3D-printed Model and guide plate for accurate resection of advanced cutaneous squamous cell carcinomas

PurposeAdvanced cutaneous squamous cell carcinomas (cSCC) can have unclear borders, and simple expanded resection may not only destroy surrounding normal tissues unnecessarily, but can also leave residual tumor cells behind. In this article, we describe a new method for resection and evaluate its accuracy.MethodsThe magnetic resonance imaging (MRI) data of 12 patients with advanced cSCC were reconstructed to obtain three-dimensional (3D) tumor models and guide plates for surgeries. Thirty-eight patients with the same cSCC stage, who underwent expanded resection, were included. The distances between the upper, lower, left and right horizontal margins and tumor pathological boundaries were classified as “positive”, “close” (0–6 mm), “adequate” (6–12 mm) or “excessive” (>12 mm). The positive margin rate and margin distance were compared between the groups.ResultsThe 3D tumor models of 12 patients were all successfully reconstructed. The positive rate of 48 surgical margins in the guide plate group was 2.1%, and the proportion of “adequate” margins was 70.8%. A total of 152 margins of 38 patients were included in the extended resection group, for which the positive rate was 13.8%; this was higher than that of the guide plate group (P = 0.045). The proportion of “adequate” margins was 27.6%, with group differences seen in the distance distribution (P < 0.01).ConclusionsIn surgical resection of advanced cSCC, compared with simple expanded resection, surgical planning using a 3D tumor model and guide plate can reduce the rate of horizontal surgical margins, and the probability of under- or over-resection.Clinical Trial Registration: http://www.chictr.org.cn, Identifier [No. ChiCTR2100050174]

Moringa oleifera leaf alleviates functional constipation via regulating the gut microbiota and the enteric nervous system in mice

Moringa oleifera Lam. leaf is not only a new food resource in China, but also a traditional medicinal plant. It is commonly used in the folk to alleviate constipation, but its laxative mechanism is not fully understood. Hence we investigated it in loperamide-induced functional constipation (FC) mice. The results showed that MOAE significantly regulated not only gastrointestinal hormones and neurotransmitters in serum but also important gastrointestinal motility factors in the enteric nervous system (ENS)-interstitial cells of Cajal (ICCs)-smooth muscle cell (SMC) network. Meanwhile, MOAE attenuated intestinal inflammation, increased cecal short-chain fatty acid levels and colonic antimicrobial peptide expression, and improved the impaired intestinal barrier function in loperamide-induced FC mice. In addition, MOAE also increased fecal water content by inhibiting the mRNA expression of colonic aquaporins (Aqp3 and Aqp4) in FC mice. Interestingly and importantly, MOAE affected the intestinal microbiota by inhibiting some key “constipation-causing” microbiota, such as Bacteroidaceae, Clostridiaceae, Bacteroides, and Ruminococcus, and promoting the growth of other important “constipation-curing” microbiota, such as Butyricoccus, Tyzzerella, and Desulfovibrio. These important taxa are significantly associated with a variety of indicators of constipation. These findings suggest that MOAE can promote defecation through its rich chemical composition to modulate the ENS-ICCs-SMCs network and the gut microecosystem

Ligand and structure-based approaches for the exploration of structure–activity relationships of fusidic acid derivatives as antibacterial agents

Introduction: Fusidic acid (FA) has been widely applied in the clinical prevention and treatment of bacterial infections. Nonetheless, its clinical application has been limited due to its narrow antimicrobial spectrum and some side effects.Purpose: Therefore, it is necessary to explore the structure–activity relationships of FA derivatives as antibacterial agents to develop novel ones possessing a broad antimicrobial spectrum.Methods and result: First, a pharmacophore model was established on the nineteen FA derivatives with remarkable antibacterial activities reported in previous studies. The common structural characteristics of the pharmacophore emerging from the FA derivatives were determined as those of six hydrophobic centers, two atom centers of the hydrogen bond acceptor, and a negative electron center around the C-21 field. Then, seven FA derivatives have been designed according to the reported structure–activity relationships and the pharmacophore characteristics. The designed FA derivatives were mapped on the pharmacophore model, and the Qfit values of all FA derivatives were over 50 and FA-8 possessed the highest value of 82.66. The molecular docking studies of the partial target compounds were conducted with the elongation factor G (EF-G) of S. aureus. Furthermore, the designed FA derivatives have been prepared and their antibacterial activities were evaluated by the inhibition zone test and the minimum inhibitory concentration (MIC) test. The derivative FA-7 with a chlorine group as the substituent group at C-25 of FA displayed the best antibacterial property with an MIC of 3.125 µM. Subsequently, 3D-QSAR was carried on all the derivatives by using the CoMSIA mode of SYBYL-X 2.0.Conclusion: Hence, a computer-aided drug design model was developed for FA, which can be further used to optimize FA derivatives as highly potent antibacterial agents

Identification of <em>CHIP</em> as a novel causative gene for autosomal recessive cerebellar ataxia

Autosomal recessive cerebellar ataxias are a group of neurodegenerative disorders that are characterized by complex clinical and genetic heterogeneity. Although more than 20 disease-causing genes have been identified, many patients are still currently without a molecular diagnosis. In a two-generation autosomal recessive cerebellar ataxia family, we mapped a linkage to a minimal candidate region on chromosome 16p13.3 flanked by single-nucleotide polymorphism markers rs11248850 and rs1218762. By combining the defined linkage region with the whole-exome sequencing results, we identified a homozygous mutation (c.493CT) in CHIP (NM_005861) in this family. Using Sanger sequencing, we also identified two compound heterozygous mutations (c.389AT/c.441GT; c.621C>G/c.707GC) in CHIP gene in two additional kindreds. These mutations co-segregated exactly with the disease in these families and were not observed in 500 control subjects with matched ancestry. CHIP colocalized with NR2A, a subunit of the N-methyl-D-aspartate receptor, in the cerebellum, pons, medulla oblongata, hippocampus and cerebral cortex. Wild-type, but not disease-associated mutant CHIPs promoted the degradation of NR2A, which may underlie the pathogenesis of ataxia. In conclusion, using a combination of whole-exome sequencing and linkage analysis, we identified CHIP, encoding a U-box containing ubiquitin E3 ligase, as a novel causative gene for autosomal recessive cerebellar ataxia

Synthesis and Biological Evaluation of Novel Fusidic Acid Derivatives as Two-in-One Agent with Potent Antibacterial and Anti-Inflammatory Activity

Fusidic acid (FA), a narrow-spectrum antibiotics, is highly sensitive to various Gram-positive cocci associated with skin infections. It has outstanding antibacterial effects against certain Gram-positive bacteria whilst no cross-resistance with other antibiotics. Two series of FA derivatives were synthesized and their antibacterial activities were tested. A new aromatic side-chain analog, FA-15 exhibited good antibacterial activity with MIC values in the range of 0.781-1.563 µM against three strains of Staphylococcus spp. Furthermore, through the assessment by the kinetic assay, similar characteristics of bacteriostasis by FA and its aromatic derivatives were observed. In addition, anti-inflammatory activities of FA and its aromatic derivatives were evaluated by using a 12-O-tetradecanoylphorbol-13-acetate (TPA) induced mouse ear edema model. The results also indicated that FA and its aromatic derivatives effectively reduced TPA-induced ear edema in a dose-dependent manner. Following, multiform computerized simulation, including homology modeling, molecular docking, molecular dynamic simulation and QSAR was conducted to clarify the mechanism and regularity of activities. Overall, the present work gave vital clues about structural modifications and has profound significance in deeply scouting for bioactive potentials of FA and its derivatives

Characteristic and mechanism of crack initiation and early growth of an additively manufactured Ti-6Al-4V in very high cycle fatigue regime

In this paper, very high cycle fatigue (VHCF) behavior of an additively manufactured (AM) Ti-6Al-4V by selective laser melting process and post-heat treated by hot-isostatic pressing is investigated by ultrasonic frequency fatigue test and rotating bending fatigue test. It is shown that the fatigue crack initiation is related to loading types in VHCF regime. Under rotating bending fatigue test, the fatigue crack initiates from specimen surface. While for ultrasonic frequency fatigue test, both the surface and the interior crack initiations are observed. For interior crack initiation, the fracture surface presents fish-eye like pattern and fine granular area (FGA) morphology. Electron backscatter diffraction and transmission electron microscopy observations indicate that there are discontinuous refined grain regions beneath the fracture surface in crack initiation and early growth region (i.e. FGA). It is proposed that the mechanism of crack initiation and early growth of titanium alloys in VHCF regime is attributed to the grain refinement caused by dislocation interaction over a number of cyclic loadings followed by cracks combined with the cracks formed at defects, alpha-phase, interfaces, etc. during cyclic loadings. The paper also indicates that the fatigue performance of the present AM Ti-6Al-4V is comparable to that of the conventionally processed Ti-6Al-4V

A mini-review of the role of vesicular glutamate transporters in Parkinson’s disease

Parkinson’s disease (PD) is a common neurodegenerative disease implicated in multiple interacting neurotransmitter pathways. Glutamate is the central excitatory neurotransmitter in the brain and plays critical influence in the control of neuronal activity. Impaired Glutamate homeostasis has been shown to be closely associated with PD. Glutamate is synthesized in the cytoplasm and stored in synaptic vesicles by vesicular glutamate transporters (VGLUTs). Following its exocytotic release, Glutamate activates Glutamate receptors (GluRs) and mediates excitatory neurotransmission. While Glutamate is quickly removed by excitatory amino acid transporters (EAATs) to maintain its relatively low extracellular concentration and prevent excitotoxicity. The involvement of GluRs and EAATs in the pathophysiology of PD has been widely studied, but little is known about the role of VGLUTs in the PD. In this review, we highlight the role of VGLUTs in neurotransmitter and synaptic communication, as well as the massive alterations in Glutamate transmission and VGLUTs levels in PD. Among them, adaptive changes in the expression level and function of VGLUTs may exert a crucial role in excitatory damage in PD, and VGLUTs are considered as novel potential therapeutic targets for PD

Long-term efficacy and stability of miniscrew-assisted rapid palatal expansion in mid to late adolescents and adults: a systematic review and meta-analysis

Abstract Background The purpose of this study is to investigate the long-term efficacy and stability of Miniscrew-assisted Rapid Palatal Expansion (MARPE), including its primary outcomes, namely the nasomaxillary complex transverse skeletal and dental expansion, and related secondary outcomes. Methods Electronic databases and manual literature searches, up to October 31, 2022, were performed. The eligibility criteria were the following: studies on patients with transverse maxillary deficiency treated with MARPE in adults and adolescents over 13.5 years of age. Results Ultimately, twelve articles were included in the analysis, one prospective and eleven retrospective observational studies. Five studies showed a moderate risk of bias, while the remaining seven studies were at a serious risk of bias. The GRADE quality of evidence was very low. MARPE is an effective treatment modality for transverse maxillary deficiency (mean success rate: 93.87%). Patients showed increased mean in the skeletal and dental transverse expansion. The basal bone composition, mean alveolar bone and mean dental expansion accounted for 48.85, 7.52, and 43.63% of the total expansion, respectively. There was a certain degree of skeletal and dental relapse over time. MARPE could also cause dental, alveolar, and periodontal side effects, and have an impact on other craniofacial bones, upper airway, and facial soft tissue. Conclusions MARPE is an effective treatment for transverse maxillary deficiency, with a high success rate and a certain degree of skeletal and dental relapse over time