Genetic screening of newborns for deafness over 11 years in Beijing, China: More infants could benefit from an expanded program.

Genetic screening of newborns for deafness plays an important role in elucidating the etiology of deafness, diagnosing it early, and intervening in it. Genetic screening of newborns has been conducted for 11 years in Beijing. It started with a chip to screen for 9 variants of 4 genes in 2012; the chip screened for 15 variants of those genes in 2018, and it now screens for 23 variants of those genes. In the current study, a comparative analysis of three screening protocols and follow-up for infants with pathogenic variants was performed. The rates of detection and hearing test results of infants with pathogenic variants were analyzed. Subjects were 493,821 infants born at 122 maternal and child care centers in Beijing from April 2012 to August 2023. Positivity increased from 4.599% for the chip to screen for 9 variants to 4.971% for the chip to screen for 15 variants, and further to 11.489% for the chip to screen for 23 variants. The carrier frequency of the GJB2 gene increased from 2.489% for the chip to screen for 9 variants and 2.422% for the chip to screen for 15 variants to 9.055% for the chip to screen for 23 variants. The carrier frequency of the SLC26A4 gene increased from 1.621% for the chip to screen for 9 variants to 2.015% for the chip to screen for 15 variants and then to 2.151% for the chip to screen for 23 variants. According to the chip to screen for 9 variants and the chip to screen for 15 variants, the most frequent mutant allele was c.235delC. According to the chip to screen for 23 variants, the most frequent mutant allele was c.109G>A. The chip to screen for 15 variants was used to screen 66.67% (14/21) of newborns with biallelic variants in the SLC26A4 gene for newly added mutations. The chip to screen for 23 variants was used to screen 92.98% (53/57) of newborns with biallelic variants in the GJB2 gene (52 cases were biallelic c.109G>A) and 25% (1/4) of newborns with biallelic variants in the SLC26A4 gene for newly added mutations. Among the infants with pathogenic variants (biallelic variants in GJB2 or SLC26A4), 20.66% (25/121) currently have normal hearing. In addition, 34.62% (9/26) of newborns who passed the hearing screening were diagnosed with hearing loss. Findings indicate that a growing number of newborns have benefited, and especially in the early identification of potential late-onset hearing loss, as the number of screening sites has increased. Conducting long-term audiological monitoring for biallelic variants in individuals with normal hearing is of paramount significance.

Enhancing oocyte in vitro maturation and quality by melatonin/bilirubin cationic nanoparticles: A promising strategy for assisted reproduction techniques.

In assisted reproduction techniques, oocytes encounter elevated levels of reactive oxygen species (ROS) during in vitro maturation (IVM). Oxidative stress adversely affects oocyte quality, hampering their maturation, growth, and subsequent development. Thus, mitigating excessive ROS to safeguard less viable oocytes during IVM stands as a viable strategy. Numerous antioxidants have been explored for oocyte IVM, yielding considerable effects; however, several aspects, including solubility, stability, and safety, demand attention and resolution. In this study, we developed nanoparticles by self-assembling endogenous bilirubin and melatonin hormone coated with bilirubin-conjugated glycol chitosan (MB@GBn) to alleviate oxidative stress and enhance oocyte maturation. The optimized MB@GBn exhibited a uniform spherical shape, measuring 128 nm in particle size, with a PDI value of 0.1807 and a surface potential of +11.35 mV. The positively charged potential facilitated nanoparticle adherence to the oocyte surface through electrostatic interaction, allowing for functional action. In vitro studies demonstrated that MB@GB significantly enhanced the maturation of compromised oocytes. Further investigation revealed MB@GB's effectiveness in scavenging ROS, reducing intracellular calcium levels, and suppressing mitochondrial polarization. This study not only offers a novel perspective on nano drug delivery systems for biomedical applications but also presents an innovative strategy for enhancing oocyte IVM.

A novel mutation in the OTOF gene in a Chinese family with auditory neuropathy.

Gene therapy for monogenic auditory neuropathy (AN) has successfully improved hearing function in target gene-deficient mice. Accurate genetic diagnosis can not only clarify the etiology but also accurately locate the lesion site, providing a basis for gene therapy and guiding patient intervention and management strategies. In this study, we collected data from a family with a pair of sisters with prelingual deafness. According to their auditory tests, subject Ⅱ-1 was diagnosed with profound sensorineural hearing loss (SNHL), Ⅱ-2 was diagnosed with AN, Ⅰ-1 was diagnosed with high-frequency SNHL, and Ⅰ-2 had normal hearing. Using whole-exome sequencing (WES), one nonsense mutation, c.4030C>T (p.R1344X), and one missense mutation, c.5000C>A (p.A1667D), in the OTOF (NM_001287489.1) gene were identified in the two siblings. Their parents were heterozygous carriers of c.5000C>A (father) and c.4030C>T (mother). We hypothesized that c.5000C>A is a novel pathogenic mutation. Thus, subject Ⅱ-1 should also be diagnosed with AN caused by OTOF mutations. These findings not only expand the OTOF gene mutation spectrum for AN but also indicate that WES is an effective approach for accurately diagnosing AN.

MoS2@MWCNTs with Rich Vacancy Defects for Effective Piezocatalytic Degradation of Norfloxacin via Innergenerated-H2O2: Enhanced Nonradical Pathway and Synergistic Mechanism with Radical Pathway.

Molybdenum disulfide (MoS2)-based materials for piezocatalysis are unsatisfactory due to their low actual piezoelectric coefficient and poor electrical conductivity. Herein, 1T/3R phase MoS2 grown in situ on multiwalled carbon nanotubes (MWCNTs) was proposed. MoS2@MWCNTs exhibited the interwoven morphology of thin nanoflowers and tubes, and the piezoelectric response of MoS2@MWCNTs was 4.07 times higher than that of MoS2 via piezoresponse force microscopy (PFM) characterization. MoS2@MWCNTs exhibited superior activity with a 91% degradation rate of norfloxacin (NOR) after actually working 24 min (as for rhodamine B, reached 100% within 18 min) by pulse-mode ultrasonic vibration-triggered piezocatalysis. It was found that piezocatalysis for removing pollutants was attributed to the synergistic effect of free radicals (•OH and O2•-) and nonfree radical (1O2, key role) pathways, together with the innergenerated-H2O2 promoting the degradation rate. 1O2 can be generated by electron transfer and energy transfer pathways. The presence of oxygen vacancies (OVs) induced the transformation of O2 to 1O2 by triplet energy transfer. The fast charge transfer in MoS2@MWCNTs heterostructure and the coexistence of sulfur vacancies and OVs enhanced charge carrier separation resulting in a prominent piezoelectric effect. This work opens up new avenues for the development of efficient piezocatalysts that can be utilized for environmental purification.

High-frequency hearing vulnerability associated with the different supporting potential of Hensen's cells: SMART-Seq2 RNA sequencing.

Hearing loss is the third most prevalent physical condition affecting communication, well-being, and healthcare costs. Sensorineural hearing loss often occurs first in the high-frequency region (basal turn), then towards the low-frequency region (apical turn). However, the mechanism is still unclear. Supporting cells play a critical role in the maintenance of normal cochlear function. The function and supporting capacity of these cells may be different from different frequency regions. Hensen's cells are one of the unique supporting cell types characterized by lipid droplets (LDs) in the cytoplasm. Here, we investigated the morphological and gene expression differences of Hensen's cells along the cochlear axis. We observed a gradient change in the morphological characteristics of Hensen's cells along the cochlear tonotopic axis, with larger and more abundant LDs observed in apical Hensen's cells. Smart-seq2 RNA-seq revealed differentially expressed genes (DEGs) between apical and basal Hensen's cells that clustered in several pathways, including unsaturated fatty acid biosynthesis, cholesterol metabolism, and fatty acid catabolism, which are associated with different energy storage capacities and metabolic potential. These findings suggest potential differences in lipid metabolism and oxidative energy supply between apical and basal Hensen's cells, which is consistent with the morphological differences of Hensen's cells. We also found differential expression patterns of candidate genes associated with hereditary hearing loss (HHL), noise-induced hearing loss (NIHL), and age-related hearing loss (ARHL). These findings indicate functional heterogeneity of SCs along the cochlear axis, contribute to our understanding of cochlear physiology and provide molecular basis evidence for future studies of hearing loss.

[Mutation spectrum analysis of 23-site chip neonatal deafness genetic screening].

Objective:To analyze the mutation spectrum of 23-site chip newborn deafness genetic screening in Beijing, and to provide basis for genetic counseling and clinical diagnosis and treatment. Methods:The study included 21 006 babies born in Beijing from December 2022 to June 2023. All subjects underwent newborn deafness genetic screening in Beijing Tongren Hospital, covering 23 variants in 4 genes, the GJB2 gene（c.35delG, c.176_191del16, c.235delC, c.299_300delAT, c.109G>A, c.257C>G, c.512insAACG, c.427C>T, c.35insG）, SLC26A4 gene（c.919-2A>G, c.2168A>G, c.1174A>T, c.1226G>A, c.1229C>T, c.1975G>C, c.2027T>A, c.589G>A, c.1707+5G>A, c.917insG, c.281C>T）, Mt12SrRNA（m.1555A>G, m.1494C>T） and GJB3 gene（c.538C>T）. The mutation detection rate and allele frequency were analyzed. Results:The overall mutation detection rate was 11.516%（2 419/21 006）, with the GJB2 gene being the most frequently involved at 9.097%（1 911/21 006）, followed by the SLC26A4 gene at 2.123%（446/21 006）, the GJB3 gene at 0.362%（76/21 006） and Mt12SrRNA at 0.176%（37/21 006）. Among the GJB2 genes, c.109G>A and c.235delC mutation detection rates were the highest, with 6.579%（1 382/21 006） and 1.795%（377/21 006）, respectively. Of the SLC26A4 genes, c.919-2A>G and c.2168A>G had the highest mutation rates of 1.423%（299/21 006） and 0.233%（49/21 106）, respectively. Regarding the allele frequency, GJB2 c.109G>A was the most common variant with an allele frequency of 3.359%（1 411/42 012）, followed by the GJB2 c.235delC at 0.897%（377/42 012） and the SLC26A4 c.919-2A>G at 0.719%（302/42 012）. Conclusion:23-site chip newborn deafness genetic screening in Beijing showed that GJB2 c.109G>A mutation detection rate and allele frequency were the highest. This study has enriched the epidemiological data of 23-site chip genetic screening mutation profiles for neonatal deafness, which can provide evidence for clinical practice.

Bilirubin ameliorates osteoarthritis via activating Nrf2/HO-1 pathway and suppressing NF-κB signalling.

Osteoarthritis (OA) is a chronic degenerative joint disease that affects worldwide. Oxidative stress plays a critical role in the chronic inflammation and OA progression. Scavenging overproduced reactive oxygen species (ROS) could be rational strategy for OA treatment. Bilirubin (BR) is a potent endogenous antioxidant that can scavenge various ROS and also exhibit anti-inflammatory effects. However, whether BR could exert protection on chondrocytes for OA treatment has not yet been elucidated. Here, chondrocytes were exposed to hydrogen peroxide with or without BR treatment. The cell viability was assessed, and the intracellular ROS, inflammation cytokines were monitored to indicate the state of chondrocytes. In addition, BR was also tested on LPS-treated Raw264.7 cells to test the anti-inflammation property. An in vitro bimimic OA microenvironment was constructed by LPS-treated Raw264.7 and chondrocytes, and BR also exert certain protection for chondrocytes by activating Nrf2/HO-1 pathway and suppressing NF-κB signalling. An ACLT-induced OA model was constructed to test the in vivo therapeutic efficacy of BR. Compared to the clinical used HA, BR significantly reduced cartilage degeneration and delayed OA progression. Overall, our data shows that BR has a protective effect on chondrocytes and can delay OA progression caused by oxidative stress.

Identification and Validation of Magnolol Biosynthesis Genes in Magnolia officinalis.

Bacterial infections pose a significant risk to human health. Magnolol, derived from Magnolia officinalis, exhibits potent antibacterial properties. Synthetic biology offers a promising approach to manufacture such natural compounds. However, the plant-based biosynthesis of magnolol remains obscure, and the lack of identification of critical genes hampers its synthetic production. In this study, we have proposed a one-step conversion of magnolol from chavicol using laccase. After leveraging 20 transcriptomes from diverse parts of M. officinalis, transcripts were assembled, enriching genome annotation. Upon integrating this dataset with current genomic information, we could identify 30 laccase enzymes. From two potential gene clusters associated with magnolol production, highly expressed genes were subjected to functional analysis. In vitro experiments confirmed MoLAC14 as a pivotal enzyme in magnolol synthesis. Improvements in the thermal stability of MoLAC14 were achieved through selective mutations, where E345P, G377P, H347F, E346C, and E346F notably enhanced stability. By conducting alanine scanning, the essential residues in MoLAC14 were identified, and the L532A mutation further boosted magnolol production to an unprecedented level of 148.83 mg/L. Our findings not only elucidated the key enzymes for chavicol to magnolol conversion, but also laid the groundwork for synthetic biology-driven magnolol production, thereby providing valuable insights into M. officinalis biology and comparative plant science.

Identification and Optimization of more Efficient Olivetolic Acid Synthases.

Introduction: Olivetolic acid (OLA) is a key intermediate in cannabidiol (CBD) synthesis, and cannabinoids are important neuroactive drugs. However, the catalytic activity of olivetolic acid synthase (OLS), the key enzyme involved in OLA biosynthesis, remains low and its catalytic mechanism is unclear. Materials and Methods: In this study, we conducted a scrupulous screening of the pivotal rate-limiting enzyme and analyzed its amino acid sites that are critical to enzyme activity as validated by experiments. Results: Through stringent enzyme screening, we pinpointed a highly active OLS sequence, OLS4. Then, we narrowed down three critical amino acid sites (I258, D198, E196) that significantly influence the OLS activity. Conclusions: Our findings laid the groundwork for the efficient biosynthesis of OLA, and thereby facilitate the biosynthesis of CBD.

Effects of Different Durations and Frequencies of Vestibular Rehabilitation in Patients With Residual Symptoms After Benign Paroxysmal Positional Vertigo Repositioning.

OBJECTIVES: This study aimed to explore the effects of different duration and daily frequency of vestibular rehabilitation (VR) in patients with residual symptoms after benign paroxysmal positional vertigo (BPPV) successful repositioning. METHOD: Patients with successful BPPV repositioning (n = 118) were divided into 3 groups according to VR duration and frequency: group A (n = 30; 15 minutes, 3 times/day), group B (n = 30; 30 minutes, 3 times/day), group C (n = 28; 15 minutes, 6 times/day), and control group D (n = 30; no VR). All patients completed the dizziness handicap inventory (DHI) and vestibular rehabilitation benefit questionnaire (VRBQ) at baseline and after 2 and 4 weeks. RESULTS: The emotional scores and the proportion of severe dizziness disability in the DHI scores were significant differences between VR groups A to C and control group D after 2 and 4 weeks (all P < .05). There were significant differences in total DHI and VRBQ scores among the VR groups A to C after 2 and 4 weeks (all P < .05). Interestingly, emotion scores were not significantly different in group A (P = .385), group B (P = .569), and group C (P = .340) between 2 and 4 weeks. Meanwhile at 2 weeks, the difference in motion-provoked dizziness score between group A and B was statistically significant (P = .02). CONCLUSIONS: A total VR duration over 4 weeks can reduce dizziness and improve VR benefits in routine therapy in patients with residual dizziness after successful BPPV repositioning. Emotional improvement can be observed after 2 weeks. VR may help to relieve motion-provoked dizziness earlier if patients are willing to consider increasing the duration to more than 15 minutes.

Analysis of audiological outcomes of children referred from a universal newborn hearing screening program over 9 years in Beijing, China.

Universal newborn hearing screening (UNHS) and audiological diagnosis are crucial for children with congenital hearing loss (HL). The objective of this study was to analyze hearing screening techniques, audiological outcomes and risk factors among children referred from a UNHS program in Beijing. A retrospective analysis was performed in children who were referred to our hospital after failing UNHS during a 9-year period. A series of audiological diagnostic tests were administered to each case, to confirm and determine the type and degree of HL. Risk factors for HL were collected. Of 1839 cases, 53.0% were referred after only transient evoked otoacoustic emission (TEOAE) testing, 46.1% were screened by a combination of TEOAE and automatic auditory brainstem response (AABR) testing, and 1.0% were referred after only AABR testing. HL was confirmed in 55.7% of cases. Ears with screening results that led to referral experienced a more severe degree of HL than those with results that passed. Risk factors for HL were identified in 113 (6.1%) cases. The main risk factors included craniofacial anomalies (2.7%), length of stay in the neonatal intensive care unit longer than 5 days (2.4%) and birth weight less than 1500 g (0.8%). The statistical data showed that age (P < 0.001) and risk factors, including craniofacial anomalies (P < 0.001) and low birth weight (P = 0.048), were associated with the presence of HL. This study suggested that hearing screening plays an important role in the early detection of HL and that children with risk factors should be closely monitored.

Spatiotemporal dedifferentiation of the global brain signal topography along the adult lifespan.

Age-related variations in many regions and/or networks of the human brain have been uncovered using resting-state functional magnetic resonance imaging. However, these findings did not account for the dynamical effect the brain's global activity (global signal [GS]) causes on local characteristics, which is measured by GS topography. To address this gap, we tested GS topography including its correlation with age using a large-scale cross-sectional adult lifespan dataset (n = 492). Both GS topography and its variation with age showed frequency-specific patterns, reflecting the spatiotemporal characteristics of the dynamic change of GS topography with age. A general trend toward dedifferentiation of GS topography with age was observed in both spatial (i.e., less differences of GS between different regions) and temporal (i.e., less differences of GS between different frequencies) dimensions. Further, methodological control analyses suggested that although most age-related dedifferentiation effects remained across different preprocessing strategies, some were triggered by neuro-vascular coupling and physiological noises. Together, these results provide the first evidence for age-related effects on global brain activity and its topographic-dynamic representation in terms of spatiotemporal dedifferentiation.

Insertion of a totally implantable vascular access device in a patient with dextrocardia and colon cancer: a case report.

Colon cancer in patients with situs inversus totalis is rarely associated with dextrocardia, and chemotherapy is commonly used for treatment. Central venous access devices are used to administer intravenous fluids and chemotherapy in patients with colon cancer. Compared with peripherally inserted central catheters and Hickman-type tunneled catheters, totally implantable vascular access devices (TIVADs) are safer and more effective. However, positioning the catheter tip may be challenging in patients with dextrocardia and situs inversus. We herein describe a novel case involving a patient with dextrocardia and colon cancer who was treated by TIVAD insertion with intracavitary electrocardiography-aided tip localization.

Newborn hearing screening program in China: a narrative review of the issues in screening and management.

Hearing loss is one of the most common sensory disorders in humans. The purpose of this review is to summarize the history and current status of newborn hearing screening in China and to investigate future developmental trends in newborn hearing screening with the intention of sharing experiences and providing a reference for other populations. In the 1980s, the research on hearing monitoring for high-risk infants led to the gradual development of newborn hearing screening in China. With the continuous improvement of screening technology, the newborn hearing screening program was gradually extended to the whole country and became a government-led multidisciplinary public health program. Genetic screening for deafness has been incorporated into newborn hearing screening in many regions of China to help screen for potential and late-onset deafness in newborns. In the future, it is necessary to further establish and improve whole life-cycle hearing screening and healthcare, conduct screening for congenital cytomegalovirus infection, and create a full-coverage, whole life course hearing screening and intervention system. Screening for deafness in China has been marked by 40 years of achievements, which have been a source of pride for entrepreneurs and comfort for patients and their families. Managing hearing screening data information more efficiently and establishing a quality control index system throughout the whole screening process are of paramount importance. The genetic screening for concurrent newborn hearing and deafness has a great clinical importance for the management of congenital deafness and prevention of ototoxicity. A hearing screening and intervention system across the whole life course should be developed.

Intolerance of uncertainty enhances generalisation of cued conditioned threat: An event-related potential study.

Overgeneralisation is one of the aetiologies of anxiety disorders and is closely associated with elevated intolerance of uncertainty (IU) levels. However, the underlying mechanisms are unclear. Considering the inconsistency of previous results and the high sensitivity of IU to uncertainty, the present study investigated the effect of IU on threat generalisation in predictable and unpredictable conditions. We compared self-reported unconditioned stimuli (US) expectancy and event-related potentials (ERPs) during generalisation in high IU (n = 34) and low IU (n = 35) participants. The results indicated that high IU was associated with higher US expectancy for generalisation stimuli (GS) than with low IU. At the electrophysiological level, compared to low IU, high IU showed increased P1 to ambiguous GS as well as decreased early late positive potential (LPP) to GS in unpredictable conditions, and no differential response to GS in late LPP in predictable conditions. These findings suggest that IU enhances threat generalisation and may be related to increased early automatic attention to ambiguous stimulus and inadequate late elaborate processing in a high uncertainty context. These findings might contribute to the treatment of mood disorders characterized by high IU.

Intrarectal Foley catheter-assisted high-intensity focused ultrasound ablation for benign uterine diseases beyond the treatment region.

OBJECTIVE: To evaluate the feasibility of using an intrarectal Foley catheter during ultrasound-guided high-intensity focused ultrasound (US-HIFU) in patients with benign uterine diseases of the posterior wall beyond the HIFU therapeutic range. METHODS: Patients were treated with US-HIFU and lesion changes were monitored using contrast-enhanced MRI from June 2020 to September 2021. A Foley catheter was inserted into the rectum to facilitate a successful US-HIFU ablation. Complications and lesion responses were recorded during the treatment and follow-up. RESULTS: Thirteen patients with 14 lesions beyond the device's treatable area were enrolled. The average placement time and insertion depth of the intrarectal Foley catheter was 7.6 ± 2.7 min and 23.2 ± 7.6 cm, respectively. A median of 50 mL degassed water was injected into the Foley catheter balloon. All 14 lesions were successfully pushed into a treatable area and subjected to HIFU. The average treatment time, irradiation time, and total therapeutic energy of HIFU were 44.2 ± 17.3 min, 394.4 ± 295.7 s, and 73.3 ± 46.6 kJ, respectively. The mean non-perfusion volume (NPV) in all treated lesions was 23.2 ± 19.2 cm3, and the mean NPV ratio was 57.8 ± 16.9%. Major complications were not observed. CONCLUSION: Intrarectal Foley catheter-assisted US-HIFU is effective and safe. Its clinical application could benefit patients with benign uterine diseases outside the HIFU therapeutic range.

A Biomimetic Nanoparticle Exerting Protection against Acute Liver Failure by Suppressing CYP2E1 Activity and Scavenging Excessive ROS.

Acute liver failure (ALF) is a severe liver disease caused by many reasons. One of them is the overdosed acetaminophen (APAP), which is metabolized into N-acetyl-p-benzoquinone imine (NAPQI), an excessive toxic metabolite, by CYP2E1, resulting in excessive reactive oxygen species (ROS), exhausted glutathione (GSH), and thereafter hepatocyte necrosis. N-acetylcysteine is the Food and Drug Administration-approved drug for detoxification of APAP, but it has limited clinical application due to the short therapeutic time window and concentration-related adverse effects. In this study, a carrier-free and bilirubin dotted nanoparticle (B/BG@N) is developed, which is formed using bilirubin and 18ß-Glycyrrhetinic acid, and bovine serum albumin (BSA) is then adsorbed to mimic the in vivo behavior of the conjugated bilirubin for hitchhiking. The results demonstrate that B/BG@N can effectively reduce the production of NAPQI as well as exhibit antioxidant effects against intracellular oxidative stress via regulating the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 signal axis and reducing the production of inflammatory factors. In vivo study shows that B/BG@N can effectively improve the clinical symptom of the mice model. This study suggests that B/BG@N own increases circulation half-life, improves accumulation in the liver, and dual detoxification, providing a promising strategy for clinical ALF treatment.

ATB0,+-targeted nanoparticles initiate autophagy suppression to overcome chemoresistance for enhanced colorectal cancer therapy.

Oxaliplatin (OXA) resistance remains the major obstacle to the successful chemotherapy of colorectal cancer (CRC). As a self-protection mechanism, autophagy may contribute to tumor drug resistance, therefore autophagy suppression could be regarded as a possible treatment option in chemotherapy. Cancer cells, especially drug-resistant tumor cells, increase their demand for specific amino acids by expanding exogenous supply and up-regulating de novo synthesis, to meet the needs for excessive proliferation. Therefore, it is possible to inhibit cancer cell proliferation through pharmacologically blocking the entry of amino acid into cancer cells. SLC6A14 (ATB0,+) is an essential amino acid transporter, that is often abnormally up-regulated in most cancer cells. Herein, in this study, we designed oxaliplatin/berbamine-coloaded, ATB0,+-targeted nanoparticles ((O + B)@Trp-NPs) to therapeutically target SLC6A14 (ATB0,+) and inhibit cancer proliferation. The (O + B)@Trp-NPs utilize the surface-modified tryptophan to achieve SLC6A14-targeted delivery of Berbamine (BBM), a compound that is found in a number of plants used in traditional Chinese medicine, which could suppress autolysosome formation though impairing autophagosome-lysosome fusion. We verified the feasibility of this strategy to overcome the OXA resistance during colorectal cancer treatment. The (O + B)@Trp-NPs significantly inhibited the proliferation and decreased the drug resistance of resistant colorectal cancer cells. In vivo, (O + B)@Trp-NPs greatly suppressed the tumor growth in tumor-bearing mice, which is consistent with the in vitro data. This research offers a unique and promising chemotherapeutic treatment for colorectal cancer.

Individual differences in contextual threat generalisation and uncertainty: The role of intolerance of uncertainty.

Threat generalisation is an adaptive process that is essential for individual survival. In contrast, over-generalisation is a pathological process that underlies the development of anxiety disorders. Intolerance of uncertainty (IU) is an individual characteristic known to influence threat generalisation by altering the responses to threat in uncertain situations. However, how it affects contextual threat generalisation remains unclear. Here, we used a novel paradigm to investigate whether contextual threat generalisation varied between individuals depending on their IU level (high or low) and the predictability of a situation (predictable or unpredictable). We analysed shock expectancy in 82 participants (age: 18-27 years) during threat acquisition and generalisation. Results showed that compared with the low IU group, the high IU group exhibited increased contextual threat generalisation to threat-related cues in unpredictable situation. These findings suggest that IU could be a marker for anxiety disorder susceptibility, as well as a target for anxiety treatment.

Optimized concurrent hearing and genetic screening in Beijing, China: A cross-sectional study.

Concurrent screening has been proven to provide a comprehensive approach for management of congenital deafness and prevention of ototoxicity. The SLC26A4 gene is associated with late-onset hearing loss and is of great clinical concern. For much earlier detection of newborns with deafness-causing mutations in the SLC26A4 gene, the Beijing Municipal Government launched a chip for optimized genetic screening of 15 variants of 4 genes causing deafness based on a chip to screen for 9 variants of 4 genes, and 6 variants of the SLC26A4 gene have now been added. To ascertain the advantage of a screening chip including 15 variants of 4 genes, the trends in concurrent hearing and genetic screening were analyzed in 2019 and 2020. Subjects were 76,460 newborns who underwent concurrent hearing and genetic screening at 24 maternal and child care centers in Beijing from January 2019 to December 2020. Hearing screening was conducted using transiently evoked otoacoustic emissions (TEOAEs), distortion product otoacoustic emissions (DPOAE), or the automated auditory brainstem response (AABR). Dried blood spots were collected for genetic testing and 15 variants of 4 genes, namely GJB2, SLC26A4, mtDNA 12S rRNA, and GJB3, were screened for using a DNA microarray platform. The initial referral rate for hearing screening decreased from 3.60% (1,502/41,690) in 2019 to 3.23% (1,124/34,770) in 2020, and the total referral rate for hearing screening dropped form 0.57% (236/41,690) in 2019 to 0.54% (187/34,770) in 2020, indicating the reduced false positive rate of newborn hearing screening and policies to prevent hearing loss conducted by the Beijing Municipal Government have had a significant effect. Positivity according to genetic screening was similar in 2019 (4.970%, 2,072/41,690) and 2020 (4.863%,1,691/34,770), and the most frequent mutant alleles were c.235 del C in the GJB2 gene, followed by c.919-2 A > G in the SLC26A4 gene, and c.299 del AT in the GJB2 gene. In this cohort study, 71.43% (5/7) of newborns with 2 variants of the SLC26A4 gene were screened for newly added mutations, and 28.57% (2/7) of newborns with 2 variants of the SLC26A4 gene passed hearing screening, suggesting that a screening chip including 15 variants of 4 genes was superior at early detection of hearing loss, and especially in early identification of newborns with deafness-causing mutations in the SLC26A4 gene. These findings have clinical significance.