Auditory change detection and visual selective attention: association between MMN and N2pc.

While the auditory and visual systems each provide distinct information to our brain, they also work together to process and prioritize input to address ever-changing conditions. Previous studies highlighted the trade-off between auditory change detection and visual selective attention; however, the relationship between them is still unclear. Here, we recorded electroencephalography signals from 106 healthy adults in three experiments. Our findings revealed a positive correlation at the population level between the amplitudes of event-related potential indices associated with auditory change detection (mismatch negativity) and visual selective attention (posterior contralateral N2) when elicited in separate tasks. This correlation persisted even when participants performed a visual task while disregarding simultaneous auditory stimuli. Interestingly, as visual attention demand increased, participants whose posterior contralateral N2 amplitude increased the most exhibited the largest reduction in mismatch negativity, suggesting a within-subject trade-off between the two processes. Taken together, our results suggest an intimate relationship and potential shared mechanism between auditory change detection and visual selective attention. We liken this to a total capacity limit that varies between individuals, which could drive correlated individual differences in auditory change detection and visual selective attention, and also within-subject competition between the two, with task-based modulation of visual attention causing within-participant decrease in auditory change detection sensitivity.

The next generation of EGFR inhibitors: a patenting perspective of PROTACs based EGFR degraders.

INTRODUCTION: Abnormal expression of epidermal growth factor receptor (EGFR) contributes to tumor development, especially in non-small cell lung cancer (NSCLC). Although multiple inhibitors have been developed to target diverse EGFR mutations and several have been approved, the inevitable drug resistance and side effect remain a challenge, which motivates novel strategies. Proteolysis-targeting chimeras (PROTACs) have been gaining momentum for their potential as novel therapeutics for human diseases by triggering protein degradation. To date, various potent and specific EGFR PROTACs have been discovered and some of them have entered clinical trials. AREAS COVERED: This review provides an overview of EGFR degraders in patents from 2016 to 2022. It provides an update of the discovery strategies, chemical structures, and molecular profiling of all available EGFR PROTACs. SciFinder, PubMed, Web of Science, EPO, and CNIPA databases were used for searching the literature and patents for EGFR PROTACs. EXPERT OPINION: By employing the PROTAC technology, highly potent and selective EGFR degraders based on four generation EGFR inhibitors have been developed, which offer a new strategy to target EGFR mutations and overcome the drug resistance. Despite the satisfactory result in vitro and in vivo studies, their therapeutic value awaits more rigorous preclinical testing and clinical investigation.

Automatic sensory change processing in adults with attention deficit and hyperactivity disorder: a visual mismatch negativity study.

In addition to higher-order executive functions, underlying sensory processing ability is also thought to play an important role in Attention-Deficit/Hyperactivity Disorder (AD/HD). An event-related potential feature, the mismatch negativity, reflects the ability of automatic sensory change processing and may be correlated with AD/HD symptoms and executive functions. This study aims to investigate the characteristics of visual mismatch negativity (vMMN) in adults with AD/HD. Twenty eight adults with AD/HD and 31 healthy controls were included in this study. These two groups were matched in age, IQ and sex. In addition, both groups completed psychiatric evaluations, a visual ERP task used to elicit vMMN, and psychological measures about AD/HD symptoms and day-to-day executive functions. Compared to trols, the late vMMN (230-330 ms) was significantly reduced in the AD/HD group. Correlation analyses showed that late vMMN was correlated with executive functions but not AD/HD symptoms. However, further mediation analyses showed that different executive functions had mediated the relationships between late vMMN and AD/HD symptoms. Our findings indicate that the late vMMN, reflecting automatic sensory change processing ability, was impaired in adults with AD/HD. This impairment could have negative impact on AD/HD symptoms via affecting day-to-day executive functions.

Discovery of highly potent and selective KRASG12C degraders by VHL-recruiting PROTACs for the treatment of tumors with KRASG12C-Mutation.

Although several covalent KRASG12C inhibitors have made great progress in the treatment of KRASG12C-mutant cancer, their clinical applications are limited by adaptive resistance, motivating novel therapeutic strategies. Through drug design and structure optimization, a series of highly potent and selective KRASG12C Proteolysis Targeting Chimeras (PROTACs) were developed by incorporating AMG510 and VHL ligand VH032. Among them, degrader YN14 significantly inhibited KRASG12C-dependent cancer cells growth with nanomolar IC50 and DC50 values, and ＞ 95 % maximum degradation (Dmax). Molecular dynamics (MD) simulation showed that YN14 induced a stable KRASG12C: YN14: VHL ternary complex with low binding free energy (ΔG). Notably, YN14 led to tumor regression with tumor growth inhibition (TGI%) rates more than 100 % in the MIA PaCa-2 xenograft model with well-tolerated dose-schedules. We also found that KRASG12C degradation exhibited advantages in overcoming adaptive KRASG12C feedback resistance over KRASG12C inhibition. Furthermore, combination of RTKs, SHP2, or CDK9 inhibitors with YN14 exhibited synergetic efficacy in KRASG12C-mutant cancer cells. Overall, these results demonstrated that YN14 holds exciting prospects for the treatment of tumors with KRASG12C-mutation and boosted efficacy could be achieved for greater clinical applications via drug combination.

Functional characterization of Alzheimer's disease genetic variants in microglia.

Candidate cis-regulatory elements (cCREs) in microglia demonstrate the most substantial enrichment for Alzheimer's disease (AD) heritability compared to other brain cell types. However, whether and how these genome-wide association studies (GWAS) variants contribute to AD remain elusive. Here we prioritize 308 previously unreported AD risk variants at 181 cCREs by integrating genetic information with microglia-specific 3D epigenome annotation. We further establish the link between functional variants and target genes by single-cell CRISPRi screening in microglia. In addition, we show that AD variants exhibit allelic imbalance on target gene expression. In particular, rs7922621 is the effective variant in controlling TSPAN14 expression among other nominated variants in the same cCRE and exerts multiple physiological effects including reduced cell surface ADAM10 and altered soluble TREM2 (sTREM2) shedding. Our work represents a systematic approach to prioritize and characterize AD-associated variants and provides a roadmap for advancing genetic association to experimentally validated cell-type-specific phenotypes and mechanisms.

Preparation of a Transient Thermal Expansion Rock Cracking Agent by Deposition Method and Its Nonisothermal Kinetics Study with Isoconversional Procedure and DAEM.

Cracking agents are indispensable and important products for national energy exploitation and large-scale infrastructure construction. Transient thermal expansion rock cracking agent is a new cracking agent product with excellent performance that has just appeared in recent years. However, it is still prepared by mechanical ball milling, which is considered not the best choice among traditional methods for preparing energetic materials. In this paper, a transient thermal expansion rock splitting agent was prepared by the chemical deposition method using carbon black and calcium peroxide as raw materials. The TG/DTG results show that the mass loss of the sample can be divided into four stages with the increase of temperature. It is worth noting that the mass loss of the TG curve of the sample during the entire thermal decomposition process is 93.385%, and the instantaneous weight loss is 78.07% (ß = 15 °C/min). Kinetic analysis of the thermal decomposition process of the samples was performed using an isotransformation program and a distributed activation energy model (DAEM). The activation energy E α of the thermal decomposition of the sample was iteratively calculated. The results show that the a-E a curve of the sample can be divided into two stages. The pyrolysis kinetics of the first stage was successfully analyzed by the DAEM method and its thermal conversion behavior was predicted. The thermal decomposition behavior of the second stage was analyzed by a traditional kinetic analysis method.

Abnormal Reactivity of Brain Oscillations to Visual Search Target in Children With Attention-Deficit/Hyperactivity Disorder.

BACKGROUND: Previous studies have shown that impaired goal-directed alpha lateralization and functional disconnection within attention networks during the cue period are significant features of attention-deficit/hyperactivity disorder (ADHD). This study aimed to explore the role of brain oscillations in the visual search process, focusing on target-induced posterior alpha lateralization, midfrontal theta synchronization, and their functional connection in children with ADHD. METHODS: Electroencephalograms were recorded from typically developing (TD) children (n = 72) and children with ADHD (n = 96) while they performed a visual search task. RESULTS: Both the TD and ADHD groups showed significant midfrontal theta event-related synchronization (ERS) and posterior alpha lateralization. Compared with TD children, children with ADHD showed significantly lower theta ERS and higher target-induced alpha lateralization. TD children showed a positive trial-based correlation between theta ERS and alpha lateralization and a negative correlation between theta ERS and reaction time variability. However, all these correlations were absent in children with ADHD. CONCLUSIONS: Abnormal brain oscillations in children with ADHD indicate insufficient executive control function and the compensation of attention networks for attention deficits in visual selective attention. Cross-frequency disconnection reflects the common deficiency of executive control in the gating of target information. Our findings provide novel evidence for interpreting the features of brain oscillations during stimulus-driven selective attention in children with ADHD.

The effects of first-dose methylphenidate on the neural signatures of visual selective attention in children with attention-deficit/hyperactivity disorder.

Although methylphenidate (MPH) has been shown to significantly improve selective attention in children with attention-deficit/hyperactivity disorder (ADHD), the neural mechanism of this effect remains unclear. We investigated the effects of first-dose MPH on the neural signatures of visual selective attention in children with ADHD. We measured the impact of first-dose MPH on electrophysiological indexes from eighteen children with ADHD (8.9-15.2 years; 15 boys) while they performed a visual search task. MPH was administered in a double-blind placebo-controlled crossover design. MPH led to decreases in behavioral error rates and reaction times. For the electrophysiological indexes, MPH significantly increased the target-elicited N2pc amplitude and posterior P3 amplitude during the selective attention process. The trial-based correlation analysis revealed that the enhanced N2pc (more negative) and P3 (more positive) promoted the behavioral response speed for children with ADHD. The lower individual P3 amplitude was associated with higher severity of inattention symptoms. The severer inattention symptoms were related to weaker MPH effect on N2pc amplitude. These findings suggest that N2pc and P3 are closely related to the mechanism of MPH in the ADHD treatment.

Population pharmacokinetics of voriconazole and initial dosage optimization in patients with talaromycosis.

The high variability and unpredictability of the plasma concentration of voriconazole (VRC) pose a major challenge for clinical administration. The aim of this study was to develop a population pharmacokinetics (PPK) model of VRC and identify the factors influencing VRC PPK in patients with talaromycosis. Medical records and VRC medication history of patients with talaromycosis who were treated with VRC as initial therapy were collected. A total of 233 blood samples from 69 patients were included in the study. A PPK model was developed using the nonlinear mixed-effects models (NONMEM). Monte Carlo simulation was applied to optimize the initial dosage regimens with a therapeutic range of 1.0-5.5 mg/L as the target plasma trough concentration. A one-compartment model with first-order absorption and elimination adequately described the data. The typical voriconazole clearance was 4.34 L/h, the volume of distribution was 97.4 L, the absorption rate constant was set at 1.1 h-1, and the bioavailability was 95.1%. Clearance was found to be significantly associated with C-reactive protein (CRP). CYP2C19 polymorphisms had no effect on voriconazole pharmacokinetic parameters. Monte Carlo simulation based on CRP levels showed that a loading dose of 250 mg/12 h and a maintenance dose of 100 mg/12 h are recommended for patients with CRP ≤ 96 mg/L, whereas a loading dose of 200 mg/12 h and a maintenance dose of 75 mg/12 h are recommended for patients with CRP > 96 mg/L. The average probability of target attainment of the optimal dosage regimen in CRP ≤ 96 mg/L and CRP > 96 mg/L groups were 61.3% and 13.6% higher than with empirical medication, and the proportion of Cmin > 5.5 mg/L decreased by 28.9%. In conclusion, the VRC PPK model for talaromycosis patients shows good robustness and predictive performance, which can provide a reference for the clinical individualization of VRC. Adjusting initial dosage regimens based on CRP may promote the rational use of VRC.

Computed Tomography-Based Determination of the Optimal Locations of Bone Tunnels for Coracoclavicular Ligament Reconstruction.

OBJECTIVE: An agreement has not been reached on optimal locations of bone tunnels for coracoclavicular ligament (CCL) reconstruction for acromioclavicular joint dislocation (ACD). This study aims to identify the convergence point (cP) between the coracoid process and clavicle in the Chinese population to assist surgeons in reconstructing the CCL for ACD. METHODS: From 2014 to 2020, 483 CT scans of the shoulders of 270 male and 213 female patients (247 right and 236 left shoulders) were collected and studied retrospectively. By overlapping the images of the transverse plane of the coracoid process and the clavicle, points a and b, and the midpoint ab (cP) were determined. Then, a series of parameters through point cP in the transverse and sagittal planes were measured. In the transverse plane this included the distance from point cP to the tip of the coracoid process (cP-cor),the distance between the medial and lateral margins of the coracoid process through point cP (Med-lat cor), the distance from point cP to the acromioclavicular joint (cP-ac), and the distance between the anteroposterior margin of the clavicle through point cP (Ap-clav). In the sagittal plane, this included the craniocaudal segment of the coracoid process (Cc-cor), and the craniocaudal segment of the clavicle (Cc-clav). The sex and side differences of these measurements were also analyzed by two radiologists. RESULTS: Based on the following measurements, point cP was determined. For male patients, the cP-cor was 28.02 ± 3.43 mm, Med-lat cor was 22.78 ± 2.80 mm, Cc-cor was 15.11 ± 2.13 mm, cP-ac was 29.24 ± 3.84 mm, Ap-clav was 18.27 ± 2.46 mm, and Cc-clav was 10.09 ± 1.56 mm. For female patients, the cP-cor was 25.20 ± 3.26 mm, Med-lat cor was 20.21 ± 2.97 mm, Cc-cor was 13.03 ± 1.77 mm, cP-ac was 26.66 ± 3.45 mm, Ap-clav was 16.10 ± 2.30 mm, and Cc-clav was 8.91 ± 1.40 mm. All the measurements of female patients were lower than those of male patients (p < 0.01). Between sides, only cP-ac of the left shoulders was significantly lower than those of the right shoulders (p < 0.05), with no significant differences in other parameters between sides (p > 0.05). CONCLUSION: The results of this study identified the locations of bone tunnel-cP in the coracoid process and clavicle for the CCL reconstruction in ACD. Moreover, the findings indicated that surgeons should be more cautious in operating on female patients and that the cP-ac of left shoulders should be set lower than that of right shoulders.

A Novel Adjustable EndoButton Fixation Assisted by 3D Printing Technology for Tibiofibular Syndesmosis Injury: A Biomechanical Study.

Purpose: The recommendations for surgical fixation of tibiofibular syndesmosis injuries are increasingly challenging for many clinical orthopedists, as international consensus has not been published for the optimal treatment of the injury. Thus, we have created a 3D-printed navigation template for a precise bone tunnel and a novel adjustable EndoButton fixation (NAE) for the ideal treatment. The purpose of this research was to evaluate the accuracy of the 3D-printed navigation template and explore the biomechanical performance of the NAE technique by comparing it with the intact syndesmosis, screw technique, and TightRope (TR) technique. Methods: Twenty-four human cadaveric legs were randomly allocated to four groups: the NAE group (n = 6), TR group (n = 6), screw group (n = 6), and intact group (n = 6). A personalized navigation template based on computed tomography scans was designed, and 3D printing models were generated for the distal tibiofibular syndesmosis. The NAE, TR, and screw group were performed via 3D-printed navigation template, respectively. All groups were tested under increasing loading forces including axial loading (from 100 N to 700 N) and torsional loading (from 1 N to 5 N), which were performed in different ankle positions. The displacements of the tibiofibular syndesmosis were analyzed using the Bose Electroforce 3510-AT biomechanical testing equipment. Results: Surgical fixations were conducted successfully through a 3D-printed navigation template. Both in axial or torsional loading experiments, no statistically significant difference was observed in the displacements among the NAE, TR, and intact groups in most situations (p > 0.05), whereas the screw group demonstrated obviously smaller displacements than the abovementioned three groups (p < 0.05). Conclusion: The 3D printing technology application may become beneficial and favorable for locating and making the bone tunnel. Also, the NAE fixation provides the performance of complete ligaments; it also restores physiologic micromotion and avoids insufficient or excessive reduction when compared to the TR and screw technique. This may offer a new fixation for the treatment of tibiofibular syndesmosis injuries that is desirable for clinical promotion.

Abrogation of HnRNP L enhances anti-PD-1 therapy efficacy via diminishing PD-L1 and promoting CD8+ T cell-mediated ferroptosis in castration-resistant prostate cancer.

Owing to incurable castration-resistant prostate cancer (CRPC) ultimately developing after treating with androgen deprivation therapy (ADT), it is vital to devise new therapeutic strategies to treat CRPC. Treatments that target programmed cell death protein 1 (PD-1) and programmed death ligand-1 (PD-L1) have been approved for human cancers with clinical benefit. However, many patients, especially prostate cancer, fail to respond to anti-PD-1/PD-L1 treatment, so it is an urgent need to seek a support strategy for improving the traditional PD-1/PD-L1 targeting immunotherapy. In the present study, analyzing the data from our prostate cancer tissue microarray, we found that PD-L1 expression was positively correlated with the expression of heterogeneous nuclear ribonucleoprotein L (HnRNP L). Hence, we further investigated the potential role of HnRNP L on the PD-L1 expression, the sensitivity of cancer cells to T-cell killing and the synergistic effect with anti-PD-1 therapy in CRPC. Indeed, HnRNP L knockdown effectively decreased PD-L1 expression and recovered the sensitivity of cancer cells to T-cell killing in vitro and in vivo, on the contrary, HnRNP L overexpression led to the opposite effect in CRPC cells. In addition, consistent with the previous study, we revealed that ferroptosis played a critical role in T-cell-induced cancer cell death, and HnRNP L promoted the cancer immune escape partly through targeting YY1/PD-L1 axis and inhibiting ferroptosis in CRPC cells. Furthermore, HnRNP L knockdown enhanced antitumor immunity by recruiting infiltrating CD8+ T cells and synergized with anti-PD-1 therapy in CRPC tumors. This study provided biological evidence that HnRNP L knockdown might be a novel therapeutic agent in PD-L1/PD-1 blockade strategy that enhanced anti-tumor immune response in CRPC.

Lack of an association between anticipatory alpha oscillations and attentional selection in children with attention-deficit/hyperactivity disorder.

OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) is characterized by attention problems. The current study investigated whether and how anticipatory alpha oscillations, the subsequent target-elicited N2 posterior-contralateral component (N2pc) and their relationship contributed to attention problems in children with ADHD. METHODS: Electroencephalograms (EEGs) were recorded from 8-13-year-old children with ADHD and typically developing children during a cued visuospatial covert attention task. RESULTS: Children with ADHD could not sustain hemispheric alpha lateralization during the late stage of the cued period. Similar to the pattern of adults, high-accuracy typically developing children showed a strong positive correlation between the degree of cue-induced anticipatory alpha lateralization and the subsequent target-evoked N2pc amplitude, the latter of which further predicted behavioral performance. However, only the aberrant "cue alpha-target N2pc" temporal relationship was related to symptom severity and behavioral performance in children with ADHD. CONCLUSIONS: We showed that the temporal association of "cue alpha-target N2pc" was already present in some typically developing children. However, children with ADHD might need more time to develop this temporal association. SIGNIFICANCE: Our results provide neurophysiological evidence that the developmental origin of covert spatial attention is related to the temporal association between low-frequency brain oscillations and event-related potentials (ERPs).

The neurovascular couplings between electrophysiological and hemodynamic activities in anticipatory selective attention.

Selective attention is thought to involve target enhancement and distractor inhibition processes. Here, we recorded simultaneous electroencephalographic (EEG) and functional near-infrared spectroscopy (fNIRS) data from human adults when they were pre-cued by the visual field of coming target, distractor, or both of them. From the EEG data, we found alpha power relatively decreased contralaterally to the to-be-attended target, as reflected by the positive-going alpha modulation index. Late alpha power relatively increased contralaterally to the to-be-suppressed distractor, as reflected by the negative-going alpha modulation index. From the fNIRS data, we found enhancements of hemodynamic activity over the contralateral hemisphere in response to both the target and the distractor anticipation but within nonoverlapping posterior brain regions. More importantly, we described the specific neurovascular modulation between alpha power and oxygenated hemoglobin signal, which showed a positive coupling effect during target anticipation and a negative coupling effect during distractor anticipation. Such flexible neurovascular couplings between EEG oscillation and hemodynamic activity seem to play an essential role in the final behavioral outcomes. These results provide unique neurovascular evidence for the dissociation of the mechanisms of target enhancement and distractor inhibition. Individual behavioral differences can be related to individual differences in neurovascular coupling.

Sound localization and auditory selective attention in school-aged children with ADHD.

This study aimed to identify the neurophysiologic bases of auditory attention deficits in children with attention-deficit/hyperactivity disorder (ADHD), focusing on the electroencephalography component of auditory spatial selective attention [the N2 anterior contralateral component (N2ac)]. EEG data were collected from 7- to 11-year-old children with ADHD (n = 54) and age-, sex-, and IQ-matched typically developing (TD) children (n = 61), while they performed an auditory spatial selective task. For behavior, the children with ADHD showed a shorter reaction time (RT) but a higher RT coefficient of variability (RTCV) than TD children. For ERPs, the TD group showed a significant "adult-like" N2ac component; however, the N2ac component was absent in children with ADHD. More importantly, the smaller N2ac component could predict longer RT in both groups, as well as higher severity of inattentive symptoms in children with ADHD. Our results indicated that 7- to 11-year-old TD children have developed an "adult-like" ability to balance auditory target selection and distractor suppression; the absence of N2ac in children with ADHD provided novel evidence supporting their dysfunctional auditory spatial selective attention.

Brain structural and functional anomalies associated with simultanagnosia in patients with posterior cortical atrophy.

Simultanagnosia is a common symptom of posterior cortical atrophy, and its association with brain structural and functional changes remains unclear. In our study, 18 posterior cortical atrophy patients with simultanagnosia, 29 patients with Alzheimer's disease and 20 cognitively normal controls were recruited and subjected to full neuropsychological evaluation, including simultanagnosia tests, and structural and resting-state functional MRI. The gray matter volume was assessed by voxel-based morphometry, while the intrinsic functional connectivity was evaluated using the reduced gray matter volume regions of interest as the seed. In contrast to the patients with Alzheimer's disease, those with posterior cortical atrophy showed the following: (1) markedly lower simultanagnosia test scores, (2) an altered regional gray matter volume of the left middle occipital gyrus and ventral occipital areas, and (3) lowered intrinsic functional connectivity with the left middle occipital gyrus, left lingual gyrus and right middle occipital gyrus separately. Additionally, the gray matter volume of the left middle occipital gyrus and left inferior occipital gyrus were each correlated with simultanagnosia in posterior cortical atrophy patients. The intrinsic functional connectivity of the left middle occipital gyrus with the right superior occipital gyrus and that of the right middle occipital gyrus with the left superior parietal gyrus were also correlated with simultanagnosia in posterior cortical atrophy patients. In summary, this study indicated that simultanagnosia is associated with gray matter reductions and decreased functional connectivity in the left middle occipital gyrus and the left inferior occipital gyrus in patients with posterior cortical atrophy.

Combined application of plant growth-promoting bacteria and iron oxide nanoparticles ameliorates the toxic effects of arsenic in Ajwain (Trachyspermum ammi L.).

Soil contamination with toxic heavy metals [such as arsenic (As)] is becoming a serious global problem because of the rapid development of the social economy. Although plant growth-promoting bacteria (PGPB) and nanoparticles (NPs) are the major protectants to alleviate metal toxicity, the study of these chemicals in combination to ameliorate the toxic effects of As is limited. Therefore, the present study was conducted to investigate the combined effects of different levels of Providencia vermicola (5 ppm and 10 ppm) and iron oxide nanoparticles (FeO-NPs) (50 mg/l-1 and 100 mg/l-1) on plant growth and biomass, photosynthetic pigments, gas exchange attributes, oxidative stress and response of antioxidant compounds (enzymatic and non-enzymatic), and their specific gene expression, sugars, nutritional status of the plant, organic acid exudation pattern As accumulation from the different parts of the plants, and electron microscopy under the soil, which was spiked with different levels of As [0 µM (i.e., no As), 50 µM, and 100 µM] in Ajwain (Trachyspermum ammi L.) seedlings. Results from the present study showed that the increasing levels of As in the soil significantly (p< 0.05) decreased plant growth and biomass, photosynthetic pigments, gas exchange attributes, sugars, and nutritional contents from the roots and shoots of the plants, and destroyed the ultra-structure of membrane-bound organelles. In contrast, increasing levels of As in the soil significantly (p< 0.05) increased oxidative stress indicators in term of malondialdehyde, hydrogen peroxide, and electrolyte leakage, and also increased organic acid exudation patter in the roots of T. ammi seedlings. The negative impact of As toxicity can overcome the application of PGPB (P. vermicola) and FeO-NPs, which ultimately increased plant growth and biomass by capturing the reactive oxygen species, and decreased oxidative stress in T. ammi seedlings by decreasing the As contents in the roots and shoots of the plants. Our results also showed that the FeO-NPs were more sever and showed better results when we compared with PGPB (P. vermicola) under the same treatment of As in the soil. Research findings, therefore, suggest that the combined application of P. vermicola and FeO-NPs can ameliorate As toxicity in T. ammi seedlings, resulting in improved plant growth and composition under metal stress, as depicted by balanced exudation of organic acids.

Association between subtalar articular surface typing and flat foot deformity: which type is more likely to cause flat foot deformity.

BACKGROUND: Previous studies have shown a wide range of anatomical classifications of the subtalar joint (STJ) in the population and this is related to the different force line structures of the foot. Different subtalar articular surface morphology may affect the occurrence and development of flat foot deformity, and there are fewer studies in this area. The main objective of our study was to determine the association of different subtalar articular surface with the occurrence and severity of flat foot deformity. METHODS: We analyzed the imaging data of 289 cases of STJ. The articular surface area, Gissane's angle and Bohler's angle of subtalar articular surface of different types were counted. The occurrence and severity of flat foot deformity in different subtalar articular surface were judged by measuring the Meary angle of foot. RESULTS: We classified 289 cases of subtalar articular surface into five types according to the morphology. According to Meary angle, the flat foot deformity of Type I and Type IV are significantly severer than Type II (P < 0.05). Type II (7.65 ± 1.38 cm2) was significantly smaller than Type I (8.40 ± 1.79 cm2) in the total joint facet area(P < 0.05). Type III (9.15 ± 1.92 cm2) was smaller than Type I (8.40 ± 1.79 cm2), II (7.65 ± 1.38 cm2) and IV (7.81 ± 1.74 cm2) (P < 0.05). Type II (28.81 ± 7.44∘) was significantly smaller than Type I (30.80 ± 4.61 degrees), and IV (32.25 ± 5.02 degrees) in the Bohler's angle (P < 0.05). Type II (128.49 ± 6.74 degrees) was smaller than Type I (131.58 ± 7.32 degrees), and IV (131.94 ± 5.80 degrees) in the Gissane's angle (P < 0.05). CONCLUSIONS: After being compared and analyzed the measurement of morphological parameters, joint facet area and fusion of subtalar articular surface were closely related to the severity of flat foot deformity and Type I and IV were more likely to develop severer flat foot deformity. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

Parallel characterization of cis-regulatory elements for multiple genes using CRISPRpath.

Current pooled CRISPR screens for cis-regulatory elements (CREs), based on transcriptional output changes, are typically limited to characterizing CREs of only one gene. Here, we describe CRISPRpath, a scalable screening strategy for parallelly characterizing CREs of genes linked to the same biological pathway and converging phenotypes. We demonstrate the ability of CRISPRpath for simultaneously identifying functional enhancers of six genes in the 6-thioguanine­induced DNA mismatch repair pathway using both CRISPR interference (CRISPRi) and CRISPR nuclease (CRISPRn) approaches. Sixty percent of the identified enhancers are known promoters with distinct epigenomic features compared to other active promoters, including increased chromatin accessibility and interactivity. Furthermore, by imposing different levels of selection pressure, CRISPRpath can distinguish enhancers exerting strong impact on gene expression from those exerting weak impact. Our results offer a nuanced view of cis-regulation and demonstrate that CRISPRpath can be leveraged for understanding the complex gene regulatory program beyond transcriptional output at scale.

In vitro Antifungal Susceptibility Profiles of Cryptococcus neoformans var. grubii and Cryptococcus gattii Clinical Isolates in Guangxi, Southern China.

This study analyzed the in vitro drug sensitivity of Cryptococcus spp. from Guangxi, Southern China. One hundred three strains of Cryptococcus were recovered from 86 patients; 14 were HIV positive and 72 were HIV negative. Ninety-two strains were identified as Cryptococcus neoformans var. grubii, while 11 strains were identified as Cryptococcus gattii (5 C. gattii sensu stricto and 6 Cryptococcus deuterogattii). The recovered strains were tested against commonly used antifungal drugs (fluconazole, amphotericin B, 5-fluorocytosine, itraconazole, and voriconazole) and to novel antifungal drugs (posaconazole and isavuconazole) using CLSI M27-A4 method. The results showed that all isolates were susceptible to most antifungal drugs, of which the minimum inhibitory concentration (MIC) ranges were as follows: 0.05-4 µg/ml for fluconazole, 0.25-1 µg/ml for amphotericin B; 0.0625-2 µg/ml for 5-fluorocytosine, 0.0625-0.25 µg/ml for itraconazole, 0.0078-0.25 µg/ml for voriconazole, 0.0313-0.5 µg/ml for posaconazole, 0.0020-0.125 µg/ml for isavuconazole for C. neoformans var. grubii isolates, and 1-16 µg/ml for fluconazole, 0.125-1 µg/ml for 5-fluorocytosine, 0.25-1 µg/ml for amphotericin B, 0.0625-0.25 µg/ml for itraconazole, 0.0156-0.125 µg/ml for voriconazole, 0.0156-0.25 µg/ml for posaconazole, and 0.0078-0.125 µg/ml for isavuconazole for C. gattii isolates. Furthermore, some C. neoformans var. grubii isolates were found to be susceptible-dose dependent to 5-fluorocytosine and itraconazole. In addition, a reduction in the potency of fluconazole against C. gattii is possible. We observed no statistical differences in susceptibility of C. neoformans var. grubii and C. gattii in the tested strains. Continuous observation of antifungal susceptibility of Cryptococcus isolates is recommended to monitor the emergence of resistant strains.