Chromatin remodeling-driven autophagy activation induces cisplatin resistance in oral squamous cell carcinoma.

It is still challenging to predict the efficacy of cisplatin-based therapy, particularly in relation to the activation of macroautophagy/autophagy in oral squamous cell carcinoma (OSCC). We studied the effect of selected chromatin remodeling genes on the cisplatin resistance and their interplay with autophagy in 3-dimensional tumor model and xenografts. We analyzed gene expression patterns in the cisplatin-sensitive UMSCC1, and a paired cisplatin-resistant UM-Cis cells. Many histone protein gene clusters involved in nucleosome assembly showed significant difference of expression. Gain- and loss-of-function analyses revealed an inverse correlation between cisplatin resistance and HIST1H3D expression, while a positive correlation was observed with HIST3H2A or HIST3H2B expression. In UM-Cis, HIST3H2A- and HIST3H2B-mediated chromatin remodeling upregulates autophagy status, which results in cisplatin resistance. Additionally, knockdown of HIST3H2A or HIST3H2B downregulated autophagy-activating genes via chromatin compaction of their promoter regions. MiTF, one of the key autophagy regulators upregulated in UM-Cis, negatively regulated transcription of HIST1H3D, suggesting an interplay between chromatin remodeling-dependent cisplatin resistance and autophagy. On comparing the staining intensity between cisplatin-sensitive and -insensitive tissues from OSCC patients, protein expression pattern of the selected histone protein genes were matched with the in vitro data. By examining the relationship between autophagy and chromatin remodeling genes, we identified a set of candidate genes with potential use as markers predicting chemoresistance in OSCC biopsy samples.

Romiplostim for treatment of thrombocytopenia in dogs: A retrospective assessment and clinical outcomes.

BACKGROUND: Romiplostim, a thrombopoietin analog, is commonly used to treat immune-mediated thrombocytopenia (ITP) in humans, but its use in dogs remains limited. OBJECTIVES: Evaluate the effects and adverse events of romiplostim administration in dogs with thrombocytopenia caused by various underlying diseases. ANIMALS: Forty-two client-owned dogs with naturally occurring thrombocytopenia at 2 referral animal hospitals. METHODS: Retrospective, multi-institutional analysis to evaluate the outcomes of romiplostim treatment in dogs. RESULTS: Among the dogs treated with romiplostim, 27 experienced an increase in platelet count and 26 maintained a platelet count within the reference range. Platelet count improvement was observed in various conditions: primary ITP (90%, n = 18/20), pancytopenia of unknown etiology (42.9%, n = 3/7), chemotherapy-induced thrombocytopenia (50%, n = 3/6), babesiosis (100%, n = 1/1), radiotherapy-induced thrombocytopenia (0%, n = 0/1), and disseminated intravascular coagulopathy (33.3%, n = 2/6). The median time for platelet recovery (>50 000/µL) after romiplostim administration was 4 days, and the median time for platelet count normalization was 7 days. Median hospitalization time for the improvement group (I) was 5 days. The survival-to-discharge rates were 85%, 40%, and 28.6% for dogs with primary ITP, secondary thrombocytopenia, and thrombocytopenia of unknown etiology, respectively. CONCLUSIONS AND CLINICAL IMPORTANCE: Romiplostim is a well-tolerated and promising treatment for primary ITP in dogs, suggesting its potential as a valuable therapeutic option for dogs with thrombocytopenia caused by various underlying conditions. These findings emphasize the need for further research to optimize romiplostim dosing and understand its role in treating secondary thrombocytopenia and pancytopenia of unknown etiology.

Clinical characteristics and outcomes of COVID-19 in children and adolescents with diabetes in Daegu, South Korea.

PURPOSE: Children with comorbidities have a higher risk of severe, coronavirus disease 2019 (COVID-19). This study investigated the clinical features and outcomes of COVID-19 in children and adolescents with diabetes between January and March 2022. METHODS: We retrospectively reviewed the medical records of 123 children and adolescents (73 with type 1 diabetes and 50 with type 2 diabetes, 59 males and 64 females) aged <18 years who had been diagnosed with diabetes. Data were collected from 7 academic medical centers in Daegu, South Korea. RESULTS: Thirty-five children with diabetes were diagnosed with COVID-19 (18 with type 1 and 17 with type 2 diabetes). Eighteen of the 35 children with diabetes and COVID-19 and 50 of the 88 children with diabetes alone received a COVID-19 vaccination. No significant differences were observed between patients with diabetes and COVID-19 and patients with diabetes alone in the type of diabetes diagnosed, sex, age, body mass index, hemoglobin A1c, or vaccination status. All children with diabetes and COVID-19 had mild clinical features and were safely managed in their homes. Fourteen children had a fever of 38℃ or higher that lasted for more than 2 days, 11 of whom were not vaccinated (p=0.004). None experienced post-COVID-19 conditions. CONCLUSION: All children and adolescents with pre-existing diabetes had mild symptoms of COVID-19 due to low disease severity, high vaccination rates, uninterrupted access to medical care, and continuous glucose monitoring. Unvaccinated children with diabetes who experienced COVID-19 presented with higher and more frequent fevers compared to vaccinated children.

A comparative analysis of canine pancreatic lipase tests for diagnosing pancreatitis in dogs.

IMPORTANCE: Early diagnosis of canine pancreatitis is challenging due to non-specific clinical signs. Currently, abdominal ultrasonography and measurement of canine pancreatic lipase (cPL) have been employed for the diagnosis of pancreatitis. OBJECTIVE: Many qualitative and quantitative commercial cPL tests have been developed and used in veterinary clinics. This study aimed to compare three different methodologies SNAP cPL, Spec cPL, and Vcheck cPL tests to assess the concordance of these assays. METHODS: Fifty serum samples were collected from 36 dogs with or without pancreatitis and subjected to SNAP cPL, Spec cPL, and Vcheck cPL tests. Agreement and correlation coefficients were calculated between the test results, and correlations were determined during the management of the patients. RESULTS: The results of the three cPL assays were strongly correlated in 47/50 serum samples (94%). Cohen's kappa analysis between the Spec cPL and Vcheck cPL showed near perfect agreement (κ = 0.960, p < 0.001), SNAP cPL and Vcheck cPL (κ = 0.920, p < 0.001), and Spec cPL and SNAP cPL (κ = 0.880, p < 0.001). The correlation coefficients (r) between data from Spec cPL and Vcheck cPL tests was calculated by Spearman's correlation test (r = 0.958, p < 0.001). Furthermore, the patterns of change in serum cPL concentrations determined using Spec cPL and Vcheck cPL were significantly consistent during the monitoring period in 11 patients. CONCLUSIONS AND RELEVANCE: Our data illustrated that Spec cPL and Vcheck cPL tests are compatible for clinical use in the diagnosis and monitoring of canine pancreatitis.

Large-scale annotated dataset for cochlear hair cell detection and classification.

Our sense of hearing is mediated by cochlear hair cells, of which there are two types organized in one row of inner hair cells and three rows of outer hair cells. Each cochlea contains 5-15 thousand terminally differentiated hair cells, and their survival is essential for hearing as they do not regenerate after insult. It is often desirable in hearing research to quantify the number of hair cells within cochlear samples, in both pathological conditions, and in response to treatment. Machine learning can be used to automate the quantification process but requires a vast and diverse dataset for effective training. In this study, we present a large collection of annotated cochlear hair-cell datasets, labeled with commonly used hair-cell markers and imaged using various fluorescence microscopy techniques. The collection includes samples from mouse, rat, guinea pig, pig, primate, and human cochlear tissue, from normal conditions and following in-vivo and in-vitro ototoxic drug application. The dataset includes over 107,000 hair cells which have been identified and annotated as either inner or outer hair cells. This dataset is the result of a collaborative effort from multiple laboratories and has been carefully curated to represent a variety of imaging techniques. With suggested usage parameters and a well-described annotation procedure, this collection can facilitate the development of generalizable cochlear hair-cell detection models or serve as a starting point for fine-tuning models for other analysis tasks. By providing this dataset, we aim to give other hearing research groups the opportunity to develop their own tools with which to analyze cochlear imaging data more fully, accurately, and with greater ease.

The Cousa objective: a long-working distance air objective for multiphoton imaging in vivo.

Multiphoton microscopy can resolve fluorescent structures and dynamics deep in scattering tissue and has transformed neural imaging, but applying this technique in vivo can be limited by the mechanical and optical constraints of conventional objectives. Short working distance objectives can collide with compact surgical windows or other instrumentation and preclude imaging. Here we present an ultra-long working distance (20 mm) air objective called the Cousa objective. It is optimized for performance across multiphoton imaging wavelengths, offers a more than 4 mm2 field of view with submicrometer lateral resolution and is compatible with commonly used multiphoton imaging systems. A novel mechanical design, wider than typical microscope objectives, enabled this combination of specifications. We share the full optical prescription, and report performance including in vivo two-photon and three-photon imaging in an array of species and preparations, including nonhuman primates. The Cousa objective can enable a range of experiments in neuroscience and beyond.

An atomic-scale multi-qubit platform.

Individual electron spins in solids are promising candidates for quantum science and technology, where bottom-up assembly of a quantum device with atomically precise couplings has long been envisioned. Here, we realized atom-by-atom construction, coherent operations, and readout of coupled electron-spin qubits using a scanning tunneling microscope. To enable the coherent control of "remote" qubits that are outside of the tunnel junction, we complemented each electron spin with a local magnetic field gradient from a nearby single-atom magnet. Readout was achieved by using a sensor qubit in the tunnel junction and implementing pulsed double electron spin resonance. Fast single-, two-, and three-qubit operations were thereby demonstrated in an all-electrical fashion. Our angstrom-scale qubit platform may enable quantum functionalities using electron spin arrays built atom by atom on a surface.

Boswellia serrata Extracts Ameliorates Symptom of Irregularities in Articular Cartilage through Inhibition of Matrix Metalloproteinases Activation and Apoptosis in Monosodium-Iodoacetate-Induced Osteoarthritic Rat Models.

The research examined the effects of Boswellia serrata extracts (BSE) on a rat model of osteoarthritis induced by monosodium iodoacetate (MIA). The severity and progression of MIA-induced osteoarthritis were assessed using microcomputed tomography imaging. Additionally, the study investigated the impact of BSE various the biomarkers associated with osteoarthritis, including anabolic and catabolic factors, pro-inflammatory factors, and apoptosis factors. The evaluation methods employed included western blot, enzyme-linked immunosorbent assay, and real-time polymerase chain reaction analysis in osteoarthritic rats. Supplementing osteoarthritic rats with BSE reduced tissue injury, cartilage destruction, and decreased in MIA-induced roughness on the articular cartilage surface. MIA-treated rats exhibited increased expressions of phosphorylation of Smad3, MMPs, p-IκB, p-NF-κB, and pro-inflammatory factors (IL-1ß, IL-6, TNF-α, and COX-2), which were mitigated by BSE supplementation. Furthermore, protein expressions related to apoptosis pathways were significantly reduced in MIA-induced rats supplemented with BSE. These findings suggested that BSE ingestion may enhance the inflammatory response, decrease JNK-dependent MMPs activation, and alleviate caspase-3-dependent apoptosis in MIA-induced osteoarthritic rat models. Consequently, BSE exhibits potential as a therapeutic agent for treating osteoarthritis.

Correction: Genetic and chemical markers for authentication of three Artemisia species: A. capillaris, A. gmelinii, and A. fukudo.

[This corrects the article DOI: 10.1371/journal.pone.0264576.].

Large-scale annotated dataset for cochlear hair cell detection and classification.

Our sense of hearing is mediated by cochlear hair cells, localized within the sensory epithelium called the organ of Corti. There are two types of hair cells in the cochlea, which are organized in one row of inner hair cells and three rows of outer hair cells. Each cochlea contains a few thousands of hair cells, and their survival is essential for our perception of sound because they are terminally differentiated and do not regenerate after insult. It is often desirable in hearing research to quantify the number of hair cells within cochlear samples, in both pathological conditions, and in response to treatment. However, the sheer number of cells along the cochlea makes manual quantification impractical. Machine learning can be used to overcome this challenge by automating the quantification process but requires a vast and diverse dataset for effective training. In this study, we present a large collection of annotated cochlear hair-cell datasets, labeled with commonly used hair-cell markers and imaged using various fluorescence microscopy techniques. The collection includes samples from mouse, human, pig and guinea pig cochlear tissue, from normal conditions and following in-vivo and in-vitro ototoxic drug application. The dataset includes over 90'000 hair cells, all of which have been manually identified and annotated as one of two cell types: inner hair cells and outer hair cells. This dataset is the result of a collaborative effort from multiple laboratories and has been carefully curated to represent a variety of imaging techniques. With suggested usage parameters and a well-described annotation procedure, this collection can facilitate the development of generalizable cochlear hair cell detection models or serve as a starting point for fine-tuning models for other analysis tasks. By providing this dataset, we aim to supply other groups within the hearing research community with the opportunity to develop their own tools with which to analyze cochlear imaging data more fully, accurately, and with greater ease.

Double-Resonance Spectroscopy of Coupled Electron Spins on a Surface.

Scanning-tunneling microscopy (STM) combined with electron spin resonance (ESR) has enabled single-spin spectroscopy with nanoelectronvolt energy resolution and angstrom-scale spatial resolution, which allows quantum sensing and magnetic resonance imaging at the atomic scale. Extending this spectroscopic tool to a study of multiple spins, however, is nontrivial due to the extreme locality of the STM tunnel junction. Here we demonstrate double electron-electron spin resonance spectroscopy in an STM for two coupled atomic spins by simultaneously and independently driving them using two continuous-wave radio frequency voltages. We show the ability to drive and detect the resonance of a spin that is remote from the tunnel junction while read-out is achieved via the spin in the tunnel junction. Open quantum system simulations for two coupled spins reproduce all double-resonance spectra and further reveal a relaxation time of the remote spin that is longer by an order of magnitude than that of the local spin in the tunnel junction. Our technique can be applied to quantum-coherent multi-spin sensing, simulation, and manipulation in engineered spin structures on surfaces.

Licochalcone A Exerts Anti-Cancer Activity by Inhibiting STAT3 in SKOV3 Human Ovarian Cancer Cells.

Licochalcone A (LicA), a major active component of licorice, has been reported to exhibit various pharmacological actions. The purpose of this study was to investigate the anticancer activity of LicA and detail its molecular mechanisms against ovarian cancer. SKOV3 human ovarian cancer cells were used in this study. Cell viability was measured using a cell counting kit-8 assay. The percentages of apoptotic cells and cell cycle arrest were determined by flow cytometry and Muse flow cytometry. The expression levels of proteins regulating cell apoptosis, cell cycle, and the signal transducer and activator of transcription 3 (STAT3) signaling pathways were examined using Western blotting analysis. The results indicated that LicA treatment inhibited the cell viability of SKOV3 cells and induced G2/M phase arrest. Furthermore, LicA induced an increase in ROS levels, a reduction in mitochondrial membrane potential, and apoptosis accompanied by an increase in cleaved caspases and cytoplasmic cytochrome c. Additionally, LicA caused a dramatic decrease in STAT3 protein levels, but not mRNA levels, in SKOV3 cells. Treatment with LicA also reduced phosphorylation of the mammalian target of rapamycin and eukaryotic translation initiation factor 4E-binding protein in SKOV3 cells. The anti-cancer effects of LicA on SKOV3 cells might be mediated by reduced STAT3 translation and activation.

A case study of group art therapy using digital media for adolescents with intellectual disabilities.

Introduction: In art therapy, digital art therapy is a new method in which clients use digital media to express themselves creatively. We wanted to explore what this means for adolescents with disabilities. The purpose of this qualitative case study was to explain what kind of experience they had when digital media was applied as an expressive and therapeutic medium in group art therapy in which adolescents with intellectual disabilities were participants and what kind of therapeutic meaning the experience had. We tried to know the therapeutic factors by extracting the implications of meaning. Methods: Participants were second-year high school students with intellectual disabilities who belonged to special classes. They were selected in an intentional purposive sampling method. Five teenagers with intellectual disabilities participated in 11 group art therapy sessions. Data were collected through interviews, observation, and digital artwork collection. Collected data were case studies analyzed using an inductive approach. In this study, the use of digital media was defined and utilized as "Digital Art Therapy" by setting the scope related to the study according to client's behavioral method. Results: As a digital generation accustomed to smartphones, the participants gained confidence by repeatedly acquiring new technologies through familiarity with the media. Interaction with the media through touch and the use of apps have promoted autonomy with interest and pleasure to disabled teenagers, allowing them to express themselves actively. In particular, digital art therapy induces a holistic sensory experience by mobilizing visual images that could represent various expressions, emotions felt in music and tactile senses that made texts for people with intellectual disabilities with difficulty in verbal communication. Discussion: Art therapy using digital media has become an important experience that provides opportunities to arouse curiosity, enjoy creative activities, and express positive emotions vividly to adolescents with intellectual disabilities who have difficulties with expression and communication and a sense of lethargy. Therefore, it is suggested that an in-depth understanding of the characteristics and differences between traditional and digital media is necessary, and that complementary use to help create therapeutic purposes and art therapy is important.

Gly-Pro-Val-Gly-Pro-Ser Peptide Fish Collagen Improves Skin Moisture and Wrinkles with Ameliorated the Oxidative Stress and Pro-inflammatory Factors in Skin Photoaging Mimic Models.

This study aimed to investigate whether low molecular fish collagen peptide (FC) from Oreochromis niloticus had protective effects on skin of photoaging mimic models. We observed that FC supplementation improved antioxidant enzymes activities and regulated the pro-inflammatory cytokines [e.g., tumor necrosis factor-α, interleukin (IL)-1ß, and IL-6] by reducing the protein expressions of pro-inflammatory factors IκBα, p65, and cyclooxygenase-2 in ultraviolet-B (UV-B) irradiated in vitro and in vivo. Furthermore, FC increased hyaluronic acid, sphingomyelin, and skin hydration by reg-ulating the mRNA expression of hyaluronic acid synthases 1∼3, serine palmitoyltransferase 1, delta 4-desaturase, sphingolipid 1, and protein expressions of ceramide synthase 4, matrix metalloproteinase (MMP)-1, -2, and -9. In UV-B irradiated in vitro and in vivo, FC down-regulated the protein expression of the c-Jun N-terminal kinase, c-Fos, c-Jun, and MMP pathways and up-reg-ulated that of the transforming growth factor-ß receptor I, collagen type I, procollagen type I, and small mothers against decapentaplegic homolog pathways. Our results suggest that FC can be effective against UV-B induced skin photoaging by improving skin dryness and wrinkle formation through antioxidant and anti-inflammatory properties.

Low-Molecular-Weight ß-1,3-1,6-Glucan Derived from Aureobasidium pullulans Exhibits Anticancer Activity by Inducing Apoptosis in Colorectal Cancer Cells.

ß-glucan, a plant polysaccharide, mainly exists in plant cell walls of oats, barley, and wheat. It is attracting attention due to its high potential for use as functional foods and pharmaceuticals. We have previously reported that low-molecular-weight Aureobasidium pullulans-fermented ß-D-glucan (LMW-AP-FBG) could inhibit inflammatory responses by inhibiting mitogen-activated protein kinases and nuclear factor-κB signaling pathways. Bases on previous results, the objective of the present study was to investigate the therapeutic potential of LMW-AP-FBG in BALB/c mice intracutaneously transplanted with CT-26 colon cancer cells onto their backs. Daily intraperitoneal injections of LMW-AP-FBG (5 mg/kg) for two weeks significantly suppressed tumor growth in mice bearing CT-26 tumors by reducing tumor proliferation and inducing apoptosis as compared to phosphate buffer-treated control mice. In addition, LMW-AP-FBG treatment reduced the viability of CT-26 cells in a dose-dependent manner by inducing apoptosis with loss of mitochondrial transmembrane potential and increased activated caspases. Taken together, LMW-AP-FBG exhibits anticancer properties both in vivo and in vitro.

A chemo-mechanical cochleostomy preserves hearing for the in vivo functional imaging of cochlear cells.

In vivo and real-time multicellular imaging enables the decoding of sensory circuits and the tracking of systemic drug uptake. However, in vivo imaging of the auditory periphery remains technically challenging owing to the deep location, mechanosensitivity and fluid-filled, bone-encased nature of the cochlear structure. Existing methods that expose the cochlea invariably cause irreversible damage to auditory function, severely limiting the experimental measurements possible in living animals. Here we present an in vivo surgical protocol that permits the imaging of cochlear cells in hearing mice. Our protocol describes a ventro-lateral approach for preserving external and middle ear structures while performing surgery, the correct mouse positioning for imaging cochlear cells with effective sound transmission into the ear, the chemo-mechanical cochleostomy for creating the imaging window in the otic capsule bone that prevents intracochlear fluid leakage by maintaining an intact endosteum, and the release of intracochlear pressure that separates the endosteum from the otic capsule bone while creating an imaging window. The procedure thus preserves hearing thresholds. Individual inner and outer hair cells, supporting cells and nerve fibers can be visualized in vivo while hearing function is preserved. This approach may enable future original investigations, such as the real-time tracking of ototoxic drug transport into the cochleae. The technique may be applied to the monitoring of sound-evoked functional activity in multiple cochlear cells, in combination with optogenetic tools, and may help to improve cochlear implantation in humans. The cochleostomy takes ~1 h and requires experience in surgery.

Limpet teeth microstructure unites auxeticity with extreme strength and high stiffness.

Materials displaying negative Poisson's ratio, referred to as auxeticity, have been found in nature and created in engineering through various structural mechanisms. However, uniting auxeticity with high strength and high stiffness has been challenging. Here, combining in situ nanomechanical testing with microstructure-based modeling, we show that the leading part of limpet teeth successfully achieves this combination of properties through a unique microstructure consisting of an amorphous hydrated silica matrix embedded with bundles of single-crystal iron oxide hydroxide nanorods arranged in a pseudo-cholesteric pattern. During deformation, this microstructure allows local coordinated displacement and rotation of the nanorods, enabling auxetic behavior while maintaining one of the highest strengths among natural materials. These findings lay a foundation for designing biomimetic auxetic materials with extreme strength and high stiffness.

Anisotropic Hyperfine Interaction of Surface-Adsorbed Single Atoms.

Hyperfine interactions have been widely used in material science, organic chemistry, and structural biology as a sensitive probe to local chemical environments. However, traditional ensemble measurements of hyperfine interactions average over a macroscopic number of spins with different geometrical locations and nuclear isotopes. Here, we use a scanning tunneling microscope (STM) combined with electron spin resonance (ESR) to measure hyperfine spectra of hydrogenated-Ti on MgO/Ag(100) at low-symmetry binding sites and thereby determine the isotropic and anisotropic hyperfine interactions at the single-atom level. Combining vector-field ESR spectroscopy with STM-based atom manipulation, we characterize the full hyperfine tensors of 47Ti and 49Ti and identify significant spatial anisotropy of the hyperfine interactions for both isotopes. Density functional theory calculations reveal that the large hyperfine anisotropy arises from highly anisotropic distributions of the ground-state electron spin density. Our work highlights the power of ESR-STM-enabled single-atom hyperfine spectroscopy in revealing electronic ground states and atomic-scale chemical environments.

Clinical features and management of snake bites in 70 dogs in Korea.

BACKGROUND: Snakebites remain a devastating and life-threatening environmental hazard. While the management of snakebites has been well described in humans, few clinical data and guidelines exist for dogs, especially in Korea. OBJECTIVES: This retrospective study evaluated the clinical features of 70 dogs with snakebite wounds in Korea. METHODS: The medical records of 72 dogs that presented to three animal hospitals from June 2008 to July 2021 were reviewed; among these, 70 dogs that met the inclusion criteria were enrolled. Their signalment, history, clinical signs, physical examination, blood analysis, treatment, and prognosis were also evaluated. RESULTS: Of 70 dog owners, 35 (50%) witnessed the bite, with a mean time between bite and hospital presentation of 9.7 ± 4.1 h in 58 dogs. Blood smears were evaluated in 45 dogs, of which 28 (62%) showed echinocytosis. Anemia and acute kidney injury were found in 21 (29%) and 2 dogs (3%), respectively. A total of 37 dogs (53%) were hospitalized, 5 (7%) of which died. CONCLUSIONS: The most significant finding was the high prevalence of echinocytosis. The data from this retrospective study could inform the management of dogs bitten by snakes in Korea.

Identifying targets to prevent aminoglycoside ototoxicity.

Aminoglycosides are potent antibiotics that are commonly prescribed worldwide. Their use carries significant risks of ototoxicity by directly causing inner ear hair cell degeneration. Despite their ototoxic side effects, there are currently no approved antidotes. Here we review recent advances in our understanding of aminoglycoside ototoxicity, mechanisms of drug transport, and promising sites for intervention to prevent ototoxicity.