Browse Articles

Transposon mediated functional genomic screening for BRAF inhibitor resistance reveals convergent Hippo and MAPK pathway activation events

Abstract Genotype-informed anticancer therapies such as BRAF inhibitors can show remarkable clinical efficacy in BRAF-mutant melanoma; however, drug resistance poses a major hurdle to successful cancer treatment. Many resistance events to targeted therapies have been identified, suggesting a complex path to improve therapeutics. Here, we showed the utility of a piggyBac transposon activation mutagenesis screen for the efficient identification of genes that are resistant to BRAF inhibition in melanoma. Although several forward genetic screens performed in the same context have identified a broad range of resistance genes that poorly overlap, an integrative analysis revealed a much smaller functional diversity of resistance mechanisms, including reactivation of the MAPK pathway, PI3K-AKT pathway, and Hippo pathway, suggesting that a relatively small number of therapeutic strategies might overcome resistance manifested by a large gene set. Moreover, we illustrated the pivotal role of the Hippo pathway effector TAZ (encoded by the WWTR1 gene) in mediating BRAF inhibition resistance through transcriptional regulation of receptor tyrosine kinases and through interactions with the E3 ubiquitin ligase NEDD4L.

Evaluating the performance of a new ergonomic laparoscopic needle holder for intracorporeal suturing

In laparoscopy, the absence of ergonomics in the instruments affects the performance and efficiency of the surgeon, increasing the likelihood of developing musculoskeletal injuries. This article presents the development of a laparoscopic needle holder with an ergonomic handle and the experience in its use with surgeons in the intracorporeal suturing task. The handle of the laparoscopic needle holder consists of a semi-spherical piece that easily adapts to the palm of the surgeon’s hand and improves the posture and ergonomics of the wrist, allowing the direct transmission of rotational movements around the longitudinal axis of the instrument towards the tip. Moreover, a spring-loaded mechanism allows the tip of the tool to be opened and closed in a normally closed configuration, with enough pressure to hold different surgical needles. Twenty-two pediatric surgery surgeons and residents, without upper extremity musculoskeletal disorders, participated in this study. Each participant performed the intracorporeal suturing task using two laparoscopic needle holders (conventional and with ergonomic handle) in a laparoscopic simulator. Motion data from both instruments were captured and the performance was assessed by means of 16 motion analysis parameters (MAPs). The performance of the residents improved markedly using the laparoscopic needle holder with ergonomic handle, obtaining statistically significant differences in 10 MAPs evaluated. The comparison of the results of each instrument showed that this ergonomic laparoscopic needle holder stood out over the conventional tool, improving psychomotor skills and the ability to control the angular position and rotational movements of the instrument on its own axis, indispensable for intracorporeal suturing. The innovative design of the laparoscopic needle holder with ergonomic handle allows for better transfer of rotational movements from the surgeon’s hand directly with the longitudinal axis to the tip, reducing extreme wrist positions and excessive effort to open and close the tip of the instrument during intracorporeal suturing.

Optimization of dried garlic physicochemical properties using a self-organizing map and the development of an artificial intelligence prediction model

Abstract The experiments were conducted at different levels of infrared power, airflow, and temperature. The relationships between the input process factors and response factors’ physicochemical properties of dried garlic were optimized by a self-organizing map (SOM), and the model was developed using machine learning. Artificial Neural Network (ANN) with 99% predicting accuracy and Self-Organizing Maps (SOM) with 97% clustering accuracy were used to determine the quality characteristics of garlic. Specifically, five key areas were identified, and valuable insights were offered for optimizing garlic production and improving its overall quality. The (aw) values for the sample ranged from 0.43 to 0.48. The maximum vitamin C content was 0.112 mg/g, followed by an air temperature of 40 °C and 0.7 m/s air velocity under 1500 W/m². The total color change values increased with IR and higher air temperature but declined with higher air velocity. Also, the garlic’s flavor strength, allicin content, water activity, and vitamin C levels decreased as the IR and air temperature increased. The results demonstrated a significant impact of the independent parameters on the response parameters (P < 0.01). Interestingly, the machine learning predictions closely matched the test data sets, providing valuable insights for understanding and controlling the factors affecting garlic drying performances.

The etiology of attention deficit disorder with hyperactivity: A protocol for an umbrella review

Introduction Attention deficit hyperactivity disorder (ADHD) is one of the common neurodevelopmental disorders and is widely prevalent worldwide. The primary symptoms of ADHD include inattention, impulsivity, and hyperactivity, which significantly impact the cognitive, behavioral, and emotional dimensions of individuals. These disorders often continue throughout adulthood and, along with associated complications, affect various domains such as personal health, academic achievement, and social interactions. The pathogenesis and contributing causes of ADHD remain unclear at present. Therefore, this study aims to perform an umbrella review of systematic reviews and meta-analyses (SRMAs) to systematically assess the quality of methodologies, potential biases, and validity of all epidemiological evidence related to risk factors for ADHD while offering a comprehensive summary of the evidence regarding these risk factors. Methods and analysis This study follows the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) and Cochrane Handbook. We will systematically search 6 databases, including The Cochrane Library Central, PubMed, Embase, Web of Science, CINAHL, and Scopus from the initial period up until 2024 (last update). We will assess the quality of the included SRMAs using the tool to assess risk of bias in systematic reviews (ROBIS), the methodological quality of systematic reviews (AMSTAR)-2, PRISMA-2020, and the grade of recommendations assessment, development and evaluation (GRADE). Two authors will use the ecological models of health behavior to classify the causes and risk factors of ADHD. Finally, we will provide descriptive and comprehensive recommendations for clinical practice and future research. Trial registration PROSPERO (CRD42024597126).

Revolutionary bamboo crash barriers utilizing sustainable materials for enhanced road safety

Systematic review on the compliance of WHO guidelines in the management of patients with advanced HIV disease in Africa: The case of cryptococcal antigen screening

Background The World Health Organization (WHO) recommended cryptococcal antigen (CrAg) screening for people presenting with advanced HIV disease (AHD) and for those with positive CrAg without evidence of meningitis to initiate preemptive antifungal medication. Data on the implementation of WHO recommendations regarding CrAg screening is limited. We estimated pooled prevalence of CrAg screening uptake, cryptococcal antigenemia, lumbar puncture, cryptococcal meningitis and initiation of preemptive antifungal medication from available eligible published studies conducted in Africa. Methods PubMed, Cochrane Library and Embase were searched for articles published between January 2011 and December 2023. CrAg uptake was defined as percentage of eligible people (CD4 ≤ 200 cells/mm3 or WHO stage III/IV) who received cryptococcal antigen testing. Stratified analysis to compare uptake and cryptococcal antigenemia between studies that involved multiple vs single sites was performed. Using random effects models, we computed the pooled estimate of CrAg screening uptake, cryptococcal antigenemia, lumbar puncture, cryptococcal meningitis, preemptive antifungals treatment and 95% confidence intervals (CIs). Results Ten studies with 18,820 individuals with AHD were analyzed. Overall, the pooled estimate of CrAg screening uptake was 57.1% (95% CI: 41.4–72.7). CrAg screening uptake was significantly lower among studies that involved multiple sites compared to those that involved single site, (47.3% vs 73.3%; p<0.001). Overall, the pooled prevalence of cryptococcal antigenemia was 9.6% (95% CI:6.4–12.9). Cryptococcal antigenemia was significantly lower among studies that involved multiple sites compared to those that involved single site, (9.1% vs 10.4%; p<0.001). Among those who tested positive for CrAg, 84.6% (95% CI: 54.1–99.0) received preemptive antifungal treatment, though nearly 25% did not undergo lumbar puncture, highlighting gaps in diagnostic follow-up. Six studies evaluated CrAg positive patients with lumbar puncture and the overall prevalence of lumbar puncture was 74.9% (48.0–94.8). The overall prevalence of cryptococcal meningitis was 58.1% (46.6–69.6). Conclusions Not screening for CrAg among people with AHD and failure to initiate antifungal medications among eligible patients with cryptococcal antigenemia presents a significant missed opportunity. Emphasis on improving CrAg screening is critical given its proven cost-effective benefits.

Exploring the relationship between physical activity and Inhibitory Function in College Students with depressive symptoms through EEG

Study protocol for a hybrid implementation-effectiveness trial of Game Changers for Cervical Cancer Prevention in Uganda

Introduction Cervical cancer (CC) is the leading cause of cancer-related deaths among Uganda women, yet rates of CC screening are very low. Training women who have recently screened to engage in advocacy for screening among women in their social network is a network-based strategy for promoting information dissemination and CC screening uptake. Methods Drawing on the Exploration, Preparation, Implementation and Sustainment (EPIS) framework for implementation science, this hybrid type 1 randomized controlled trial (RCT) of a peer-led, group advocacy training intervention, Game Changers for Cervical Cancer Prevention (GC-CCP), will examine efficacy for increasing CC screening uptake as well as how it can be implemented and sustained in diverse clinic settings. In the Preparation phase we will prepare the four study clinics for implementation of GC-CCP and the expected increase in demand for CC screening, by using qualitative methods (stakeholder interviews and client focus groups) to identify and address structural barriers to easy access to CC screening. In the Implementation phase, GC-CCP will be implemented over 36 months at each clinic, with screened women (index participants) enrolled as research participants receiving the intervention in the first 6 months as part of a parallel group RCT overseen by the research study team to evaluate efficacy for CC screening uptake among their enrolled social network members. All research participants will be assessed at baseline and months 6 and 12. Intervention implementation and supervision will then be transitioned to clinic staff and offered as part of usual care in the subsequent 30 months as part of the Sustainability phase. Using the RE-AIM framework, we will evaluate engagement in GC-CCP and CC advocacy (reach), alter CC screening (effectiveness), adoption into clinic operations, implementation outcomes (acceptability, feasibility, fidelity, cost-effectiveness) and maintenance. Discussion This is one of the first studies to use a network-driven approach and empowerment of CC screened peers as change agents to increase CC screening. If shown to be an effective and sustainable implementation strategy for promoting CC screening, this peer advocacy model could be applied to other preventative health behaviors and disease contexts. Trial registration NIH Clinical Trial Registry NCT06010160 (clinicaltrials.gov; date: 8/17/2023).

Case studies of different types of precipitation at Ny-Ålesund, Arctic

Secondary metabolites of Alternaria alternate appraisal of their SARS-CoV-2 inhibitory and anti-inflammatory potentials

This study identifies the secondary metabolites from Alternaria alternate and evaluates their ACE-2: Spike RBD (SARS-CoV-2) inhibitory activity confirmed via immunoblotting in human lung microvascular endothelial cells. In addition, their in vitro anti-inflammatory potential was assessed using a cell-based assay in LPS-treated RAW 264.7 macrophage cells. Two novel compounds, altenuline (1), phthalic acid bis (7’/7’’ pentyloxy) isohexyl ester (2), along with 1-deoxyrubralactone (3) alternariol-5-O-methyl ether (4) and alternariol (5) were identified. Molecular docking and in vitro studies showed that compounds 2 and 4 were promising to counteract SARS-CoV-2 attachment to human ACE-2. Thus, they are considered promising natural anti-viral agents. SwissADME in silico analysis was conducted to predict the drug-like potential. Immunoblotting analysis confirmed that the tested compounds (1–4) demonstrated downregulation of ACE-2 expression in the endothelial cells from the lungs with variable degrees. Furthermore, the tested compounds (1–4) showed promising anti-inflammatory activities through TNF-α: TNFR2 inhibitory activity and their inhibitory effect on the proinflammatory cytokines (TNF-α and IL-6) in LPS-stimulated monocytes. In conclusion, our study, for the first time, provides beneficial experimental confirmation for the efficiency of the A. alternate secondary metabolites for the treatment of COVID-19 as they hinder SARS-CoV-2 infection and lower inflammatory responses initiated by SARS-CoV-2. A. alternate and its metabolites are considered in developing preventative and therapeutic tactics for COVID-19.

A resilience assessment framework for slopes considering multiple performance indicators

Effects of plasma-activated water on germination ‎and initial seedling growth of wheat

In this research, the effect of seed halopriming with plasma activated water (PAW) on wheat germination parameters have been studied. Response surface methodology was used to investigate the effect of three factors including: 1) type of water (distilled water, 0.2 and 0.4 min/mL PAW), 2) priming time (1, 3 and 5 h), and 3) salinity of the priming solution (0, 25 and 50 mmol/L NaCl) on wheat germination parameters. The results revealed that increasing PAW levels up to 0.18 min/mL led to an increase in seed germination percentage, seedling weight (both fresh and dry), seedling length, vigor indexes A and B, and water uptake and decreasing mean germination time. Increasing the level of PAW by more than 0.18 min/mL had a negative effect on these parameters. The fresh and dry weight of the seedlings respectively at the 0.18 and 0.2 min/mL levels of PAW, in all salinity levels, had the highest value. The effect of halopriming on enhancing seedling length was more than other characteristics. The optimum ranges of PAW, salinity and priming time were 0.13 min/mL, 10.3 mmol/L and 120.22 min for germination percentage, 0.18 min/mL, 15 mmol/L and 191.24 min for seedling fresh weight, 0.15 min/mL, 13.84 mmol/L and 221.2 min for seedling dry weight, 0.33 min/mL, 24.36 mmol/L and 152.62 min for mean germination time, 0.11 min/mL, 19.03 mmol/L and 177.77 min for vigor indexes A and 0.1 min/mL, 18.1 mmol/L and 178.99 min for vigor indexes B.

Biocementation beyond the Petri dish, scaling up to 900 L batches and a meter-scale column

Abstract Microbial-induced calcite precipitation (MICP), which leverages ureolytic microorganisms, has received significant attention during the past decade as a promising method for sustainable building and geoenvironmental applications. However, transitioning from lab-scale experimentation to volumes suitable for practical use poses challenges. This study addresses these obstacles by screening and analyzing over 50 strains sourced from (i) a natural environment in the canton of Ticino in Switzerland; (ii) microorganism banks; and (iii) an industry-scale bioreactor. Several ureolytic Sporosarcina species have been identified in the natural environment, and their ureolytic potential has been compared with that of other strains. A reference, banked microorganism yielded the highest ureolysis rate. When this latter strain was inoculated in 900 L batches and continuously cultivated at 5400 L, no contamination issues were observed, and the reference strain remained the dominant species. The produced culture, obtained under an optimized medium composition involving the circular valorization of NH4 +, was subsequently used to induce the biocementation of a 650 kg column of 0–1 mm sand. The results reveal the successful stabilization of the whole mass, with undrained Tresca strength values ranging from 90 to 140 kPa. This research lays the groundwork for scalable MICP production, which is capable of meeting the demands of real-world building and geoenvironmental projects.

Predicting vasovagal reactions to needles from video data using 2D-CNN with GRU and LSTM

When undergoing or about to undergo a needle-related procedure, most people are not aware of the adverse emotional and physical reactions (so-called vasovagal reactions; VVR), that might occur. Thus, rather than relying on self-report measurements, we investigate whether we can predict VVR levels from the video sequence containing facial information measured during the blood donation. We filmed 287 blood donors throughout the blood donation procedure where we obtained 1945 videos for data analysis. We compared 5 different sequences of videos—45, 30, 20, 10 and 5 seconds to test the shortest video duration required to predict VVR levels. We used 2D-CNN with LSTM and GRU to predict continuous VVR scores and to classify discrete (low and high) VVR values obtained during the blood donation. The results showed that during the classification task, the highest achieved F1 score on high VVR class was 0.74 with a precision of 0.93, recall of 0.61, PR-AUC of 0.86 and an MCC score of 0.61 using a pre-trained ResNet152 model with LSTM on 25 frames and during the regression task the lowest root mean square error achieved was 2.56 using GRU on 50 frames. This study demonstrates that it is possible to predict vasovagal responses during a blood donation using facial features, which supports the further development of interventions to prevent VVR.

Sex-specific association of immunological markers in CS-delivered newborns with pre-pregnancy body mass index and gestational weight gain of mothers

Abstract Just as overweight and obesity may impair immunity, excessive body weight-related parameters of women in the pre-conception period and during pregnancy are possible detrimental factors for fetal programming of the immune system in their offspring. We investigated the relationship of pre-pregnancy body mass index (pBMI) and gestational weight gain (GWG) of mothers with the placental transport rate (PTR) of IgG antibodies and antineutrophil cytoplasmatic antibodies against lactoferrin (Lf-ANCA) and their concentration in umbilical cord blood serum (UCS), verifying the sex-specificity of this relationship. The examined group of this cross-sectional pilot study consisted of 101 pregnant women and their healthy CS-delivered newborn children. The concentration of antibodies in maternal serum (MS) and UCS were determined by ELISA method. PTR was assessed as a ratio of the concentration of antibodies in the UCS and MS. A significantly lower PTR of IgG and their concentration in the UCS were demonstrated in newborns of mothers with an excessive pBMI compared to those with pBMI < 25 and the association was more pronounced in male newborns. The lowest PTR of beneficial IgG and their concentration in the UCS as well as the highest PTR of detrimental Lf-ANCA and their concentration in UCS were observed in newborns born to mothers with co-occurrence of both an excessive pBMI and GWG. It seems that maternal preconception overweight and obesity along with an excessive GWG can be a predictor of unfavorable immune effects in fetuses. Further studies are needed to explain the role of maternal weight-related parameters in the development of immunological health of their offspring.

Association between asymptomatic submicroscopic and microscopic malaria infections and anemia: A study in southern Benin

Introduction Recently, efforts to eliminate malaria have shifted focus from symptomatic cases alone to include asymptomatic carriers, who are now recognized as significant contributors to the disease’s transmission and control. This study examines the relationship between asymptomatic malaria infection and hemoglobin levels in Benin. Methods A cohort in Benin was enrolled and categorized into three age groups (under 5 years, 5–15 years, and over 15 years) for follow-up from August to November 2021. Participants were monitored over two months and assessed for malaria infection through microscopy and polymerase chain reaction (PCR) during their three visits. A questionnaire was employed to gather general and clinical characteristics. Multivariate models were utilized to analyze the associations between asymptomatic infection, anemia, and hemoglobin levels. Results Among 393 participants, 58.2% were diagnosed at enrolment with malaria via PCR, and 30.5% through microscopy. Anemia, defined as hemoglobin levels < 11 g/dL, was observed in 40.5% of the cohort. The risk of anemia declined with increasing age (OR for ages 5–15: 0.64, 95% CI [0.37; 1.09]; OR for over 15 years: 0.34, 95% CI [0.20; 0.59]) compared to children under 5. Individuals with both microscopic and submicroscopic infections exhibited higher odds of anemia (respectively OR = 4.15, 95% CI [2.41; 7.13] and OR = 2.09 [1.22; 3.57]) relative to those uninfected. Hemoglobin levels were consistently lower in participants with microscopic malaria across all age groups (β = -2.73, 95% CI [-3.41; -2.05] for those under 5, β = -1.35, 95% CI [-1.89; -0.82] for ages 5–15, and β = -0.72, 95% CI [-1.34; -0.07]) compared to non-infected individuals. Discussion Our findings suggest that asymptomatic malaria infections, including submicroscopic cases, are associated with anemia and decreased hemoglobin levels. This underscores the importance of employing ultrasensitive diagnostic methods for such infections and acknowledging their potential health implications.

Utilizing machine learning to predict hospital admissions for pediatric COVID-19 patients (PrepCOVID-Machine)

Modelling sensory attenuation as Bayesian causal inference across two datasets

Introduction To interact with the environment, it is crucial to distinguish between sensory information that is externally generated and inputs that are self-generated. The sensory consequences of one’s own movements tend to induce attenuated behavioral- and neural responses compared to externally generated inputs. We propose a computational model of sensory attenuation (SA) based on Bayesian Causal Inference, where SA occurs when an internal cause for sensory information is inferred. Methods Experiment 1investigates sensory attenuation during a stroking movement. Tactile stimuli on the stroking finger were suppressed, especially when they were predictable. Experiment 2 showed impaired delay detection between an arm movement and a video of the movement when participants were moving vs. when their arm was moved passively. We reconsider these results from the perspective of Bayesian Causal Inference (BCI). Using a hierarchical Markov Model (HMM) and variational message passing, we first qualitatively capture patterns of task behavior and sensory attenuation in simulations. Next, we identify participant-specific model parameters for both experiments using optimization. Results A sequential BCI model is well equipped to capture empirical patterns of SA across both datasets. Using participant-specific optimized model parameters, we find a good agreement between data and model predictions, with the model capturing both tactile detections in Experiment 1 and delay detections in Experiment 2. Discussion BCI is an appropriate framework to model sensory attenuation in humans. Computational models of sensory attenuation may help to bridge the gap across different sensory modalities and experimental paradigms and may contribute towards an improved description and understanding of deficits in specific patient groups (e.g. schizophrenia).

Elevated D-dimer on admission may predict poor prognosis in childhood influenza associated encephalopathy

Assessment of temporospatial and kinematic gait parameters using human pose estimation in patients with Parkinson’s disease: A comparison between near-frontal and lateral views

Gait disturbance is one of the most common symptoms in patients with Parkinson’s disease (PD) that is closely associated with poor clinical outcomes. Recently, video-based human pose estimation (HPE) technology has attracted attention as a cheaper and simpler method for performing gait analysis than marker-based 3D motion capture systems. However, it remains unclear whether video-based HPE is a feasible method for measuring temporospatial and kinematic gait parameters in patients with PD and how this function varies with camera position. In this study, treadmill and overground walking in 24 patients with early PD was measured using a motion capture system and two smartphone cameras placed on the near-frontal and lateral sides of the subjects. We compared the differences in temporospatial gait parameters and kinematic characteristics between joint position data obtained from the 3D motion capture system and the markerless HPE. Our results confirm the feasibility of analyzing gait in patients with PD using HPE. Although the near-frontal view, where the heel and toe are clearly visible, is effective for estimating temporal gait parameters, the lateral view is particularly well-suited for assessing spatial gait parameters and joint angles. However, in clinical settings where lateral recordings are not feasible, near-frontal view recordings can still serve as a practical alternative to motion capture systems.