A novel recessive mutation in OXR1 is identified in patient with hearing loss recapitulated by the knockdown zebrafish.

Hereditary hearing loss is a highly genetically heterogeneous disorder. More than 150 genes have been identified to link to human non-syndromic hearing impairment. To identify genetic mutations and underlying molecular mechanisms in affected individuals and families with congenital hearing loss, we recruited a cohort of 389 affected individuals in 354 families for whole-exome sequencing analysis. In this study, we report a novel homozygous missense variant (c.233A > G, p.Lys78Arg) in the OXR1 gene, which was identified in a 4-year-old girl with sensorineural hearing loss. OXR1 encodes Oxidation Resistance 1 and is evolutionarily conserved from zebrafish to human. We found that the ortholog oxr1b gene is expressed in the statoacoustic ganglion (SAG, a sensory ganglion of ear) and posterior lateral line ganglion (pLL) in zebrafish. Knockdown of oxr1b in zebrafish resulted in a significant developmental defect of SAG and pLL. This phenotype can be rescued by co-injection of wild-type human OXR1 mRNAs, but not mutant OXR1 (c.233A > G) mRNAs. OXR1-associated pathway analysis revealed that mutations of TBC1D24, a TLDc-domain-containing homolog gene of OXR1, have previously been identified in patients with hearing loss. Interestingly, mutations or knockout of OXR1 interacting molecules such as ATP6V1B1 and ESR1 are also associated with hearing loss in patients or animal models, hinting an important role of OXR1 and associated partners in cochlear development and hearing function.

Obacunone inhibits RANKL/M-CSF-mediated osteoclastogenesis by suppressing integrin- FAK-Src signaling.

Disrupted osteoblastogenesis or aberrant activation of osteoclastogenesis usually results in the break of bone homeostasis thus causing bone-associated diseases like osteoporosis. Obacunone, as a natural compound present in citrus fruits, has been demonstrated for various biological activities including anti-cancer and anti-inflammatory properties. However, the role of obacunone in regulating osteoclastogenesis has not been elucidated so far. Here, using in vitro cell models of RANKL (Receptor activator of nuclear factor-kB ligand) and M-CSF (Macrophage-colony-stimulating factor)-induced osteoclastogenesis, we showed that obacunone inhibited osteoclast differentiation in RAW264.7 cells and bone marrow macrophages (BMMs), as evidenced by obacunone dose-dependent reduction in numbers of osteoclasts and downregulated expressions of osteoclastogenesis-associated key genes. The anti-osteoclastic properties of obacunone were associated with downregulated expressions of Integrin α1 and attenuated activation of Focal adhesion kinase (FAK) and Steroid receptor coactivator (Src) signaling. Functional Integrin α1 blockade or FAK-Src inhibition suppressed RANKL/M-CSF-induced osteoclastogenesis, while Integrin α1 overexpression or FAK/Src activation partially attenuated obacunone's effects on suppressing RANKL/M-CSF-induced osteoclast differentiation. Furthermore, in vivo administration of obacunone displayed super therapeutic effects in attenuating ovariectomy-induced bone loss in mice, as indicated by decreases in serum biomarkers of bone turnover, restoring of femur fracture maximum force, and reversing of the worsened bone-related parameters in ovariectomized animals. Taken together, these findings demonstrate that obacunone has pharmacological activities to suppress osteoclast differentiation through modulating the Integrin-FAK-Src pathway, and suggest that obacunone is a therapeutic candidate for the treatment and prevention of bone diseases such as osteoporosis.

Partial collapse of DNA tetrahedron for miRNA assay with duplex-specific nuclease-assisted amplification.

We establish a facile electrochemical approach for detecting miRNA. Programmable DNA tetrahedron is designed using thiol groups for electrode modification, the amino group for the localization of electrochemical species and a hairpin structure that responds to target miRNA. In addition, duplex-specific nuclease-assisted amplification helps improve the sensitivity of this biosensor. The target-initiated partial collapse of the DNA tetrahedron event integrates recognition, electrode immobilization, signal recruitment and amplification. By measuring the sharp silver stripping peak, the highly sensitive detection of miRNA is achieved, which also performs satisfactorily challenging biological samples. This method is featured with simple operation, high sensitivity and practical utility, exhibiting great application potential in clinical diagnosis.

Hemifacial microsomia is linked to a rare homozygous variant V162I in FRK and validated in zebrafish.

OBJECTIVES: Hemifacial microsomia (HFM) is a common birth defect involving the first and second branchial arch derivatives. Although several chromosomal abnormalities and causal gene variants have been identified, genetic etiologies in a majority of cases with HFM remain unknown. This study aimed to identify genetic mutations in affected individuals with HFM. METHODS: Whole-exome sequencing and bioinformatics analysis were performed for 16 affected individuals and their family members. Sanger sequencing was applied for confirmation of selected mutations. Zebrafish embryos were used for in situ hybridization of candidate gene, microinjection with antisense morpholino, and cartilage staining. RESULTS: A homozygous missense mutation (c.484G > A; p.V162I) in the FRK gene was identified in an 18-year-old girl with HFM and dental abnormalities. Heterozygous mutation of this mutation was identified in her parents, who are first cousins in a consanguineous family. FRK is highly expressed in the Meckel's cartilage during embryonic development in mouse and zebrafish. Knockdown of frk in zebrafish showed a lower length and width ratio of Meckel's cartilage, abnormal mandibular jaw joint, and disorganized ceratobranchial cartilage and bone. CONCLUSIONS: We identified a recessive variant in the FRK gene as a novel candidate gene for a patient with HFM and mandibular hypoplasia and revealed its effects on craniofacial and embryonic development in zebrafish.

Roll-to-Roll DNA Nanomachine for Ultrasensitive Electrochemical Determination of miRNA.

MicroRNAs (miRNAs) are a family of endogenous noncoding RNAs with the functions of gene regulation, which serve as promising markers for a range of diseases such as diabetic foot ulcers, cancers, etc. In this work, we engineered a roll-to-roll DNA nanomachine for highly sensitive electrochemical detection of miRNA. A dumbbell-structured DNA probe could be transitioned to be wheel-structured conformation upon target recognition, which rolls around track strands on the surface of gold nanoparticles (AuNPs) in the presence of nicking endonuclease. The resulting single strands on AuNPs are activated for the second round of rolling at the DNA-modified electrode interface, leading to the variation of electrochemical responses. The roll-to-roll amplification behavior allows a wide detection range with a limit of detection as low as 10 aM. The practicability is also demonstrated by the application in human serum samples with satisfactory results. It is expected that the proposed electrochemical method offers a new paradigm to develop miRNA assays based on DNA nanotechnology.

A modified method to treat severe asymptomatic pre-existing degeneration of adjacent segment: a retrospective case-control study.

BACKGROUND: Pre-existing degeneration of adjacent segment is an important risk factor for adjacent-segment degeneration (ASD), but only limited and controversial studies have addressed its management. METHODS: We retrospectively analyzed patients with symptomatic degeneration of the L5/S1 segment warranting surgical interference and severe asymptomatic degeneration of the L4/5 segment. Of these patients, those who underwent interbody fusion of the causative (L5/S1) segment and distraction of the intervertebral space and facet fusion of the adjacent L4/5 segment were included in Group A (n = 103), while those who underwent interbody fusion of both the L5/S1 and L4/5 segments were included in Group B (n = 81). Clinical and radiographic outcomes were evaluated. RESULTS: Mean follow-up time was 58.5 months (range, 48-75 months). We found no significant difference in clinical outcomes or incidence of ASD in the L3/4 segment between Groups A and B. Compared with Group B, Group A experienced less bleeding (315 ± 84 ml vs. 532 ± 105 ml), shorter operation time (107 ± 34 min vs. 158 ± 55 min) and lower costs (US $13,830 ± $2640 vs. US $16,020 ± $3380; P < 0.05). In Group A, the disc height ratio (DHR) of the L4/5 segment was significantly increased from a preoperative value of 0.40 ± 0.13 to a last-follow-up value of 0.53 ± 0.18 (P < 0.05), while the degree of canal stenosis (DCS) was decreased from a preoperative value of 34.3 ± 11.2% to a last-follow-up value of 15.9 ± 9.3 % (P < 0.05). CONCLUSIONS: This modified method could be effective in treating severe asymptomatic pre-existing degeneration of adjacent segment in the lumbar spine.

Cascading effects caused by fenoxycarb in freshwater systems dominated by Daphnia carinata and Dolerocypris sinensis.

To evaluate the aquatic hazards of the insect juvenile hormone analogue fenoxycarb, a single application (0, 48.8, 156.3, 500, 1600, and 5120 µg/L) of it was done in indoor freshwater systems dominated by Daphnia carinata (daphnid) and Dolerocypris sinensis (ostracoda). The responses of zooplankton (counted by abundance and the activity and immuno-reactive content of free N-Acetyl-ß-D-glucosaminidase (NAGase)), phytoplankton (counted by chlorophyll and phycocyanin), planktonic bacteria and fungi, and some water quality parameters were investigated in a period of 35 d. Results of the study showed that the ostracoda was more sensitive than daphnid, with time-weighted average (TWA)-based no observed effect concentrations (NOECs) to be 8.45 and 12.66 µg/L in systems without humic acid addition (HA-) and to be 6.37 and 9.54 µg/L in systems with humic acid addition (HA+). The duration of treatment-related effects in the ostracoda population was longer than the daphnid population (21 vs. 14 days). Besides, the data analysis indicated that the toxicity of fenoxycarb was significantly enhanced in the HA+ systems. Owing to the reduced grazing pressure, the concentrations of chlorophyll and phycocyanin increased in the two highest treatments. The increase in photosynthesis along with a reduced animal excretion led to an increase in pH and a decrease in nutrient contents. These changes seemed to have an effect on the microbial communities. For example, the abundances of some opportunistic pathogens of aquatic animals (e.g. Aeromonas and Cladosporium) and organic-pollutant-degrading microorganisms (e.g. Ancylobacter and Azospirillum) increased significantly in microbial communities, but the abundances of Pedobacter, Candidatus Planktoluna, and Rhodobacter (photosynthetic bacteria) markedly decreased. This study provides useful information to understand the ecotoxicological impacts of fenoxycarb at the population and community levels while integrating the effects of HA on toxicity.

Orai1 Promotes Osteosarcoma Metastasis by Activating the Ras-Rac1-WAVE2 Signaling Pathway.

BACKGROUND The purpose of this study was to investigate whether Orai1 plays a role in the metastasis of osteosarcoma. MATERIAL AND METHODS The expression of Orai1 was silenced by small interfering RNAs against Orai1 (Orai1 siRNA) in osteosarcoma MG-63 cells. Various experiments were carried out to detect the changes in migration, invasion, and adhesion ability of these osteosarcoma cells. Furthermore, the activity of Rac1, Wave2, and Ras was detected using Western blot analysis. Moreover, the Rac1 and Ras inhibitors were used to confirm whether the Ras-Rac1-WAVE2 signaling pathway was involved in osteosarcoma metastasis promoted by Orai1. RESULTS We found that the migration, invasion, and adhesion ability of MG-63 cells were significantly reduced after silencing Orai1 expression (p<0.05). Moreover, the activity of the Rac1-WAVE2 signaling pathway was significantly inhibited after silencing of Orai1 expression (p<0.05). After the Rac1 inhibitor was added, Orai1 siRNA could not further inhibit migration, invasion, and adhesion of the osteosarcoma cells. Further experiments showed that Ras activity was significantly inhibited after silencing Orai1 expression (p<0.05). Moreover, Orai1 siRNA did not further inhibit the activity of the Rac1-WAVE2 signaling pathway nor did it further inhibit the migration, invasion, and adhesion ability of osteosarcoma cells following the addition of Ras inhibitors. CONCLUSIONS Orai1 activates the Ras-Rac1-WAVE2 signaling pathway to promote metastasis of osteosarcoma. Abnormal expression or function of Orai1 may be an important cause of osteosarcoma metastasis.

A preliminary study of 3.0-T magnetic resonance diffusion tensor imaging in cervical spondylotic myelopathy.

PURPOSE: To compare diffusion tensor imaging (DTI) parameters of the spinal cord between patients with cervical spondylotic myelopathy (CSM) and normal subjects, and investigate their significance in the clinical diagnosis, surgical planning and post-operative evaluation of CSM. METHODS: Routine sequence magnetic resonance imaging (MRI) and DTI scans were performed in 50 normal subjects and 60 cases of CSM with 3.0-T MR. DTI images, apparent diffusion coefficient (ADC) and fractional anisotropy (FA) colormaps corresponding to spinal cord cross-sections were obtained. The spinal cord function of CSM patients was measured using modified Japanese Orthopaedic Association (mJOA) scoring and Nurick grade at different times. The changes in DTI parameters and their correlation with spinal cord function scores were analysed by SPSS 19. RESULTS: There were significant differences in DTI parameters of the spinal cord between normal subjects and patients with CSM (ADC: 1.119 ± 0.087 vs. 1.395 ± 0.091, P < 0.01; FA: 0.661 ± 0.057 vs. 0.420 ± 0.080, P < 0.01). The FA values at the maximal compression level of the spinal cord in the patients with CSM were significantly associated with the mJOA score pre-operatively, 1 week, and 1, 3 and 6 months post-operatively, with Pearson's correlation coefficients of 0.58 (P < 0.01), 0.53 (P < 0.05), and 0.51 (P < 0.05), 0.54 (P < 0.05) and 0.55 (P < 0.05), respectively. However, the FA values were significantly negatively associated with the Nurick grade, with Pearson's correlation coefficients of - 0.40 (P < 0.05), - 0.39 (P < 0.05), and -0.41 (P < 0.05), - 0.45 (P < 0.05) and - 0.44 (P < 0.05), respectively. CONCLUSIONS: DTI may play a significant role in diagnosing and predicting the development of CSM. These slides can be retrieved under Electronic Supplementary Material.

The feasibility of inserting a C1 pedicle screw in patients with ponticulus posticus: a retrospective analysis of eleven patients.

BACKGROUND: Ponticulus posticus is a common anatomic variation that can be mistaken for a broad posterior arch during C1 pedicle screw placement. When the atlas lateral mass screws are placed via the posterior arch, injury to the vertebral artery may result. To our knowledge, there are few clinical studies that have analyzed the feasibility of C1 pedicle screw fixation in patients with ponticulus posticus, in clinical practice. PURPOSE: To evaluate the feasibility of inserting a C1 pedicle screw in patients with ponticulus posticus. METHODS: Between January 2008 and January 2012, 11 consecutive patients with atlantoaxial instability, and with a ponticulus posticus at C1, underwent posterior fusion surgery in our institution. According to preoperative computed tomography (CT) reconstruction, a complete ponticulus posticus was found unilaterally in nine patients and bilaterally in two. Postoperative CT reconstructive imaging was performed to assess whether C1 pedicle screw placement was successful. Patients were followed up at regular intervals and evaluated for symptoms of ponticulus posticus syndrome. RESULTS: Thirteen C1 pedicles (atlas vertebral artery groove), each with a complete ponticulus posticus, were successfully inserted with thirteen 3.5- or 4.0-mm diameter pedicle screws, without resection of the bony anomaly. No intraoperative complications (venous plexus, vertebral artery, or spinal cord injury) occurred. The mean follow-up period was 21 (range 14-30) months. Postoperative CT reconstructive images showed that all 13 pedicle screws were inserted in the C1 pedicles without destruction of the atlas pedicle cortical bone. In the follow-up period, none of the patients demonstrated clinical symptoms of ponticulus posticus syndrome or developed bone fusion. CONCLUSION: Three-dimensional CT imaging should be considered prior to C1 pedicle screw fixation in patients with ponticulus posticus, to avoid mistaking the ponticulus posticus for a widened dorsal arch of the atlas. If there is no ponticulus posticus syndrome preoperatively, C1 pedicle screw fixation can be successfully performed without removing the bony anomaly.

Synergism of herbicide toxicity by 5-aminolevulinic acid is related to physiological and ultra-structural disorders in crickweed (Malachium aquaticum L.).

Selection of effective herbicides to control weeds has been one of the major objectives of scientists. This study determines the differential tolerance or susceptibility of crickweed (Malachium aquaticum L.) to various concentration combinations of 5-aminolevulinic acid (ALA) (1, 10 and 100mg/L) and propyl 4-(2-(4,6-dimethoxypyrimidin-2-yloxy)benzylamino)benzoate (ZJ0273) (100, 200, and 500mg/L). ALA was applied as pre- and post-treatment alone or in combination with ZJ0273. Results showed that ZJ0273 stress alone imposed negative effects on M. aquaticum seedling's growth, net photosynthetic rates and SPAD values, and the rate of decline was consistently increased with the increase in ZJ0273 concentration. The ZJ0273 treatment showed a gradual decrease in the activities of antioxidant enzymes peroxidase (POD), superoxide dismutase (SOD), and ascorbate peroxidase (APX), and increase in the accumulation of malondialdehyde (MDA). Changes in chloroplast swelling, increased number of plastoglobuli, disruption of thylakoid, disintegrated mitochondria and turbid nucleoplasm were noticed. Moreover, SDS-PAGE analysis of total proteins revealed that herbicide stress in the leaves was associated with the decrease or disappearance of some protein bands. Further, two-dimensional gel electrophoresis (2-DE) results showed that proteins in different spots were classified into three types for M. aquaticum. These results indicate that the combined treatment of ALA and ZJ0273 synergizes the herbicide toxicity which is different from its independent effects on M. aquaticum and thus, could improve weed control efficacy.

Genome re-sequencing suggested a weedy rice origin from domesticated indica-japonica hybridization: a case study from southern China.

MAIN CONCLUSION: Whole-genome re-sequencing of weedy rice from southern China reveals that weedy rice can originate from hybridization of domesticated indica and japonica rice. Weedy rice (Oryza sativa f. spontanea Rosh.), which harbors phenotypes of both wild and domesticated rice, has become one of the most notorious weeds in rice fields worldwide. While its formation is poorly understood, massive amounts of rice genomic data may provide new insights into this issue. In this study, we determined genomes of three weedy rice samples from the lower Yangtze region, China, and investigated their phylogenetics, population structure and chromosomal admixture patterns. The phylogenetic tree and principle component analysis based on 46,005 SNPs with 126 other Oryza accessions suggested that the three weedy rice accessions were intermediate between japonica and indica rice. An ancestry inference study further demonstrated that weedy rice had two dominant genomic components (temperate japonica and indica). This strongly suggests that weedy rice originated from indica-japonica hybridization. Furthermore, 22,443 novel fixed single nucleotide polymorphisms were detected in the weedy genomes and could have been generated after indica-japonica hybridization for environmental adaptation.

RAS Dataset: A 3D Cardiac LGE-MRI Dataset for Segmentation of Right Atrial Cavity.

The current challenge in effectively treating atrial fibrillation (AF) stems from a limited understanding of the intricate structure of the human atria. The objective and quantitative interpretation of the right atrium (RA) in late gadolinium-enhanced magnetic resonance imaging (LGE-MRI) scans relies heavily on its precise segmentation. Leveraging the potential of artificial intelligence (AI) for RA segmentation presents a promising solution. However, the successful implementation of AI in this context necessitates access to a substantial volume of annotated LGE-MRI images for model training. In this paper, we present a comprehensive 3D cardiac dataset comprising 50 high-resolution LGE-MRI scans, each meticulously annotated at the pixel level. The annotation process underwent rigorous standardization through crowdsourcing among a panel of medical experts, ensuring the accuracy and consistency of the annotations. Our dataset represents a significant contribution to the field, providing a valuable resource for advancing RA segmentation methods.

Zeolitic imidazolate framework-8 encapsulating carbon nanodots and silver nanoparticles for fluorescent detection of H2O2 and glucose.

In this study, a novel fluorescent biosensor is developed for the detection of H2O2 and glucose based on Zeolitic Imidazolate Framework-8 (ZIF-8) nanocomposites. ZIF-8 encapsulating carbon nanodot (CD) exhibits bright fluorescence emission. After further loading of AgNP, the fluorescence is quenched, which is mainly based on the excited electron transfer from CD to AgNP. Besides, the excitation wavelength of CD falls within the adsorption range of AgNP, which leads to efficient inhibition of the excitation energy. The as-prepared AgNP-CD-ZIF-8 nanocomposites can be utilized as a highly sensitive platform for the analysis of H2O2 and glucose. In the presence of glucose, H2O2 can be generated by the catalysis of glucose oxidase (GOD), which induces the etching of AgNP and subsequent recovery of CD-ZIF-8 fluorescence. This "turn on" biosensor can be applied for facile and convenient quantification of H2O2. It can also be further extended to detect glucose in real samples after combining specific catalytic effect of GOD. The analytical performances are excellent, which demonstrates great potential for practical utility.

Experiments on physical ablation of long bone using microwave ablation; defining optimal settings using ex- and in-vivo experiments.

BACKGROUND: Improved survival of cancer patients leads to more skeletal metastatic lesions that need local therapies for tumor control and pain relief. Not all tumors are radiosensitive and alternative therapies are direly needed. Microwave ablation (MWA) is a technique for minimally invasive local tumor control by physical ablation. In soft tissue local temperature ablation is more common, but studies on bone tissue are limited. To ensure safe and effective treatment, studies on local tumor ablation in bone are needed. METHOD: Microwave ablation was performed on sheep bone, for both in- and ex-vivo settings. Both a slow-cooking MWA protocol (gradually increasing wattage in the first two minutes of ablation) and a fast-cooking protocol (no warm-up period) were used. Heat distribution through the bone during ablation was determined by measuring temperature at 10- and 15mm from the ablation probe (= needle). Ablation size after procedure was measured using nitro-BT staining. RESULTS: In-vivo ablations led to up to six times larger halos than ex-vivo with the same settings. Within both ex- and in-vivo experiments, no differences in halo size or temperature were found for different wattage levels (65W vs 80W). Compared to a fast cooking protocol, a two-minute slow cooking protocol led to increased temperatures and larger halos. Temperatures at 10- and 15mm distance from the needle no longer increased after six minutes. Halo sizes kept increasing over time without an evident plateau. CONCLUSION: Microwave ablation is technically effective for creating cell death in (sheep) long bone. It is recommended to start ablations with a slow-cooking period, gradually increasing the surrounding tissue temperature in two minutes from 40 to 90°C. Ex-vivo results cannot simply be translated to in-vivo.

Ultrasensitive miRNA biosensor amplified by ladder hybridization chain reaction on triangular prism structured DNA.

Accurate and sensitive analysis of biomarkers is a promising way to provide comprehensive physio-pathological information that is significant for early diagnosis of certain diseases. miRNA is a type of noncoding small RNAs which are involved in the regulation of a number of cellular processes. It has been regarded as an important tumor biomarker. Herein, we have constructed a three-dimensional DNA layer on electrode interface and achieved ladder hybridization chain reaction strategy for the enrichment of electrochemical signals. In addition, duplex-specific nuclease catalyzed amplification is previously performed on magnetic nanocomposites, which further improves the sensitivity for the detection of target miRNA initiator. This approach shows great molecular recognition efficiency as well as cascade signal amplification. The analytical performances are superior. In addition, the identification of cancer cell types according to target biomarker information is achieved and the testing results in clinical serum samples further demonstrate its great potential utility for diagnosis.

Mechanical bone strength decreases considerably after microwave ablation-Ex-vivo and in-vivo analysis in sheep long bones.

BACKGROUND: Bone metastases are on the rise due to longer survival of cancer patients. Local tumor control is required for pain relief. Microwave ablation (MWA) is a technique for minimally invasive local tumor treatment. Tumor tissue is destroyed by application of local hyperthermia to induce necrosis. Given the most common setting of palliative care, it is generally considered beneficial for patients to start mobilizing directly following treatment. No data on mechanical strength in long bones after MWA have been published so far. MATERIALS AND METHODS: In- and ex-vivo experiments on sheep tibias were performed with MWA in various combinations of settings for time and power. During the in-vivo part sheep were sacrificed one or six weeks after ablation. Mechanical strength was examined with a three-point bending test for ablations in the diaphysis and with an indentation test for ablations in the metaphysis. RESULTS: MWA does not decrease mechanical strength in the diaphysis. In the metaphysis strength decreased up to 50% six weeks after ablation, which was not seen directly after ablation. CONCLUSION: MWA appears to decrease mechanical strength in long bone metaphysis up to 50% after six weeks, however strength remains sufficient for direct mobilization. The time before normal strength is regained after the remodeling phase is not known.

Black Phosphorus Nanosheets Grafted with Gold Nanorods and Carbon Nanodots for Synergistic Antitumor Therapy.

Synergetic photothermal/photodynamic/chemotherapy receives significant attention for precise in vivo cancer treatment. Despite plenty of encouraging photosensitizers explored, integrated nanoagents with multiple functions are still highly desired. In this study, novel nanocomposites coupling black phosphorus (BP) nanosheets, gold nanorods (AuNRs), carbon nanodots (CDs), and doxorubicin (Dox) are prepared. The nanoagents exhibit high antitumor activity on account of their broad light absorption, excellent catalytic ability, and significant photothermal and photodynamic effects. CDs not only emit bright fluorescence for accurate diagnosis and guiding of tumor treatment but also catalyze the generation of ROS for photodynamic therapy (PDT). The released Dox induces apoptosis of cells and increases the levels of H2O2 to promote PDT. AuNRs are the main photothermal therapy (PTT) material that converts light into heat. Moreover, BP can be used to enhance both PTT and PDT efficiencies, and the two therapy modes can be cooperatively reinforced. It is also found that the local immune microenvironment of the tumors is activated. The strategy makes good use of the features of each component. Satisfactory antitumor phenomena are well confirmed by in vitro and in vivo results. This study provides new insights into enhanced synergetic therapy, highlighting the great utility of BP-based nanoagents in the field of nanomedicine.

Case Report: Identification of Two Variants of ALG13 in Families With or Without Seizure and Binocular Strabismus: Phenotypic Spectrum Analysis.

Background: Genetic causes in most affected children with intellectual disability and/or development delay remain unknown. Methods: To identify potential variants responsible for these disorders, we recruited 161 affected families and performed whole-exome sequencing and associated bioinformatics analysis. Results: In the present study, we report the identification of variants in the ALG13 gene in two of the families. In family 1, a known pathogenic missense variant (c.23T > C; p.V8A) of ALG13 was identified in a boy and his mother. In family 2, a novel missense variant (c.862C > G; p.L288V) of the same gene was identified in the affected boy and his phenotypically normal mother. Genotype-phenotype correlation analysis by comparing reported 28 different variants (HGMD) showed that three major phenotypes, including various seizures/epilepsy, intellectual disability, and development delay (such as growth, speech, motor, etc.), are present in most affected individuals. However, other phenotypes, such as strabismus and absence of seizure in our second patient, are not reported if any, which may represent a unique case of X-linked recessive nonsyndromic disorder caused by a mutation in ALG13. Conclusion: We identified two missense variants in ALG13 in a cohort of 161 families with affected individuals diagnosed as intellectual disability and/or development delay. A novel c.862C > G mutation may represent a case of X-linked recessive.