PCIS1, encoded by a pentatricopeptide protein co-expressed gene, is required for splicing of three mitochondrial nad transcripts in angiosperms.

Group II introns are large catalytic RNAs, which reside mainly within genes encoding respiratory complex I (CI) subunits in angiosperms' mitochondria. Genetic and biochemical analyses led to the identification of many nuclear-encoded factors that facilitate the splicing of the degenerated organellar introns in plants. Here, we describe the analysis of the PPR Co-expressed Intron Splicing1 (PCIS1) factor, which was identified in-silico by its co-expression pattern with many PPR proteins. PCIS1 is well conserved in land plants but has no sequence similarity with any known protein motifs. PCIS1 mutant lines are arrested in embryogenesis and can be maintained by the temporal expression of the gene under the embryo-specific ABI3 promoter. The pABI3::PCIS1 mutant plants display low germination and stunted growth phenotypes. RNA-seq and RT-qPCR analyses of wild type and mutant plants indicated that PCIS1 is a novel splicing cofactor that is pivotal for the maturation of several nad transcripts in Arabidopsis mitochondria. These phenotypes are tightly associated with respiratory complex I defects and altered plant growth. Our data further emphasizes the key roles of nuclear-encoded cofactors that regulate the maturation and expression of mitochondrial transcripts for the biogenesis of the oxidative phosphorylation (OXPHOS) system, and hence for plant physiology. The discovery of novel splicing factors other than typical RNA-binding proteins suggests further complexity of splicing mechanisms in plant mitochondria.

Regional Periprosthetic Joint Infection Centers: The Time Has Come for a Paradigm Change in the Treatment of Periprosthetic Joint Infection.

INTRODUCTION: Periprosthetic joint infection (PJI) is a rare, yet devastating complication with high mortality rates, unpredictable treatment outcomes, and high costs. The purpose of this study was to determine 90-day and 1-year mortality rates at a specialized PJI center, assess the impact of delayed referral to a PJI center on outcomes, and determine the cost of PJI treatment prior to referral to a PJI center. METHODS: A review of our institution's PJI registry was performed to identify patients who had a chronic PJI treated with a 2-stage exchange arthroplasty at our PJI Center from 2017 to 2021. Patients not referred from an external location were excluded. Mortality at 90 days and 1 year was collected. The date of infection diagnosis until the date of referral was recorded. Outcomes were documented as failure of treatment at the final clinical follow-up. The number and type of prior infection treatment were documented for each patient. The estimated cost was calculated using established PJI literature. RESULTS: There were 172 patients (182 joints) who met inclusion criteria during this timeframe. The 90-day and 1-year mortality rates were 0 and 3.9%, respectively. There was a higher failure rate in patients referred > 90 days after the diagnosis of chronic PJI (23 versus 11%, P = 0.031). The total cost of PJI treatment prior to referral for this group of patients was $6.9 million. CONCLUSION: Implementation of a specialized PJI referral center leads to lower mortality rates, improved outcomes, and decreased cost for the healthcare system.

BMScope: A scoping review to chart the evolving clinical study landscape in brain and leptomeningeal metastasis.

BACKGROUND: Recent studies have challenged the notion that patients with brain metastasis (BM) or leptomeningeal metastasis (LM) should be excluded from systemic therapy clinical trials. This scoping study summarises the BM/LM clinical studies published between 2010 and 2023. METHODS: MEDLINE, CINAHL, CAB Abstracts, PsycINFO, Cochrane Library, HINARI, International Pharmaceutical Abstracts, PubMed, Scopus, Web of Science, and EMBASE electronic databases were searched on 21 June 2021. An updated search was performed on 21 February 2023. Eligible studies should involve investigation of a therapeutic intervention in solid tumour patients with BM and/or LM and a reported patient outcome. Extracted study-level data, included study type, publication date, geographical location, number of BM/LM patients in study, primary tumour type and type of therapeutic intervention. RESULTS: 4921 unique studies were eligible for analysis. The key finding is that BM/LM clinical research is expanding globally, both observational studies and clinical trials. Despite the shift over time towards a higher proportion of systemic therapy trials, the majority still do not include patients with symptomatic disease and lack reporting of BM/LM specific endpoints. Globally, there has been a trend to more international collaboration in BM/LM clinical studies. CONCLUSIONS: This analysis of the BM/LM literature charts the evolving landscape of studies involving this previously excluded population. Given the increasing clinical research activity, particularly involving late-stage systemic therapy trials, it is imperative that due consideration is given to the intracranial activity of new investigational agents. Wider adoption of standardised reporting of intracranial-specific endpoints will facilitate evaluation of relative intracranial efficacy.

The association between skeletal muscle mass and sensorineural hearing loss upon cisplatin-based chemoradiotherapy in patients with head and neck squamous cell carcinoma.

INTRODUCTION: Patients with head and neck squamous cell carcinoma (HNSCC) treated with cisplatin-based chemoradiotherapy (CRT) frequently experience irreversible sensorineural hearing loss (SNHL). Patients with low lumbar skeletal muscle index (LSMI) may experience higher serum peak dosages of cisplatin. This study investigated whether pre-treatment low LSMI is associated with increased SNHL upon cisplatin-based CRT. MATERIALS AND METHODS: LSMI was assessed using routine pre-treatment CT scans. Pure tone audiometry was performed at baseline and at follow-up to assess treatment-related SNHL. Linear mixed models were used to reveal a potential association between the continuous variable LSMI and SNHL. RESULTS: This retrospective cohort study included 81 patients and found a significant association between low LSMI and increased treatment-related SNHL at pure tone frequencies vital for the perception of speech (averaged of 1, 2, and 4 kHz) (p = 0.048). CONCLUSIONS: HNSCC patients with low LSMI suffer increased treatment-related SNHL upon cisplatin-based CRT.

Prepare Romania: study protocol for a randomized controlled trial of an intervention to promote pre-exposure prophylaxis adherence and persistence among gay, bisexual, and other men who have sex with men.

BACKGROUND: Gay, bisexual, and other men who have sex with men (GBMSM) represent a high-risk group for HIV transmission in Romania, yet they possess few resources for prevention. Despite having no formal access to pre-exposure prophylaxis (PrEP) through the health system, GBMSM in Romania demonstrate a high need for and interest in this medication. In anticipation of a national rollout of PrEP, this study tests the efficacy of a novel strategy, Prepare Romania, that combines two evidence-based PrEP promotion interventions for GBMSM living in Romania. METHODS: This study uses a randomized controlled trial design to examine whether GBMSM living in Romania receiving Prepare Romania, a culturally adapted counseling and mobile health intervention (expected n = 60), demonstrate greater PrEP adherence and persistence than those assigned to a PrEP education control arm (expected n = 60). Participants from two main cities in Romania are prescribed PrEP and followed-up at 3 and 6 months post-randomization. PrEP adherence data are obtained through weekly self-report surveys and dried blood spot testing at follow-up visits. Potential mediators (e.g., PrEP use motivation) of intervention efficacy are also assessed. Furthermore, Prepare Romania's implementation (e.g., proportion of enrolled participants attending medical visits, intervention experience) will be examined through interviews with participants, study implementers, and healthcare officials. DISCUSSION: The knowledge gained from this study will be utilized for further refinement and scale-up of Prepare Romania for a future multi-city effectiveness trial. By studying the efficacy of tools to support PrEP adherence and persistence, this research has the potential to lay the groundwork for PrEP rollout in Romania and similar contexts. Trial registration This study was registered on ClinicalTrials.gov, identifier NCT05323123 , on March 25, 2022.

An improved high-performance liquid chromatography (HPLC) method for detection of variations in the hydroxyproline content of tissue homogenates from Paracoccidioides brasiliensis-infected mice.

Background: Paracoccidioidomycosis (PCM) is a severe granulomatous disease. The hallmark of this mycosis is fibrin degradation and granuloma formation as a result of a wound-healing process in the context of excessive inflammation. Therefore, as the content of collagen can be assessed by the methodology described in this manuscript, we propose that the content of hydroxyproline (HYP) be employed as a new and efficient measurement of granulomatous lesions developed. To estimate the level of HYP the major byproduct of the degradation process, we hypothesized that this simple and efficient technique could serve as a marker of disease severity. Methods: Five B10.A female mice were infected with P. brasiliensis and, after 15 days, the omentum was removed, subjected to histopathological analysis or processed (i.e. deproteinized and derivatized), and further analyzed on a reverse phase HPLC using a C-18 column. The omentum of five uninfected controls was also collected and similarly analyzed. Results: Infected mice showed numerous, disseminated paracoccidioidomycotic lesions, as well as marked collagen deposits, as observed in histopathologic analysis, and high levels of HYP. Normal uninfected mice showed no granulomas, little or no deposits of collagen fibers, and very low levels of HYP, as evaluated by HPLC. Our results show that the disease intensity as evaluated number and the morphology of the granulomatous lesions were correlated to the HYP levels using small tissue samples from the omentum, the main target organ of P. brasiliensis. Conclusions: Here we propose an alternative methodology to follow disease evolution and, to some extent, fungal load in experimental P. brasiliensis infection and suggest its usefulness to other diseases with pronounced fibrin degradation.

Population pharmacokinetics of Dolutegravir in African Children: results from the CHAPAS-4 trial.

We characterised population pharmacokinetics in 42 African children receiving once-daily 25 mg (14-<20 kg) or 50 mg (>20 kg) dolutegravir. Co-administration with emtricitabine and tenofovir alafenamide reduced dolutegravir bioavailability by 19.6% (95%CI: 8.13-30.8%) compared to zidovudine or abacavir with lamivudine. Nevertheless, concentrations remained above efficacy targets, confirming current dosing recommendations.

Hyperbolic discounting underpins response curves of mammalian avoidance behaviour.

As humans clear natural habitat, they are brought into increased conflict with wild animals. Some conflict is direct (e.g. elevated exposure of people to predators), some indirect (e.g. abandoning suitable habitat because of human activity). The magnitude of avoidance is expected to track frequency of human activity, but the type of response is an open question. We postulated that animals do not respond passively to increased disturbance nor does response follow a power law; instead, their ability to estimate magnitude leads to 'discounting' behaviour, as in classic time-to-reward economic models in which individuals discount larger value (or risk) in more distant time. We used a 10-year camera dataset from southern California to characterize response curves of seven mammal species. Bayesian regressions of two non-discounting models (exponential and inverse polynomial) and two discounting models (hyperbolic and harmonic) revealed that the latter better fit response curves. The Arps equation, from petroleum extraction modelling, was used to estimate a discount exponent, a taxon-specific 'sensitivity' to humans, yielding a general model across species. Although discounting can mean mammal activity recovers rapidly after disturbance, increased recreational pressure on reserves limits recovery potential, highlighting a need to strike a balance between animal conservation and human use.

Intensity Modulated Therapy for Patients With Breast Cancer. Practical Guidelines and Tips for an Effective Treatment Planning Strategy.

Purpose: Practical guidelines and tips for effective and robust radiation therapy treatment planning for patients with breast cancer are addressed for fixed-field intensity modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT) techniques. The concepts described here are general and valid on all treatment planning systems. However, some details shown here have been applied to the Varian platforms used at the authors' institutions. Methods and Materials: The specific aspects of using C-arm- or O-ring-mounted linear accelerators are covered in the document, as well as tips for dealing with certain resource constraints, target cropping, and skin flash aiming to reduce risks of skin toxicity and to manage (residual after breath control) respiration motion or edema. Results: A decision tree is presented, and practical solutions for cases where a target volume is contoured or not and where volumetric modulated arc therapy or fixed-beam intensity modulation should be applied and details about the technical implementation (tangential IMRT, butterfly IMRT or VMAT, and large partial VMAT arcs) are discussed. Target cropping and skin flash implications are discussed in detail, and links to plan robustness are outlined. Conclusions: Practical guidelines for breast planning are presented and summarized with a decision tree and technical summaries.

Increased prevalence of valgus constitutional alignment subtypes in a South African arthritic population group using the coronal plane alignment of the knee (CPAK) classification.

BACKGROUND: Knee alignment philosophies and patient specific models to improve patient reported outcomes are gaining increasing attention. The coronal plane alignment of the knee (CPAK) classification describes nine knee phenotypes and then proposes surgical alignment strategies to achieve constitutional alignment. The CPAK classification has been validated in Australian, European, Asian and North American population groups. To date no African data has been analyzed using CPAK. METHODS: A total of 344 arthritic patients (608 knees) with appropriate long leg radiographs were classified based on the CPAK type. Measurements included mechanical hip-knee-angle(mHKA), medial proximal tibial angle (mMPTA) and lateral distal femoral angle (mLDFA) and the derived calculations of joint line obliquity (JLO) and arithmetic hip-knee-angle (aHKA). RESULTS: The sample population was 77.9% (n = 268) female with a mean age of 68.4 ± 9.2 years. The most common CPAK types in order were type 3 (n = 174; 28.6%), type 2 (n = 155; 25.5%), type 1 (n = 94; 15.5%) and type 6 (n = 80; 13.2%). The most common limb alignment types were valgus (CPAK types 3,6,9; 41.8%). CONCLUSION: This study, which investigated arthritic patients from a single institution in South Africa, shows a divergence of CPAK phenotypic knee patterns relative to other international studies, with much higher proportions of valgus phenotypes (3 and 6). This regional difference should be further investigated in other South African and African population samples and used to adapt the surgical strategies employed by local surgeons.

Interaction proteomics analysis to provide insight into TFAMoplex-mediated transfection.

In an earlier investigation, our group introduced the TFAMoplex, a transfection agent based on the mitochondrial transcription factor A (TFAM) protein, which complexes DNA into nanoparticles. The original TFAMoplex further contained a bacterial phospholipase to achieve endosomal escape, and the vaccinia-related kinase 1 (VRK1), which significantly boosted the transfection efficiency of the system by an unknown mechanism. This study aims at replacing VRK1 within the TFAMoplex with dynein light chain proteins, specifically RP3, to directly tether the complexes to the dynein motor complex for enhanced cytosolic transport. To confirm the interaction between the dynein complex and the resulting fusion protein, we examined the binding kinetics of TFAM-RP3 to the dynein intermediate chains 1 and 2. Furthermore, we established a proteomics-based assay to compare cytosolic protein interactions of different TFAMoplex variants, including the RP3-modified version and the original VRK1-containing system. In the group of the VRK1-containing TFAMoplex, significant shifts of protein interactors were observed, especially for nucleolar proteins. Leveraging this knowledge, we incorporated one of these nuclear proteins, leucine-rich repeat-containing protein 59 (LRRC59), into the TFAMoplex, resulting in a significant improvement of transfection properties compared to the RP3-modified system and comparable levels versus the original, VRK1-containing version. This study not only advances our comprehension of the TFAMoplex system but also offers broader insights into the potential of protein engineering for designing effective gene delivery systems.

Template-based copying in chemically fuelled dynamic combinatorial libraries.

One of science's greatest challenges is determining how life can spontaneously emerge from a mixture of molecules. A complicating factor is that life and its molecules are inherently unstable-RNA and proteins are prone to hydrolysis and denaturation. For the de novo synthesis of life or to better understand its emergence at its origin, selection mechanisms are needed for unstable molecules. Here we present a chemically fuelled dynamic combinatorial library to model RNA oligomerization and deoligomerization and shine new light on selection and purification mechanisms under kinetic control. In the experiments, oligomers can only be sustained by continuous production. Hybridization is a powerful tool for selecting unstable molecules, offering feedback on oligomerization and deoligomerization rates. Moreover, we find that templation can be used to purify libraries of oligomers. In addition, template-assisted formation of oligomers within coacervate-based protocells changes its compartment's physical properties, such as their ability to fuse. Such reciprocal coupling between oligomer production and physical properties is a key step towards synthetic life.

Cortical plasticity is associated with blood-brain barrier modulation.

Brain microvessels possess the unique properties of a blood-brain barrier (BBB), tightly regulating the passage of molecules from the blood to the brain neuropil and vice versa. In models of brain injury, BBB dysfunction and the associated leakage of serum albumin to the neuropil have been shown to induce pathological plasticity, neuronal hyper-excitability, and seizures. The effect of neuronal activity on BBB function and whether it plays a role in plasticity in the healthy brain remain unclear. Here we show that neuronal activity induces modulation of microvascular permeability in the healthy brain and that it has a role in local network reorganization. Combining simultaneous electrophysiological recording and vascular imaging with transcriptomic analysis in rats, and functional and BBB-mapping MRI in human subjects, we show that prolonged stimulation of the limb induces a focal increase in BBB permeability in the corresponding somatosensory cortex that is associated with long-term synaptic plasticity. We further show that the increased microvascular permeability depends on neuronal activity and involves caveolae-mediated transcytosis and transforming growth factor ß signaling. Our results reveal a role of BBB modulation in cortical plasticity in the healthy brain, highlighting the importance of neurovascular interactions for sensory experience and learning.

Data Fusion of Acoustic and Optical Emission from Laser-Induced Plasma for In Situ Measurement of Rare Earth Elements in Molten LiCl-KCl.

Molten salts have a significant potential for use as next-generation nuclear reactor coolants and in pyroprocessing for the recycling of used nuclear fuel. However, the molten salt composition needs to be known at all times, and high temperatures and intense ionizing radiation pose challenges for the monitoring instrumentation. Although the technique of laser-induced breakdown spectroscopy (LIBS) has been studied for in situ measurements of molten salts, trials to improve its monitoring accuracy using chemometrics are lacking. In this study, a data fusion technique using the LIBS optical and laser-induced acoustic (LIA) signals was investigated to enhance the measurement accuracy for molten salt monitoring. Prediction models were constructed using the partial least-squares method, and the variable importance in projection scores was analyzed to evaluate the effect of incorporating the LIA signal into the analysis. This study investigates rare earth elements Eu, Er, and Pr found not only in nuclear but also in other settings such as laser and magnetic materials. The analysis of LIBS data without data fusion resulted in a root-mean-square error of prediction (RMSEP) of 0.0774-0.0913 wt %, whereas the prediction model using data fusion led to approximately 18-40% enhanced RMSEP (0.0461-0.0679 wt %). The results suggest that fusing the LIBS data with the simultaneously recorded LIA data can improve the monitoring accuracy of rare earth element composition in molten salts.

Cholinergic modulation in the vertebrate auditory pathway.

Acetylcholine (ACh) is a prevalent neurotransmitter throughout the nervous system. In the brain, ACh is widely regarded as a potent neuromodulator. In neurons, ACh signals are conferred through a variety of receptors that influence a broad range of neurophysiological phenomena such as transmitter release or membrane excitability. In sensory circuitry, ACh modifies neural responses to stimuli and coordinates the activity of neurons across multiple levels of processing. These factors enable individual neurons or entire circuits to rapidly adapt to the dynamics of complex sensory stimuli, underscoring an essential role for ACh in sensory processing. In the auditory system, histological evidence shows that acetylcholine receptors (AChRs) are expressed at virtually every level of the ascending auditory pathway. Despite its apparent ubiquity in auditory circuitry, investigation of the roles of this cholinergic network has been mainly focused on the inner ear or forebrain structures, while less attention has been directed at regions between the cochlear nuclei and midbrain. In this review, we highlight what is known about cholinergic function throughout the auditory system from the ear to the cortex, but with a particular emphasis on brainstem and midbrain auditory centers. We will focus on receptor expression, mechanisms of modulation, and the functional implications of ACh for sound processing, with the broad goal of providing an overview of a newly emerging view of impactful cholinergic modulation throughout the auditory pathway.

Ultraprocessed Foods at Home and Children's Attentional Bias Toward Those Foods.

This study examines the association between exposure to ultraprocessed foods at home and children's attentional bias for those foods.

Correction: Populations of arable weed species show intra-specific variability in germination base temperature but not in early growth rate.

[This corrects the article DOI: 10.1371/journal.pone.0240538.].

Velocimetry of GHz elastic surface waves in quartz and fused silica based on full-field imaging of pump-probe reflectometry.

This study reports an imaging method for gigahertz surface acoustic waves in transparent layers using infrared subpicosecond laser pulses in the ablation regime and an optical pump-probe technique. The reflectivity modulations due to the photoelastic effect of generated multimodal surface acoustic waves were imaged by an sCMOS camera illuminated by the time-delayed, frequency-doubled probe pulses. Moving the delay time between 6 . 0 n s to 11 . 5 n s , image stacks of wave field propagation were created. Two representative samples were investigated: wafers of isotropic fused silica and anisotropic x-cut quartz. Rayleigh (SAW) and longitudinal dominant high-velocity pseudo-surface acoustic wave (HVPSAW) modes could be observed and tracked along a circular grid around the excitation center, allowing the extraction of angular profiles of the propagation velocity. In quartz, the folding of a PSAW was observed. A finite element simulation was developed to predict the measurement results. The simulation and measurement were in good agreement with a relative error of 2 % to 5 %. These results show the potential for fast and full-field imaging of laser-generated ultrasonic surface wave modes, which can be utilized for the characterization of thin transparent samples such as semiconductor wafers or optical crystals in the gigahertz frequency range.