Sound-localization-related activation and functional connectivity of dorsal auditory pathway in relation to demographic, cognitive, and behavioral characteristics in age-related hearing loss.

Background: Patients with age-related hearing loss (ARHL) often struggle with tracking and locating sound sources, but the neural signature associated with these impairments remains unclear. Materials and methods: Using a passive listening task with stimuli from five different horizontal directions in functional magnetic resonance imaging, we defined functional regions of interest (ROIs) of the auditory "where" pathway based on the data of previous literatures and young normal hearing listeners (n = 20). Then, we investigated associations of the demographic, cognitive, and behavioral features of sound localization with task-based activation and connectivity of the ROIs in ARHL patients (n = 22). Results: We found that the increased high-level region activation, such as the premotor cortex and inferior parietal lobule, was associated with increased localization accuracy and cognitive function. Moreover, increased connectivity between the left planum temporale and left superior frontal gyrus was associated with increased localization accuracy in ARHL. Increased connectivity between right primary auditory cortex and right middle temporal gyrus, right premotor cortex and left anterior cingulate cortex, and right planum temporale and left lingual gyrus in ARHL was associated with decreased localization accuracy. Among the ARHL patients, the task-dependent brain activation and connectivity of certain ROIs were associated with education, hearing loss duration, and cognitive function. Conclusion: Consistent with the sensory deprivation hypothesis, in ARHL, sound source identification, which requires advanced processing in the high-level cortex, is impaired, whereas the right-left discrimination, which relies on the primary sensory cortex, is compensated with a tendency to recruit more resources concerning cognition and attention to the auditory sensory cortex. Overall, this study expanded our understanding of the neural mechanisms contributing to sound localization deficits associated with ARHL and may serve as a potential imaging biomarker for investigating and predicting anomalous sound localization.

Automatic Detection of Scalp High-Frequency Oscillations Based on Deep Learning.

Scalp high-frequency oscillations (sHFOs) are a promising non-invasive biomarker of epilepsy. However, the visual marking of sHFOs is a time-consuming and subjective process, existing automatic detectors based on single-dimensional analysis have difficulty with accurately eliminating artifacts and thus do not provide sufficient reliability to meet clinical needs. Therefore, we propose a high-performance sHFOs detector based on a deep learning algorithm. An initial detection module was designed to extract candidate high-frequency oscillations. Then, one-dimensional (1D) and two-dimensional (2D) deep learning models were designed, respectively. Finally, the weighted voting method is used to combine the outputs of the two model. In experiments, the precision, recall, specificity and F1-score were 83.44%, 83.60%, 96.61% and 83.42%, respectively, on average and the kappa coefficient was 80.02%. In addition, the proposed detector showed a stable performance on multi-centre datasets. Our sHFOs detector demonstrated high robustness and generalisation ability, which indicates its potential applicability as a clinical assistance tool. The proposed sHFOs detector achieves an accurate and robust method via deep learning algorithm.

Boosting Sono-immunotherapy of Prostate Carcinoma through Amplifying Domino-Effect of Mitochondrial Oxidative Stress Using Biodegradable Cascade-Targeting Nanocomposites.

Sono-immunotherapy faces challenges from poor immunogenicity and low response rate due to complex biological barriers. Herein, we prepared MCTH nanocomposites (NCs) consisting of disulfide bonds (S-S) doped mesoporous organosilica (MONs), Cu-modified protoporphyrin (CuPpIX), mitochondria-targeting triphenylphosphine (TPP), and CD44-targeting hyaluronic acid (HA). MCTH NCs efficiently accumulate at the tumor site due to the overexpressed CD44 receptors on the membrane of the cancer cells. Under the function of HAase and glutathione (GSH), MCTH degrades and exposes TPP to deliver CuPpIX to the mitochondrial site and induce a reactive oxygen species (ROS) burst in situ under ultrasound irradiations, thereby causing severe mitochondria dysfunction. This cascade-targeting ability of MCTH NCs not only reinforces oxidative stress in cancer cells but also amplifies immunogenic cell death (ICD) to stimulate the body's immune response and alleviate the tumor immunosuppressive microenvironment. These NCs significantly enhance the infiltration of immune cells into the tumor, particularly CD8+ T cells, for a powerful antitumor sono-immunotherapy. The proposed cascade-targeting strategy holds promise for strengthening sono-immunotherapy for prostate cancer treatment and overcoming the limitations of traditional immunotherapy.

A deep learning framework for intracranial aneurysms automatic segmentation and detection on magnetic resonance T1 images.

OBJECTIVES: To design a deep learning-based framework for automatic segmentation and detection of intracranial aneurysms (IAs) on magnetic resonance T1 images and test the robustness and performance of framework. METHODS: A retrospective diagnostic study was conducted based on 159 IAs from 136 patients who underwent the T1 images. Among them, 127 cases were randomly selected for training and validation, and 32 cases were used to assess the accuracy and consistency of our algorithm. We developed and assembled three convolutional neural networks for the segmentation and detection of IAs. The segmentation and detection performance of the model were compared with the ground truth, and various metrics were calculated at the voxel level, IAs level, and patient level to show the performance of our framework. RESULTS: Our assembled model achieved overall Dice, voxel-level sensitivity, specificity, balanced accuracy, and F1 score of 0.802, 0.874, 0.9998, 0.937, and 0.802, respectively. A coincidence greater than 0.7 between the aneurysms predicted by the model and the ground truth was considered as a true positive. For IAs detection, the sensitivity reached 90.63% with 0.58 false positives per case. The volume of IAs segmented by our model showed a high agreement and consistency with the volume of IAs labeled by experts. CONCLUSION: The deep learning framework is achievable and robust for IAs segmentation and detection. Our model offers more clinical application opportunities compared to digital subtraction angiography (DSA)-based, CTA-based, and MRA-based methods. CLINICAL RELEVANCE STATEMENT: Our deep learning framework effectively detects and segments intracranial aneurysms using clinical routine T1 sequences, showing remarkable effectiveness and offering great potential for improving the detection of latent intracranial aneurysms and enabling early identification. KEY POINTS: •There is no segmentation method based on clinical routine T1 images. Our study shows that the proper deep learning framework can effectively localize the intracranial aneurysms. •The T1-based segmentation and detection method is more universal than other angiography-based detection methods, which can potentially reduce missed diagnoses caused by the absence of angiography images. •The deep learning framework is robust and has the potential to be applied in a clinical setting.

An inducible hACE2 transgenic mouse model recapitulates SARS-CoV-2 infection and pathogenesis in vivo.

The classical manifestation of COVID-19 is pulmonary infection. After host cell entry via human angiotensin-converting enzyme II (hACE2), the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus can infect pulmonary epithelial cells, especially the AT2 (alveolar type II) cells that are crucial for maintaining normal lung function. However, previous hACE2 transgenic models have failed to specifically and efficiently target the cell types that express hACE2 in humans, especially AT2 cells. In this study, we report an inducible, transgenic hACE2 mouse line and showcase three examples for specifically expressing hACE2 in three different lung epithelial cells, including AT2 cells, club cells, and ciliated cells. Moreover, all these mice models develop severe pneumonia after SARS-CoV-2 infection. This study demonstrates that the hACE2 model can be used to precisely study any cell type of interest with regard to COVID-19-related pathologies.

Thermal Contact Response of a Transversely Isotropic Magneto-Electro-Elastic Coating.

The magneto-electro-elastic (MEE) medium is a typical intelligent material with promising application prospects in sensors and transducers, whose thermal contact response is responsible for their sensitivity and stability. An effective thermal contact model between a moving sphere and a coated MEE medium with transverse isotropy is established via a semi-analytical method (SAM) to explore its thermal contact response. First, a group of frequency response functions for the magneto-electro-thermo-elastic field of a coated medium are derived, assuming that the coating is perfectly bonded to the substrate. Then, with the aid of the discrete convolution-fast Fourier transform algorithm and conjugate gradient method, the contact pressure and heat flux can be determined. Subsequently, the induced elastic, thermal, electric and magnetic fields in the coating and substrate can be obtained via influence coefficients relating the induced field and external loads. With the proposed method, parametric studies on the influence of the sliding velocity and coating property are conducted to investigate the thermal contact behavior and resulting field responses of the MEE material. The sliding velocity and thermal properties of the coating have a significant effect on the thermal contact response of the MEE material; the coupled multi-field response can be controlled by changing the coating thickness between ~0.1 a0 and a0.

Three Novel ARID1B Variations in Coffin-Siris Syndrome Patients.

Coffin-Siris syndrome (CSS) (OMIM #135900) involves multiple congenital malformations, including hypotonia, short stature, sparse scalp hair, a coarse face, prominent eyebrows, a wide mouth, delayed bone age, and hypoplastic or absent fifth fingers/toes or nails, together with developmental delay. The cause of CSS is suggested to be related to alterations in the BRG- or HRBM-associated factor (BAF) pathway in humans. In this gene family, pathogenic variations in the AT-rich interactive domain-containing protein 1B (ARID1B) gene are revealed to be a significant element causing neurodevelopmental disability in patients with CSS. Herein, we describe the clinical features and gene variations in four Chinese patients with CSS. All the patients shared common features of short fifth fingers/toes or hypoplastic nails, coarse facial features, thick eyebrows, long cilia, a flat nasal bridge, a broad nose, a wide mouth, a high palate, and hypotonia. Besides, they had an intellectual disability, language, and motor developmental delay. Candidate genes were screened for variations using polymerase chain reaction (PCR) and sequencing. The variations were sequenced by next-generation sequencing and confirmed by first-generation sequencing. Exome sequencing suggested four de novo variations in the ARID1B gene in four unrelated patients. These included two frameshift variations (c.3581delC, c.6661_6662insG) and two nonsense variations (c.1936C>T, c.2248C>T). Of the four variations, three variations were novel. The results in our present study broaden the understanding of the disease and further interpret the molecular genetic mechanism of these rare variations in CSS.

New Insights into the Mechanism of Nucleation of ZrO2 Inclusions at High Temperature.

It is difficult to observe the nucleation mechanism of inclusions in real-time. In this study, the nucleation process of zirconium oxide inclusions was systematically studied by classical nucleation theory and first principles. Zr deoxidized steel with 100 ppm Zr addition was processed into metallographic samples for scanning electron microscopy energy-dispersive spectroscopy observation. The electrolytic sample was analyzed by micro X-ray diffraction and transmission electron microscopy, and the zirconium oxide in the sample was determined to be ZrO2. The nucleation rate and radius of the ZrO2 inclusions were calculated by classical nucleation theory, and they were compared with the experimental values. There was a considerable difference between the experimental and theoretical values of the nucleation rate. The effect of the nucleation size was analyzed by first-principles calculation, and the thermodynamic properties of ZrO2 clusters and nanoparticles were analyzed by constructing (ZrO2)n (n = 1-6) clusters. The thermodynamic properties of ZrO2 calculated by first principles were consistent with the values in the literature. Based on two-step nucleation theory, the nucleation pathway of ZrO2 is as follows: Zratom + Oatom → (ZrO2)n → (ZrO2)2 → core (ZrO2 particle)-shell ((ZrO2)2 cluster) nanoparticle → (ZrO2)bulk.

The long-awaited synthesis and self-assembly of a small rigid C3-symmetric trilactam.

The challenging synthesis of a fused C3-symmetric trilactam (1) was executed in racemic and enantiomerically pure form. The rigidity, symmetry and high density of hydrogen bonding motifs make 1 an attractive candidate for self-assembly study, which revealed different hydrogen bond patterns in the crystals of rac-1-d3 and (+)-(SSS)-1.

Mass-ratio and complementarity effects simultaneously drive aboveground biomass in temperate Quercus forests through stand structure.

Forests play a key role in regulating the global carbon cycle, a substantial portion of which is stored in aboveground biomass (AGB). It is well understood that biodiversity can increase the biomass through complementarity and mass-ratio effects, and the contribution of environmental factors and stand structure attributes to AGB was also observed. However, the relative influence of these factors in determining the AGB of Quercus forests remains poorly understood. Using a large dataset retrieved from 523 permanent forest inventory plots across Northeast China, we examined the effects of integrated multiple tree species diversity components (i.e., species richness, functional, and phylogenetic diversity), functional traits composition, environmental factors (climate and soil), stand age, and structure attributes (stand density, tree size diversity) on AGB based on structural equation models. We found that species richness and phylogenetic diversity both were not correlated with AGB. However, functional diversity positively affected AGB via an indirect effect in line with the complementarity effect. Moreover, the community-weighted mean of specific leaf area and height increased AGB directly and indirectly, respectively; demonstrating the mass-ratio effect. Furthermore, stand age, density, and tree size diversity were more important modulators of AGB than biodiversity. Our study highlights that biodiversity-AGB interaction is dependent on the regulation of stand structure that can be even more important for maintaining high biomass than biodiversity in temperate Quercus forests.

The lncRNA CASC9 alleviates lipopolysaccharide-induced acute kidney injury by regulating the miR-424-5p/TXNIP pathway.

OBJECTIVE: This study aimed to clarify the mechanism by which the long non-coding RNA cancer susceptibility candidate 9 (CASC9) alleviates sepsis-related acute kidney injury (S-AKI). METHODS: A lipopolysaccharide (LPS)-induced AKI model was established to simulate S-AKI. HK-2 human renal tubular epithelial cells were treated with LPS to establish an in vitro model, and mice were intraperitoneally injected with LPS to generate an in vivo model. Subsequently, the mRNA expression of inflammatory and antioxidant factors was validated by quantitative reverse transcription polymerase chain reaction (RT-qPCR). Reactive oxygen species (ROS) production was assessed using an assay kit. Apoptosis was detected by western blotting and fluorescence-activated cell sorting. RESULTS: CASC9 was significantly downregulated in the LPS-induced AKI model. CASC9 attenuated cell inflammation and apoptosis and enhanced the antioxidant capacity of cells. Regarding the mechanism, miR-424-5p was identified as the downstream target of CASC9, and the interaction between CASC9 and miR-424-5p promoted thioredoxin-interacting protein (TXNIP) expression. CONCLUSIONS: CASC9 alleviates LPS-induced AKI in vivo and in vitro, and CASC9 directly targets miR-424-5p and further promotes the expression of TXNIP. We have provided a possible reference strategy for the treatment of S-AKI.

Suspended Membrane Evaporators Integrating Environmental and Solar Evaporation for Oily Wastewater Purification.

Solar-driven evaporation is promising in oily wastewater treatment, in particular for emulsions, but conventional evaporators suffer from pore blocking by residual oil or contamination by volatile oil compounds in the condensed water. In the current research, we develop a suspended membrane evaporator integrating solar evaporation with oil-in-water emulsion separation. The heating and evaporating interface is separated from the rejecting interface to avoid oil escape and improve heat management. A temperature gradient forms on the membrane surface that can promote evaporation performance by combining both solar and environmental evaporation. Such an evaporator achieves a maximum evaporation rate of 1.645 kg/(m2·h) as well as an apparent evaporation efficiency of 111.9%. Moreover, the superhydrophilic and superoleophobic membrane shows excellent oil repellence and emulsion rejection, which can achieve an oil removal efficiency above 98.8% in oil-in-water emulsion separation, and high evaporation rate recovery in cycling tests. A scaled-up membrane evaporator array produces ∼8 kg/(m2·d) of clean water from oily wastewater in outdoor experiments, further demonstrating the strong purification performance of this evaporator in oily wastewater treatment.

Sandwich-Structured Photothermal Wood for Durable Moisture Harvesting and Pumping.

Moisture capture coupled with photothermal regeneration provides an alternative and sustainable way to acquire fresh water. Composite moisture absorbents based on hygroscopic salts are environmentally friendly, economically feasible, and of high efficiency but suffer from the unavoidable desiccant leakage during absorption and evaporation-induced salt accumulation on material surfaces during desorption. In this study, we develop a superhydrophobic-hydrophilic-hydrophobic photothermal wood embedded with CaCl2 to promote the durability of the absorbents. The sandwich structure serves as a liquid/vapor gate allowing vapor transport but forbidding liquid permeation, enabling the condensation and evaporation within the wood. Beyond moisture harvesting, the sandwich-structured photothermal wood exhibits potential in indoor dehumidification by pumping the moisture through an absorption-desorption cycle.

Effects of emergency treatment mode of damage-control orthopedics in pelvic fracture complicated with multiple fractures.

OBJECTIVE: This study aimed to observe the application effect of emergency treatment mode of damage-control orthopedics (DCO) in pelvic fracture complicated with multiple fractures. METHODS: Ninety-four patients with pelvic fracture complicated with multiple fractures in our hospital were recruited and divided into two groups according to the random number table method, with 47 cases in each group. Patients in the control group received traditional methods for emergency treatment (early complete treatment), and patients in the research group received DCO for emergency treatment (treatment performed in stages according to patient's physiological tolerance, with simplified initial surgery, followed by ICU resuscitation, and finally definitive surgery). The two groups were compared in terms of mortality, the incidence of acidosis and hypothermia three days after the first surgery, surgery-related indexes (time of the first surgery, blood transfusion volume, intraoperative blood loss, recovery time of temperature, and length of hospital stay), coagulation function indexes (activated partial thromboplastin time (APTT), thrombin time (TT), prothrombin time (PT) and fibrinogen (FIB)), postoperative reduction of fracture, complication rate, and quality of life. RESULTS: The incidences of acidosis, hypothermia, and mortality three days after the first surgery in the research group were lower than those in the control group (P<0.05). Compared with the control group, the research group experienced shorter time of the first surgery, less intraoperative blood transfusion volume, less intraoperative blood loss, shorter recovery time of body temperature, and shorter length of hospital stay (P<0.05). Seven days after surgery, PT, TT and APTT decreased and FIB increased in both groups (P<0.05), PT, TT and APTT in the research group were lower than those in the control group (P<0.05), while FIB was higher (P<0.05). The good rate of reduction in the research group was higher than that in the control group (P=0.025). The incidence of complications in the research group was lower than that in the control group (P=0.049). Six months after surgery, the scores of physiological function (PF), body pain (BP), role physical (RP), emotional function (EF), social function (SF), vitality, and general health (GH) of the research group were higher than those of the control group (P<0.05), but there was no significant difference in mental health (MH) between the two groups (P>0.05). CONCLUSION: The emergency treatment mode of DCO is effective in pelvic fracture complicated with multiple fractures, which can effectively improve postoperative reduction of patients, improve the coagulation function, reduce complications, and improve the quality of life.

A human cell-based SARS-CoV-2 vaccine elicits potent neutralizing antibody responses and protects mice from SARS-CoV-2 challenge.

To curb the pandemic of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), multiple platforms have been employed toward a safe and highly effective vaccine. Here, we develop a novel cell-based vaccine candidate, namely K562-S, by utilizing human cell K562 as a cellular carrier to display Spike (S) protein of SARS-CoV-2 on the membrane. Analogous to the traditional inactivated vaccine, K562-S cells can be propagated to a large scale by culturing and completely lose their viability after exposure to X-ray irradiation or formalin. We in turn demonstrated high immunogenicity of formalin-inactivated K562-S vaccine in both mouse and non-human primates and its protective efficacy in mice. In mice, immunization with inactivated K562-S vaccines can elicit potent neutralizing antibody (nAb) responses persisting longer than 5 months. We consequently showed in a hACE2 mouse model of SARS-CoV-2 infection that a two-shot vaccination with adjuvanted K562-S rendered greater than 3 log reduction in viral lung load and concomitant ameliorated lung pathology. Of importance, the administration of the same regimen in non-human primates was able to induce a neutralizing antibody titer averaging three-fold higher relative to human convalescent serum. These results together support the promise of K562-based, S-protein-expressing vaccines as a novel vaccination approach against SARS-CoV-2. Importantly, with a powerful capacity to carry external genes for cell-based vectors, this platform could rapidly generate two- and multiple-valent vaccines by incorporating SARS-CoV-2 mutants, SARS-CoV, or MERS-CoV.

Structural and functional basis for pan-CoV fusion inhibitors against SARS-CoV-2 and its variants with preclinical evaluation.

The COVID-19 pandemic poses a global threat to public health and economy. The continuously emerging SARS-CoV-2 variants present a major challenge to the development of antiviral agents and vaccines. In this study, we identified that EK1 and cholesterol-coupled derivative of EK1, EK1C4, as pan-CoV fusion inhibitors, exhibit potent antiviral activity against SARS-CoV-2 infection in both lung- and intestine-derived cell lines (Calu-3 and Caco2, respectively). They are also effective against infection of pseudotyped SARS-CoV-2 variants B.1.1.7 (Alpha) and B.1.1.248 (Gamma) as well as those with mutations in S protein, including N417T, E484K, N501Y, and D614G, which are common in South African and Brazilian variants. Crystal structure revealed that EK1 targets the HR1 domain in the SARS-CoV-2 S protein to block virus-cell fusion and provide mechanistic insights into its broad and effective antiviral activity. Nasal administration of EK1 peptides to hACE2 transgenic mice significantly reduced viral titers in lung and intestinal tissues. EK1 showed good safety profiles in various animal models, supporting further clinical development of EK1-based pan-CoV fusion inhibitors against SARS-CoV-2 and its variants.

Biodiversity increased both productivity and its spatial stability in temperate forests in northeastern China.

Although the relationship between biodiversity and ecosystem functioning has been extensively studied, it remains unclear if the relationships of biodiversity with productivity and its spatial stability vary along productivity gradients in natural ecosystems. Based on a large dataset from 2324 permanent forest inventory plots across northeastern China, we examined the intensity of species richness (SR) and tree size diversity (Hd) effects on aboveground wood productivity (AWP) and its spatial stability among different productivity levels. Structural equation modeling was applied, integrating abiotic (climate and soil) and biotic (stand density) factors. Our results demonstrated that both SR and Hd positively affected AWP and its spatial stability, and the intensity of these positive effects decreased with increasing productivity. At low productivity levels, SR and Hd increased spatial stability by reducing spatial variability and increasing mean AWP. At high productivity levels, stability increased only through mean AWP increase. Moreover, temperature and stand density affected the AWP directly and indirectly via biodiversity, and the strength and direction of these effects varied among different productivity levels. We concluded that biodiversity could simultaneously enhance productivity and its spatial stability in temperate forests, and that the effect intensity was uniform along productivity gradients, which provided a new perspective on relationships within biodiversity-ecosystem functioning.