders and system effects found in previous studies. Regional factors likely only account for a small share of the difference in disability duration between compensation systems., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature.)

Purpose: Workers' compensation claims consist of occupational injuries severe enough to meet a compensability threshold. Theoretically, systems with higher thresholds should have fewer claims but greater average severity. For research that relies on claims data, particularly cross-jurisdictional comparisons of compensation systems, this results in collider bias that can lead to spurious associations confounding analyses. In this study, I use real and simulated claims data to demonstrate collider bias and problems with methods used to account for it., Methods: Using Australian claims data, I used a linear regression to test the association between claim rate and mean disability durations across Statistical Areas. Analyses were repeated with nesting by state/territory to account for variations in compensability thresholds across compensation systems. Both analyses are repeated on left-censored data. Simulated claims data are analysed with Cox survival analyses to illustrate how left-censoring can reverse effects., Results: The claim rate within a Statistical Area was inversely associated with disability duration. However, this reversed when Statistical Areas were nested by state/territory. Left-censoring resulted in an attenuation of the unnested association to non-significance, while the nested association remained significantly positive. Cox regressions with simulated claims data demonstrated how left-censoring can reverse effects., Conclusions: Collider bias can seriously confound work disability research, particularly cross-jurisdictional comparisons. Work disability researchers must grapple with this challenge by using appropriate study designs and analytical approaches, and considering how it affects the interpretation of results., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Using time-resolved wide-angle X-ray scattering, we investigated the early stages (10 μs-1 ms) of crystallization of supercooled water, obtained by the ultrafast heating of high- and low-density amorphous ice (HDA and LDA) up to a temperature T = 205 K ± 10 K. We have determined that the crystallizing phase is stacking disordered ice ( I sd ), with a maximum cubicity of χ = 0.6, in agreement with predictions from molecular dynamics simulations at similar temperatures. However, we note that a growing small portion of hexagonal ice ( I h ) was also observed, suggesting that within our timeframe, I sd starts annealing into I h . The onset of crystallization, in both amorphous ice, occurs at a similar temperature, but the observed final crystalline fraction in the LDA sample is considerably lower than that in the HDA sample. We attribute this discrepancy to the thickness difference between the two samples.

Susceptibility to the rubber hand illusion (RHI) varies. To date, however, there is no consensus explanation of this variability. Previous studies, focused on the role of multisensory integration, have searched for neural correlates of the illusion. But those studies have failed to identify a sufficient set of functionally specific neural correlates. Because some evidence suggests that frontal α power is one means of tracking neural instantiations of self, we hypothesized that the higher the frontal α power during the eyes-closed resting state, the more stable the self. As a corollary, we infer that the more stable the self, the less susceptible are participants to a blurring of boundaries-to feeling that the rubber hand belongs to them. Indeed, we found that frontal α amplitude oscillations negatively correlate with susceptibility. Moreover, since lower frequencies often modulate higher frequencies, we explored the possibility that this might be the case for the RHI. Indeed, some evidence suggests that high frontal α power observed in low-RHI participants is modulated by δ frequency oscillations. We conclude that while neural correlates of multisensory integration might be necessary for the RHI, sufficient explanation involves variable intrinsic neural activity that modulates how the brain responds to incompatible sensory stimuli., (© The Author(s) 2022. Published by Oxford University Press.)

The structural changes of water upon deep supercooling were studied through wide-angle x-ray scattering at SwissFEL. The experimental setup had a momentum transfer range of 4.5 Å -1 , which covered the principal doublet of the x-ray structure factor of water. The oxygen-oxygen structure factor was obtained for temperatures down to 228.5 ± 0.6 K. Similar to previous studies, the second diffraction peak increased strongly in amplitude as the structural change accelerated toward a local tetrahedral structure upon deep supercooling. We also observed an anomalous trend for the second peak position of the oxygen-oxygen structure factor (q 2 ). We found that q 2 exhibits an unprecedented positive partial derivative with respect to temperature for temperatures below 236 K. Based on Fourier inversion of our experimental data combined with reference data, we propose that the anomalous q 2 shift originates from that a repeat spacing in the tetrahedral network, associated with all peaks in the oxygen-oxygen pair-correlation function, gives rise to a less dense local ordering that resembles that of low-density amorphous ice. The findings are consistent with that liquid water consists of a pentamer-based hydrogen-bonded network with low density upon deep supercooling.

Background: Rumination, a tendency to focus on negative self-related thoughts, is a central symptom of depression. Studying the self-related aspect of such symptoms is challenging because of the need to distinguish self effects from the emotional content of task stimuli. This study employed an emotionally neutral self-related paradigm to investigate possible altered self-processing in depression and its link to rumination., Methods: People with major depressive disorder ( n = 25) and controls ( n = 25) underwent task-based electro-encephalogram recording. We studied late event-related potentials, along with low-frequency oscillatory power. We compared electroencephalogram metrics between groups and correlated them with depressive symptoms and reported rumination., Results: Participants with major depressive disorder displayed a difference in late positive potentials across frontocentral electrodes between self-related and non-self-related conditions. We found no such difference in controls. The magnitude of this difference was positively correlated with depressive symptoms and reported rumination. Participants with major depressive disorder also had elevated theta oscillation power at central electrodes in self-related conditions, a finding that we did not see in controls., Limitations: Patients with major depressive disorder were medicated at the time of the study. The group studied was primarily female, so the observed effects may have been sex-specific., Conclusion: Rumination appears to be linked to altered self-related processing in depression, independent of stimuli-related emotional confounds. This connection between self-related processing and depression may point to a self disorder as a core component of depression., Competing Interests: Competing interests: None declared., (© 2021 CMA Joule Inc. or its licensors.)

Sertraline is one of the most commonly prescribed antidepressants. Major depressive disorder (MDD) is characterized by spontaneous thoughts that are laden with negative affect-a "malignant sadness". Prior neuroimaging studies have identified abnormal resting-state functional connectivity (rsFC) in the spontaneous brain networks of MDD patients. But how antidepressant medication acts to relieve the experience of depression as well as adjust its associated spontaneous networks and mood-regulation circuits remains an open question. In this study, we recruited 22 drug-naïve MDD patients along with 35 normal controls and investigated whether the functional integrity of cortical networks associated with spontaneous thoughts is modulated by sertraline treatment. We attempted to predict post-treatment effects based upon what we observed in the pre-treatment rsFC of drug-naïve MDD patients. In the result, we demonstrated that (1) after the sertraline treatment, the medial temporal lobe of default network (DN MTL ) and mood regulation pathway-the fronto-parietal control network (FPCN), the thalamus, and the salience network (SN)-were restored to normal connectivity, relative to the pre-treatment condition; however, the altered connections of FPCN-core DN (DN CORE ), FPCN-SN, and intra-FPCN among MDD patients remained impaired; (2) thalamo-prefrontal connectivity provides moderate predictive power (r 2  = 0.63) for the effectiveness of sertraline treatment. In summary, our findings contribute to a body of evidence that suggests salubrious effects of sertraline treatment primarily involve the FPCN-thalamus-SN pathway. The pre-treatment rsFC in this pathway could serve as a predictor of sertraline treatment outcome., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

We report observations of nanosecond nonuniform colloidal dynamics in a free flowing liquid jet using ultrafast x-ray speckle visibility spectroscopy. Utilizing a nanosecond double-bunch mode, the Linac Coherent Light Source free electron laser produced pairs of femtosecond coherent hard x-ray pulses. By exploring anisotropy in the visibility of summed speckle patterns which relates to the correlation functions, we evaluate not only the average particle flow rate in a colloidal nanoparticle jet, but also the nonuniform flow field within. The methodology presented here establishes the foundation for the study of nano- and atomic-scale inhomogeneous fluctuations in complex matter using x-ray free electron laser sources.

Objectives: To identify geographic hotspots and coldspots of work disability burden and their associated sociodemographic factors in Australia., Methods: Using Australian workers' compensation and census data, we calculated weeks of compensated time off work per 1000 labor force, an indicator of work disability burden, at Statistical Area Level 4, the smallest level of labor force data produced by the Australian Bureau of Statistics. Records included all claims with at least 1 day of compensated time off work lodged between 2010 and 2015. Work disability burden was z-transformed by state and territory and mapped across Australia. Statistical Areas that were more than 1 standard deviation from the state or territory mean were considered hotspots and coldspots. We tested several sociodemographic factors as predictors of work disability burden., Results: Work disability burden hotspots were concentrated in lower socioeconomic suburbs and exurbs of state capitals, in addition to several regional areas. Coldspots were primarily in wealthy central urban and suburban areas. Factors associated with greater work disability burden include higher area socioeconomic disadvantage, rurality, lower labor force participation, higher unemployment, higher proportion of work in production industries and in blue-collar occupations, and higher numbers of those with core activity limitations, those aged 65+ years, and foreign-born residents., Conclusions: Work disability burden is unequally distributed across Australia and strongly influenced by sociodemographic and occupational factors. The findings can guide more efficient allocation of resources for work disability prevention and rehabilitation., (© 2021 Wiley Periodicals LLC.)

Background: In 2012, the Australian state of New South Wales passed legislation that reformed its workers' compensation system. Section 39 introduced a five-year limit on income replacement, with the first affected group having their benefits cease in December 2017. There is limited evidence on how this will affect their healthcare service use and where they will go for financial support., Methods: Multiple data sources will be linked: administrate workers' compensation claims data from the State Insurance Regulatory Authority (SIRA), universal health insurance data from the Medical Benefits Schedule (MBS) and Pharmaceutical Benefits Scheme (PBS), state hospital and emergency department data, and social welfare data from the Department of Social Services' Data Over Multiple Individual Occurrences (DOMINO). An estimated 4,125 injured workers had their benefits cease due to Section 39. These will form the exposure group who will be compared to 1) a similar group of workers' compensation claimants who have had at least two years of compensated time off work but whose benefits did not cease due to Section 39; and 2) a community comparison group drawn from state hospital and emergency department records.An accredited third party will link the data, which will be accessible only via secure virtual machine. Initial analyses will compare the prevalence and incidence of service use across groups in both the year before and year after benefit cessation; the community control will be assigned the median benefit cessation date in lieu of an actual date. To estimate the impact of benefit cessation due to Section 39, we will conduct time series analysis of the prevalence and incidence of service use., Discussion: This study will provide much-needed evidence on the consequences of long-term benefit cessation, particularly on subsequent healthcare and welfare service use., Competing Interests: Statement of Conflicts of Interest: The authors receive partial salary support from the State Insurance Regulatory Authority grant, who are also the workers’ compensation data custodians.

The coronavirus disease (COVID-19) caused by SARS-CoV-2 is creating tremendous human suffering. To date, no effective drug is available to directly treat the disease. In a search for a drug against COVID-19, we have performed a high-throughput x-ray crystallographic screen of two repurposing drug libraries against the SARS-CoV-2 main protease (M pro ), which is essential for viral replication. In contrast to commonly applied x-ray fragment screening experiments with molecules of low complexity, our screen tested already-approved drugs and drugs in clinical trials. From the three-dimensional protein structures, we identified 37 compounds that bind to M pro In subsequent cell-based viral reduction assays, one peptidomimetic and six nonpeptidic compounds showed antiviral activity at nontoxic concentrations. We identified two allosteric binding sites representing attractive targets for drug development against SARS-CoV-2., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Fatty acid photodecarboxylase (FAP) is a photoenzyme with potential green chemistry applications. By combining static, time-resolved, and cryotrapping spectroscopy and crystallography as well as computation, we characterized Chlorella variabilis FAP reaction intermediates on time scales from subpicoseconds to milliseconds. High-resolution crystal structures from synchrotron and free electron laser x-ray sources highlighted an unusual bent shape of the oxidized flavin chromophore. We demonstrate that decarboxylation occurs directly upon reduction of the excited flavin by the fatty acid substrate. Along with flavin reoxidation by the alkyl radical intermediate, a major fraction of the cleaved carbon dioxide unexpectedly transformed in 100 nanoseconds, most likely into bicarbonate. This reaction is orders of magnitude faster than in solution. Two strictly conserved residues, R451 and C432, are essential for substrate stabilization and functional charge transfer., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)