Aims. The exposure-response relationship of bevacizumab may be confounded by various factors, i.e. baseline characteristics, time-dependent target engagement and recursive relationships between exposure and response. This work aimed at investigating the exposure-response relationships of bevacizumab in mCRC patients while mitigating potential sources of bias. Methods. Bevacizumab pharmacokinetics was described using target-mediated drug disposition (TMDD) modeling. The relationships between target kinetics, and progression-free (PFS) and overall (OS) survivals were assessed using joint pharmacokinetic and parametric hazard function models. Both potential biases due to prognostic-driven and response-driven of the concentration-effect relationship were mitigated. These models were used to evaluate the effect of increased antigen target levels and clearance, as well as intensified dosing regimen, on survival. Results. Estimated target-mediated pharmacokinetic parameters in 130 assessed patients were: baseline target levels (R0=8.4 nM), steady-state dissociation constant (KSS=10 nM) and antibody-target complexes elimination constant (kint=0.52 day-1). Distribution of R0 was significantly associated with an increased baseline CEA and circulating VEGF levels, and the presence of extra-hepatic metastases. Unbound target levels (R) significantly influenced both progression and death hazard functions. Increased R0 or CL values led to decreased bevacizumab unbound concentrations, increased R levels, and shortened PFS and OS, whereas increasing bevacizumab dose led to decreased R and longer survival. Conclusion. This study is the first to show the relationship between bevacizumab concentrations, target involvement and clinical efficacy by mitigating potential sources of bias. Most of target amount may be tumoral in mCRC. A more in-depth description of this relationship should be made in future studies.

The invasion of alien plant species poses a threat to native community’s composition and diversity. However, the invasiveness of alien plants and invisibility of native communities should be depended on the interactions between biotic and abiotic factors, such as natural enemies and nutrient availability. In a study, we simulated the invasion of nine invasive plants into native plant communities with two levels of nutrient availability and natural enemies suppression. We explored how the biotic and abiotic factors affect the response of alien target species and the resistance of native communities to invasion. The results showed that enemy release (i.e., presence of enemy) increased biomass proportion of alien plants and decreased that of native community under without nutrient addition. Furthermore, we also found that the negative effect of enemy suppression on the evenness of native community and the root-to-shoot ratio of alien target species was greatest under nutrient addition. Therefore, nutrient deficiency and natural enemies might promote the invasive success of alien species in native community, whereas nutrient addition and enemy suppression can better enhance the resistance of native plant communities to invasion.

In spite of the high potential shown by spiking neural networks (e.g., temporal patterns), training them remains an open and complex problem [1]. In practice, while in theory these networks are computationally as powerful as mainstream artificial neural networks [2], they have not reached the same accuracy levels yet. The major reason for such situation seems to be represented by the lack of adequate training algorithms for deep spiking neural networks, since spike signals are not differentiable, i.e. no direct way to compute a gradient is provided. Recently a novel training method, based on the (digital) simulation of certain quantum systems, has been suggested. It has already shown interesting advantages, among which the fact that no gradient is required to be computed. In this work, we apply this approach to the problem of training spiking neural networks and we show that this recent training method is capable of training deep and complex spiking neural networks on the MNIST data set.

This paper proposes a fault-tolerant control strategy for the air path system of a turbocharged diesel engine, considering the simultaneous presence of matched and mismatched external disturbances, additive and loss of effectiveness fault modes in the EGR and VGT subsystems. Firstly, a disturbance observer based on H ∞ theory is designed for estimating additive faults and external disturbances, and the upper bound of observation error is obtained. Based on the observation information, an integral sliding mode surface is designed, and the effectiveness of the sliding mode surface is analyzed. For the loss of effectiveness faults in the actuators, a novel adaptive update sliding mode controller is designed. The proposed control algorithm can get the fault information of the system and achieve fault-tolerant control of through controller reconstruction. Ultimately, the effectiveness of the proposed method is validated through simulations and comparative analysis.

A document by Ahmed Gamal Sayed. Click on the document to view its contents.

The present study combined behavioral measures and EEG to investigate the impact of emotional valence on both auditory and written word processing. Participants were first presented with a series of auditory words with varying emotional valence (positive, neutral and negative) produced in neutral tone, which they rated according to valence level. Subsequently they performed a surprise recognition task with written stimuli (half being foils). Our results revealed a significant valence/arousal effect on word recognition; written words with high-arousal and either positive or negative valence were recognized with higher accuracy compared to low-arousal neutral ones. EEG analyses revealed an effect of valence only for words presented in written format; no effects were found for auditory words. For written words, both positive and negative valence elicited a larger P2 response in comparison to neutral valence, indicating allocation of attentional resources. Critically, a reduced N400 was observed only for negative words, suggesting facilitated processing of unpleasant information perhaps due to better encoding during the auditory presentation. Overall, our study provides valuable insights into the cognitive mechanisms involved in integrating emotional information presented in distinct modalities, shedding light on the influence of valence on word recognition.

Background: Recently，epidermal growth factor receptor (EGFR) -targeting drugs have benefited thousands of patients with EGFR mutation-positive (EGFR MUT+) non-small-cell lung cancer (NSCLC). Nevertheless, nearly all patients with NSCLC who were sensitive to first- or second-generation EGFR-tyrosine kinase inhibitors (EGFR-TKIs), finally developed resistance. Therefore, numerous clinicians have focused on improving the clinical effect of first-generation EGFR-TKIs (1st-gen EGFR-TKIs). Methods: To analyze the therapeutic outcomes of individuals with progressive NSCLC, a retroactive assessment was performed on 86 patients who were medicated with only icotinib or combined with pemetrexed and platinum-based chemotherapy at The First Affiliated Hospital of Henan University of Science and Technology (HAUST). Results: Eighty-six patients with NSCLC-bearing EGFR-sensitive mutations were retroactively analyzed. The results showed statistical significance in PFS (P = 0.049) and disease control rate DCR (P = 0.031) between icotinib + chemotherapy and icotinib alone, especially in the brain metastases (P = 0.021) and L-858R mutation subgroups (P = 0.05). According to the findings of the multivariate analysis, treatment (P = 0.033) and EGFR mutation status (P = 0.019) were significant predictive variables. The OS comparison between icotinib + chemotherapy and icotinib alone were not significantly different. The study included a total of 1242 patients, of which 648 obtained combined treatment and 594 obtained first-generation EGFR-TKI monotherapy. Analyzing the relevant data from multiple studies, the results showed significant improvements in ORR (RR: 0.63, 95% CI: 0.49–0.82, P = 0.0006), PFS (RR: 0.61, 95% CI: 0.47–0.79, P = 0.0002), and OS (RR: 0.67, 95% CI: 0.51–0.88, P = 0.004) for those on combination therapy. However, there was also an increase in treatment-emergent AEs among these patients. Conclusion: In summary, administering first-generation EGFR-TKI concurrently with chemotherapy provides an edge in the therapeutic management of locally or severely advanced NSCLC that is EGFR-positive. Therefore, EGFR mutation-positive NSCLC (EGFR MUT+ NSCLC) patients in this condition may find it advantageous to consider using 1st-gen EGFR-TKIs in conjunction with chemotherapy (1st-gen EGFR-TKIs + Chemo).

IntroductionMultiple sclerosis is an infrequent inflammatory disease of the central nervous system (CNS) that is distinguished by its assorted clinical and radiological presentations [1, 2]. Tumefactive demyelination, or tumefactive multiple sclerosis, stands apart as a distinctive entity within this spectrum. Demyelinating lesions in the central nervous system (CNS) are a sign of these diseases. These lesions can be big, measuring 2 cm or more in diameter, or small, measuring between 0.5 cm and 2 cm, but have the potential to cause mass effects. This unique feature may result in these lesions being initially misidentified as tumor-like space-occupying lesions; however, they typically exhibit a characteristic appearance on radiographic imaging and are clinically benign [3–5]. Tumefactive demyelination, which is distinct from multiple sclerosis, occurs at an estimated rate of about 1-2 per 1000 cases of MS, although some studies propose a higher incidence ranging from 1.4% to 8% [6–7]. However, tumefactive demyelinating lesions can occur concurrently with autoimmune diseases (e.g., Sjogren disease, lupus erythematosus, neuromyelitis optica), infectious diseases (e.g., HIV), malignancy (e.g., renal cell carcinoma), drug-related conditions (e.g., tacrolimus, fingolimod), and postinfectious conditions (e.g., acute disseminated encephalomyelitis, acute hemorrhage leukoencephalitis). Tumefactive demyelination can show up on its own at the start of a disease or as other diseases progress, but the pathophysiology of how it happens is not well understood. On magnetic resonance imaging (MRI) scans, these lesions can appear either as a single large lesion or several lesions exhibiting varying degrees of contrast enhancement. We present here a case study involving a thirty-year-old female who presented with a fever lasting three days followed by Wernicke’s aphasia without right-sided weakness and whose MRI findings were consistent with tumefactive brain demyelination.

Most foundational work on the evolution and migration of plant species relies on genomic data from contemporary samples. Ancient plant samples can give us access to allele sequences and distributions on the landscape dating back to the mid Holocene or earlier (Gugerli et al., 2005). Nuclear DNA from ancient wood, however, has been mostly inaccessible until now. In a From the Cover article in this issue of Molecular Ecology, Wagner et al. (2023) present the first nuclear genomes from ancient to subfossil oak wood, including two samples dated to the 15th century and one that dates to more than 3,500 years ago. These first assembled nuclear genomes from ancient trees open the possibility for investigating species adaptation, migration, divergence, and hybridization in the deep past. They pave the way for what we hope will be a new era in the use of paleogenomics to study Holocene tree histories.

Ecological divergence due to habitat difference plays a prominent role in the formation of new species but the genetic architecture during ecological speciation and the mechanism underlying phenotypic divergence remain less understood. Two wild rice species (O. rufipogon and O. nivara) are a progenitor-derivative species pair with ecological divergence and provide a unique system for studying ecological adaptation/speciation. Here, we constructed a high-resolved linkage map and conducted a quantitative trait locus (QTL) analysis of 19 phenotypic traits using an F2 population generated from a cross between the two wild rice species. We identified 113 QTLs associated with interspecific divergence of 16 quantitative traits, with effect sizes ranging from 1.61% to 34.1% in terms of the percentage of variation explained (PVE). The distribution of effect sizes of QTLs followed a negative exponential, suggesting that a few genes of large effect and many genes of small effect were responsible for the phenotypic divergence. We observed 18 clusters of QTLs (QTL hotspots) on 11 chromosomes, significantly more than that expected by chance, demonstrating the importance of coinheritance of loci/genes in ecological adaptation/speciation. Analysis of effect direction and v-test statistics revealed that interspecific differentiation of most traits was driven by divergent natural selection, supporting the argument that ecological adaptation/speciation would proceed rapidly under coordinated selection on multiple traits. Our findings provide new insights into the understanding of genetic architecture of ecological adaptation and speciation in plants and helps effective manipulation of specific genes or gene cluster in rice breeding.

Background: Tricuspid regurgitation velocity (TRV), measured by echocardiography, is a surrogate marker for pulmonary hypertension. Limited pediatric studies have considered the association between TRV and surrogate markers of end-organ disease. Methods: Therefore, we conducted a cross-sectional study that evaluated the prevalence of elevated TRV ≥ 2.5 m/s and its associations with renal and cerebrovascular outcomes in children with SCD 1-21 years of age in two large sickle cell cohorts, the University of Alabama at Birmingham (UAB) sickle cell cohort, and the Sickle Cell Clinical and Research Intervention Program (SCCRIP) cohort at St. Jude Children’s Research hospital. We hypothesized that patients with sickle cell disease with elevated TRV would have higher odds of having either albuminuria or cerebrovascular disease. Results: We identified 166 children from the UAB cohort (mean age: 13.49 ± 4.47 years) and 325 children from the SCCRIP cohort (mean age: 13.41 ± 3.99 years) with echocardiography. The prevalence of an elevated TRV was 21% in both UAB and SCCRIP cohorts. Elevated TRV was significantly associated with cerebrovascular disease (OR 1.88 (95% CI: 1.12- 3.15)) and persistent albuminuria (OR: 1.81 (95% CI: 1.07– 3.06)) after adjusting for age, sex, treatment, and site. Conclusion: This cross-sectional, multicenter study identifies associations between surrogate markers of pulmonary hypertension with kidney disease and cerebrovascular disease. A prospective study should be performed to evaluate the longitudinal outcomes for patients with multiple surrogate markers of end-organ disease.

The present study proposes an exposure model for indoor PM2.5 levels during cooking activities in poorly ventilated Kazakh houses with high emission levels. It aims to identify influencing factors of PM2.5 concentration patterns during cooking and explain the mechanisms underlying the build-up and downtrend of PM2.5 concentrations. The methodology integrates PM2.5 sampling, monitoring, and modeling to predict household PM2.5 levels and estimate daily concentrations, employing USEPA’s IAQX v1.1 for simulating the one-zone concept for cooking-related PM2.5 concentrations in multiple households. During cooking, PM2.5 concentrations varied between 13 and 266 µg/m3. Kitchen size, air exchange, type of food, and cooking methods were key factors influencing the observed concentrations. The model demonstrated high accuracy (R>0.9). The contribution of cooking to household air pollutant (HAP) PM2.5 levels ranged from 9% to 94%. This impact was more pronounced in warmer months. In colder months, outdoor PM levels and household ventilation were the primary factors regulating indoor air concentrations. The present study is among the first attempts to assess exposure to HAP in Central Asia, providing foundational insights into the poorly understood indoor air quality of Kazakh houses. Future research should refine models to account for individual behaviors and house types, improving accuracy and representativeness.

Neurodegenerative diseases impact the structure and operation of the nervous system, causing progressive and irreparable harm. The absence of distinguishable symptoms in the early stages of neurodegenerative diseases makes diagnosis challenging. Additionally, it can be difficult to pinpoint the precise neurodegenerative disorder affecting a patient as the symptoms of these conditions frequently overlap. Numerous studies have shown that pathological changes occur years before clinical signs appear. Therefore, it is crucial to discover blood-based biomarkers for neurodegenerative diseases for easier and faster diagnosis. Proximity Extension Assay is a unique proteomics method that uses antibodies linked to oligonucleotides for quantifying proteins with real-time PCR. Proximity Extension Assay can identify even low-quantity proteins using a small volume of specimens with increased sensitivity compared to conventional methods. In this article, we reviewed the employment of Proximity Extension Assay technology to detect biomarkers or protein profiles for several neurodegenerative diseases.

Reforestation after forest clearcutting is an effective measure to increase soil organic carbon (SOC) sequestration. However, the soil C balance and functions of microbial communities under reforestation remain to be determined. Samples of organic (0-2 cm) and mineral (2-10 cm) horizons were collected from the 7-, 15-, 20-, 29-, and 36-year-old forest stands of Chinese fir developed after plantation clearcutting in subtropical climate zone under the condition of phosphorus limitation. Particulate organic carbon (POC), mineral-associated organic carbon (MAOC), microbial phospholipid fatty acids (PLFAs), and enzymatic activities for C, nitrogen (N), and phosphorus (P) acquisition were analyzed. The lowest contents of POC (10 %) and MAOC (13 %) in the organic horizon were found in 7-year-old stands due to the slow tree regrowth and extensive decomposition of SOC in the first years of forest regrowth. POC (2.0x) and MAOC (0.8x) increases in the organic horizon with forest age were attributed to the stand development and accumulation of above and belowground litter. The organic horizon had a higher POC: MAOC ratio than the mineral (0.7-1.1 vs. 0.2-0.5), indicating lower SOC stability in the first one. A positive correlation of the Gram-positive to Gram-negative bacteria (G+:G-) ratio with the POC: MAOC ratio may point to developing specific substrate utilization strategies for microbial communities. Microorganisms were limited by C and P; however, the C limitation was alleviated in the 36-year-old plots in the organic horizon due to increased litter input. Microbial C and P limitations increased with total PLFAs and the G+:G- ratio, indicating the strong influence of community structure on nutrient acquisition from SOC. Thus, soil C sequestration under reforestation of Chinese fir can be controlled by microbial community structure and metabolic limitation, which both shifted with the stand age.

We report the first case of egg burying behaviour in a neotropical direct-developing frog. An amplectant pair of Pristimantis chocoensis was found and we recorded oviposition and the subsequent burying of the clutch by the female. Both parents remained near the nest during the following day. This rare observation sheds light over the intricate reproductive behaviours of terrestrial amphibians and suggests that the evolution of direct development has selected for highly specialized forms of parenting.

Background: The prevalence of infertility has rarely been synthesized at the global level. Objective: To conduct a systematic review and meta-analysis to assess the community-based global prevalence of infertility. Search Strategy: PubMed, MEDLINE, Web of Science, and Science Direct were searched from inception until October 2022. Selection Criteria: Studies were included if they were published in English, had quantitative data, and reported the community-based prevalence of infertility. Data Collection and Analysis: Two authors independently extracted data. Random-effects meta-analysis was used to derive the pooled prevalence of infertility. Variations in the prevalence estimates in different subgroups. Univariate meta-regression was used to explore possible sources of heterogeneity. Main Results: The findings indicated the pooled prevalence of infertility was 12.87% (95% CI,12.41%-13.33%). The prevalences of primary infertility and secondary infertility were 7.34% and 6.01%, respectively. The overall prevalence of infertility among people was the highest in Africa (16.73%) and lowest in the North America (8.84%). Lower prevalence in cohort or prospective follow-up studies (9.75%) than in cross-sectional studies (12.93%). Women aged 35 and above had a higher prevalence of infertility (11.68%) compared to women below 35 years old (5.92%). The prevalence of infertility increased with the number of years, and increased with the degree of literature bias from low to high. Conclusions: This community-based study estimated the global prevalence of infertility to be 12.87% and suggested that an upward trend of the prevalence of infertility may persist in the future.

Introduction: Limited data exist on the gross motor abilities of children with cystic fibrosis (CF). The objective of this quality improvement project was to implement a systematic gross motor assessment in children with CF ages 4-12 years. Methods: Physical therapists aimed to evaluate at least 50% of eligible children at our CF Center over 1 year using the Bruininks-Oseretsky Test of motor Proficiency, second edition (BOT-2), a norm referenced assessment for gross motor skills, with delays defined by scores less than 18 th percentile. Demographic and clinical data including body mass index, hospitalizations, genotype, and comorbidities were collected. Basic descriptive statistics summarized patient information. Parametric and non-parametric methods compared groups of interest. Linear regression assessed associations between BOT-2 measures and clinical characteristics. Results: Of the 105 eligible children, 72 (69%) completed the BOT-2 over 1 year. Forty-five (62.5%) scored below average in at least one category. Impaired strength (22.2%) was most common, followed by impaired balance (16.7%), running speed and agility (15.3%), and bilateral coordination (8.3%). Eleven (15.5%) scored below average on their total motor composite score (TMC). Increased age, comorbidities and hospitalizations were associated with a lower TMC. Conclusions: The BOT-2 was successfully implemented as part of routine CF care to screen for gross motor delays. Results suggest that a high percentage of children with CF, especially older children with comorbid conditions or a history of hospitalization, have impaired gross motor function. These findings support the need for routine gross motor evaluations and physical therapy interventions within pediatric CF clinics.

Soil fungi are involved in the decomposition of organic matter, and they alter soil structure and physicochemical properties and drive the material cycle and energy flow in terrestrial ecosystems. Grazing exclusion is one of the most common measures used to restore degraded grasslands worldwide. However, changes in soil fungal community characteristics during grazing exclusion in different types of grasslands are unknown. Here, we investigated the effects of a 9-year grazing exclusion on soil properties, fungal community composition and diversity in three grassland types (temperate desert, temperate steppe and mountain meadow). The results showed that in the 0-5 cm soil layer, grazing exclusion significantly affected the physicochemical parameters of all three studied grassland types. In the 5-10 cm soil layer, grazing exclusion significantly increased total phosphorus (TP) in temperate deserts by 34.1%, while significantly decreasing bulk density (BD) by 9.8% and the nitrogen: phosphorus ratio (N:P) by 47.1%. The soil fungal community composition differed among the grassland types, For example, significant differences were found among the three grassland types for the Glomeromycota and Mucoromycota, Grazing exclusion, grassland type, and the interaction between the two did not significantly affect soil fungal α-diversity or community composition(P > 0.05), but significantly altered fungal β-diversity (P < 0.05). Overall, our results highlight the importance of soil nutrient content, especially soil Kjeldahl nitrogen, total phosphorus and organic carbon on fungal diversity, and the results provide key insights into how soil fungi respond to grazing exclusion in different grassland types.