Historic dog furs unravel the origin and artificial selection of modern Nordic Lapphund and Elkhound dog breeds.

The origins and extreme morphological evolution of the modern dog breeds are poorly studied because the founder populations are extinct. Here, we analyse eight 100-200 years old dog fur samples obtained from traditional North Swedish clothing, to explore the origin and artificial selection of the modern Nordic Lapphund and Elkhound dog breeds. Population genomic analysis confirmed the Lapphund and Elkhound breeds to originate from the local dog population, and showed a distinct decrease in genetic diversity in agreement with intense breeding. We identified eleven genes under positive selection during the breed development. In particular, the MSRB3 gene, associated with breed-related ear morphology, was selected in all Lapphund and Elkhound breeds, and functional assays showed that a SNP mutation in the 3'UTR region suppresses its expression through miRNA regulation. Our findings demonstrate analysis of near-modern dog artifacts as an effective tool for interpreting the origin and artificial selection of the modern dog breeds.

Report on Pseudoaneurysm Caused by Injury of Internal Carotid Artery During Endoscopic Pituitary Surgery and Rebleeding After Treatment With Willis Covered Stent.

OBJECTIVE: Report on a case of pseudoaneurysm which was caused by injury of the internal carotid artery (ICA) during endoscopic endonasal surgery (EES), which was followed by rebleeding after treatment with a Willis covered stent. METHODS: A woman, aged 68, underwent EES for the treatment of a pituitary adenoma. During the surgery, the right ICA was injured, and successfully hemostasis by packed with cottonoid and gelatin sponge. Besides, cerebral angiography was performed in the interventional operating room for the purpose of discovering the formation of a pseudoaneurysm in the cavernous sinus segment of ICA, which was treated with a covered stent. After successfully placing the covered stent, the patient was promptly transferred to the general operating room for the removal of the cottonoid and to address the bleeding once again. The authors employ crushed muscles and cottonoid to locally compress and stop bleeding. Owing to concerns about the risk of rebleeding in the patient, after stent implantation, the patient did not utilize antiplatelet drugs. After the surgery, the patient developed occlusion of the right ICA and massive cerebral infarction in the right hemisphere. Dehydration, anti-infection, rehabilitation, hyperbaric oxygen, as well as related treatments, were given. The cottonoid was removed in EES 2 months postsurgery, and no instances of bleeding were observed. Six months after surgery, the patient had clear consciousness and hemiplegia in the left limb, with a Glasgow Outcome Scale score of 4. RESULTS: The ICA was injured during EES, which resulted in the formation of a pseudoaneurysm, the Willis stent was adopted for treatment, and there was a risk of rebleeding after the nasal packing (cottonoid, crushed muscles) was removed immediately. CONCLUSIONS: The ICA was injured during EES after bleeding was controlled by packing with cottonoid, crushed muscles, etc, subsequently, the patient was given intravascular treatment, it is advised to make thorough preparations and, after a suitable period, remove nasal packing in the hybrid operating room to address unexpected situations and unforeseen circumstances.

Diagnostic Significance of DCE-MRI-Related Quantitative Parameters for Nasal Cavity and Sinus Tumors.

Objective: Our aim was to explore the diagnostic value of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI)-related quantitative parameters for benign and malignant nasal cavity and sinus tumors. Methods: A total of 78 patients with nasal sinus tumors admitted to People's Hospital of Qingdao Chengyang District in China were enrolled in our study, Of the patients, 41 were diagnosed as having benign tumors and 37 as having malignant tumors by pathological diagnosis. All patients received DCE-MRI scans before surgery to derive time-intensity curves (TICs) and related quantitative parameters (flux rate constant [Kep], transfer constant [Ktrans], extravascular volume fraction [Ve]). The diagnostic surgical pathology results were used as the gold standard to analyze the diagnostic effect of TIC and related quantitative parameters of DCE-MRI, and the receiver operating characteristic (ROC) curves were plotted to determine the values of each parameter in predicting nasal sinus tumors. Results: The percentage of class I in the benign group was significantly higher than in the malignant group (P < .05); the percentage of class III in the benign group was significantly lower than in the malignant group (P < .05); the percentage of class II in the 2 groups was comparable (P > .05). Kep, Ktrans and Ve in the benign group were 0.338±0.124, 0.061±0.035 and 0.532±0.138, respectively; Kep, Ktrans and Ve in the malignant group were 0.785±0.211, 0.441±0.125 and 0.327±0.048, respectively. The levels of Kep and Ktrans were significantly lower in the benign group than in the malignant group (all P < .05); the levels of Ve were significantly higher in the benign group than in the malignant group (P < .05). The optimal Kep cut-off value for predicting malignant nasal sinus tumors was 0.510 min-1, with a sensitivity of 81.4% and specificity of 89.5%; the optimal Ktrans cut-off value for predicting malignant nasal sinus tumors was 0.206 min-1, with a sensitivity of 84.3% and specificity of 89.7%; the optimal Ve cut-off value for predicting malignant nasal sinus tumors was 0.384 min-1, with a sensitivity of 71.8% and specificity of 82.4%. Conclusion: DCE-MRI-related quantitative parameters are ideal for the diagnosis of benign and malignant nasal sinus tumors. This modality provides more data for the identification of the nature of the tumor, and thus merits clinical promotion and application.

Clinical Characteristics and Gene Mutations of Two Families with MODY 3 in Inner Mongolia.

Objective: This study aimed to analyze the clinical characteristics and gene mutations of two families with maturity-onset diabetes of the young 3 (MODY 3) in Inner Mongolia. Methods: Fifty-three patients in Inner Mongolia suspected of having MODY 3 were enrolled in this study according to clinical manifestations. Blood samples were collected, and all exons of the HNF1α gene were analyzed; the second-generation DNA of the splicing regions of the gene was determined by direct sequencing. Results: In Family 1, the proband, mother, and uncle all carried the missense heterozygous mutation on exon 2 of the HNF1α gene (c.512G>A, p.Arg171Gln), and both the proband and uncle had MODY 3. In Family 2, the proband, grandfather, father, uncle I, and uncle II all carried a missense mutation on exon 2 (c.391C>t, p.Arg131Trp), and all had MODY 3. The blood glucose control in these patients was stable while they were being treated with oral sulfonylurea hypoglycemic drugs alone or with insulin. Uncle II had serious macrovascular and microvascular complications. Conclusion: Maturity-onset diabetes of the young 3 gene mutations (c.512G>A, p.Arg171Gln) and (c.391C>T, p.Arg131Trp) may be the main pathogenic genes of the two families with MODY 3. The two gene mutations found in this study have not been reported previously in China.

Recent strategies targeting Embryonic Ectoderm Development (EED) for cancer therapy: Allosteric inhibitors, PPI inhibitors, and PROTACs.

The polycomb repressive complex 2 (PRC2), which comprised of the core subunits: Enhancer of Zeste Homolog 2 (EZH2), Suppressor of Zeste 12 (SUZ12), and Embryonic Ectoderm Development (EED), is an essential epigenetic gene silencer responsible for depositing repressive histone H3 lysine 27 trimethylation (H3K27me3) marks on chromatin. The aberrant activity of PRC2 is closely involved in tumorigenesis and progression, making its inhibition a viable strategy for epigenetic cancer therapy. Although the clinical development of small PRC2 inhibitors has made impressive progress, with one EZH2 inhibitor approved for cancer therapy and several other candidates in clinical trials, current EZH2 inhibitors are limited to treating certain hematological malignancies and have acquired drug resistance. EED is essential for PRC2 stabilization and allosterically stimulating PRC2 activity because it functions as a scaffold protein and an H3K27me3-recognizing protein. Thus, due to its novel mechanism of action, targeting EED provides a promising new strategy for inhibiting PRC2 function and exhibits the potential to overcome the issues encountered by EZH2 inhibitors. This review provides a comprehensive overview of available cancer therapy strategies that target EED, including allosteric inhibitors, protein-protein interaction (PPI) inhibitors, and proteolysis-targeting chimeras (PROTACs).

Anatomical Study on the Safety of Anterior Cervical Craniovertebral Fusion with Clival Screw Placement in Children Aged 1-6 Years.

OBJECTIVE: This study aimed to investigate the safety of clival screw placement in children aged 1-6 years. METHODS: The cranial computed tomography data of 92 children aged 1-6 years were divided into three groups, according to age, for three-dimensional reconstruction. Three clival screw placement points were defined: (1) median point A at the middle and upper third of the tripartite distance from the spheno-occipital synchondrosis to the base of the skull; (2, 3) critical points B and C on the horizontal line with point A, where the screw placement passage was parallel to the sagittal plane. Parameters such as the passage length and angle were measured for horizontal, vertical facial, and extreme screw placement. RESULTS: The length parameters of the clival screw placement increased with age, and the screw passage length was the shortest for the vertical facial type in each age group. There were significant differences in all three groups between the length of screw placement in the vertical bone surface, the length of screw placement in the horizontal direction, and the length of screw placement on the limit at points A, B, and C (P < 0.05); the length of screw placement on the vertical bone surface was the shortest. There was no significant difference between the horizontal screw length at point A and the extreme screw length (P > 0.05). The difference between the horizontal screw length and the extreme screw length in the groups aged 1-2 years and 5-6 years was statistically significant (P < 0.05), and the horizontal screw length was longer. CONCLUSION: The cranial slope of children aged 1-6 years has the morphological basis for the placement of 3.5 mm screws, and each placement point has a safe angle range for screw placement.

Research progress of dual inhibitors targeting crosstalk between histone epigenetic modulators for cancer therapy.

Abnormal epigenetics is a critical hallmark of human cancers. Anticancer drug discovery directed at histone epigenetic modulators has gained impressive advances with six drugs available for cancer therapy and numerous other candidates undergoing clinical trials. However, limited therapeutic profile, drug resistance, narrow safety margin, and dose-limiting toxicities pose intractable challenges for their clinical utility. Because histone epigenetic modulators undergo intricate crosstalk and act cooperatively to shape an aberrant epigenetic profile, co-targeting histone epigenetic modulators with a different mechanism of action has rapidly emerged as an attractive strategy to overcome the limitations faced by the single-target epigenetic inhibitors. In this review, we summarize in detail the crosstalk of histone epigenetic modulators in regulating gene transcription and the progress of dual epigenetic inhibitors targeting this crosstalk.

Design, synthesis, and biological evaluation of novel dual inhibitors targeting lysine specific demethylase 1 (LSD1) and histone deacetylases (HDAC) for treatment of gastric cancer.

LSD1 and HDAC are physical and functional related to each other in various human cancers and simultaneous pharmacological inhibition of LSD1 and HDAC exerts synergistic anti-cancer effects. In this work, a series of novel LSD1/HDAC bifunctional inhibitors with a styrylpyridine skeleton were designed and synthesized based on our previously reported LSD1 inhibitors. The representative compounds 5d and 5m showed potent activity against LSD1 and HDAC at both molecular and cellular level and displayed high selectivity against MAO-A/B. Moreover, compounds 5d and 5m demonstrated potent antiproliferative activities against MGC-803 and HCT-116 cancer cell lines. Notably, compound 5m showed superior in vitro anticancer potency against a panel of gastric cancer cell lines than ORY-1001 and SP-2509 with IC50 values ranging from 0.23 to 1.56 µM. Compounds 5d and 5m significantly modulated the expression of Bcl-2, Bax, Vimentin, ZO-1 and E-cadherin, induced apoptosis, reduced colony formation and suppressed migration in MGC-803 cancer cells. In addition, preliminary absorption, distribution, metabolism, excretion (ADME) studies revealed that compounds 5d and 5m showed acceptable metabolic stability in human liver microsomes with minimal inhibition of cytochrome P450s (CYPs). Those results indicated that compound 5m could be a promising lead compound for further development as a therapeutic agent in gastric cancers via LSD1 and HDAC dual inhibition.

Effects of Surgery Combined with Chemoradiotherapy on Short- and Long-Term Outcomes of Early-Stage Nasopharyngeal Carcinoma.

OBJECTIVE: The efficacy of surgery as the primary treatment modality for nasopharyngeal carcinoma (NPC) is yet to be clarified. Therefore, we aimed to explore the short- and long-term efficacy of surgery for early-stage NPC. METHODS: We retrospectively evaluated 341 patients diagnosed with early-stage NPC between September 2010 and December 2015. Among them, 58 patients underwent endoscopic nasopharyngectomy combined with chemoradiotherapy, whereas 283 patients underwent conventional chemoradiotherapy. The patients who underwent concurrent chemoradiotherapy or radiotherapy alone were matched to patients who underwent surgery in a 1:2 ratio using propensity score matching to analyze the clinical efficacy of each therapeutic modality. The primary endpoint was survival, and the secondary endpoints were tumor regression rate and reduction in Epstein-Barr virus (EBV)-DNA levels. RESULTS: After matching, 156 patients were enrolled (58 patients in the surgery group; 98 patients in the non-surgery group). The baseline data of the matched patients had good inter-group comparability (All P>0.05). The surgery group had significantly higher 5-year overall survival (98.30% vs. 91.70%), disease-free survival (98.30% vs. 81.40%), and recurrence-free survival (100.00% vs. 90.10%) rates than did the non-surgery group (All P<0.05). In total, 0 and 14 patients in the surgery and non-surgery groups, respectively, had residual cancer at the end of treatment (P=0.001). All patients in the surgery group tested negative for EBV-DNA, whereas two patients in the non-surgery group tested positive. The incidence of hematologic toxicity during treatment was similar between the two groups (All P>0.05). Still, the incidence of severe oral mucositis was lower in the surgery group than in the non-surgery group (37.9% vs. 54.08%, P=0.051). CONCLUSION: Surgery can improve the clearance rate of EB virus and reduce tumor residue. Surgery may be a safe and effective treatment for early NPC.

Genomic regions under selection in the feralization of the dingoes.

Dingoes are wild canids living in Australia, originating from domestic dogs. They have lived isolated from both the wild and the domestic ancestor, making them a unique model for studying feralization. Here, we sequence the genomes of 10 dingoes and 2 New Guinea Singing Dogs. Phylogenetic and demographic analyses show that dingoes originate from dogs in southern East Asia, which migrated via Island Southeast Asia to reach Australia around 8300 years ago, and subsequently diverged into a genetically distinct population. Selection analysis identifies 50 positively selected genes enriched in digestion and metabolism, indicating a diet change during feralization of dingoes. Thirteen of these genes have shifted allele frequencies compared to dogs but not compared to wolves. Functional assays show that an A-to-G mutation in ARHGEF7 decreases the endogenous expression, suggesting behavioral adaptations related to the transitions in environment. Our results indicate that the feralization of the dingo induced positive selection on genomic regions correlated to neurodevelopment, metabolism and reproduction, in adaptation to a wild environment.

Structural variation during dog domestication: insights from gray wolf and dhole genomes.

Several processes like phenotypic evolution, disease susceptibility and environmental adaptations, which fashion the domestication of animals, are largely attributable to structural variations (SVs) in the genome. Here, we present high-quality draft genomes of the gray wolf (Canis lupus) and dhole (Cuon alpinus) with scaffold N50 of 6.04 Mb and 3.96 Mb, respectively. Sequence alignment comprising genomes of three canid species reveals SVs specific to the dog, particularly 16 315 insertions, 2565 deletions, 443 repeats, 16 inversions and 15 translocations. Functional annotation of the dog SVs associated with genes indicates their enrichments in energy metabolisms, neurological processes and immune systems. Interestingly, we identify and verify at population level an insertion fully covering a copy of the AKR1B1 (Aldo-Keto Reductase Family 1 Member B) transcript. Transcriptome analysis reveals a high level of expression of the new AKR1B1 copy in the small intestine and liver, implying an increase in de novo fatty acid synthesis and antioxidant ability in dog compared to gray wolf, likely in response to dietary shifts during the agricultural revolution. For the first time, we report a comprehensive analysis of the evolutionary dynamics of SVs during the domestication step of dogs. Our findings demonstrate that retroposition can birth new genes to facilitate domestication, and affirm the importance of large-scale genomic variants in domestication studies.

Three-dimensional digitizing and anatomic study of lumbar vertebral canal and pedicle in children.

INTRODUCTION: Spinal pedicle screw internal fixation has been widely used in adult spine injury fixation. Due to being in a period of continuous growth and development, the spine of children at different ages shows different characteristics from adults in terms of anatomy, physiological function, and biomechanics. Furthermore, because the pedicle of children is small, has large anatomic variation, and has complex adjacent relationships, the surgical risk is extremely high. How to improve the screwing accuracy is the key to the success of children's pedicle internal fixation. Therefore, applying the concept of digitized and individualized screwing will be of great significance to children's pedicle screwing. AIM: To investigate the morphologies, development patterns, and aging characteristics of the lumbar vertebral pedicle (LVP) in children aged 6-11 years, and to provide a theoretical basis for screw implantation and related biomechanical studies. MATERIAL AND METHODS: A total of 60 children aged 6-11 years were selected for the intergroup measurement and statistical analysis of their lumbar diameter, pedicle diameter, screw canal length (SCL), etc. RESULTS: Generally, the vertebral foramen diameter (ID), sagittal diameter (SD), pedicle width (PW), and SCL as well as the pedicle height (PH) exhibited an increasing trend with age and increasing vertebral sequence among children aged 6-11 years. CONCLUSIONS: By observing the LVP in children using 3D digital reconstruction technology, the morphology of the spinal canal and pedicles at different lumbar segments showed obvious development patterns, and the best treatment protocol should be selected according to the LVP characteristics in clinical applications.

EEG patterns from acute to chronic stroke phases in focal cerebral ischemic rats: correlations with functional recovery.

Monitoring the neural activities from the ischemic penumbra provides critical information on neurological recovery after stroke. The purpose of this study is to evaluate the temporal alterations of neural activities using electroencephalography (EEG) from the acute phase to the chronic phase, and to compare EEG with the degree of post-stroke motor function recovery in a rat model of focal ischemic stroke. Male Sprague-Dawley rats were subjected to 90 min transient middle cerebral artery occlusion surgery followed by reperfusion for seven days (n = 58). The EEG signals were recorded at the pre-stroke phase (0 h), acute phase (3, 6 h), subacute phase (12, 24, 48, 72 h) and chronic phase (96, 120, 144, 168 h) (n = 8). This study analyzed post-stroke seizures and polymorphic delta activities (PDAs) and calculated quantitative EEG parameters such as the alpha-to-delta ratio (ADR). The ADR represented the ratio between alpha power and delta power, which indicated how fast the EEG activities were. Forelimb and hindlimb motor functions were measured by De Ryck's test and the beam walking test, respectively. In the acute phase, delta power increased fourfold with the occurrence of PDAs, and the histological staining showed that the infarct was limited to the striatum and secondary sensory cortex. In the subacute phase, the alpha power reduced to 50% of the baseline, and the infarct progressed to the forelimb cortical region. ADRs reduced from 0.23 ± 0.09 to 0.04 ± 0.01 at 3 h in the acute phase and gradually recovered to 0.22 ± 0.08 at 168 h in the chronic phase. In the comparison of correlations between the EEG parameters and the limb motor function from the acute phase to the chronic phase, ADRs were found to have the highest correlation coefficients with the beam walking test (r = 0.9524, p < 0.05) and De Ryck's test (r = 0.8077, p < 0.05). This study measured EEG activities after focal cerebral ischemia and showed that functional recovery was closely correlated with the neural activities in the penumbra. Longitudinal EEG monitoring at different phases after a stroke can provide information on the neural activities, which are well correlated with the motor function recovery.

[Clinical comparative study on the influence of acupoint sticking therapy in dog days and in non-dog days to the quality of life of allergic rhinitis patients].

OBJECTIVE: To observe and compare the influence of acupoint sticking therapy in dog days and in non-dog days to the quality of life of allergic rhinitis patients. METHODS: Fifty-five cases were divided into group A (the acupoint sticking therapy in dog days group, 28 cases) and group B (the acupoint sticking therapy in non-dog day group, 27 cases) randomly. The acupoint sticking therapy description (Dazhui (GV 14), Fengmen (BL 12), Feishu (BL 13) etc. was used in both groups. Five times of acupoint sticking therapy were given to patients in group A during dog days in 2010, while another 5 times of acupoint sticking therapy were given to patients in group B before the dog days. The Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) was used to evaluate the effects before, after and half a year after treatment. RESULTS: The scores of behavior problems, nasal symptoms and quality of life in RQLQ of both groups all decreased after treatment (all P < 0.01). The score of emotion reaction of group A in the follow-up period decreased compared with that before treatment (P < 0.05). The scores of non-nasal-or-ocular symptoms, ocular symptoms and emotion reaction after treatment and in the follow-up period all decreased than those before treatment (P < 0.01, P < 0.05). The decreasing degrees of scores of non-nasal-or-ocular symptoms, ocular symptoms, emotion reaction and quality of life after treatment and in the follow-up period in group A were all greater than those in group B (P < 0.01, P < 0.05). CONCLUSION: In the same season, both acupoint sticking therapy in dog days and in non-dog dags can improve the symptoms of allergic rhinitis, but the improving degree to quality of life in the method of acupoint sticking in dog days is greater.

Nitric oxide, actin reorganization and vacuoles change are involved in PEG 6000-induced stomatal closure in Vicia faba.

Water deficit and the resulting osmotic stress affect stomatal movement. There are two types of signals, hydraulic and chemical signals, involving in the regulation of stomatal behavior responses to osmotic stress. Compared with the chemical signals, little has been known about the hydraulic signals and the corresponding signal transduction network and regulatory mechanisms. Here, using an epidermal-strip bioassay and laser-scanning confocal microscopy, we provide evidence that nitric oxide (NO) generation in Vicia faba guard cells can be induced by hydraulic signals. We used polyethylene glycol (PEG) 600 to simulate hypertonic conditions. This hydraulic signal led to stomatal closure and rapid promotion of NO production in guard cells. The effects were decreased by NO scavenger 2-(4-carboxyphenyl)-4,4,5, 5-tetramethylimidazoline-1-oxyl-3-oxide (c-PTIO) and NO synthase (Enzyme Commission 1.14.13.39) inhibitor N(G)-nitro-L-Arg-methyl ester (L-NAME). These results indicate that PEG 6000 induces stomatal closure by promoting NO production. Cytochalasin B (CB) inhibited stomatal closure induced by PEG 6000 but did not prevent the increase of endogenous NO levels, indicating that microfilaments polymerization participate in stomatal closure induced by PEG 6000, and may act downstream of NO signaling. In addition, big vacuoles split into many small vacuoles were observed in response to PEG 6000 and sodium nitroprusside (SNP) treatment, and CB inhibited these changes of vacuoles, the stomatal closure was also been inhibited. Collectively, these results suggest that the stomatal closure induced by PEG 6000 may be intimately associated with NO levels, reorganization of actin filaments and the changes of vacuoles, showing a crude outline of guard-cells signaling process in response to hydraulic signals.

[Clinical characteristics and therapy of severe Mycoplasma pneumonia in children].

OBJECTIVE: To study the clinical characteristics, therapeutic regimen and outcome of severe Mycoplasma pneumonia (MP) in children. METHODS: Clinical data of 79 children with MP, including 69 mild and 10 severe cases, were retrospectively analyzed. The 10 children with severe MP were followed-up. RESULTS: In severe MP cases, the fever duration prior to hospitalization and the total fever duration were more prolonged, peripheral blood leucocytes counts, C-reactive protein and erythrocyte sedimentation rate increased, and serum IgM and IgE levels increased as compared to mild MP cases. Of the 10 cases of severe MP, 4 manifested as pulmonary consolidation, 4 as pulmonary consolidation complicated by moderate to large pleural effusion and 2 as progressively worsening pulmonary radiographic findings. Nine severe MP cases were administered with glucocorticoid as well as antibiotics, and the therapeutic effect was satisfactory. In the convalescence stage, bronchofiberoscope lavages were used in 5 severe cases because of persistent pulmonary consolidation. CONCLUSIONS: Severe MP was characterized by rapid progression, pulmonary consolidation, moderate to severe pleural effusion, obviously increased inflammatory indexes, and poor therapeutic reaction to simple macrolide antibiotics. Besides antibiotics, glucocorticoid should be used for severe MP cases as soon as possible. For severe cases with persistent pulmonary consolidation, bronchofiberoscope lavages are recommended.