Exploring the Tumor-Associated Risk of Mesenchymal Stem Cell Therapy in Veterinary Medicine.

Mesenchymal stem cell (MSC) therapy has been actively applied in veterinary regenerative medicine to treat various canine and feline diseases. With increasing emphasis on safe cell-based therapies, evaluations of their tumorigenic potential are in great demand. However, a direct confirmation of whether tumors originate from stem cells or host cells is not easily achievable. Additionally, previous studies evaluating injections of high doses of MSCs into nude mice did not demonstrate tumor formation. Recent research focused on optimizing MSC-based therapies for veterinary patients, such as MSC-derived extracellular vesicles in treating different diseases. This progress also signifies a broader shift towards personalized veterinary medicine, where treatments can be tailored to individual pets based on their unique genetic profiles. These findings related to different treatments using MSCs emphasize their future potential for veterinary clinical applications. In summary, because of lower tumor-associated risk of MSCs as compared to embryonic and induced pluripotent stem cells, MSCs are considered a suitable source for treating various canine and feline diseases.

An algorithm to detect dicrotic notch in arterial blood pressure and photoplethysmography waveforms using the iterative envelope mean method.

Background and Objective: Detection of the dicrotic notch (DN) within a cardiac cycle is essential for assessment of cardiac output, calculation of pulse wave velocity, estimation of left ventricular ejection time, and supporting feature-based machine learning models for noninvasive blood pressure estimation, and hypotension, or hypertension prediction. In this study, we present a new algorithm based on the iterative envelope mean (IEM) method to detect automatically the DN in arterial blood pressure (ABP) and photoplethysmography (PPG) waveforms. Methods: The algorithm was evaluated on both ABP and PPG waveforms from a large perioperative dataset (MLORD dataset) comprising 17,327 patients. The analysis involved a total of 1,171,288 cardiac cycles for ABP waveforms and 3,424,975 cardiac cycles for PPG waveforms. To evaluate the algorithm's performance, the systolic phase duration (SPD) was employed, which represents the duration from the onset of the systolic phase to the DN in the cardiac cycle. Correlation plots and regression analysis were used to compare the algorithm with an established DN detection technique (second derivative). The marking of the DN temporal location was carried out by an experienced researcher using the help of the 'find_peaks' function from the scipy PYTHON package, serving as a reference for the evaluation. The marking was visually validated by both an engineer and an anesthesiologist. The robustness of the algorithm was evaluated as the DN was made less visually distinct across signal-to-noise ratios (SNRs) ranging from -30 dB to -5 dB in both ABP and PPG waveforms. Results: The correlation between SPD estimated by the algorithm and that marked by the researcher is strong for both ABP (R2(87343) =.99, p<.001) and PPG (R2(86764) =.98, p<.001) waveforms. The algorithm had a lower mean error of dicrotic notch detection (s): 0.0047 (0.0029) for ABP waveforms and 0.0046 (0.0029) for PPG waveforms, compared to 0.0693 (0.0770) for ABP and 0.0968 (0.0909) for PPG waveforms for the established 2nd derivative method. The algorithm has high accuracy of DN detection for SNR of >= -9 dB for ABP waveforms and >= -12 dB for PPG waveforms indicating robust performance in detecting the DN when it is less visibly distinct. Conclusion: Our proposed IEM- based algorithm can detect DN in both ABP and PPG waveforms with low computational cost, even in cases where it is not distinctly defined within a cardiac cycle of the waveform ('DN-less signals'). The algorithm can potentially serve as a valuable, fast, and reliable tool for extracting features from ABP and PPG waveforms. It can be especially beneficial in medical applications where DN-based features, such as SPD, diastolic phase duration, and DN amplitude, play a significant role.

Radiographic and computed tomographic characteristics of intraluminal tracheal adenoma in a cat.

A 13-year-old spayed female Persian cat presented with dyspnea and nasal discharge. Thoracic radiography revealed a dome-shaped soft-tissue opacity in the carina. Computed tomography confirmed a soft tissue-attenuating mass in the carina and the left and right proximal main bronchi that appeared to arise from the tracheal wall. Tracheoscopy revealed an intraluminal broad-based mass with multilobulated borders at the same location. Histopathological evaluation revealed a benign neoplastic process of the glandular epithelial lineage, which was considered an adenoma. Tracheal adenomas should be included in the differential diagnosis of tracheal masses.

Quantification of the Carbon-Coating Effect on the Interfacial Behavior of Graphite Single Particles.

The effect of carbon coating on the interfacial charge transfer resistance of natural graphite (NG) was investigated by a single-particle measurement. The microscale carbon-coated natural graphite (NG@C) particles were synthesized by the simple wet-chemical mixing method using a phenolic resin as the carbon source. The electrochemical test results of NG@C using the conventional composite electrodes demonstrated desirable rate capability, cycle stability, and enhanced kinetic property. Moreover, the improvements in the composite electrodes were confirmed with the electrochemical parameters (i.e., charge transfer resistance, exchange current density, and solid phase diffusion coefficient) analyzed by a single-particle measurement. The surface carbon coating on the NG particles reduced the interfacial charge transfer resistance (Rct) and increased the exchange current density (i0). The Rct decreased from 81-101 (NG) to 49-67 Ω cm2 (NG@C), while i0 increased from 0.25-0.32 (NG) to 0.38-0.52 mA cm-2 (NG@C) after the coating process. The results suggested both electrochemically and quantitatively that the outer uniformly coated surface carbon layer on the graphite particles can improve the solid-liquid interface and other kinetic parameters, therefore enhancing the rate capabilities to obtain the high-power anode materials.

Retrospective evaluation of prognosis and survival with various immunosuppressants in 82 dogs diagnosed with meningoencephalitis of unknown etiology (2010-2021).

BACKGROUND: Meningoencephalomyelitis of unknown etiology (MUE) is a comprehensive term for non-infectious inflammatory brain diseases of the central nervous system (CNS) caused by abnormal autoimmune responses. This study aims to compare the differences in survival and clinical response of MUE according to the adjuvant immunosuppressant use. Medical records of 82 dogs diagnosed with MUE were reviewed retrospectively. RESULTS: The overall survival time was 769 days (range 14-2687 days). The median survival time for each adjunctive was: leflunomide 1035 days (range 126-2163 days), mycophenolate mofetil 865 days (range 39-2191 days), cyclosporin 441 days (range 11-2176 days), cytosine arabinoside 754 days (range 6-1898 days) and a combination of mycophenolate mofetil and cytosine arabinoside 132 days (range 23-1227 days). There was no significant difference in the incidence rate of adverse events according to the immunosuppressants, but moderate to severe anemia was confirmed in 3 patients (18.7%) in the leflunomide group. CONCLUSIONS: The survival time and response rate of MUE dogs differed depending on which adjunctive immunosuppressants were used. Leflunomide showed a long survival time and a relatively good response rate in dogs with MUE. However, a large-scale further study with standardized doses of immunosuppressants and supportive treatment and constant monitoring interval is needed.

Computed tomographic measurements of pancreatic thickness in clinically normal dogs.

Pancreatic thickness is an indicator for evaluating pancreatic diseases. The transverse and cross-sectional pancreatic thickness observed on computed tomography (CT) may differ. This study aimed to provide a normal reference range for pancreatic thickness on the transverse plane based on body weight (BW) and assess pancreatic thickness to aorta (P/Ao) ratio. In addition, we aimed to establish the normal short and long dimensions of the pancreas based on cross-sectional image through the long axis of the pancreas using multiplanar reconstruction (MPR). The short dimension to aorta (S/Ao) and long dimension to aorta (L/Ao) ratios were also established in clinically normal dogs. The pancreatic thickness was measured using CT results of 205 clinically normal dogs. The pancreatic thickness on the transverse plane and the short and long dimensions in the cross-sectional image of the pancreas were measured using MPR. The diameter of the Ao was measured on the transverse plane and the P/Ao, S/Ao, and L/Ao ratios were calculated. Our study showed that the mean normal pancreatic thicknesses (mean ± standard deviation [SD]) of the pancreatic body, left and right lobe in the transverse plane were 10.92 ± 2.54 mm, 8.92 ± 2.26 mm and 9.96 ± 2.24 mm, respectively. The P/Ao ratios of the pancreatic body, left and right lobes were 1.85 ± 0.33, 1.50 ± 0.27 and 1.68 ± 0.29, respectively. The mean short dimension (mean ± SD) in the cross-sectional image of the pancreatic body, left and right lobe were 8.98 ± 1.97 mm, 7.99 ± 1.89 mm and 8.76 ± 2.03 mm, respectively. In conclusion, pancreatic thickness increased with BW, while the P/Ao, S/Ao, and L/Ao ratios could be used regardless of BW.

Non-canonical pathway for Rb inactivation and external signaling coordinate cell-cycle entry without CDK4/6 activity.

Cyclin-dependent kinases 4 and 6 (CDK4/6) are critical for initiating cell proliferation by inactivating the retinoblastoma (Rb) protein. However, mammalian cells can bypass CDK4/6 for Rb inactivation. Here we show a non-canonical pathway for Rb inactivation and its interplay with external signals. We find that the non-phosphorylated Rb protein in quiescent cells is intrinsically unstable, offering an alternative mechanism for initiating E2F activity. Nevertheless, this pathway incompletely induces Rb-protein loss, resulting in minimal E2F activity. To trigger cell proliferation, upregulation of mitogenic signaling is required for stabilizing c-Myc, thereby augmenting E2F activity. Concurrently, stress signaling promotes Cip/Kip levels, competitively regulating cell proliferation with mitogenic signaling. In cancer, driver mutations elevate c-Myc levels, facilitating adaptation to CDK4/6 inhibitors. Differentiated cells, despite Rb-protein loss, maintain quiescence through the modulation of c-Myc and Cip/Kip levels. Our findings provide mechanistic insights into an alternative model of cell-cycle entry and the maintenance of quiescence.

Palmar-plantar erythrodysesthesia syndrome resulting from toceranib phosphate in a dog with apocrine gland anal sac adenocarcinoma: a case report.

An 11-year-old neutered male Miniature Poodle with a stage 3 apocrine gland adenocarcinoma was started on chemotherapy with toceranib phosphate after surgery. Beginning on day 10 of toceranib, the dog's foot pads became erythematous and hyperkeratinized. The dog complained of pain, inability to walk, depression, and loss of appetite. The symptoms resolved when toceranib was discontinued and reappeared when toceranib was resumed. Grade 3 palmar-plantar erythrodysesthesia was identified as an adverse event of toceranib based on the VCOG-CTCAE and Naranjo scale. Although very rare in veterinary medicine, clinicians should consider that palmar-plantar erythrodysesthesia can occur after toceranib administration.

Sequential activation of E2F via Rb degradation and c-Myc drives resistance to CDK4/6 inhibitors in breast cancer.

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) are key therapeutic agents in the management of metastatic hormone-receptor-positive breast cancer. However, the emergence of drug resistance limits their long-term efficacy. Here, we show that breast cancer cells develop CDK4/6i resistance via a sequential two-step process of E2F activation. This process entails retinoblastoma (Rb)-protein degradation, followed by c-Myc-mediated amplification of E2F transcriptional activity. CDK4/6i treatment halts cell proliferation in an Rb-dependent manner but dramatically reduces Rb-protein levels. However, this reduction in Rb levels insufficiently induces E2F activity. To develop CDK4/6i resistance, upregulation or activating mutations in mitogenic or hormone signaling are required to stabilize c-Myc levels, thereby augmenting E2F activity. Our analysis of pre-treatment tumor samples reveals a strong correlation between c-Myc levels, rather than Rb levels, and poor therapeutic outcomes after CDK4/6i treatment. Moreover, we propose that proteasome inhibitors can potentially reverse CDK4/6i resistance by restoring Rb levels.

Angiopoietin-2 blockade suppresses growth of liver metastases from pancreatic neuroendocrine tumors by promoting T cell recruitment.

Improving the management of metastasis in pancreatic neuroendocrine tumors (PanNETs) is critical, as nearly half of patients with PanNETs present with liver metastases, and this accounts for the majority of patient mortality. We identified angiopoietin-2 (ANGPT2) as one of the most upregulated angiogenic factors in RNA-Seq data from human PanNET liver metastases and found that higher ANGPT2 expression correlated with poor survival rates. Immunohistochemical staining revealed that ANGPT2 was localized to the endothelial cells of blood vessels in PanNET liver metastases. We observed an association between the upregulation of endothelial ANGPT2 and liver metastatic progression in both patients and transgenic mouse models of PanNETs. In human and mouse PanNET liver metastases, ANGPT2 upregulation coincided with poor T cell infiltration, indicative of an immunosuppressive tumor microenvironment. Notably, both pharmacologic inhibition and genetic deletion of ANGPT2 in PanNET mouse models slowed the growth of PanNET liver metastases. Furthermore, pharmacologic inhibition of ANGPT2 promoted T cell infiltration and activation in liver metastases, improving the survival of mice with metastatic PanNETs. These changes were accompanied by reduced plasma leakage and improved vascular integrity in metastases. Together, these findings suggest that ANGPT2 blockade may be an effective strategy for promoting T cell infiltration and immunostimulatory reprogramming to reduce the growth of liver metastases in PanNETs.

Machine Learning of Physiologic Waveforms and Electronic Health Record Data: A Large Perioperative Data Set of High-Fidelity Physiologic Waveforms.

Perioperative morbidity and mortality are significantly associated with both static and dynamic perioperative factors. The studies investigating static perioperative factors have been reported; however, there are a limited number of previous studies and data sets analyzing dynamic perioperative factors, including physiologic waveforms, despite its clinical importance. To fill the gap, the authors introduce a novel large size perioperative data set: Machine Learning Of physiologic waveforms and electronic health Record Data (MLORD) data set. They also provide a concise tutorial on machine learning to illustrate predictive models trained on complex and diverse structures in the MLORD data set.

Identification of Sympetrum depressiusculum Sélys, 1841 in South Korea (Odonata: Libellulidae) According to Morphology and Genetic Markers.

In South Korea, both Sympetrum depressiusculum Sélys, 1841 (Odonata: Libellulidae), which is distributed throughout Europe and from Russia to the Korean Peninsula, and Sympetrum frequens Sélys, 1883, which is endemic to Japan, are recorded. However, the identity of South Korean populations and the validity of listing the two species have not yet been settled. In this study, we collected seventy-four individuals of Sympetrum species from South Korea (five localities), Russia, The Netherlands, and Japan. These samples were examined for morphology and sequenced for partial COI, 16S rRNA, and a nuclear internal spacer (ITS) region, after which these molecular data were combined with available public data from Russia, Japan, and The Netherlands. Major morphological characters that have been used to distinguish the two species and phylogenetic, network, and structure analyses all consistently suggest that South Korean populations form a single species. Consequently, it could be valid to treat South Korean populations as one species, S. depressiusculum, by applying the senior name. Nevertheless, the validity of maintaining each as an independent species in other countries may need additional study considering that our samples were focused more on South Korea and limited for Europe, Russia, and Japan.

Preclinical Study on Biodistribution of Mesenchymal Stem Cells after Local Transplantation into the Brain.

Therapeutic efficacy of mesenchymal stem cells (MSCs) is determined by biodistribution and engraftment in vivo. Compared to intravenous infusion, biodistribution of locally transplanted MSCs are partially understood. Here, we performed a pharmacokinetics (PK) study of MSCs after local transplantation. We grafted human MSCs into the brains of immune-compromised nude mice. Then we extracted genomic DNA from brains, lungs, and livers after transplantation over a month. Using quantitative polymerase chain reaction with human Alu-specific primers, we analyzed biodistribution of the transplanted cells. To evaluate the role of residual immune response in the brain, MSCs expressing a cytosine deaminase (MSCs/CD) were used to ablate resident immune cells at the injection site. The majority of the Alu signals mostly remained at the injection site and decreased over a week, finally becoming undetectable after one month. Negligible signals were transiently detected in the lung and liver during the first week. Suppression of Iba1-positive microglia in the vicinity of the injection site using MSCs/CD prolonged the presence of the Alu signals. After local transplantation in xenograft animal models, human MSCs remain predominantly near the injection site for limited time without disseminating to other organs. Transplantation of human MSCs can locally elicit an immune response in immune compromised animals, and suppressing resident immune cells can prolong the presence of transplanted cells. Our study provides valuable insights into the in vivo fate of locally transplanted stem cells and a local delivery is effective to achieve desired dosages for neurological diseases.

THOC2 expression and its impact on 5-fluorouracil resistance in glioblastoma multiforme.

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with poor prognosis and limited treatment options. While 5-fluorouracil (5-FU) has not been widely employed in GBM therapy, emerging research indicates its potential for effectiveness when combined with advanced drug delivery systems to improve its transport to brain tumors. This study aims to investigate the role of THOC2 expression in 5-FU resistance in GBM cell lines. We evaluated diverse GBM cell lines and primary glioma cells for 5-FU sensitivity, cell doubling times, and gene expression. We observed a significant correlation between THOC2 expression and 5-FU resistance. To further investigate this correlation, we selected five GBM cell lines and developed 5-FU resistant GBM cells, including T98FR cells, through long-term 5-FU treatment. In 5-FU challenged cells, THOC2 expression was upregulated, with the highest increase in T98FR cells. THOC2 knockdown in T98FR cells reduced 5-FU IC50 values, confirming its role in 5-FU resistance. In a mouse xenograft model, THOC2 knockdown attenuated tumor growth and extended survival duration after 5-FU treatment. RNA sequencing identified differentially expressed genes and alternative splicing variants in T98FR/shTHOC2 cells. THOC2 knockdown altered Bcl-x splicing, increasing pro-apoptotic Bcl-xS expression, and impaired cell adhesion and migration by reducing L1CAM expression. These results suggest that THOC2 plays a crucial role in 5-FU resistance in GBM and that targeting THOC2 expression could be a potential therapeutic strategy for improving the efficacy of 5-FU-based combination therapies in GBM patients.

Enhanced antitumor efficacy of mesenchymal stem cells expressing cytosine deaminase and 5-fluorocytosine combined with α-galactosylceramide in a colon cancer model.

Cancer immunotherapy has emerged as a promising approach for treating various malignancies. In this study, we investigated the combined therapeutic effects of mesenchymal stem cells expressing cytosine deaminase (MSC/CD) and 5-fluorocytosine (5-FC) with α-galactosylceramide (α-GalCer) in a colon cancer model. Our findings demonstrated that the combination of MSC/CD, 5-FC, and α-GalCer resulted in enhanced antitumor activity compared to the individual treatments. This was evidenced by increased infiltration of immune cells, such as natural killer T (NKT) cells, antigen-presenting cells (APCs), T cells, and natural killer (NK) cells, in the tumor microenvironment, as well as elevated expression of proinflammatory cytokines and chemokines. Furthermore, we observed no significant hepatotoxicity following the combined treatment. Our study highlights the potential therapeutic benefits of combining MSC/CD, 5-FC, and α-GalCer for colon cancer treatment and contributes valuable insights to the field of cancer immunotherapy. Future research should focus on elucidating the underlying mechanisms and exploring the applicability of these findings to other cancer types and immunotherapy strategies.

Measurement of brainstem diameter in small-breed dogs using magnetic resonance imaging.

Measurement of brainstem diameters (midbrain, pons, and medulla oblongata)is of potential clinical significance, as changes in brainstem size may decrease or increase due to age, neurodegenerative disorders, or neoplasms. In human medicine, numerous studies have reported the normal reference range of brainstem size, which is hitherto unexplored in veterinary medicine, particularly for small-breed dogs. Therefore, this study aims to investigate the reference range of brainstem diameters in small-breed dogs and to correlate the measurements with age, body weight (BW), and body condition score (BCS). Herein, magnetic resonance (MR) images of 544 small-breed dogs were evaluated. Based on the exclusion criteria, 193 dogs were included in the midbrain and pons evaluation, and of these, 119 dogs were included in the medulla oblongata evaluation. Using MR images, the height and width of the midbrain, pons, and medulla oblongata were measured on the median and transverse plane on the T1-weighted image. For the medulla oblongata, two points were measured for each height and width. The mean values of midbrain height (MH), midbrain width (MW), pons height (PH), pons width (PW), medulla oblongata height at the fourth ventricle level (MOHV), medulla oblongata height at the cervicomedullary (CM) junction level (MOHC), rostral medulla oblongata width (RMOW), and caudal medulla oblongata width (CMOW) were 7.18 ± 0.56 mm, 17.42 ± 1.21 mm, 9.73 ± 0.64 mm, 17.23 ± 1.21 mm, 6.06 ± 0.53 mm, 5.77 ± 0.40 mm, 18.93 ± 1.25 mm, and 10.12 ± 1.08 mm, respectively. No significant differences were found between male and female dogs for all the measurements. A negative correlation was found between age and midbrain diameter, including MH (p < 0.001) and MW (p = 0.002). All brainstem diameters were correlated positively with BW (p < 0.05). No significant correlation was found between BCS and all brainstem diameters. Brainstem diameters differed significantly between breeds (p < 0.05), except for MW (p = 0.137). This study assessed linear measurements of the brainstem diameter in small-breed dogs. We suggest that these results could be useful in assessing abnormal conditions of the brainstem in small-breed dogs.

Quantifiable peptide library bridges the gap for proteomics based biomarker discovery and validation on breast cancer.

Mass spectrometry (MS) based proteomics is widely used for biomarker discovery. However, often, most biomarker candidates from discovery are discarded during the validation processes. Such discrepancies between biomarker discovery and validation are caused by several factors, mainly due to the differences in analytical methodology and experimental conditions. Here, we generated a peptide library which allows discovery of biomarkers in the equal settings as the validation process, thereby making the transition from discovery to validation more robust and efficient. The peptide library initiated with a list of 3393 proteins detectable in the blood from public databases. For each protein, surrogate peptides favorable for detection in mass spectrometry was selected and synthesized. A total of 4683 synthesized peptides were spiked into neat serum and plasma samples to check their quantifiability in a 10 min liquid chromatography-MS/MS run time. This led to the PepQuant library, which is composed of 852 quantifiable peptides that cover 452 human blood proteins. Using the PepQuant library, we discovered 30 candidate biomarkers for breast cancer. Among the 30 candidates, nine biomarkers, FN1, VWF, PRG4, MMP9, CLU, PRDX6, PPBP, APOC1, and CHL1 were validated. By combining the quantification values of these markers, we generated a machine learning model predicting breast cancer, showing an average area under the curve of 0.9105 for the receiver operating characteristic curve.

High-Strength Epoxy Nanocomposites Reinforced with Photochemically Treated CNTs.

A carbon nanotube (CNT)/epoxy nanocomposite was prepared using a photochemical surface modification process of CNTs. The vacuum ultraviolet (VUV)-excimer lamp treatment created reactive sites on the CNT surface. Increasing the irradiation time increased the oxygen functional groups and changed the oxygen bonding state such as C=O, C-O, and -COOH. By the VUV-excimer irradiation on CNTs, the epoxy infiltrated well between the CNT bundles and formed a strong chemical bond between CNT and epoxy. The tensile strength and elastic modulus of the nanocomposites with VUV-excimer irradiated sample during 30 min (R30) were found to increase by 30 and 68% compared to using pristine CNT, respectively. R30 was not pulled out and remained embedded in the matrix until the fracture occurred. The VUV-excimer irradiation is an effective surface modification and functionalization method for improving the mechanical properties of CNT nanocomposite materials.

Assessment of Risks and Benefits of Using Antibiotics Resistance Genes in Mesenchymal Stem Cell-Based Ex-Vivo Therapy.

Recently, ex-vivo gene therapy has emerged as a promising approach to enhance the therapeutic potential of mesenchymal stem cells (MSCs) by introducing functional genes in vitro. Here, we explored the need of using selection markers to increase the gene delivery efficiency and evaluated the potential risks associated with their use in the manufacturing process. We used MSCs/CD that carry the cytosine deaminase gene (CD) as a therapeutic gene and a puromycin resistance gene (PuroR) as a selection marker. We evaluated the correlation between the therapeutic efficacy and the purity of therapeutic MSCs/CD by examining their anti-cancer effect on co-cultured U87/GFP cells. To simulate in vivo horizontal transfer of the PuroR gene in vivo, we generated a puromycin-resistant E. coli (E. coli/PuroR) by introducing the PuroR gene and assessed its responsiveness to various antibiotics. We found that the anti-cancer effect of MSCs/CD was directly proportional to their purity, suggesting the crucial role of the PuroR gene in eliminating impure unmodified MSCs and enhancing the purity of MSCs/CD during the manufacturing process. Additionally, we found that clinically available antibiotics were effective in inhibiting the growth of hypothetical microorganism, E. coli/PuroR. In summary, our study highlights the potential benefits of using the PuroR gene as a selection marker to enhance the purity and efficacy of therapeutic cells in MSC-based gene therapy. Furthermore, our study suggests that the potential risk of horizontal transfer of antibiotics resistance genes in vivo can be effectively managed by clinically available antibiotics.

UBAP2 plays a role in bone homeostasis through the regulation of osteoblastogenesis and osteoclastogenesis.

Osteoporosis is a condition characterized by decreased bone mineral density (BMD) and reduced bone strength, leading to an increased risk of fractures. Here, to identify novel risk variants for susceptibility to osteoporosis-related traits, an exome-wide association study is performed with 6,485 exonic single nucleotide polymorphisms (SNPs) in 2,666 women of two Korean study cohorts. The rs2781 SNP in UBAP2 gene is suggestively associated with osteoporosis and BMD with p-values of 6.1 × 10-7 (odds ratio = 1.72) and 1.1 × 10-7 in the case-control and quantitative analyzes, respectively. Knockdown of Ubap2 in mouse cells decreases osteoblastogenesis and increases osteoclastogenesis, and knockdown of ubap2 in zebrafish reveals abnormal bone formation. Ubap2 expression is associated with E-cadherin (Cdh1) and Fra1 (Fosl1) expression in the osteclastogenesis-induced monocytes. UBAP2 mRNA levels are significantly reduced in bone marrow, but increased in peripheral blood, from women with osteoporosis compared to controls. UBAP2 protein level is correlated with the blood plasma level of the representative osteoporosis biomarker osteocalcin. These results suggest that UBAP2 has a critical role in bone homeostasis through the regulation of bone remodeling.