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Traumatic brain injury (TBI) is characterized by acute neurological dysfunction and associated with the development of chronic traumatic encephalopathy (CTE) and Alzheimer’s disease. We previously showed that cis phosphorylated tau ( cis P-tau), but not the trans form, contributes to tau pathology and functional impairment in an animal model of severe TBI. Here we found that in human samples obtained post TBI due to a variety of causes, cis P-tau is induced in cortical axons and cerebrospinal fluid and positively correlates with axonal injury and clinical outcome. Using mouse models of severe or repetitive TBI, we showed that cis P-tau elimination with a specific neutralizing antibody administered immediately or at delayed time points after injury, attenuates the development of neuropathology and brain dysfunction during acute and chronic phases including CTE-like pathology and dysfunction after repetitive TBI. Thus, cis P-tau contributes to short-term and long-term sequelae after TBI, but is effectively neutralized by cis antibody treatment. Induction of the cis form of phosphorylated tau ( cis P-tau) has previously been shown to occur in animal models of traumatic brain injury (TBI), and blocking this form of tau using antibody was beneficial in a rodent model of severe TBI. Here the authors show that cis P-tau induction is a feature of several different forms of TBI in humans, and that administration of cis P-tau targeting antibody to rodents reduces or delays pathological features of TBI.

Background DNA N6-methyldeoxyadenosine (6mA) is rarely present in mammalian cells and its nuclear role remains elusive. Results Here we show that hypoxia induces nuclear 6mA modification through a DNA methyltransferase, METTL4, in hypoxia-induced epithelial-mesenchymal transition (EMT) and tumor metastasis. Co-expression of METTL4 and 6mA represents a prognosis marker for upper tract urothelial cancer patients. By RNA sequencing and 6mA chromatin immunoprecipitation-exonuclease digestion followed by sequencing, we identify lncRNA RP11-390F4.3 and one novel HIF-1α co-activator, ZMIZ1, that are co-regulated by hypoxia and METTL4. Other genes involved in hypoxia-mediated phenotypes are also regulated by 6mA modification. Quantitative chromatin isolation by RNA purification assay shows the occupancy of lncRNA RP11-390F4.3 on the promoters of multiple EMT regulators, indicating lncRNA-chromatin interaction. Knockdown of lncRNA RP11-390F4.3 abolishes METTL4-mediated tumor metastasis. We demonstrate that ZMIZ1 is an essential co-activator of HIF-1α. Conclusions We show that hypoxia results in enriched 6mA levels in mammalian tumor cells through METTL4. This METTL4-mediated nuclear 6mA deposition induces tumor metastasis through activating multiple metastasis-inducing genes. METTL4 is characterized as a potential therapeutic target in hypoxic tumors.

A Mandarin conditional sentence with the form [p, jiu q], where jiu is a preverbal particle, can (but not always) convey the minimal sufficiency interpretation that nothing more — other than p — needs to be true in order for q to be true. Moreover, the exclusive focus expression zhiyao can be inserted in p without changing the minimal sufficiency interpretation. This paper proposes an exhaustification-based semantic account, according to which: (i) jiu is a special exhaustivity operator over a conditional structure, giving rise to what I call the at least component; (ii) the at least component is subject to another layer of exhaustification by a covert exhaustivity operator O, giving rise to the minimal sufficiency reading; and (iii) zhiyao is an agreement marker inside the antecedent clause which signals the existence of O at the root level. Previous accounts of conditional jiu are also reviewed and discussed.

Background Duplication cysts are benign congenital anomalies of the gastrointestinal tract. Most manifest with symptoms within the first two years of life, and the majority are diagnosed in children (1). The clinical manifestations of duplication cysts vary depending on their location, size, and the presence of heterotopic mucosa. The most common location for these cysts is the ileum, although they can also occur in the stomach, duodenum, jejunum, colon, and rectum (2). Complications such as volvulus, intussusception, recurrent hemorrhage, and malignant degeneration have been reported (3). Despite advances in preoperative imaging, establishing a definitive diagnosis remains challenging. Enteric duplication cysts may rarely be associated with Salmonella infection and, in exceptional cases, postoperative bacteremia. Recognizing this possibility is crucial for optimal patient care. Case presentation A 3-year-old boy presented with a 3-day history of intermittent, diffuse abdominal pain. Although initial investigations were nonspecific, he was diagnosed with an ileal duplication cyst and underwent complete cyst resection during exploratory laparotomy. Macroscopic and microscopic examinations confirmed a duplication cyst comprising intestinal mucosa and muscle layers. On postoperative day 1, he developed Salmonella group C1 bacteremia and completed a 10-day course of ceftriaxone before discharge. Conclusion We report a case of a non-communicating ileal duplication cyst in a 3-year-old boy, complicated by partial bowel obstruction and Salmonella group C1 bacteremia. To our knowledge, this represents the first documented case of proven Salmonella bacteremia temporally associated with surgical manipulation of an ileal duplication cyst.

Pedicle screws are commonly employed to restore spinal stability and correct deformities. The Renaissance robotic system was developed to improve the accuracy of pedicle screw placement. In this study, we developed an intraoperative classification system for evaluating the accuracy of pedicle screw placements through secondary registration. Furthermore, we evaluated the benefits of using the Renaissance robotic system in pedicle screw placement and postoperative evaluations. Finally, we examined the factors affecting the accuracy of pedicle screw implantation. Through use of the Renaissance robotic system, the accuracy of Kirschner-wire (K-wire) placements deviating <3 mm from the planned trajectory was determined to be 98.74%. According to our classification system, the robot-guided pedicle screw implantation attained an accuracy of 94.00% before repositioning and 98.74% after repositioning. However, the malposition rate before repositioning was 5.99%; among these placements, 4.73% were immediately repositioned using the robot system and 1.26% were manually repositioned after a failed robot repositioning attempt. Most K-wire entry points deviated caudally and laterally. The Renaissance robotic system offers high accuracy in pedicle screw placement. Secondary registration improves the accuracy through increasing the precision of the positioning; moreover, intraoperative evaluation enables immediate repositioning. Furthermore, the K-wire tends to deviate caudally and laterally from the entry point because of skiving, which is characteristic of robot-assisted pedicle screw placement.

Recognition of modified histone species by distinct structural domains within ‘reader’ proteins plays a critical role in the regulation of gene expression. Readers that simultaneously recognize histones with multiple marks allow transduction of complex chromatin modification patterns into specific biological outcomes. Here we report that chromatin regulator tripartite motif-containing 24 (TRIM24) functions in humans as a reader of dual histone marks by means of tandem plant homeodomain (PHD) and bromodomain (Bromo) regions. The three-dimensional structure of the PHD-Bromo region of TRIM24 revealed a single functional unit for combinatorial recognition of unmodified H3K4 (that is, histone H3 unmodified at lysine 4, H3K4me0) and acetylated H3K23 (histone H3 acetylated at lysine 23, H3K23ac) within the same histone tail. TRIM24 binds chromatin and oestrogen receptor to activate oestrogen-dependent genes associated with cellular proliferation and tumour development. Aberrant expression of TRIM24 negatively correlates with survival of breast cancer patients. The PHD-Bromo of TRIM24 provides a structural rationale for chromatin activation through a non-canonical histone signature, establishing a new route by which chromatin readers may influence cancer pathogenesis. TRIM24 links histone code to breast cancer The post-translational modification of histones is a crucial mechanism in the regulation of gene expression. The modifications occur in combinations that must be faithfully translated by histone reader proteins. A study of the crystal structure of the transcription and chromatin regulator TRIM24 shows it to be a unique histone reader capable of combinatorial recognition of dual marks on the histone H3 tail. TRIM24 is involved in activation of oestrogen-dependent genes and is aberrantly expressed in breast cancer, and this work establishes a new route by which chromosome readers may influence carcinogenesis. A crystal structure of the tandem PHD and bromodomain regions of the transcription and chromatin regulator TRIM24 reveals combinatorial recognition of dual marks on the histone H3 tail. TRIM24 is involved in activation of oestrogen-dependent genes and is aberrantly expressed in breast cancer.

Background To examine the association between health literacy, level of disease knowledge, and adherence behavior among patients with type 2 diabetes. Methods A cross-sectional survey study of 1059 Mandarin- and Taiwanese-speaking patients aged 20 years or older with type 2 diabetes was conducted. The demographic profiles of the sample strata were determined by analyzing the Taiwanese National Health Insurance Database. Participants were enrolled and completed questionnaires between April and November of 2015. The patients were assessed using a self-developed questionnaire with high internal consistency (KR-20 = .84). Results Construct validity was supported by Confirmatory Factor Analysis. Respondents scored lowest in diet-related knowledge. Health literacy and diabetes knowledge were significantly greater when patients cared for themselves with additional caretaker assistance. Patient age, gender, and educational attainment were associated with adherence behavior. Conclusion This study conducted a nation-wide survey of patients with diabetes and the results showed that respondents possessed fairly strong diabetes-specific health literacy and knowledge. However, health literacy shouldn’t be assessed as an isolated concept. Instead, it should be assessed in conjunction with adherence behavior.

Interleukin 33 (IL-33) is among the earliest-released cytokines in response to allergens that orchestrate type 2 immunity. The prolyl cis-trans isomerase PIN1 is known to induce cytokines for eosinophil survival and activation by stabilizing cytokines mRNAs, but the function of PIN1 in upstream signaling pathways in asthma is unknown. Here we show that interleukin receptor associated kinase M (IRAK-M) is a PIN1 target critical for IL-33 signaling in allergic asthma. NMR analysis and docking simulations suggest that PIN1 might regulate IRAK-M conformation and function in IL-33 signaling. Upon IL-33-induced airway inflammation, PIN1 is activated for binding with and isomerization of IRAK-M, resulting in IRAK-M nuclear translocation and induction of selected proinflammatory genes in dendritic cells. Thus, the IL-33-PIN1-IRAK-M is an axis critical for dendritic cell activation, type 2 immunity and IL-33 induced airway inflammation. IL-33 orchestrates type 2 immunity in allergic asthma. Here the authors show, using biochemical, structural and patient data, that upon IL-33 or allergic challenge, the isomerase Pin1 modifies IRAK-M to control the production of pro-inflammatory cytokines in the setting of airway inflammation.

The functional role of adult neurogenesis in the hippocampus remains the subject of intense speculation. One recent hypothesis is that adult-born neurons contribute to the endocrine and behavioural outputs of the stress response. Here we show a genetic model system to ablate neurogenesis by inducibly deleting Tbr2 gene function specifically in the hippocampus and corroborate our findings in a radiation-based model of neurogenesis deprivation. We found that mice with ablation of new neurons in the dentate gyrus exhibit reduced anxiety during the dark cycle. After restraint stress, corticosterone levels in neurogenesis-deficient mice decreased more quickly than controls and were more sensitive to suppression by dexamethasone. Furthermore, glucocorticoid receptor target genes and neuronal activity markers showed reduced expression after stress in neurogenesis-deficient mice. These findings suggest that newborn neurons in the hippocampus are involved in sensing and eliciting an appropriate response to stress. Adult hippocampal neurogenesis is involved in the response to stress but whether it exerts a positive or negative effect remains unclear. Here the authors ablate hippocampal neurogenesis in mice and find that the effects on anxiety behaviour depend on the time of day, and that neurogenesis specifically impairs the response to stress during the dark cycle.

The artificial kidney, one of the greatest medical inventions in the 20th century, has saved innumerable lives with end stage renal disease. Designs of artificial kidney evolved dramatically in decades of development. A hollow-fibered membrane with well controlled blood and dialysate flow became the major design of the modern artificial kidney. Although they have been well established to prolong patients’ lives, the modern blood purification system is still imperfect. Patient’s quality of life, complications, and lack of metabolic functions are shortcomings of current blood purification treatment. The direction of future artificial kidneys is toward miniaturization, better biocompatibility, and providing metabolic functions. Studies and trials of silicon nanopore membranes, tissue engineering for renal cell bioreactors, and dialysate regeneration are all under development to overcome the shortcomings of current artificial kidneys. With all these advancements, wearable or implantable artificial kidneys will be achievable.