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Abstract This paper investigates and technically demonstrates a capacitive power transfer (CPT) system applicable to the charging of emerging very‐low‐power portable devices. The constant‐current operation of the primary LCL compensation in CPT is implemented and analysed to simplify the system design process and minimize the configuration on the receiving side. Additionally, the system design considerations for the capacitive coupler and the diode rectifier are presented based on the battery charging specifications. All the design concepts and considerations are validated through experimentation with a 13.56 MHz CPT system, which achieves load‐independent constant‐current output from full‐load to light‐load (one‐tenth of the full load) charging operations.

Abstract The aberrant expression of specific long noncoding RNAs (lncRNAs) has been associated with cognitive and psychiatric disorders. Although a growing number of lncRNAs are now known to regulate neural cell development and function, relatively few lncRNAs have been shown to underlie animal behavior. Pnky is an evolutionarily conserved, neural lncRNA that regulates brain development. Using mouse genetic strategies, we show that Pnky has sex-specific roles in mouse behavior and that this lncRNA can underlie specific behavior by functioning in trans. Male Pnky-knockout mice have decreased context generalization in a paradigm of associative fear learning and memory. In female Pnky-knockout mice, there is an increase in the acoustic startle response, a behavior that is altered in affective disorders. Remarkably, expression of Pnky from a bacterial artificial chromosome transgene decreases the acoustic startle response in female Pnky-knockout mice, demonstrating that Pnky can modulate specific animal behavior by functioning in trans. More broadly, these studies illustrate how specific lncRNAs can underlie cognitive and mood disorders.

Abstract The prevalence of multidrug resistant (MDR) bacterial infections continues to rise as the development of antibiotics needed to combat these infections remains stagnant. MDR enterococci are a major contributor to this crisis. A potential therapeutic approach for combating MDR enterococci is bacteriophage (phage) therapy, which uses lytic viruses to infect and kill pathogenic bacteria. While phages that lyse some strains of MDR enterococci have been identified, other strains display high levels of resistance and the mechanisms underlying this resistance are poorly defined. Here, we use a CRISPR interference (CRISPRi) screen to identify a genetic locus found on a mobilizable plasmid from Enterococcus faecalis involved in phage resistance. This locus encodes a putative serine recombinase followed by a Type IV restriction enzyme (TIV-RE) that we show restricts the replication of phage phi47 in vancomycin-resistant E. faecalis. We further find that phi47 evolves to overcome restriction by acquiring a missense mutation in a TIV-RE inhibitor protein. We show that this inhibitor, termed type IV restriction inhibiting factor A (tifA), binds and inactivates diverse TIV-REs. Overall, our findings advance our understanding of phage defense in drug-resistant E. faecalis and provide mechanistic insight into how phages evolve to overcome antiphage defense systems.

Abstract Quantitative assessment of retinal microvasculature in optical coherence tomography angiography (OCTA) images is important for studying, diagnosing, monitoring, and guiding the treatment of ocular and systemic diseases. However, the OCTA user community lacks universal and transparent image analysis tools that can be applied to images from a range of OCTA instruments and provide reliable and consistent microvascular metrics from diverse datasets. We present a retinal extension to the OCTA Vascular Analyser (OCTAVA) that addresses the challenges of providing robust, easy-to-use, and transparent analysis of retinal OCTA images. OCTAVA is a user-friendly, open-source toolbox that can analyse retinal OCTA images from various instruments. The toolbox delivers seven microvascular metrics for the whole image or subregions and six metrics characterising the foveal avascular zone. We validate OCTAVA using images collected by four commercial OCTA instruments demonstrating robust performance across datasets from different instruments acquired at different sites from different study cohorts. We show that OCTAVA delivers values for retinal microvascular metrics comparable to the literature and reduces their variation between studies compared to their commercial equivalents. By making OCTAVA publicly available, we aim to expand standardised research and thereby improve the reproducibility of quantitative analysis of retinal microvascular imaging. Such improvements will help to better identify more reliable and sensitive biomarkers of ocular and systemic diseases.

Background: Reliable animal models are critical for preclinical research and should closely mimic the disease. With respect to route of infection, pathogenic agent, disease progression, clinical signs, and histopathological changes. Sheep have similar bone micro- and macrostructure as well as comparable biomechanical characteristics to humans. Their use in bone research is established, however their use in bone infection research is limited. This systematic review will summarise the key features of the available bone infection models using sheep, providing a reference for further development, validation, and application. Method: This systematic review was designed according to the PRISMA guidelines and registered with PROSPERO. Quality was assessed using SYRICLE's risk of bias tool adapted for animal studies. PubMed, MEDLINE, Web of Science and EMBASE were searched until March 2022.1921 articles were screened by two independent reviewers, and 25 were included for analysis. Results: Models have been developed in nine different breeds. Staphylococcus aureus was used in the majority of models, typically inoculating 108 colony forming units in tibial or femoral cortical defects. Infection was established with either planktonic or biofilm adherent bacteria, with or without foreign material implanted. Most studies used both radiological and microbiological analyses to confirm osteomyelitis. Conclusions: There is convincing evidence supporting the use of sheep in bone infection models of clinical disease. The majority of sheep studied demonstrated convincing osteomyelitis and tolerated the infection with minimal complications. Furthermore, the advantages of comparable biology and biomechanics may increase the success for translating in vivo results to successful therapies. The Translational potential of this article: In the realm of preclinical research, the translation to viable clinical therapies is often perilous, and the quest for reliable and representative animal models remains paramount. This systematic review accentuates the largely untapped potential of sheep as large animal models, especially in bone infection research. The anatomical and biomechanical parallels between sheep and human bone structures position sheep as an invaluable asset for studying osteomyelitis and periprosthetic joint infection. This comprehensive exploration of the literature demonstrates the robustness and translational promise of these models. Furthermore, this article underscores the potential applicability for sheep in developing effective therapeutic strategies for human bone infections.

ObjectiveA favorable effect of ultra-high dose rate (FLASH) radiation on normal tissue-sparing has been indicated in several preclinical studies. In these studies, the adverse effects of radiation damage were reduced without compromising tumor control. Most studies of proton FLASH investigate these effects within the entrance of a proton beam. However, the real advantage of proton therapy lies in the Spread-out Bragg Peak (SOBP), which allows for giving a high dose to a target with a limited dose to healthy tissue at the entrance of the beam. Therefore, a clinically relevant investigation of the FLASH effect would be of healthy tissues within a SOBP. Our study quantified the tissue-sparing effect of FLASH radiation on acute and late toxicity within an SOBP in a murine model.Material/MethodsRadiation-induced damage was assessed for acute and late toxicity in the same mice following irradiation with FLASH (Field dose rate of 60 Gy/s) or conventional (CONV, 0.34 Gy/s) dose rates. The right hindleg of unanesthetized female CDF1 mice was irradiated with single-fraction doses between 19.9-49.7 Gy for CONV and 30.4-65.9 Gy for FLASH with 5-8 mice per dose. The leg was placed in the middle of a 5 cm SOBP generated from a mono-energetic beam using a 2D range modulator. Acute skin toxicity quantified by hair loss, moist desquamation and toe separation was monitored daily within 29 days post-treatment. Late toxicity of fibrotic development measured by leg extendibility was monitored biweekly until 30 weeks post-treatment.ResultsComparison of acute skin toxicity following radiation indicated a tissue-sparing effect of FLASH compared to conventional single-fraction radiation with a mean protection ratio of 1.40 (1.35-1.46). Fibrotic development similarly indicated normal tissue sparing with a 1.18 (1.17-1.18) protection ratio. The acute skin toxicity tissue sparing was similar to data from entrance-beam irradiations of Sørensen et al. (4).ConclusionFull dose-response curves for acute and late toxicity after CONV and FLASH radiation were obtained. Radiation within the SOBP retains the normal-tissue-sparing effect of FLASH with a dose-modifying factor of 40% for acute skin damage and 18% for fibrotic development.

Background and purpose: Daily target re-delineation in online adaptive radiotherapy (oART) introduces uncertainty. The aim of this study was to evaluate artificial intelligence (AI) generated contours and inter-observer target variation among radiotherapy technicians in cone-beam CT (CBCT) guided oART of bladder cancer. Materials and methods: For each of 10 consecutive patients treated with oART for bladder cancer, one CBCT was randomly selected and retrospectively included. The bladder (CTV-T) was AI-segmented (CTV-TAI). Seven radiotherapy technicians independently reviewed and edited CTV-TAI, generating CTV-TADP. Contours were benchmarked against a ground truth contour (CTV-TGT) delineated blindly from scratch. CTV-TADP and CTV-TAI were compared to CTV-TGT using volume, dice similarity coefficient, and bidirectional local distance. Dose coverage (D99%>95 %) of CTV-TGT was evaluated for treatment plans optimized for CTV-TAI and CTV-TADP with clinical margins. Inter-observer variation among CTV-TADP was assessed using coefficient of variation and generalized conformity index. Results: CTV-TGT ranged from 48.7 cm3 to 211.6 cm3. The median [range] volume difference was 4.5 [−17.8, 42.4] cm3 for CTV-TADP and −15.5 [−54.2, 4.3] cm3 for CTV-TAI, compared to CTV-TGT. Corresponding dice similarity coefficients were 0.87 [0.71, 0.95] and 0.84 [0.64, 0.95]. CTV-TGT was adequately covered in 68/70 plans optimized on CTV-TADP and in 6/10 plans optimized on CTV-TAI with clinical margins. The median [range] coefficient of variation was 0.08 [0.05, 0.11] and generalized conformity index was 0.78 [0.71, 0.88] among CTV-TADP. Conclusions: Target re-delineation in CBCT-guided oART of bladder cancer demonstrated non-isotropic inter-observer variation. Manual adjustment of AI-generated contours was necessary to cover ground truth targets.

This paper presents formulations for time-based first-order and second-order high-pass, shelf, and notch filters. These formulations are an extension to the existing literature where low-pass filters are already developed using a multiphase controlled oscillator in conjunction with a phase detector and charge pump. The presented high-pass filter expands the circuit by introducing a current-controlled delay line (CCDL) that provides a direct path from input to output. By combining the high-pass filter with the low-pass filter, we show that shelf and notch filters can be obtained without an increase in circuit complexity compared to the high-pass filter. The results show good matching between the ideal small signal and the simulated time-based large signal frequency response. The simulated of total harmonic distortion for the filters shows an increase in distortion due to the nonlinearities introduced by the CCDL for the high-pass, notch, and shelf filter compared to the existing low-pass filter. The derivation of the new filter types allows the creation of complex high-order time-based filters by combining multiple first- or second-order filters.

Digital integrated electronics benefits from its higher abstraction level, allowing optimisation methods and automated workflows. However, analogue integrated circuit design is still predominantly done manually, leading to lengthy design cycles. This paper proposes a new systematic design approach for the sizing of analogue integrated circuits to address this issue. The method utilises a surrogate optimisation technique that approximates a simple monomial function based on few simulation results. These monomials are convex and can be optimised using a simple linear optimisation routine, resulting in a single global optimal solution. We show that monomial functions, in many cases, have an analytic relation to integrated circuits, making them well suited for the application. The method is demonstrated by designing a 14 MHz pseudodifferential voltage-controlled oscillator (VCO) with minimised current consumption and is manufactured in a 180 nm process. The measured total current matches the predicted and is lower than that for other similar state-of-the-art VCOs.

With the use of in vitro new approach methodologies (NAMs) for the assessment of non-combustible next-generation nicotine delivery products, new extrapolation methods will also be required to interpret and contextualize the physiological relevance of these results. Quantitative in vitro to in vivo extrapolation (QIVIVE) can translate in vitro concentrations into in-life exposures with physiologically-based pharmacokinetic (PBPK) modelling and provide estimates of the likelihood of harmful effects from expected exposures. A major challenge for evaluating inhalation toxicology is an accurate assessment of the delivered dose to the surface of the cells and the internalized dose. To estimate this, we ran the multiple-path particle dosimetry (MPPD) model to characterize particle deposition in the respiratory tract and developed a PBPK model for nicotine that was validated with human clinical trial data for cigarettes. Finally, we estimated a Human Equivalent Concentration (HEC) and predicted plasma concentrations based on the minimum effective concentration (MEC) derived after acute exposure of BEAS-2B cells to cigarette smoke (1R6F), or heated tobacco product (HTP) aerosol at the air liquid interface (ALI). The MPPD-PBPK model predicted the in vivo data from clinical studies within a factor of two, indicating good agreement as noted by WHO International Programme on Chemical Safety (2010) guidance. We then used QIVIVE to derive the exposure concentration (HEC) that matched the estimated in vitro deposition point of departure (POD) (MEC cigarette = 0.38 puffs or 11.6 µg nicotine, HTP = 22.9 puffs or 125.6 µg nicotine) and subsequently derived the equivalent human plasma concentrations. Results indicate that for the 1R6F cigarette, inhaling 1/6th of a stick would be required to induce the same effects observed in vitro, in vivo. Whereas, for HTP it would be necessary to consume 3 sticks simultaneously to induce in vivo the effects observed in vitro. This data further demonstrates the reduced physiological potency potential of HTP aerosol compared to cigarette smoke. The QIVIVE approach demonstrates great promise in assisting human health risk assessments, however, further optimization and standardization are required for the substantiation of a meaningful contribution to tobacco harm reduction by alternative nicotine delivery products.

Immunocompromised patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can have a longer duration of viral shedding and persistence of symptoms. The optimal treatment strategy for these patients remains to be established. This case describes a male in his late sixties with follicular lymphoma and persistent symptoms of infection with SARS-CoV-2 variant BA.2 who was treated with remdesivir five times over a period of six months. The clinical effect of remdesivir treatment decreased over time, and further viral sequencing revealed the emergence of mutations across the SARS-CoV-2 genome. Due to the lack of other treatment options, the patient was treated with a combination of remdesivir and molnupiravir for 10 days, and epcoritamab was discontinued, which led to the cessation of symptoms. This case illustrates the risk of a diminished effect of remdesivir with prolonged use and the need for treatment guidelines for immunocompromised patients with persistent COVID-19.

Background and objectiveTreatments of lymphoma can lead to reduced physical functioning, cancer-related fatigue, depression, anxiety, and insomnia. These side effects can negatively impact the cancer survivor's quality of life. Mounting evidence indicates that physical activities are highly therapeutic in mitigating the short- and long-term side effects of cancer treatments. Yet, lymphoma survivors' participation in physical activities remains suboptimal, which has been further exacerbated by the deleterious effects of isolation during the COVID-19 pandemic. The Lymfit intervention aims to offer motivational support, expert guidance, and a personalized exercise prescription to optimize physical activities among lymphoma survivors. This proof-of-concept study explores implementation feasibility (retention, technical and safety), and the preliminary effects of Lymfit on various health outcomes.MethodThis was a single-armed trial with a pre-and post-test design. Twenty lymphoma survivors were recruited to participate in the 12-week Lymfit intervention. Wearable activity trackers (Fitbit) were given to participants as a motivational tool and for data collection purposes. Participants received a personalized exercise prescription designed by a kinesiologist. Physiologic metrics were collected by the Fitbit monitors and were stored in the Lymfit database. Self-reported questionnaires measuring health outcomes were collected at baseline and post-intervention.ResultsThe retention rate of this trial was 70%. Minimal technical issues and no adverse effects were reported. Lymfit led to significant improvements in sleep disturbances and the ability to participate in social activities and decreased fear of cancer recurrence. It also increased daily steps and decreased sedentary time in participants who did not meet the recommended physical activity guidelines.SignificanceWith access to resources and fitness centers being limited during the pandemic, the Lymfit intervention filled an immediate need to provide physical activity guidance to lymphoma survivors. Findings provide preliminary support that implementing the Lymfit intervention is feasible and demonstrated promising results.

Introduction: ß-chloroprene (2-chloro-1,3-butadiene; CP) causes lung tumors after inhalation exposures in rats and mice. Mice develop these tumors at lower exposures than rats. In rats CP exposures cause depletion of lung glutathione (GSH).Methods: PBPK models developed to relate the appearance of mouse lung tumors with rates of CP metabolism to reactive metabolites or total amounts metabolized during exposures have been expanded to include production of reactive metabolites from CP. The extended PBPK model describes both the unstable oxirane metabolite, 2-CEO, and metabolism of the more stable oxirane, 1-CEO, to reactive metabolites via microsomal oxidation to a diepoxide, and linked production of these metabolites to a PK model predicting GSH depletion with increasing CP exposure. Key information required to develop the model were available from literature studies identifying: 1) microsomal metabolites of CP, and 2) in vitro rates of clearance of CP and 1-CEO from active microsomal preparations from mice, rats, hamsters and humans.Results: Model simulation of concentration dependence of disproportionate increases in reactive metabolite concentrations as exposures increases and decreases in tissue GSH are consistent with the dose-dependence of tumor formation. At the middle bioassay concentrations with a lung tumor incidence, the predicted tissue GSH is less than 50% background. These simulations of reduction in GSH are also consistent with the gene expression results showing the most sensitive pathways are Nrf2-regulation of oxidative stress and GSH metabolism.Discussion: The PBPK model is used to correlate predicted tissue exposure to reactive metabolites with toxicity and carcinogenicity of CP.

Worldwide, millions of persons have received multiple COVID-19 vaccinations and subsequently recovered from SARS-CoV-2 Omicron breakthrough infections. In 2 small, matched cohorts (n = 12, n = 24) in Denmark, we found Omicron BA.1/BA.2 breakthrough infection after 3-dose BNT162b2 vaccination provided improved Omicron BA.5 neutralization over 3-dose vaccination alone.

The Mekong River provides water, food security, and many other valuable benefits to the more than 60 million Southeast Asian residents living within its basin. However, the Mekong River Basin is increasingly stressed by changes in climate, land cover, and infrastructure. These changes can affect water quantity and quality and exacerbate related hazards such as land subsidence and saltwater intrusion, resulting in multiple compounding risks for neighboring communities. In this study, we demonstrate the connection between climate change, groundwater availability, and social vulnerability by linking the results of a numerical groundwater model to land cover and socioeconomic data at the Cambodia-Vietnam border in the Mekong River Delta region. We simulated changes in groundwater availability across 20 years and identified areas of potential water stress based on domestic and agriculture-related freshwater demands. We then assessed adaptive capacity to understand how communities may be able to respond to this stress to better understand the growing risk of groundwater scarcity driven by climate change and overextraction. This study offers a novel approach for assessing risk of groundwater scarcity by linking the effects of climate change to the socioeconomic context in which they occur. Increasing our understanding of how changes in groundwater availability may affect local populations can help water managers better plan for the future, leading to more resilient communities.

Current computational technologies hold promise for prioritizing the testing of the thousands of chemicals in commerce. Here, a case study is presented demonstrating comparative risk-prioritization approaches based on the ratio of surrogate hazard and exposure data, called margins of exposure (MoEs). Exposures were estimated using a U.S. EPA’s ExpoCast predictive model (SEEM3) results and estimates of bioactivity were predicted using: 1) Oral equivalent doses (OEDs) derived from U.S. EPA’s ToxCast high-throughput screening program, together with in vitro to in vivo extrapolation and 2) thresholds of toxicological concern (TTCs) determined using a structure-based decision-tree using the Toxtree open source software. To ground-truth these computational approaches, we compared the MoEs based on predicted noncancer TTC and OED values to those derived using the traditional method of deriving points of departure from no-observed adverse effect levels (NOAELs) from in vivo oral exposures in rodents. TTC-based MoEs were lower than NOAEL-based MoEs for 520 out of 522 (99.6%) compounds in this smaller overlapping dataset, but were relatively well correlated with the same (r2 = 0.59). TTC-based MoEs were also lower than OED-based MoEs for 590 (83.2%) of the 709 evaluated chemicals, indicating that TTCs may serve as a conservative surrogate in the absence of chemical-specific experimental data. The TTC-based MoE prioritization process was then applied to over 45,000 curated environmental chemical structures as a proof-of-concept for high-throughput prioritization using TTC-based MoEs. This study demonstrates the utility of exploiting existing computational methods at the pre-assessment phase of a tiered risk-based approach to quickly, and conservatively, prioritize thousands of untested chemicals for further study.

Due to high levels of deforestation, Bolivia's per capita CO2 emissions are currently among the highest in the world. Indeed, at more than 25 tCO2eq/person/year, they far exceed the per capita emissions of the United States and the United Arab Emirates. Achieving Net Zero would require a complete change of the current resource-intensive development model and would especially have to adjust the incentives that are promoting the rapid expansion of soybean farming and cattle ranching in the Bolivian Amazon and Chiquitano forests. This paper identifies the main sources of emissions in Bolivia and the most cost-effective measures to reduce them, under the condition that the selected measures do not decrease average incomes nor increase poverty compared to the Business-as-Usual scenario. The paper estimates the magnitude of the investment needed to reduce net emissions to zero by 2050 at about $150 billion or 7.8% of Bolivia's GDP between 2022 and 2050. To make sure that poor people are not hurt by the Net Zero strategy, most of the funds should be used to promote alternative and more sustainable economic opportunities for Bolivians, including resilient and diverse agro-forestry activities, zero-deforestation beef production, nature-based tourism, high value-added wood products, scientific research, etc. These alternative opportunities should include women as much as possible, so as to provide more gender equal opportunities than the traditional activities at the agricultural frontier. The paper reviews different financing options and proposes a simple, easily verifiable, performance-based mechanism, that shares the costs and benefits of reduced deforestation fairly. Finally, the paper discusses the main social, economic, and political challenges to achieving these goals.

BackgroundInternet-based cognitive behavioral therapy (iCBT) has been demonstrated to be cost- and clinically effective. There is a need, however, for increased therapist contact for some patient groups. Combining iCBT with traditional face-to-face (FtF) consultations in a blended format may produce a new treatment format (B-CBT) with multiple benefits from both traditional CBT and iCBT, such as individual adaptation, lower costs than traditional therapy, wide geographical and temporal availability, and possibly lower threshold to implementation. ObjectiveThe primary aim of this study is to compare directly the clinical effectiveness of B-CBT with FtF-CBT for adult major depressive disorder. MethodsA 2-arm randomized controlled noninferiority trial compared B-CBT for adult depression with treatment as usual (TAU). The trial was researcher blinded (unblinded for participants and clinicians). B-CBT comprised 6 sessions of FtF-CBT alternated with 6-8 web-based CBT self-help modules. TAU comprised 12 sessions of FtF-CBT. All participants were aged 18 or older and met the diagnostic criteria for major depressive disorder and were recruited via a national iCBT clinic. The primary outcome was change in depression severity on the 9-item Patient Health Questionnaire (PHQ-9). Secondary analyses included client satisfaction (8-item Client Satisfaction Questionnaire [CSQ-8]), patient expectancy (Credibility and Expectancy Questionnaire [CEQ]), and working (Working Alliance Inventory [WAI] and Technical Alliance Inventory [TAI]). The primary outcome was analyzed by a mixed effects model including all available data from baseline, weekly measures, 3-, 6, and 12-month follow-up. ResultsA total of 76 individuals were randomized, with 38 allocated to each treatment group. Age ranged from 18 to 71 years (SD 13.96) with 56 (74%) females. Attrition rate was 20% (n=15), which was less in the FtF-CBT group (n=6, 16%) than in the B-CBT group (n=9, 24%). As many as 53 (70%) completed 9 or more sessions almost equally distributed between the groups (nFtF-CBT=27, 71%; nB-CBT=26, 68%). PHQ-9 reduced 11.38 points in the FtF-CBT group and 8.10 in the B-CBT group. At 6 months, the mean difference was a mere 0.17 points. The primary analyses confirmed large and significant within-group reductions in both groups (FtF-CBT: β=–.03; standard error [SE] 0.00; P

Post‐fledging brood division is a poorly understood, yet widespread suite of avian behaviours that includes both division of parental care and spatial division of a brood. For most species, the differences in parental care between adult males and females and the behavioural mechanisms explaining spatial patterns of brood division are unknown. We studied brood division in golden‐winged warblers Vermivora chrysoptera to describe the spatial and behavioural characteristics of brood division and assess hypotheses describing the potential benefits of brood division. Female golden‐winged warblers are known to travel farther from their nests than males within the post‐fledging period, although the mechanism resulting in this spatial pattern is unknown. From 2010 to 2012, we monitored radio‐marked golden‐winged warbler fledglings from fledging until independence from adult care at three sites in the western Great Lakes region of North America. We observed no significant differences in provisioning, parental attendance, daily distance traveled and fledgling begging between male‐ and female‐reared sub‐broods. We also did not observe a relationship between parental sex and fledgling sex or mass. However, female‐reared sub‐broods exhibited a unique period of relatively consistent directional movement on days 8–10 after fledging, which resulted in females traveling farther from the nests than males. Our observations were not fully consistent with any previously proposed hypotheses about the benefits of brood division. Brood division is a complex behaviour that may have a suite of benefits, including predation defense and provisioning efficiency, that are not fully understood.

Abstract. Introduction:. Low back pain (LBP) is the leading course of years lived with disability. Unfortunately, not much knowledge exists about distinct trajectories of recovery from disability after LBP and their potential psychological predictors. Objectives:. Hence, the aim of the present study was to identify trajectories of functional disability in LBP and their potential baseline psychological predictors. Methods:. A 1-year consecutive cohort (N = 1048) of patients with LBP referred to the Spine Centre if they have not improved satisfactorily from a course of treatment in primary care after 1 to 2 months were assessed by self-report questionnaires at their first visit and at 6- and 12-month follow-up. Data from patients who responded to the Roland Morris Disability Questionnaire at least twice (N = 747) were used to assess trajectories of functional disability by Latent Growth Mixture Modeling. The following measures were used as baseline predictors of the trajectories: Pain Intensity Numerical Rating Scales, Pain Catastrophizing Scale, Tampa Scale for Kinesiophobia, and Hospital Anxiety and Depression Scale. Results:. Four distinct trajectories were identified: high-stable (22.0%), high-decreasing (20.4%), medium-stable (29.7%), and low-decreasing (27.9%). Using the low-decreasing trajectory as reference, baseline pain intensity, depressive symptoms, and pain-catastrophizing predicted membership of all 3 symptomatic trajectories. However, using the high-decreasing trajectory as reference, age, baseline pain intensity, and depression were predictors of the high-stable trajectory. Conclusion:. In particular, the finding of a high-stable trajectory characterized by high levels of baseline psychological distress is of potential clinical importance because psychological distress may be targeted by cognitive behavioral therapeutic approaches.

Uropathogenic Escherichia coli (UPEC) is the main etiological agent of urinary tract infection (UTI), a widespread infectious disease of great impact on human health. This is further emphasized by the rapidly increase in antimicrobial resistance in UPEC, which compromises UTI treatment. UPEC biology is highly complex since uropathogens must adopt extracellular and intracellular lifestyles and adapt to different niches in the host. In this context, the implementation of forefront ‘omics’ technologies has provided substantial insight into the understanding of UPEC pathogenesis, which has opened the doors for new therapeutics and prophylactics discovery programs. Thus, ‘omics’ technologies applied to studies of UPEC during UTI, or in models of UTI, have revealed extensive lists of factors that are important for the ability of UPEC to cause disease. The multitude of large ‘omics’ datasets that have been generated calls for scrutinized analysis of specific factors that may be of interest for further development of novel treatment strategies. In this review, we describe main UPEC determinants involved in UTI as estimated by ‘omics’ studies, and we compare prediction of factors across the different ‘omics’ technologies, with a focus on those that have been confirmed to be relevant under UTI-related conditions. We also discuss current challenges and future perspectives regarding analysis of data to provide an overview and better understanding of UPEC mechanisms involved in pathogenesis which should assist in the selection of target sites for future prophylaxis and treatment.

Safranine O is widely used in the bioenergetics community as an indicator dye to determine membrane potentials and as an electron transfer mediator in potentiometric titrations. Here we show that two different commercial preparations of Safranine O contain less than sixty percent by weight of the title compound, with the rest primarily consisting of two closely related safranine isomers. All three major isomer components were isolated using reverse phase HPLC and their structures determined using mass spectrometry and two-dimensional NMR. These Safranines have two-electron midpoint potentials ranging from -272 to -315 mV vs. SHE. We have also investigated the absorption and fluorescence spectra of the compounds and found that they display distinct spectral and photophysical properties. While this mixture may aid in Safranine O's utility as a mediator compound, membrane potential measurements must take this range of dye potentials into account.

The SARS-CoV-2 Omicron variant BA.2 sublineage is rapidly replacing earlier Omicron lineages, suggesting BA.2 has increased vaccine evasion properties. We measured neutralization titers of authentic BA.1 and BA.2 isolates in serum samples from persons who received the BNT162b2 booster vaccine. All samples neutralized BA.1 and BA.2 at equal median values.

The National Toxicology Program (NTP) reported that chronic exposure to varying dietary concentrations of 4-methylimidazole (4-MeI) increased lung tumors in female and male mice [1]. In this study, mice (male and female B6C3F1 mice) were either administered 4-MeI by oral gavage (0, 50, 100, 200, or 300 mg/kg/day) for 2 days or exposed for 5 and 28 days to 4-MeI in the diet (0, 150, 300, 1250, or 2500 ppm) and whole transcriptome (RNA-Sequencing) data from 4-MeI-exposed B6C3F1 mice to determine whether changes occurred in the target (lung) and nontarget (liver) tissues. This analysis was conducted to provide information with which to evaluate biological processes affected by exposure to 4-MeI, with a focus on identifying key events that could be used to propose a plausible mode of action (MoA) for mouse lung tumors [2].

Buildings play a vital role in reaching the targets stated by the Intergovernmental Panel on Climate Change to limit global warming to 1.5 degrees. Increasing the use of wood in construction is a proposed upcoming strategy to reduce the embodied greenhouse gas emissions of buildings. This study examines existing life cycle assessments of wooden buildings. The aim is to investigate embodied greenhouse gas emission results reported, as well as methodological approaches applied in existing literature. The study applies the protocol for Systematic Literature Reviews and finds 79 relevant papers. From the final sample, the study analyses 226 different scenarios in-depth in terms of embodied emissions, life cycle assessment method, life cycle inventory modelling and biogenic carbon approach. The analysis shows that the average reported values of embodied greenhouse gas emissions of wooden buildings are one-third to half of the embodied emissions reported from buildings in general. Additionally, from the analysis of the final sample we find that the majority of wooden building life cycle assessments apply similar methods and often leave out biogenic carbon from the assessment or simply do not declare it. This implies that the focus on variability in the different methods applied in wooden building life cycle assessments needs to be increased to establish the relationship between methodological choices and embodied emissions of wooden buildings. Further, transparency and conformity in biogenic carbon accounting in life cycle assessments is essential to enhance comparability between life cycle assessment studies and to avoid distortions in embodied GHG emission results.

ABSTRACT Orientia tsutsugamushi is the etiologic agent of scrub typhus, the deadliest of all diseases caused by obligate intracellular bacteria. Nucleomodulins, bacterial effectors that dysregulate eukaryotic transcription, are being increasingly recognized as key virulence factors. How they translocate into the nucleus and their functionally essential domains are poorly defined. We demonstrate that Ank13, an O. tsutsugamushi effector conserved among clinical isolates and expressed during infection, localizes to the nucleus in an importin β1-independent manner. Rather, Ank13 nucleotropism requires an isoleucine at the thirteenth position of its fourth ankyrin repeat, consistent with utilization of eukaryotic RaDAR (RanGDP-ankyrin repeats) nuclear import. RNA-seq analyses of cells expressing green fluorescent protein (GFP)-tagged Ank13, nucleotropism-deficient Ank13I127R, or Ank13ΔF-box, which lacks the F-box domain essential for interacting with SCF ubiquitin ligase, revealed Ank13 to be a nucleomodulin that predominantly downregulates transcription of more than 2,000 genes. Its ability to do so involves its nucleotropism and F-box in synergistic and mutually exclusive manners. Ank13 also acts in the cytoplasm to dysregulate smaller cohorts of genes. The effector’s toxicity in yeast heavily depends on its F-box and less so on its nucleotropism. Genes negatively regulated by Ank13 include those involved in the inflammatory response, transcriptional control, and epigenetics. Importantly, the majority of genes that GFP-Ank13 most strongly downregulates are quiescent or repressed in O. tsutsugamushi-infected cells when Ank13 expression is strongest. Ank13 is the first nucleomodulin identified to coopt RaDAR and a multifaceted effector that functions in the nucleus and cytoplasm via F-box-dependent and -independent mechanisms to globally reprogram host cell transcription. IMPORTANCE Nucleomodulins are recently defined effectors used by diverse intracellular bacteria to manipulate eukaryotic gene expression and convert host cells into hospitable niches. How nucleomodulins enter the nucleus, their functional domains, and the genes that they modulate are incompletely characterized. Orientia tsutsugamushi is an intracellular bacterial pathogen that causes scrub typhus, which can be fatal. O. tsutsugamushi Ank13 is the first example of a microbial protein that coopts eukaryotic RaDAR (RanGDP-ankyrin repeats) nuclear import. It dysregulates expression of a multitude of host genes with those involved in transcriptional control and the inflammatory response being among the most prominent. Ank13 does so via mechanisms that are dependent and independent of both its nucleotropism and eukaryotic-like F-box domain that interfaces with ubiquitin ligase machinery. Nearly all the genes most strongly downregulated by ectopically expressed Ank13 are repressed in O. tsutsugamushi-infected cells, implicating its importance for intracellular colonization and scrub typhus molecular pathogenesis.