Regeneration of Cochlear Hair Cells and Hearing Recovery through Hes1 Modulation with siRNA Nanoparticles in Adult Guinea Pigs.

Deafness is commonly caused by the irreversible loss of mammalian cochlear hair cells (HCs) due to noise trauma, toxins, or infections. We previously demonstrated that small interfering RNAs (siRNAs) directed against the Notch pathway gene, hairy and enhancer of split 1 (Hes1), encapsulated within biocompatible poly(lactic-co-glycolic acid) nanoparticles (PLGA NPs) could regenerate HCs within ototoxin-ablated murine organotypic cultures. In the present study, we delivered this sustained-release formulation of Hes1 siRNA (siHes1) into the cochleae of noise-injured adult guinea pigs. Auditory functional recovery was measured by serial auditory brainstem responses over a nine-week follow-up period, and HC regeneration was evaluated by immunohistological evaluations and scanning electron microscopy. Significant HC restoration and hearing recovery were observed across a broad tonotopic range in ears treated with siHes1 NPs, beginning at three weeks and extending out to nine weeks post-treatment. Moreover, both ectopic and immature HCs were uniquely observed in noise-injured cochleae treated with siHes1 NPs, consistent with de novo HC production. Our results indicate that durable cochlear HCs were regenerated and promoted significant hearing recovery in adult guinea pigs through reversible modulation of Hes1 expression. Therefore, PLGA-NP-mediated delivery of siHes1 to the cochlea represents a promising pharmacologic approach to regenerate functional and sustainable mammalian HCs in vivo.

Semisynthetic and SAR Studies of Amide Derivatives of Neocrotocembraneic Acid as Potential Antitumor Agents.

A series of novel amide derivatives of cembranoid neocrotocembraneic acid were designed and synthesized. The antiproliferative activities of these derivatives were evaluated against three human tumor cell lines (the human cervical cancer cell line HeLa, chronic myeloid leukemia cell line K562 and leukemia multidrug-resistant cell line K562/A02). Some of the synthesized compounds exhibited moderate to good activity against all three cancer cell lines. Particularly, compound 8a exhibited more potent antiproliferative activity than the reference drug etoposide against drug-resistant cell line K562/A02, indicating that it possessed a great potential for further development as a multidrug resistance modulator by structural modification.

Synthesis and Evaluation of New Podophyllotoxin Derivatives with in Vitro Anticancer Activity.

A series of novel podophyllotoxin derivatives were designed and synthesized. The cytotoxic activities of these compounds were tested against three tumor cell lines (HeLa, K562, and K562/A02). Most of the derivatives (IC50 = 1-20 µM) were found to have stronger cell growth inhibitory activity than positive control etoposide. Among them, 4ß-N-[(E)-(5-((4-(4-nitrophenyl)-piperazin-1-yl)methyl)furan-2-yl)prop-2-en-1-amine]-4-desoxy-podophyllotoxin (9l) demonstrated significant inhibitory activity against HeLa, K562, and K562/A02 cell lines with IC50 values of 7.93, 6.42, 6.89 µM, respectively.

18F-labeled somatostatin analogs for somatostatin receptors (SSTRs) targeted PET imaging of neuroendocrine tumors (NETs).

PURPOSE: A novel 18F-radiolabeled somatostatin analogue, [Al18F]NODA-MPAA-HTA, was synthesized and evaluated for positron emission tomography (PET) imaging of Neuroendocrine tumors (NETs). [Al18F]NODA-MPAA-HTA was designed and synthesized by conjugating 18F nuclide with a modified KE108 peptide, a somatostatin analog with high affinity for all five subtypes of somatostatin receptors (SSTR 1-5), through coupling a bifunctional chelator (NODA) to target somatostatin receptor (SSTR) positive tumors. METHODS: The amino group of KE108 peptide, a SSTRs-targeting pharmacophore, was conjugated with the carboxyl group of NODA by a condensation reaction to obtain the labeling precursor of [Al18F]NODA-MPAA-HTA, in which its precursor was obtained through Fmoc solid-phase methods. A novel methodology for Al18F labeling of chelating agent-biomolecule conjugates was used to synthesize [Al18F]NODA-MPAA-HTA. In vitro stabilities of [Al18F]NODA-MPAA-HTA were evaluated by incubating it in saline or bovine serum for 2 h. Ex vivo biodistribution and in vivo imaging of [Al18F]NODA-MPAA-HTA were further investigated to evaluate its SSTRs targeting ability and feasibility for the diagnosis of NETs using PET imaging. RESULTS: [Al18F]NODA-MPAA-HTA was synthesized using a one-step 18F-AlF labeling procedure resulting in moderate radiochemical yield (60-80 %, non-decay corrected) and high radiochemical purity (>95 %). It exhibited good hydrophilicity and excellent stability in vitro, with a molar activity of 122 GBq/µmol. At 30 min and 60 min, the uptake of [Al18F] NODA-MPAA-HTA by HEK293-SSTR2 cells was 5.47 ± 0.97 %/105 cells and 12.11 ± 0.32 %/105 cells, respectively. The affinity of [Al18F]NODA-MPAA-HTA for SSTR2 was determined to be 8.77 ± 1.14 nM. In micro-PET imaging of HEK293-SSTR2 tumor-bearing mice, [Al18F]NODA-MPAA-HTA showed high tumor uptake of radioactivity and a high tumor-to-muscle ratio. Biodistribution results confirmed that radioactivity uptake in the tumor was significantly higher than that in the muscle by more than five-fold (P<0.001). Furthermore, the relatively low bone uptake of [Al18F]NODA-MPAA-HTA suggested that defluorination did not occur in vivo. These preliminary results provide experimental evidence for further study of Al18F-labeled somatostatin analogues as tumor probes for PET imaging of NETs. CONCLUSION: Fluorine-18 is widely used as a radionuclide for the production of radiopharmaceuticals for positron emission tomography (PET). Due to its short half-life (T1/2,109.8 min), its ease of production will facilitate the widespread dissemination of this radiopharmaceutical. A high-quality [Al18F]NODA-MPAA-HTA was synthesized with satisfactory yield. This radiopharmaceutical demonstrated higher tumor uptake and better tumor-to-muscle contrast, resulting to excellent image quality. These findings suggest that the novel 18F-labeled somatostatin analogue, [Al18F]NODA-MPAA-HTA, is a promising tool for PET imaging of NETs.

Preparation of phosphorylated starch by dry-heating in the presence of pyrophosphate and its calcium-phosphate solubilizing ability.

Starch was phosphorylated through dry-heating in the presence of pyrophosphate at various conditions, and the characteristics of phosphorylated starch (PS) were examined. Starch phosphorylation increases as the pH increases from 3 to 6, but diminishes at pH 7. Increased temperatures enhance phosphorylation. Data from (31)P NMR suggests that starch phosphorylation occurs mainly at the C3-OH and C6-OH of the glucose residue. The phosphate linkage is mainly due to monostarch monophosphate. Although starch had almost no calcium phosphate-solubilising capacity, this capacity was markedly enhanced by phosphorylation. X-ray diffraction analysis indicates that the crystal structure of hydroxyapatite was not present in the calcium phosphate-PS complex.

2-Cyano-2-methyl-propanamide.

In the crystal structure of the title compound, C(5)H(8)N(2)O, mol-ecules are linked via pairs of N-H⋯O hydrogen bonds, forming inversion dimers. These dimers are linked via pairs of N-H⋯H hydrogen bonds into zigzag chains propagating along [101].

Metalloprotease ADAM10 inhibition mitigates acute liver injury via repression of intrahepatic inflammation.

BACKGROUND: Acute liver injury (ALI) is associated with the occurrence and progress of intrahepatic inflammation. Recent studies have shown that ADAM10, a significant member of metalloproteinase family, has modulated the inflammation level in various neurologic diseases. However, it is elusive whether ADAM10 regulation exert a hepatic protective effect on ALI by the suppression of inflammation level. The study aimed to explore the regulated function of ADAM10 on acute liver injury. METHODS: C57BL/6J mice (eight-week-old male) were carried out intraperitoneal injection of tetrachloromethane (CTC) to provoke ALI. ADAM10 loaded in adeno-associated viral vectors (AAV-ADAM10) or short hairpin RNA loaded in lentivirus aimed at murine ADAM10 mRNA (sh-RNA-ADAM10) were respectively delivered to mice via tail intravenous injection to achieve overexpression or silence of ADAM10. Western blotting, reverse transcription-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), immunohistochemical (IHC) and hematoxylin and eosin (HE) staining were conducted to measure ADAM10 alteration, inflammation level, histology and liver function. RESULTS: We show that the expression of ADAM10 markedly increases in CTC-induced injured liver tissues. Moreover, we demonstrate that the knockdown of ADAM10 attenuates the intrahepatic inflammation and protects hepatic histology and function in ALI mice; however, the overexpression of ADAM10 aggravates inflammation and liver lesion. CONCLUSIONS: The above suggested that the inhibition of ADAM10 ameliorates ALI through inhibiting inflammation. Our research provides novel view on the ADAM10 modulation of process of ALI by the inflammation aspect and verify a potential target for the therapy of ALI in the future.

Two new species of the spider genus Sinamma Lin amp; Li, 2014 (Araneae, Tetrablemmidae) from Guangdong Province, China.

Two new species of the genus Sinamma Lin Li, 2014, Sinamma quadrata Tong Li, sp. nov. (male, female) and Sinamma yingae Tong Li, sp. nov. (male, female) are described from Guangdong, China. The geographic distribution of the genus is updated and a key to all known species is provided.

Gold Catalyst Anchored to Pre-Reduced Co3O4 Nanorods for the Hydrodeoxygenation of Vanillin Using Alcohols as Hydrogen Donors.

The preparation of highly dispersed metal catalysts with strong electronic metal-support interactions (EMSIs) is of great significance. In this study, oxygen vacancies (OVs) were generated on the surfaces of Co3O4 nanorods (NRs) through NaBH4 treatment, and then the generated surface OVs were used to anchor gold clusters. The resulting catalyst was used for the hydrodeoxygenation (HDO) of vanillin based on transfer hydrogenation with alcohol donors. The conversion of vanillin and the selectivity to 2-methoxy-4-methylphenol (MMP) both reached 99% under the optimized reaction conditions, and these values were significantly higher than those obtained for the gold catalyst supported on the untreated Co3O4 NRs. The obtained results were verified by theoretical calculations and experimental data and confirmed the existence of strong EMSIs between the OV-enriched Co3O4 NRs (Co3O4 NRs-OVs) and the gold clusters, which allows electron transfer from the Co3O4 NRs to gold. Increasing the number of electrons on the gold surface can promote the catalytic hydrogen transfer of alcohol, in addition to selectively adsorbing the C═O group in vanillin to improve the selectivity toward MMP. This strategy based on the OV-anchoring of metals onto the surface of a support can be extended to other metals, thereby providing a promising method for the design of advanced and highly efficient metal catalysts.

Synthesis of Large-Area MXenes with High Yields through Power-Focused Delamination Utilizing Vortex Kinetic Energy.

Evaluating the delamination process in the synthesis of MXenes (2D transition metal carbides and nitrides) is critical for their development and applications. However, the preparation of large defect-free MXene flakes with high yields is challenging. Here, a power-focused delamination (PFD) strategy is demonstrated that can enhance both the delamination efficiency and yield of large Ti3 C2 Tx MXene nanosheets through repetitive precipitation and vortex shaking processes. Following this protocol, a colloidal concentration of 20.4 mg mL-1 of the Ti3 C2 Tx MXene can be achieved after five PFD cycles, and the yield of the basal-plane-defect-free Ti3 C2 Tx nanosheets reaches 61.2%, which is 6.4-fold higher than that obtained using the sonication-exfoliation method. Both nanometer-thin devices and self-supporting films exhibit excellent electrical conductivities (≈25 000 and 8260 S cm-1 for a 1.8 nm thick monolayer and 11 µm thick film, respectively). Hydrodynamic simulations reveal that the PFD method can efficiently concentrate the shear stress on the surface of the unexfoliated material, leading to the exfoliation of the nanosheets. The PFD-synthesized large MXene nanosheets exhibit superior electrical conductivities and electromagnetic shielding (shielding effectiveness per unit volume: 35 419 dB cm2 g-1 ). Therefore, the PFD strategy provides an efficient route for the preparation of high-performance single-layer MXene nanosheets with large areas and high yields.

N,4-Dimethyl-benzamide.

In the crystal of the title compound, C(9)H(11)NO, mol-ecules are connected via inter-molecular N-H⋯O hydrogen bonds, forming a one-dimensional network in the b-axis direction. The dihedral angle between the amide group and the benzyl ring is 13.8 (2)°.

N-Ethyl-3,5-dinitro-benzamide.

In the title mol-ecule, C(9)H(9)N(3)O(5), the dihedral angle between the mean planes of the amide group and the benzene ring is 31.24 (14)°. In the crystal, N-H⋯O hydrogen bonds link the mol-ecules to form one-dimensional chains propagating in [100].

2-Chloro-5-chloro-meth-yl-1,3-thia-zole.

In the title compound, C(4)H(3)Cl(2)NS, the chloro-methyl C and 2-position Cl atoms lie close to the mean plane of the thia-zole ring [deviations = 0.0568 (2) and 0.0092 (1) Å, respectively]. No classical hydrogen bonds are found in the crystal structure.

2-(o-Tol-yloxy)benzoic acid.

In the crystal structure of the title compound, C(14)H(12)O(3), mol-ecules are linked via inter-molecular O-H⋯O hydrogen bonds, resulting in dimer formation. The dihedral angle between the two phenyl rings is 76.2 (2)°.

A new genus and two new species of oonopid spiders from Tibet, China (Araneae, Oonopidae).

A new genus, Paramolotra Tong & Li, gen. nov., including two new species, Paramolotra pome Tong & Li, sp. nov. (♂♀) and Paramolotra metok Tong & Li, sp. nov. (♂♀), is described from Tibet, China. Morphological descriptions and photographic illustrations of the two new species are given.

A novel approach for modulating the spatial distribution of fat globules in acid milk gel and its effect on the perception of fat-related attributes.

Modulating the inhomogeneous distribution of fat globules within an emulsion gel is now being considered an effective method to increase the perception of fat-related sensory attributes. However, the methods for preparing the inhomogeneous gel were relatively complicated in previous studies. In the present study, milks enriched with different sizes of fat globule were obtained and then used to prepare glucono-δ-lactone-induced milk gels. The gels with different spatial distributions of fat globules were obtained through natural creaming. To ensure the high fat content layer exist on the gel surface, the two gels made from the same milk were superimposed from the bottom to form a new gel. In situ confocal microscopy showed that under the same overall fat content, the superimposed gel containing larger fat globules (L-L gel) exhibited the greatest inhomogeneity in microstructure with the highest average surface fat area fraction (10.9%), and the largest difference in fat content between the surface and the inside layers (9.1%). To illustrate the effect of inhomogeneous distribution of fat globules in gels on the perception of fat-related attributes, quantitative descriptive sensory analysis as well as the lubrication properties measurement under simulated oral processing conditions were carried out. The results showed the superimposed gels exhibited higher creaminess ratings and lower friction coefficients at 20 mm/s than those of the original gels. Overall, the study modulated the spatial distribution of fat globules in acid milk gels through natural creaming and superimposition and illustrated its positive effect on the perception of fat-related sensory attributes.

Electrophysiological assessment and pharmacological treatment of blast-induced tinnitus.

Tinnitus, the phantom perception of sound, often occurs as a clinical sequela of auditory traumas. In an effort to develop an objective test and therapeutic approach for tinnitus, the present study was performed in blast-exposed rats and focused on measurements of auditory brainstem responses (ABRs), prepulse inhibition of the acoustic startle response, and presynaptic ribbon densities on cochlear inner hair cells (IHCs). Although the exact mechanism is unknown, the "central gain theory" posits that tinnitus is a perceptual indicator of abnormal increases in the gain (or neural amplification) of the central auditory system to compensate for peripheral loss of sensory input from the cochlea. Our data from vehicle-treated rats supports this rationale; namely, blast-induced cochlear synaptopathy correlated with imbalanced elevations in the ratio of centrally-derived ABR wave V amplitudes to peripherally-derived wave I amplitudes, resulting in behavioral evidence of tinnitus. Logistic regression modeling demonstrated that the ABR wave V/I amplitude ratio served as a reliable metric for objectively identifying tinnitus. Furthermore, histopathological examinations in blast-exposed rats revealed tinnitus-related changes in the expression patterns of key plasticity factors in the central auditory pathway, including chronic loss of Arc/Arg3.1 mobilization. Using a formulation of N-acetylcysteine (NAC) and disodium 2,4-disulfophenyl-N-tert-butylnitrone (HPN-07) as a therapeutic for addressing blast-induced neurodegeneration, we measured a significant treatment effect on preservation or restoration of IHC ribbon synapses, normalization of ABR wave V/I amplitude ratios, and reduced behavioral evidence of tinnitus in blast-exposed rats, all of which accorded with mitigated histopathological evidence of tinnitus-related neuropathy and maladaptive neuroplasticity.

COVID-19 Super Spreading Event Amongst Elderly Individuals - Jilin Province, China, January 2021.

SUMMARY: What is already known on this topic? Clusters of COVID-19 cases often happened in small settings (e.g., families, offices, school, or workplaces) that facilitate person-to-person virus transmission, especially from a common exposure. What is added by this report? On January 10 and 11, 2021, an individual gave three product promotional lectures in Tonghua City, Jilin Province, that ultimately led to a 74-case cluster of COVID-19. Our investigation determined the outbreak to be an import-related COVID-19 superspreading cluster event in which elderly, retired people were exposed to the infected individual during his promotional lectures, which were delivered in a confined space and lasted several hours. What are the implications for public health practice? Routine activities, such as attending a lecture in a classroom, can provide an environment conducive to COVID-19 superspreading events because respiratory viruses can spread easily and widely. We suggest local government to strengthen infection control management, reduce unnecessary indoor large gathering activities, and promote wearing of masks, especially during wintertime in the north of China. Health education for elderly people should promote use of effective personal protection and emphasize the importance of wearing masks.

Index and First-Generation Cases in a COVID-19 Outbreak - Jilin Province, China, 2021.

What is already known on this topic? Contact tracing and testing with isolated medical care of identified cases is a key strategy for interrupting chains of transmission of COVID-19 and reducing mortality associated with COVID-19. At the early phases of the COVID-19 pandemic, due to test capacity limitations, case finding often started from suspected cases. What is added by this report? The index patient infected 74 individuals who were close contacts that were identified through contact tracing, and exposed individuals were monitored in quarantine with daily polymerase chain reaction (PCR) testing. All individuals were asymptomatic initially, but all PCR-positive individuals eventually developed symptoms. Infectivity was documented up to 8 days before being confirmed as a symptomatic case, approximately 4 days before turning PCR positive. What are the implications for public health practice? During an outbreak, we suggest tracing close contacts from both PCR-positive individuals and suspected cases, rather than from suspected cases alone. Due to the long period of infectivity before turning PCR positive or developing symptoms, close contacts that had contact with a newly PCR positive case within 4 days should be judged as at risk of being infected; close contacts that had contact within 8 days of a newly symptomatic case should be judged as at risk being infected.

2-Amino-4-(3-fluoro-phen-yl)-6-(naphthalen-1-yl)pyridine-3-carbonitrile.

There are two independent mol-ecules in the asymmetric unit of the title compound, C(22)H(14)FN(3), which differ slightly in the relative orientations of the naphthyl and phenyl groups with respect to the pyridyl ring framework. In one mol-ecule, the naphthyl ring system and the phenyl ring form dihedral of angles 56.50 (2) and 48.23 (3)°, respectively, with the pyridyl ring plane. In the other mol-ecule, the corresponding dihedral angles are 50.01 (2) and 51.1 (3)°, respectively. In the crystal, inter-molecular N-H⋯N hydrogen bonds connect the independent mol-ecules into dimers.