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Cognate interactions between autoreactive B and T cells promote systemic lupus erythematosus pathogenesis by inter alia facilitating spontaneous germinal center (GC) formation. Whereas both myeloid and B cell APCs express B7 ligands (CD80 and CD86), the prevailing model holds that dendritic cell costimulation is sufficient for CD28-dependent T cell activation. In this study, we report that B cell–intrinsic CD80/CD86 deletion unexpectedly abrogates GCs in murine lupus. Interestingly, absent GCs differentially impacted serum autoantibodies. In keeping with distinct extrafollicular and GC activation pathways driving lupus autoantibodies, lack of GCs correlated with loss of RNA-associated autoantibodies but preserved anti-dsDNA and connective tissue autoantibody titers. Strikingly, even heterozygous B cell CD80/CD86 deletion was sufficient to prevent autoimmune GCs and RNA-associated autoantibodies. Together, these findings identify a key mechanism whereby B cells promote lupus pathogenesis by providing a threshold of costimulatory signals required for autoreactive T cell activation.

The effects of traction load, plate thickness, and pin radius on stress and deformation distribution were investigated by simulation symmetrical pin traction experiment and analytical calculation methods. At the beginning of traction, both contact angle and maximum stress increase with the traction load. As the traction continues, maximum stress is steady and only the contact angle increases with the traction load. The stress concentration increases with the decrease of pin radius and does not change with other parameters under the same pin radius. The increase of specimen thickness can only reduce the contact angle but does not lessen the stress concentration, and thicker specimens can bear more traction load when reaching the same contact angle. Strengthening during deformation is caused not only by the increase of dislocation density in martensite matrix but also by retained austenite (RA) strain-induced martensite transformation (SIMT), which is conducive to the transfer of plastic deformation.

Background: Fibrotic cardiac remodeling is a maladaptive response to acute or chronic injury that leads to arrhythmia and progressive heart failure. The underlying mechanisms remain unclear. We performed high-throughput RNA sequencing to analyze circular RNA profile in human cardiac disease and developed transgenic mice to explore the roles of circNlgn. Methods and Results: Using RNA sequencing, we found that circular neuroligin RNA (circNlgn) was highly upregulated in myocardial tissues of patients with selected congenital heart defects with cardiac overload. Back-splicing of the neuroligin gene led to the translation of a circular RNA–derived peptide (Nlgn173) with a 9-amino-acid nuclear localization motif. Binding of this motif to the structural protein LaminB1 facilitated the nuclear localization of Nlgn173. CHIP analysis demonstrated subsequent binding of Nlgn173 to both ING4 (inhibitor of growth protein 4) and C8orf44-SGK3 (serum and glucocorticoid-inducible kinase-3) promoters, resulting in aberrant collagen deposition, cardiac fibroblast proliferation, and reduced cardiomyocyte viability. Three-dimensional ultrasound imaging of circNlgn-transgenic mice showed impaired left ventricular function, with further impairment when subjected to left ventricular pressure overload compared with WT (wild type) mice. Nuclear translocation of Nlgn173, dysregulated expression of ING4 and C8orf44-SGK3, and immunohistochemical markers of cardiac fibrosis were detected in a panel of 145 patient specimens. Phenotypic changes observed in left ventricular pressure overload and transgenic mice were abrogated with silencing of circNlgn or its targets ING4 and SGK3. Conclusions: We show that a circular RNA can be translated into a novel protein isoform. Dysregulation of this process contributes to fibrosis and heart failure in cardiac overload–induced remodeling. This mechanism may hold therapeutic implications for cardiac disease.

Trehalose, a naturally nontoxic disaccharide that does not exist in mammals, stabilizes cell membrane integrity under oxidative stress conditions, the mechanism of which is still unclear. Here, we analyzed the effects of trehalose on sheep epididymis epithelial cell (EEC) proliferation and its possible mechanisms. To study the effect of trehalose on EECs, EECs were isolated from testes of 12-month-old sheep; cell counting kit-8 (CCK-8) was used to measure the growth of the cells. Cell proliferation was evaluated by assaying cell cycle and apoptosis, and RT-PCR was utilized to identify the epididymal molecular markers glutathione peroxidase 5 (GPX5) and androgen receptor (AR). Next, reactive oxygen species (ROS) content was evaluated by a dichloro-dihydro-fluorescein diacetate (DCFH-DA) probe. Superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) activities were evaluated by enzyme chemistry methods, and GPX5 expression was evaluated by qRT-PCR and enzyme-linked immunosorbent assay (ELISA). The results showed that 100 mM trehalose significantly improved the proliferation potential of EECs, in which the cells could be serially passaged 14 times with continued normal GPX5 and AR marker gene expression in vitro. The trehalose can increase significantly a proportion of EECs in S phase (P) and decrease significantly the apoptotic rate of EECs (P) compared to the control. Moreover, the trehalose decreased ROS significantly (P) and increased CAT (P) and GSH-Px (P) activities significantly in EECs. GPX5 mRNA and protein expression were also significantly upregulated in trehalose-treated EECs (P and P respectively). Our study suggested that exogenous trehalose exhibited antioxidant activity through increasing the activities of CAT, GSH-Px, and the expression level of GPX5 and could be employed to maintain vitality of sheep EECs during long-term in vitro culture.

Polymorphisms in TACI, a BAFF family cytokine receptor, are linked to diverse human immune disorders, including common variable immunodeficiency (CVID) and systemic lupus erythematosus (SLE). Functional studies of individual variants show modest impacts on surface TACI expression and/or downstream signal transduction, indicating that relatively subtle variation in TACI activity can impact human B cell biology. However, significant complexity underlies TACI biology, including both positive and negative regulation of physiologic and pathogenic B cell responses. To model these contradictory events, we compared the functional impact of TACI deletion on separate models of murine SLE driven by T cell-independent and -dependent breaks in B cell tolerance. First, we studied whether reduced surface TACI expression was sufficient to protect against progressive BAFF-mediated systemic autoimmunity. Strikingly, despite a relatively modest impact on surface TACI levels, TACI haploinsufficiency markedly reduced pathogenic RNA-associated autoantibody titers and conferred long-term protection from BAFF-driven lupus nephritis. In contrast, B cell-intrinsic TACI deletion exerted a limited impact of autoantibody generation in murine lupus characterized by spontaneous germinal center formation and T cell-dependent humoral autoimmunity. Together, these combined data provide new insights into TACI biology and highlight how TACI signals must be tightly regulated during protective and pathogenic B cell responses.

Many older people admitted to hospital are malnourished/at risk of malnourishment (30%), have swallowing problems (55%), are frail (25%), have sarcopenia (50%) or a combination of these. On admission to hospital frail older people are at significant risk of worsening nutritional status and prolonged hospital stay. Nutritional status should be identified, documented, food intake monitored and where appropriate they should be referred to the dietitian. The question remains, do staff recognise that frail older people may not eat their food increasing their risk of poor nutrition and outcome. Methods Older people admitted to a ‘Frailty’ Ward were directly observed during lunchtime by WD. The Minimal Eating Observation Form –Version II (MEOF-II) was used to document how much they ate. Frailty status (CFS), presence of Sarcopenia (Sarc-F) and whether a referral to dietetics or speech and language therapy (SLT) was completed. Results 39 patients were observed. Mean age was 82.38 years; median CFS 6 (3–8); median Sarc-F 4(0–9). Median MEOF II was 0 (0–5). Two patients were referred to dietetics and 4 to SLT. 7/40 (17,5%) were at high risk for undernutrition, a further 8/40(20%) were at moderate risk. 82% were severely frail, the remaining were mildly frail. 94% (16/17) exhibited sarcopenia. There was significant correlation between MEOF II and CFS (r = 0.4887, p = 0.00162); MEOFII and Sarc-F (r = 0.4395, p = 0.00512). There was correlation between CFS and Sarc-F (r = 0.80296, p Conclusion Frail older adults are often undernourished on admission to hospital. Nutritional intake is often poor with acute illness. Screening, observation and monitoring of nutritional intake should highlight concerns and needs for intervention. These study high lights that a significant number of older people are frail, fail to complete meals, are at significant risk of under nutrition, yet proactive intervention does not occur.

Circular RNAs (circRNAs) are a type of endogenous non-coding RNA that were discovered to regulate gene expression through multiple pathways. Metastasis remains one of the biggest obstacles in cancer treatment. In this review, we focus on circRNAs involved in cancer tumorigenesis and metastasis. We present recently identified tumor-related circRNAs and discuss their functioning in tumor progression and metastasis. These circRNAs are categorized into different functional mechanisms, including microRNA (miRNA) sponging, protein binding, regulation of host genes, translation of circRNAs, and exosomal circRNAs. Additionally, the indirect functions of circRNAs that regulate epithelial-mesenchymal transition and autophagy are also discussed., Graphical Abstract, Large numbers of differentially expressed circRNAs have been identified in tumors and metastasis. Gain-of-function and loss-of-function approaches have been developed to manipulate specific circRNA expression in order to modulate tumor development. circRNAs may be used as potential biomarkers for early diagnosis and may be targets for therapeutic strategies.

Metastatic cancer cells invade surrounding tissues by forming dynamic actin-based invadopodia, which degrade the surrounding extracellular matrix and allow cancer cell invasion. Regulatory RNAs, including circular RNA, have been implicated in this process. By microarray, we found that the circular RNA circSKA3 was highly expressed in breast cancer cells and human breast cancer tissues. We further found that the invasive capacity of breast cancer cells was positively correlated with circSKA3 expression, through the formation of invadopodia. Mechanistically, we identified Tks5 and integrin β1 as circSKA3 binding partners in these tumor-derived invadopodia. Ectopic circSKA3 expression conferred increased tumor invasiveness in vitro and in vivo. We further identified the RNA-protein binding sites between circSKA3, Tks5 and integrin β1. In tumor formation assays, we found that circSKA3 expression promoted tumor progression and invadopodium formation. Mutation of the circSKA3 binding sites or transfection with blocking oligos abrogated the observed effects. Thus, we provide evidence that the circular RNA circSKA3 promotes tumor progression by complexing with Tks5 and integrin β1, inducing invadopodium formation.

MicroRNAs are short, evolutionarily conserved noncoding RNAs that are critical for the control of normal cellular physiology. In the retina, photoreceptors are highly specialized neurons that transduce light into electrical signals. Photoreceptors, however, are unable to process visual stimuli without the support of the retinal pigment epithelium (RPE). The RPE performs numerous functions to aid the retina, including the generation of visual chromophore and metabolic support. Recent work has underscored how microRNAs enable vision through their contributions to RPE functions. This review focuses on the biogenesis and control of microRNAs in rodents and humans, the roles microRNAs play in RPE function and degeneration, and how microRNAs could serve as potential therapeutics and biomarkers for visual diseases.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of both lung cancer and head and neck squamous cell carcinoma demonstrating clear benefit over traditional chemotherapy alone in the metastatic setting. While the overwhelming majority of ICI trial participants have been White patients, results of these trials have been broadly applied to patients of all ethnic/racial backgrounds. It has, therefore, not been well defined if response to ICIs differs between ethnic/racial populations or socio-economic groups.We reviewed response to ICI of 208 patients with diagnoses of lung or head and neck cancers treated with ICI between 2015 and 2020 at one of three clinical pavilions associated with the Dan L. Duncan Comprehensive Cancer Center at Baylor College of Medicine in Houston, TX. Two of these pavilions (Harris Health System and the Michael E. DeBakey Veterans Affairs Medical Center) serve large minority patient populations and provide equal access of care to patients regardless of means. Of the 208 patients, 175 had a diagnosis of lung cancer [non-small cell lung carcinoma (NSCLC) or small cell lung cancer (SCLC)] and 33 had a diagnosis of head and neck squamous cell carcinoma (HNSCC); 38% self-identified as Black, 45% as non-Hispanic White, and 18% as Hispanic. The objective response rate (ORR) was similar for lung cancer (31.4%) and HNSCC patients (27.3%) (p=0.894). Statistically, the ORR for Hispanic and Black patients did not differ compared to non-Hispanic White patients (H 23.7%, B 28.6%, W 35.5%; H vs. W p=0.189; B vs. W p=0.338). When considering patients treated with ICI monotherapy, the ORR for Hispanic patients dropped to 13.3% and was significantly lower than the ORR of the non-Hispanic White patients while the ORR of Black and non-Hispanic White patients remained about the same (B 29.3% and W 34.6%, H vs. W p=0.0285; B vs. W p=0.5131). Immune related adverse events (irAEs) were the lowest in the Hispanic population occurring in only 30% of patients compared to 50% of patients exhibiting irAEs in the Black and non-Hispanic white cohorts.ICIs demonstrate comparable anti-tumor effects in lung cancer (NSCLC + SCLC) and HNSCC during routine clinical practice regardless of race or ethnicity. The significantly lower ORR observed in our cohort for Hispanic patients, particularly when used as monotherapy, is an unexpected finding and will require additional study to identify potential biological and non-biological confounders which could contribute to reduced ICI effectiveness in this patient population.

Chemoresistance of triple negative breast cancer against paclitaxel (PAX) is one of the major issues for the patients under chemotherapy. However, the mechanism by which the breast cancer cells are resistant to PAX remains unclear. Here, we identified a circular RNA of angiomotin-like 1 (circAMOTL1) as an important player which may be responsible for the adverse resistance against PAX in breast cancer cells. The circAMOTL1 were overexpressed in MDA-MB-231 breast cancer cells via transfection of circAMOTL1 construct. Overexpression of circAMOTL1 caused significant increase of cell viability, reduction of apoptosis, and enhancement of invasion when MDA-MB-231 cells were exposed to PAX compared to those cells with vector control. Moreover, these resistant effects could be blocked by the application of circAMOTL1 siRNA. In these circAMOTL1 overexpressing cells, we found notable increase of both phosphorylated and total AKT protein, which suggested that AKT might be the downstream factor mediating the resistant effects. Consequently, the gene and protein expression of AKT related pro-apoptotic (BAX and BAK) and anti-apoptotic (BCL-2) factors were significantly changed by circAMOTL1 as well. These results suggest circAMOTL1 may play an important role in the PAX resistance of breast cancer cells via regulation of AKT pathway, facilitation of anti-apoptotic protein and inhibition of pro-apoptotic protein. While providing a new mechanism of PAX resistance in breast cancer cells, our findings may lay groundwork for a novel therapeutic target of the breast cancer treatment in the future.

Circular RNAs represent a large class of non-coding RNAs that are extensively expressed in mammals. However, the functions of circular RNAs are largely unknown. We recently reported that the circular RNA circ-Ccnb1 could bind with H2AX in p53 mutant cells and suppressed mutant p53 in tumor progression. Here we found that circ-Ccnb1 could interact with both Ccnb1 and Cdk1 proteins. Normally, Ccnb1 and Cdk1 proteins form a complex, allowing Ccnb1 to function as an all-or-none switch for cell mitosis. The interaction of circ-Ccnb1 with Ccnb1 and Cdk1 proteins dissociated the formation of Ccnb1-Cdk1 complex, by forming a large complex containing circ-Ccnb1, Ccnb1 and Cdk1. Formation of this large complex may occur in cytosol and nuclei, and Ccnb1 loses its roles in enhancing cell migration, invasion, proliferation and survival. In vivo, ectopic delivery of circ-Ccnb1 inhibited tumor growth and extended mouse viability. These results have added another layer of mechanisms for circ-Ccnb1 to regulate tumor progression in vitro and in vivo.

We aimed to describe the treatment of comminuted fractures of the base of the thumb metacarpal using a cemented bone-K-wire frame. Between March 2010 and January 2016, 41 fractures of the base of the thumb were treated using a cemented bone-K-wire frame. The mean age of the patients was 34 years. The patients’ history included a fall onto the hand in 7 cases, direct trauma in 31 cases, and polytrauma with an unclear mechanism of injury in 3 cases. At the final follow-up, hand grip and pinch strength were measured using a dynamometer. All measurements were compared with those of the opposite hand. The patients were assessed functionally using the Smith and Cooney score.All K-wires were left in place until the bone healed. Bone healing was achieved in all thumbs in an average of 5.2 weeks. Follow-up averaged 27 months. The mean hand pinch and grip strength was 8.7 kg ± 2.4 kg and 38.4 kg ± 5.9 kg, respectively. The mean measurements on the opposite side were 9.2 kg ± 2.5 kg and 40.2 kg ± 6.6 kg, respectively. Based on the Smith and Cooney score, we obtained an average score of 87 ± 9.3, with 25 excellent, 9 good, and 2 fair results. The cemented bone-K-wire frame is an external fixator alternative that can be used for treating comminuted intra-articular fractures of the base of the thumb metacarpal. The system is cheap, easy to apply, and provides rigid fixation, resulting in good functional recovery.

The emerging interest in the search for alternatives to synthetic preservatives has led to various successful research studies exploring the use of yeasts as potential biological control agents and producers of biopreservatives. The findings that yeasts could be used as producers of biopreservatives lacked some engineering considerations regarding cost-effective process design for scale-up, although partial process optimization using renewable agro-waste has been achieved. This study investigated the biological stoichiometry and bioenergetic parameters during yeast growth and secondary metabolites production i.e., biopreservatives from non-Saccharomyces yeasts using grape pomace extract (GPE), a type of agro-waste, as a fermentation medium. This was achieved by reconfirming the optimum production conditions previously found for Candida pyralidae Y1117, Pichia kluyveri Y1125, and Pichia kluyveri Y1164 in GPE broth as a fermentation medium, conditions under which a high amount of yeast cells were obtained. High-density cell cultures were produced, from which the yeast cell pellets were harvested, dried, and combusted for the determination of elemental analysis, heat of combustion, biological stoichiometry, and bioenergetic parameters. This work generated biological stoichiometric models and bioenergetics information that could assist in the design of yeast biochemical conversion system when GPE is used as fermentation medium, thereby, addressing the biochemical engineering aspects that were lacking in a previous biopreservative production study using Candida pyralidae Y1117, Pichia kluyveri Y1125, and Pichia kluyveri Y1164.

Santos et al. analyze cancer patient vaccine antigen-specific T cells for the importance of immune checkpoint molecule and gene pathway expression. CTLA-4 and PD-1 pathways are significantly correlated to T cell response and clinical outcomes, and sequence of pathway blockade is critical., Immune and molecular profiling of CD8 T cells of patients receiving DC vaccines expressing three full-length melanoma antigens (MAs) was performed. Antigen expression levels in DCs had no significant impact on T cell or clinical responses. Patients who received checkpoint blockade before DC vaccination had higher baseline MA-specific CD8 T cell responses but no evidence for improved functional responses to the vaccine. Patients who showed the best clinical responses had low PD-1 expression on MA-specific T cells before and after DC vaccination; however, blockade of PD-1 during antigen presentation by DC had minimal functional impact on PD-1high MA-specific T cells. Gene and protein expression analyses in lymphocytes and tumor samples identified critical immunoregulatory pathways, including CTLA-4 and PD-1. High immune checkpoint gene expression networks correlated with inferior clinical outcomes. Soluble serum PD-L2 showed suggestive positive association with improved outcome. These findings show that checkpoint molecular pathways are critical for vaccine outcomes and suggest specific sequencing of vaccine combinations., Graphical Abstract

Germinal centers (GCs) are major sites of clonal B cell expansion and generation of long-lived, high-affinity antibody responses to pathogens. Signaling through TLRs on B cells promotes many aspects of GC B cell responses, including affinity maturation, class switching, and differentiation into long-lived memory and plasma cells. A major challenge for effective vaccination is identifying strategies to specifically promote GC B cell responses. Here, we have identified a mechanism of regulation of GC B cell TLR signaling, mediated by αv integrins and noncanonical autophagy. Using B cell-specific αv-KO mice, we show that loss of αv-mediated TLR regulation increased GC B cell expansion, somatic hypermutation, class switching, and generation of long-lived plasma cells after immunization with virus-like particles (VLPs) or antigens associated with TLR ligand adjuvants. Furthermore, targeting αv-mediated regulation increased the magnitude and breadth of antibody responses to influenza virus vaccination. These data therefore identify a mechanism of regulation of GC B cells that can be targeted to enhance antibody responses to vaccination.

TP53 mutations occur in many different types of cancers that produce mutant p53 proteins. The mutant p53 proteins have lost wild-type p53 activity and gained new functions that contribute to malignant tumor progression. Different p53 mutations create distinct profiles in loss of wild-type p53 activity and gain of functions. Targeting the consequences generated by the great number of p53 mutations would be extremely complex. Therefore, in this study we used a workaround and took advantage of the fact that mutant p53 cannot bind H2AX. Using this, we developed a new approach to repress the acquisition of mutant p53 functions. We show here that the delivery of a circular RNA circ-Ccnb1 inhibited the function of three p53 mutations. By microarray analysis and real-time PCR, we detected decreased circ-Ccnb1 expression levels in patients bearing breast carcinoma. Ectopic delivery of circ-Ccnb1 inhibited tumor growth and extended mouse viability. Using proteomics, we found that circ-Ccnb1 precipitated p53 in p53 wild-type cells, but instead precipitated Bclaf1 in p53 mutant cells. Further experiments showed that H2AX serves as a bridge, linking the interaction of circ-Ccnb1 and wild-type p53, thus allowing Bclaf1 to bind Bcl2 resulting in cell survival. In the p53 mutant cells, circ-Ccnb1 formed a complex with H2AX and Bclaf1, resulting in the induction of cell death. We found that this occurred in three p53 mutations. These results shed light on the possible development of new approaches to inhibit the malignancy of p53 mutations.

Radiation therapy (RT) is one of the primary modalities for triple-negative breast cancer (TNBC) treatment. However, due to the pro-metastatic potential of radiation and the intrinsic radiation resistance of some tumors, many patients experience RT failure, which leads to cancer relapse and distant metastasis. This preclinical study evaluated the efficacy of the antagonist of the SDF-1 receptor CXCR4, AMD3100, as a radiosensitizer in TNBC models. The combined effect of ionizing radiation and AMD3100 was determined in vitro by surviving fraction, cell cycle distribution, Bax and Bcl-2 expression, and apoptosis assays in a TNBC cell line (MDA-MB-231). For in vivo studies, human xenograft athymic nude mice were used. Treatment of TNBC cells with AMD3100 significantly augmented cellular radiosensitivity. Radiosensitivity was enhanced specifically through increased Bax expression, reduced Bcl-2 expression, prolonged G2-M arrest, and increased apoptosis. Combined treatment with AMD3100 and irradiation also enhanced tumor growth delay, with an enhancement factor ranging from 1.5 to 1.8. These findings support the evaluation of antagonists of the SDF-1 receptor CXCR4, such as AMD3100, as potent radiosensitizers in TNBC.

We conducted the first real-time continuous vertical measurements of particle extinction (bext), gaseous NO2, and black carbon (BC) from ground level to 260 m during two severe winter haze episodes at an urban site in Beijing, China. Our results illustrated four distinct types of vertical profiles: (1) uniform vertical distributions (37 % of the time) with vertical differences less than 5 %, (2) higher values at lower altitudes (29 %), (3) higher values at higher altitudes (16 %), and (4) significant decreases at the heights of ∼ 100–150 m (14 %). Further analysis demonstrated that vertical convection as indicated by mixing layer height, temperature inversion, and local emissions are three major factors affecting the changes in vertical profiles. Particularly, the formation of type 4 was strongly associated with the stratified layer that was formed due to the interactions of different air masses and temperature inversions. Aerosol composition was substantially different below and above the transition heights with ∼ 20–30 % higher contributions of local sources (e.g., biomass burning and cooking) at lower altitudes. A more detailed evolution of vertical profiles and their relationship with the changes in source emissions, mixing layer height, and aerosol chemistry was illustrated by a case study. BC showed overall similar vertical profiles as those of bext (R2 = 0.92 and 0.69 in November and January, respectively). While NO2 was correlated with bext for most of the time, the vertical profiles of bext ∕ NO2 varied differently for different profiles, indicating the impact of chemical transformation on vertical profiles. Our results also showed that more comprehensive vertical measurements (e.g., more aerosol and gaseous species) at higher altitudes in the megacities are needed for a better understanding of the formation mechanisms and evolution of severe haze episodes in China.

The aim of this paper was to introduce a simple and effective method to aid in isolation and stabilization of Dupuytren cords for collagenase injection. Tongue depressors were used to isolate and stabilize the cord during the injection procedure. The area to be injected was sterilely prepared. An assistant was then directed to place a tongue depressor on both sides of the cord. A total of 35 patients with Dupuytren disease were treated. Follow-up lasted two years. Post-operative Disabilities of the Arm, Shoulder and Hand (DASH) scores was 4±2. Health-related quality of life measured with the EQ-5D index was 0.89±0.4. Recurrence rates of metacarpophalangeal joint and proximal interphalangeal joint were 11% and 14% respectively, using a flexion contracture of 20° to define recurrence. Collagenase treatment using a modified injection method with the aid of tongue depressors are a safe, effective way to treat Dupuytren contractures of the fingers. The technique can isolate the cord, which improves visualization of the cord. It may allow improved accuracy with needle placement and helps to decrease the complications and recurrence.

Recent studies have identified critical roles for B cells in triggering autoimmune germinal centers (GCs) in systemic lupus erythematosus (SLE) and other disorders. The mechanisms whereby B cells facilitate loss of T cell tolerance, however, remain incompletely defined. Activated B cells produce interleukin 6 (IL-6), a proinflammatory cytokine that promotes T follicular helper (TFH) cell differentiation. Although B cell IL-6 production correlates with disease severity in humoral autoimmunity, whether B cell–derived IL-6 is required to trigger autoimmune GCs has not, to our knowledge, been addressed. Here, we report the unexpected finding that a lack of B cell–derived IL-6 abrogates spontaneous GC formation in mouse SLE, resulting in loss of class-switched autoantibodies and protection from systemic autoimmunity. Mechanistically, B cell IL-6 production was enhanced by IFN-γ, consistent with the critical roles for B cell–intrinsic IFN-γ receptor signals in driving autoimmune GC formation. Together, these findings identify a key mechanism whereby B cells drive autoimmunity via local IL-6 production required for TFH differentiation and autoimmune GC formation.

Delayed or impaired wound healing is a major health issue worldwide, especially in patients with diabetes and atherosclerosis. Here we show that expression of the circular RNA circ-Amotl1 accelerated healing process in a mouse excisional wound model. Further studies showed that ectopic circ-Amotl1 increased protein levels of Stat3 and Dnmt3a. The increased Dnmt3a then methylated the promoter of microRNA miR-17, decreasing miR-17-5p levels but increasing fibronectin expression. We found that Stat3, similar to Dnmt3a and fibronectin, was a target of miR-17-5p. Decreased miR-17-5p levels would increase expression of fibronectin, Dnmt3a, and Stat3. All of these led to increased cell adhesion, migration, proliferation, survival, and wound repair. Furthermore, we found that circ-Amotl1 not only increased Stat3 expression but also facilitated Stat3 nuclear translocation. Thus, the ectopic expressed circ-Amotl1 and Stat3 were mainly translocated to nucleus. In the presence of circ-Amotl1, Stat3 interacted with Dnmt3a promoter with increased affinity, facilitating Dnmt3a transcription. Ectopic application of circ-Amotl1 accelerating wound repair may shed light on skin wound healing clinically.

Circular RNAs (circRNAs) are a subclass of noncoding RNAs widely expressed in mammalian cells. We report here the tumorigenic capacity of a circRNA derived from angiomotin-like1 (circ-Amotl1). Circ-Amotl1 is highly expressed in patient tumor samples and cancer cell lines. Single-cell inoculations using circ-Amotl1-transfected tumor cells showed a 30-fold increase in proliferative capacity relative to control. Agarose colony-formation assays similarly revealed a 142-fold increase. Tumor-take rate in nude mouse xenografts using 6-day (219 cells) and 3-day (9 cells) colonies were 100%, suggesting tumor-forming potential of every cell. Subcutaneous single-cell injections led to the formation of palpable tumors in 41% of mice, with tumor sizes >1 cm3 in 1 month. We further found that this potent tumorigenicity was triggered through interactions between circ-Amotl1 and c-myc. A putative binding site was identified in silico and tested experimentally. Ectopic expression of circ-Amotl1 increased retention of nuclear c-myc, appearing to promote c-myc stability and upregulate c-myc targets. Expression of circ-Amotl1 also increased the affinity of c-myc binding to a number of promoters. Our study therefore reveals a novel function of circRNAs in tumorigenesis, and this subclass of noncoding RNAs may represent a potential target in cancer therapy.

CONTEXT: To analyze the dynamic changes of serum thyrotrophin receptor antibody (TRAb) and thyroid peroxidase antibody (TPOAb) in Graves’ disease (GD) patients before and after radioactive iodine (RAI) treatment and to investigate if TRAb and TPOAb play a role in the occurrence of early hypothyroidism after (131)I therapy for Graves’ hyperthyroidism. SUBJECTS AND METHODS: A total of 240 patients newly diagnosed with GD were selected to study. A clinical and laboratory assessment was performed before and at 3, 6, and 12 months after (131)I therapy. Chemiluminescent immunoassays were used to detect serum free triiodothyronine (FT3), free thyroxine (FT4), sensitive thyroid-stimulating hormone (TSH) and TPOAb concentration. Radio-receptor assay was used to measure serum TRAb concentration. According to the early onset of hypothyroidism in a year after RAI therapy, patients were divided into early hypothyroidism group (group A) and non-early hypothyroidism group (group B). RESULTS: In both groups, serum TRAb and TPOAb increased at 3 months, reached the highest level at 6 months and returned to the baseline at 12 months after RAI therapy. TRAb showed a significant difference between the two groups at 6 months (P

As major chemical components of airborne fine particulate matter (PM2.5), organic carbon (OC) and elemental carbon (EC) have vital impacts on air quality, climate change, and human health. Because OC and EC are closely associated with fuel combustion, it is helpful for the scientific community and policymakers assessing the efficacy of air pollution control measures to study the impact of control measures and regional transport on OC and EC levels. In this study, hourly mass concentrations of OC and EC associated with PM2.5 were semi-continuously measured from March 2013 to February 2018. The results showed that annual mean OC and EC concentrations declined from 14.0 to 7.7 µg m−3 and from 4.0 to 2.6 µg m−3, respectively, from March 2013 to February 2018. In combination with the data of OC and EC in previous studies, an obvious decreasing trend in OC and EC concentrations was found, which was caused by clean energy policies and effective air pollution control measures. However, no obvious change in the ratios of OC and EC to the PM2.5 mass (on average, 0.164 and 0.049, respectively) was recorded, suggesting that inorganic ions still contributed a lot to PM2.5. Based on the seasonal variations in OC and EC, it appeared that higher OC and EC concentrations were still observed in the winter months, with the exception of winter of 2017–2018. Traffic policies executed in Beijing resulted in nighttime peaks of OC and EC, caused by heavy-duty vehicles and heavy-duty diesel vehicles being permitted to operate from 00:00 to 06:00 (China standard time, UTC+8, for all times throughout the paper). In addition, the fact that there was no traffic restriction in weekends led to higher concentrations on weekends compared to weekdays. Significant correlations between OC and EC were observed throughout the study period, suggesting that OC and EC originated from common emission sources, such as exhaust of vehicles and fuel combustion. OC and EC levels increased with enhanced SO2, CO, and NOx concentrations while the O3 and OC levels were enhanced simultaneously when O3 concentrations were higher than 50 µg m−3. Non-parametric wind regression analysis was performed to examine the sources of OC and EC in the Beijing area. It was found that there were distinct hot spots in the northeast wind sector at wind speeds of approximately 0–6 km h−1, as well as diffuse signals in the southwestern wind sectors. Source areas further away from Beijing were assessed by potential source contribution function (PSCF) analysis. A high-potential source area was precisely pinpointed, which was located in the northwestern and southern areas of Beijing in 2017 instead of solely in the southern areas of Beijing in 2013. This work shows that improvement of the air quality in Beijing benefits from strict control measures; however, joint prevention and control of regional air pollution in the regions is needed for further improving the air quality. The results provide a reference for controlling air pollution caused by rapid economic development in developing countries.

Volatility plays a key role in affecting mass concentrations and the lifetime of aerosol particles in the atmosphere, yet our knowledge of aerosol volatility in relatively polluted environment, e.g., north China, remains poor. Here aerosol volatility in Beijing in summer 2017 and 2018 was measured using a thermodenuder (TD) coupled with an Aerodyne high-resolution aerosol mass spectrometer (AMS) and a soot particle AMS. Our results showed overall similar thermograms for most non-refractory aerosol species compared with those reported in previous studies. However, high mass fraction remaining and NO+/NO2+ ratio for chloride and nitrate, each above 200 ∘C, indicated the presence of considerable metallic salts and organic nitrates in Beijing. The volatility distributions of organic aerosol (OA) and four OA factors that were resolved from positive matrix factorization were estimated using a mass transfer model. The ambient OA comprised mainly semi-volatile organic compounds (SVOCs; 63 %) with an average effective saturation concentration (C*) of 0.55 µg m−3, suggesting overall more volatile properties than OA in megacities of Europe and the US. Further analysis showed that the freshly oxidized secondary OA was the most volatile OA factor (SVOC = 70 %) followed by hydrocarbon-like OA (HOA). In contrast, the volatility of more oxidized oxygenated OA (MO-OOA) was comparable to that of cooking OA with SVOC on average accounting for 60.2 %. We also compared the volatility of ambient and black-carbon-containing OA. Our results showed that the BC-containing primary OA (POA) was much more volatile than ambient POA (C*=0.69 µg m−3 vs. 0.37 µg m−3), while the BC-containing SOA was much less volatile, highlighting the very different composition and properties between BC-containing and ambient aerosol particles.

The complement system is a key player in innate immunity and a major effector arm of humoral immunity. Its activating components are a group of plasma proteins, whose triggering consists of a series of sequential protease-based steps similar to the coagulation, fibrinolytic, and contact pathways. Complement activation is linked to cellular responses by the recognition of cleaved complement protein fragments by receptors on leukocytes and vascular cells. The three primary roles of complement in host defense against infection are to (1) activate an inflammatory response; (2) opsonize microbial pathogens for immune adherence; and (3) damage membranes, including lysis of susceptible organisms. The complement cascade is amplified at several steps so that it has the potential to induce a rapid and massive opsonic and inflammatory response. Complement activation is normally highly targeted and strictly regulated to focus this response. However, complement activation also contributes to tissue injury in infectious, autoimmune, and acute and chronic inflammatory diseases. This chapter gives an overview of the “workings” of the complement system, a brief review of complement deficiency, and discussion of the role of complement in diseases of inflammation, autoimmunity, and debris disposal.

Winter has the worst air pollution of the year in the megacity of Beijing. Despite extensive winter studies in recent years, our knowledge of the sources, formation mechanisms and evolution of aerosol particles is not complete. Here we have a comprehensive characterization of the sources, variations and processes of submicron aerosols that were measured by an Aerodyne high-resolution aerosol mass spectrometer from 17 December 2013 to 17 January 2014 along with offline filter analysis by gas chromatography/mass spectrometry. Our results suggest that submicron aerosols composition was generally similar across the winter of different years and was mainly composed of organics (60 %), sulfate (15 %) and nitrate (11 %). Positive matrix factorization of high- and unit-mass resolution spectra identified four primary organic aerosol (POA) factors from traffic, cooking, biomass burning (BBOA) and coal combustion (CCOA) emissions as well as two secondary OA (SOA) factors. POA dominated OA, on average accounting for 56 %, with CCOA being the largest contributor (20 %). Both CCOA and BBOA showed distinct polycyclic aromatic hydrocarbons (PAHs) spectral signatures, indicating that PAHs in winter were mainly from coal combustion (66 %) and biomass burning emissions (18 %). BBOA was highly correlated with levoglucosan, a tracer compound for biomass burning (r2 = 0.93), and made a considerable contribution to OA in winter (9 %). An aqueous-phase-processed SOA (aq-OOA) that was strongly correlated with particle liquid water content, sulfate and S-containing ions (e.g. CH2SO2+) was identified. On average aq-OOA contributed 12 % to the total OA and played a dominant role in increasing oxidation degrees of OA at high RH levels (> 50 %). Our results illustrate that aqueous-phase processing can enhance SOA production and oxidation states of OA as well in winter. Further episode analyses highlighted the significant impacts of meteorological parameters on aerosol composition, size distributions, oxidation states of OA and evolutionary processes of secondary aerosols.

Sterols are the important active ingredients of fungal secondary metabolites to induce death of tumor cells. In our previous study, we found that ergosterol peroxide (5α, 8α-epidioxiergosta-6, 22-dien-3β-ol), purified from Ganoderma lucidum, induced human cancer cell death. Since the amount of purified ergosterol peroxide is not sufficient to perform in vivo experiments or apply clinically, we developed an approach to synthesize ergosterol peroxide chemically. After confirming the production of ergosterol peroxide, we examined the biological functions of the synthetic ergosterol peroxide. The results showed that ergosterol peroxide induced cell death and inhibited cell migration, cell cycle progression, and colony growth of human hepatocellular carcinoma cells. We further examined the mechanism associated with this effect and found that treatment with ergosterol peroxide increased the expression of Foxo3 mRNA and protein in HepG2 cells. The upstream signal proteins pAKT and c-Myc, which can inhibit Foxo3 functions, were clearly decreased in HepG2 cells treated with ergosterol peroxide. The levels of Puma and Bax, pro-apoptotic proteins, were effectively enhanced. Our results suggest that ergosterol peroxide stimulated Foxo3 activity by inhibiting pAKT and c-Myc and activating pro-apoptotic protein Puma and Bax to induce cancer cell death.

Tuberculous pleurisy (TP) diagnosis remains difficult, with the sensitivity of Xpert MTB/RIF (Xpert) and mycobacterial culture (culture) only about 30-50%. We aimed to assess the diagnostic performance of a cell-free Mycobacterium tuberculosis DNA test (cf-TB) in pleural effusion for TP.Adults (≥18 years) with suspected TP presenting with pleural effusion were consecutively recruited, and pleural effusion specimens were prospectively collected in Beijing Chest Hospital, Beijing, China. After centrifuging pleural effusion, sediments were used for culture, Xpert and T-SPOT.TB assay, whereas supernatants were used for cf-TB and adenosine deaminase assay. The diagnostic performance was assessed against a composite reference standard.From June 2015 to December 2018, we prospectively evaluated 286 adults with suspected TP. One hundred twenty-two participants were classified as definite TP based on the prespecified composite reference standard. The cf-TB produced a sensitivity of 79.5% (97/122, 95% confidence interval (CI) 72.4- 86.7) for definite TP, which was superior to Xpert (38.5% (29.9-47.2); 47/122; p 0.001) and culture (27.1% (19.2-34.9); 33/122; p 0.001). With pleural effusion Xpert and/or culture as the reference standard, cf-TB showed 96.6% (57/59, 95% CI 92.0-100.0) sensitivity, which was also significantly higher than Xpert (79.7%, 95% CI 69.4-89.9; 47/59; p 0.004) and culture (55.9%, 95% CI: 43.3-68.6; 33/59; p 0.001).The cf-TB clearly showed improved sensitivity compared with Xpert and culture. We recommend cf-TB as the first-line test for TP diagnosis.

The B cell survival cytokine BAFF has been linked with the pathogenesis of systemic lupus erythematosus (SLE). BAFF binds distinct BAFF-family surface receptors, including the BAFF-R and transmembrane activator and CAML interactor (TACI). Although originally characterized as a negative regulator of B cell activation, TACI signals are critical for class-switched autoantibody (autoAb) production in BAFF transgenic mice. Consistent with this finding, a subset of transitional splenic B cells upregulate surface TACI expression and contribute to BAFF-driven autoAb. In the current study, we interrogated the B cell signals required for transitional B cell TACI expression and Ab production. Surprisingly, despite established roles for dual BCR and TLR signals in autoAb production in SLE, signals downstream of these receptors exerted distinct impacts on transitional B cell TACI expression and autoAb titers. Whereas loss of BCR signals prevented transitional B cell TACI expression and resulted in loss of serum autoAb across all Ig isotypes, lack of TLR signals exerted a more limited impact restricted to autoAb class-switch recombination without altering transitional B cell TACI expression. Finally, in parallel with the protective effect of TACI deletion, loss of BAFF-R signaling also protected against BAFF-driven autoimmunity. Together, these findings highlight how multiple signaling pathways integrate to promote class-switched autoAb production by transitional B cells, events that likely impact the pathogenesis of SLE and other BAFF-dependent autoimmune diseases.

The extensive applications of Cynomorium species and their rich bioactive secondary metabolites have inspired many pharmacological investigations. Previous research has been conducted to examine the biological activities and numerous interesting pharmaceutical activities have been reported. However, the antitumor activities of these species are unclear. To understand the potential anticancer activity, we screened Cynomorium coccineum and Cynomorium songaricum using three different extracts of each species. In this study, the selected extracts were evaluated for their ability to decrease survival rates of five different cancer cell lines. We compared the cytotoxicity of the three different extracts to the anticancer drug vinblastine and one of the most well-known medicinal mushrooms Amaurederma rude. We found that the water and alcohol extracts of C. coccineum at the very low concentrations possessed very high capacity in decreasing the cancer cells viability with a potential inhibition of tumorigenesis. Based on these primitive data, we subsequently tested the ethanol and the water extracts of C. coccineum, respectively in in vitro and in vivo assays. Cell cycle progression and induction of programmed cell death were investigated at both biological and molecular levels to understand the mechanism of the antitumor inhibitory action of the C. coccineum. The in vitro experiments showed that the treated cancer cells formed fewer and smaller colonies than the untreated cells. Cell cycle progression was inhibited, and the ethanol extract of C. coccineum at a low concentration induced accumulation of cells in the G1 phase. We also found that the C. coccineum&rsquo, s extracts suppressed viability of two murine cancer cell lines. In the in vivo experiments, we injected mice with murine cancer cell line B16, followed by peritoneal injection of the water extract. The treatment prolonged mouse survival significantly. The tumors grew at a slower rate than the control. Down-regulation of c-myc expression appeared to be associated with these effects. Further investigation showed that treatment with C. coccineum induced the overexpression of the tumor suppressor Foxo3 and other molecules involved in inducing autophagy. These results showed that the C. coccineum extract exerts its antiproliferative activity through the induction of cell death pathway. Thus, the Cynomorium plants appear to be a promising source of new antineoplastic compounds.

B cells are known to promote the pathogenesis of systemic lupus erythematosus (SLE) via the production of pathogenic anti-nuclear antibodies. However, the signals required for autoreactive B cell activation and the immune mechanisms whereby B cells impact lupus nephritis pathology remain poorly understood. The B cell survival cytokine B cell activating factor of the TNF Family (BAFF) has been implicated in the pathogenesis of SLE and lupus nephritis in both animal models and human clinical studies. Although the BAFF receptor has been predicted to be the primary BAFF family receptor responsible for BAFF-driven humoral autoimmunity, in the current study we identify a critical role for signals downstream of Transmembrane Activator and CAML Interactor (TACI) in BAFF-dependent lupus nephritis. Whereas transgenic mice overexpressing BAFF develop progressive membranoproliferative glomerulonephritis, albuminuria and renal dysfunction, TACI deletion in BAFF-transgenic mice provided long-term (about 1 year) protection from renal disease. Surprisingly, disease protection in this context was not explained by complete loss of glomerular immune complex deposits. Rather, TACI deletion specifically reduced endocapillary, but not mesangial, immune deposits. Notably, although excess BAFF promoted widespread breaks in B cell tolerance, BAFF-transgenic antibodies were enriched for RNA- relative to DNA-associated autoantigen reactivity. These RNA-associated autoantibody specificities were specifically reduced by TACI or Toll-like receptor 7 deletion. Thus, our study provides important insights into the autoantibody specificities driving proliferative lupus nephritis, and suggests that TACI inhibition may be novel and effective treatment strategy in lupus nephritis.

Circular RNAs are a large group of noncoding RNAs that are widely expressed in mammalian cells. Genome-wide analyses have revealed abundant and evolutionarily conserved circular RNAs across species, which suggest specific physiological roles of these species. Using a microarray approach, we detected increased expression of a circular RNA circ-Dnmt1 in eight breast cancer cell lines and in patients with breast carcinoma. Silencing circ-Dnmt1 inhibited cell proliferation and survival. Ectopic circ-Dnmt1 increased the proliferative and survival capacities of breast cancer cells by stimulating cellular autophagy. We found that circ-Dnmt1-mediated autophagy was essential in inhibiting cellular senescence and increasing tumor xenograft growth. We further found that ectopically expressed circ-Dnmt1 could interact with both p53 and AUF1, promoting the nuclear translocation of both proteins. Nuclear translocation of p53 induced cellular autophagy while AUF1 nuclear translocation reduced Dnmt1 mRNA instability, resulting in increased Dnmt1 translation. From here, functional Dnmt1 could then translocate into the nucleus, inhibiting p53 transcription. Computational algorithms revealed that both p53 and AUF1 could bind to different regions of circ-Dnmt1 RNA. Our results showed that the highly expressed circular RNA circ-Dnmt1 could bind to and regulate oncogenic proteins in breast cancer cells. Thus circ-Dnmt1 appears to be an oncogenic circular RNA with potential for further preclinical research.

Steatosis is a pivotal event in the initiation and progression of nonalcoholic fatty liver disease (NAFLD) which can be driven by peroxisome proliferator-activated receptor-α (PPAR-α) dysregulation. Through examining the effect of PPAR-α on fatty liver development, we found that PPAR-α is a target of miR-17-5p. Transgenic mice expressing miR-17 developed fatty liver and produced higher levels of triglyceride and cholesterol but lower levels of PPAR-α. Ectopic expression of miR-17 enhanced cellular steatosis. Gain-of-function and loss-of-function experiments confirmed PPAR-α as a target of miR-17-5p. On the other hand, PPAR-α bound to the promoter of miR-17 and promoted its expression. The feed-back loop between miR-17-5p and PPAR-α played a key role in the induction of steatosis and fatty liver development. Mice with high levels of miR-17-5p were sensitive to Dexamethasone-induced fatty liver formation. Inhibition of miR-17-5p suppressed this process and enhanced PPAR-α expression in mice treated with Dexamethasone. Clofibrate, Ciprofibrate, and WY-14643: three agents used for treatment of metabolic disorders, were found to promote PPAR-α expression while decreasing miR-17-5p levels and inhibiting steatosis. Our studies show that miR-17-5p inhibitor and agents used in metabolic disorders may be applied in combination with Dexamethasone in the treatment of anti-inflammation, immunosuppression, and cancer patients.

The chemical profiles of essential oils isolated from nine populations of Helichrysum splendidum were obtained by gas chromatography. Plants were harvested in both summer and winter seasons in two provinces of South Africa. Essential oils originating from Limpopo Province were characterized by high levels of β-phellandrene, 1,8-cineole, δ-cadinene, α-cadinol, τ-cadinol, and β-pinene. These could be clearly distinguished through multivariate analysis from those collected in Mpumalanga Province. The Mpumalanga oils contained germacrene D, spathulenol and bicyclogermacrene as major constituents. Seasonal variations in the volatile compositions and yields were observed. A prediction model obtained through orthogonal projection to latent structures discriminant analysis was used to compare the essential oil profiles to that of a commercial H. splendidum sample, in addition to those reported for Zimbabwean specimens. One of the specimens from Zimbabwe differed substantially from all the others, indicating the existence of more chemotypes. The structures of the oil-bearing trichomes, as observed on the leaf surfaces using scanning electron microscopy, were investigated and are described for the first time. Since this investigation forms part of an ongoing screening of plants to identify natural alternatives to synthetic fungicides, the essential oils were tested in vitro against several economically important pathogens of fruit. Essential oils from Mpumalanga specimens totally inhibited the growth of Alternaria alternata from avocado and Colletotrichum gloeosporioides isolated from mango at a concentration of 500 μL/L in a toxic medium assay. The presence of high concentrations of germacrene D, spathulenol and bicyclogermacrene probably contributed to the antifungal properties of these essential oils.

To further our understanding of the role of solution chemistry in directing nucleation processes new experimental and computational data are presented on the solution and crystallisation chemistry of tolfenamic acid (TA), a benchmark polymorphic compound. With these, and previously published data, we were able to establish that TA is rapidly fluctuating between conformers in solution with either solvated monomers or dimers present depending on the solvent. Hence, despite the fact that conformational polymorphs can be obtained from crystallisations in ethanol, we found no links between solution chemistry and crystallisation outcomes. We discuss the implications of these conclusions for the nature of the nucleation pathway via dimers and clusters and raise experimental questions about how best to undertake relevant crystallisation studies.

Severe skeletal open bite associated with posterior vertical maxillary excess and mandibular deformity is considered a difficult problem in orthodontic and surgical treatment. This study used a navigation system for the correction of severe skeletal open bite in order to accurately transfer the virtual plan to the actual operation and achieve precise rigid internal fixation in bimaxillary osteotomies of the jaws. Twelve patients with a severe skeletal open bite associated with vertical maxillary excess and mandibular deformity were recruited. All patients underwent Le Fort I osteotomy and bilateral sagittal split ramus osteotomy with the guidance of this navigation system. Computed tomography and cephalometric examinations were performed to evaluate the correction of the deformity. Deviations between the simulated plan and actual postoperative outcome were measured to determine the precision of the surgery. Satisfactory and stable results were achieved in all patients postoperatively, without complications or relapse during follow-up. Photographs and cephalometric evaluations showed that the facial profile and occlusion were improved. Assessment of the deviations between the simulated plan and actual postoperative outcome showed that the navigation system can precisely transfer the virtual plan to the actual operation. The results suggest that the navigation system can accurately transfer the virtual plan to the actual operation during bimaxillary jaw osteotomies, without relapse, in patients with a severe skeletal open bite.

Together with Penicillium moulds, Geotrichum citri-aurantii (sour rot) is a major cause of citrus fruit decay. Fifty-nine commercially available essential oils and some of their major components were screened to determine their effects on the mycelial growth of G. citri-aurantii using toxic medium assays. Nine of these essential oils totally inhibited the mycelial growth of the pathogen at 1000 μl/l. Gas chromatographic analysis revealed the compositions of the most effective oils. Exposure to the vapours of selected essential oils (Thymus vulgaris, Citrus aurantium var. amara, Cymbopogon citratus, Cymbopogon martinii, Origanum vulgare, Geranium graveolens roseum Bourbon) proved fungistatic, rather than fungicidal, towards the pathogen. ‘Valencia’ oranges, inoculated with G. citri-aurantii, were treated with the most promising botanicals. Essential oils (1000 μl/l) of C. citratus, C. martinii, O. vulgare and G. graveolens roseum Bourbon, incorporated into coating or applied as a curative dip, resulted in a drastic reduction in decay when compared to the negative control. No physiological breakdown of the fruit was evident at this concentration. C. citratus (lemongrass) was selected as the most cost-effective option for control of G. citri-aurantii. Previous commercial trials indicated the protective properties of Mentha spicata essential oil against Penicillium digitatum. To develop an effective multi-target protection product against G. citri-aurantii, P. digitatum and Penicillium italicum, essential oil of C. citratus was combined with that of M. spicata. A toxic medium, containing both essential oils, each at 750 μl/l, totally controlled all three pathogens. Although individual essential oil-amended coatings have previously been applied for postharvest control, this study proposes a mixture of these essential oils for control of two serious citrus pathogens (G. citri-aurantii, P. digitatum), in addition to P. italicum.

Delayed or impaired wound healing is a major public health issue worldwide, especially in patients with diabetes mellitus and vascular atherosclerosis. MicroRNAs have been identified as key regulators of wound healing. Here, we show that miR-Pirate378a transgenic mice (and thus have inhibited miR-378a-5p function) display enhanced wound healing. Expression of vimentin and β3 integrin, two important modulators of wound healing, is markedly elevated in the transgenic mice. MiR-Pirate378a-transfected cells display greater mobility during migration assays, which was hypothesized to be due to the upregulation of vimentin and β3 integrin. Both molecules were confirmed to be targets of miR-378a, and thus their expression could be rescued by miR-Pirate378a. Overexpression of vimentin also contributed to fibroblast differentiation, and upregulation of β3 integrin was responsible for increased angiogenesis. Mice treatment with miR-Pirate378a-conjugated nanoparticles displayed enhanced wound healing. Thus, we have demonstrated that knockdown of miR-378a increased the expression of its target proteins, vimentin, and β3 integrin, which accelerated fibroblast migration and differentiation in vitro and enhanced wound healing in vivo.