Schizophrenia has been primarily associated with dopamine dysfunction, and treatments have been developed that target the dopamine pathway in the central nervous system. However, accumulating ...evidence has shown that the core pathophysiology of schizophrenia might involve dysfunction in dopaminergic, glutamatergic, serotonergic, and gamma-aminobutyric acid (GABA) signaling, which may lead to aberrant functioning of interneurons that manifest as cognitive, behavioral, and social dysfunction through altered functioning of a broad range of macro- and microcircuits. The interactions between neurotransmitters can be modeled as nodes and edges by using graph theory, and oxidative balance, immune, and glutamatergic systems may represent multiple nodes interlocking at a central hub; imbalance within any of these nodes might affect the entire system. Therefore, this review attempts to address novel treatment targets beyond the dopamine hypothesis, including glutamate, serotonin, acetylcholine, GABA, and inflammatory cytokines. Furthermore, we outline that these treatment targets can be possibly integrated with novel treatment strategies aimed at different symptoms or phases of the illness. We anticipate that reversing anomalous activity in these novel treatment targets or combinations between these strategies might be beneficial in the treatment of schizophrenia.
Aim
To assess the connection between mitophagy and hypoxia‐induced apoptosis in osteoblasts and whether simvastatin alleviates bone resorption in apical periodontitis through modulation of ...mitophagy‐related apoptosis.
Methodology
Hypoxia‐induced generation of reactive oxygen species in mitochondria and changes in mitochondrial membrane potential were evaluated, respectively, by MitoSOX and JC‐1 fluorescence dye signalling. Accumulation of mitophagy markers PTEN‐induced putative kinase 1 (PINK1) and Parkin in mitochondria was examined by Western blotting and immunofluorescence microscopy. Osteoblast apoptosis was assessed by Western analysis of cleaved‐poly (adenosine diphosphate ribose) polymerase (PARP). In a rat model of induced apical periodontitis, the therapeutic effect of simvastatin and its action on osteoblast mitophagy and apoptosis were examined. anova, Fisher's and Student's t‐test were used for data analysis.
Results
Hypoxia‐induced mitochondrial dysfunction and stimulated mitophagy in osteoblasts. Hypoxia also provoked apoptosis in osteoblasts and inhibition of mitophagy decreased hypoxia‐augmented apoptotic activity. Simvastatin alleviated hypoxia‐induced mitochondrial dysfunction, mitophagy and apoptosis. The protective action of simvastatin against apoptosis was related to its antimitophagy activity. Experiments in the rat model of induced apical periodontitis supported the laboratory findings. Simvastatin treatment mitigated periapical bone loss and reduced the activities of apoptosis and mitophagy in regional osteoblasts.
Conclusions
The results suggest that modulation of osteoblast mitophagy may help diminish bone loss associated with inflammation and has potential as an auxiliary therapy for apical periodontitis.
Empathy is a multi-dimensional concept with affective and cognitive components, the latter often referred to as Theory of Mind (ToM). Impaired empathy is prevalent in people with neuropsychiatric ...disorders, such as personality disorder, psychopathy, and schizophrenia, highlighting the need to develop therapeutic interventions to address this. Repetitive transcranial magnetic stimulation (rTMS), a non-invasive therapeutic technique that has been effective in treating various neuropsychiatric conditions, can be potentially used to modulate empathy. To our knowledge, no systematic reviews or meta-analyses in this field have been conducted. The aim of the current study was to review the literature on the use of rTMS to modulate empathy in adults. Seven electronic databases (AMED, Cochrane library, EMBASE, Medline, Pubmed, PsycInfo, and Web of Science) were searched using appropriate search terms. Twenty-two studies were identified, all bar one study involved interventions in healthy rather than clinical populations, and 18 of them, providing results for 24 trials, were included in the meta-analyses. Results showed an overall small, but statistically significant, effect in favour of active rTMS in healthy individuals. Differential effects across cognitive and affective ToM were evident. Subgroup analyses for cognitive ToM revealed significant effect sizes on excitatory rTMS, offline paradigms, and non-randomised design trials. Subgroup analyses for affective ToM revealed significant effect sizes on excitatory rTMS, offline paradigms, and non-randomised design trials. Meta-regression revealed no significant sources of heterogeneity. In conclusion, rTMS may have discernible effects on different components of empathy. Further research is required to examine the effects of rTMS on empathy in clinical and non-clinical populations, using appropriate empathy tasks and rTMS protocols.
Bacteria display an abundance of cellular forms and can change shape during their life cycle. Many plausible models regarding the functional significance of cell morphology have emerged. A greater ...understanding of the genetic programs underpinning morphological variation in diverse bacterial groups, combined with assays of bacteria under conditions that mimic their varied natural environments, from flowing freshwater streams to diverse human body sites, provides new opportunities to probe the functional significance of cell shape. Here we explore shape diversity among bacteria, at the levels of cell geometry, size, and surface appendages (both placement and number), as it relates to survival in diverse environments. Cell shape in most bacteria is determined by the cell wall. A major challenge in this field has been deconvoluting the effects of differences in the chemical properties of the cell wall and the resulting cell shape perturbations on observed fitness changes. Still, such studies have begun to reveal the selective pressures that drive the diverse forms (or cell wall compositions) observed in mammalian pathogens and bacteria more generally, including efficient adherence to biotic and abiotic surfaces, survival under low-nutrient or stressful conditions, evasion of mammalian complement deposition, efficient dispersal through mucous barriers and tissues, and efficient nutrient acquisition.
There has been a growing interest and continuous investment in advanced surface transportation technologies for more than two decades, especially areas related to connected and automated vehicles ...(CAV). Interest escalated when Google entered the domain in early 2010s, followed by establishment of multiple vehicle technology companies. Toward the end of 2010s, it looked like vehicles with advanced technologies were on the verge of becoming a widespread reality in our daily commute. Waymo indicated that individuals would be able to ride in self-driving cars in multiple locations. Uber were developing and testing a robo-taxi service. Automated shuttles and highly automated trucks were being deployed at various places for demonstration and data collection. As of today, many envisioned CAV applications that could dramatically change the ways we utilize our transportation systems have yet been realized. 'Safety' is likely one of the primary reasons for delayed adoption of CAV technologies. To maximize CAV's safety benefits, these technologies need to be designed by considering their users - drivers and others who also use and share the surface transportation systems. This presentation will discuss a handful of research studies that examine people's attitudes and understanding of CAV technologies in relationship to safety. Additionally, findings on the impact of education and training in relation to user interactions with them and their safety implications will be presented. This presentation will conclude with research needs in the safety and human factors domains of CAV.
Abstract
Front-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) therapy is the standard of care for lung cancer patients with sensitising EGFR mutations (exon 19 deletion or ...L858R mutation). Several phase III studies have demonstrated the superiority of gefitinib, erlotinib (first generation of TKIs) or afatinib (second generation) to chemotherapy in progression-free survival and response rates. Drug-related toxicities, such as diarrhoea, acneiform skin rash, mucositis, and paronychia, are frequently encountered in patients who receive EGFR TKIs. Other rare side-effects, such as hepatic impairment and interstitial lung disease, should be identified early and managed carefully. Patients with uncommon EGFR mutations, such as G719X, S768I, and L861Q, may require special selection of EGFR TKIs. The combination of erlotinib plus bevacizumab has been accepted in certain parts of the world as an alternative front-line treatment. This review article summarizes the studies leading to the establishment of EGFR TKIs in EGFR-mutant lung cancer patients. The side-effect profiles of the current EGFR TKIs in these large trials are listed, and the management of uncommon EGFR mutations is discussed. Finally, the potential role of combination front-line treatment is discussed.
Protein disulfide isomerase a4 (PDIA4) is implicated in the growth and death of tumor cells; however, its molecular mechanism and therapeutic potential in cancer are unclear. Here, we found that ...PDIA4 expression was upregulated in a variety of tumor cell lines and human lung adenocarcinoma tissues. Knockdown and overexpression of PDIA4 in tumor cells showed that PDIA4 facilitated cell growth via the reduction of caspases 3 and 7 activity. Consistently, Lewis lung carcinoma cells overexpressing PDIA4 grew faster than did parental cells in tumor-bearing mice, as shown by a reduced survival rate, increased tumor size and metastasis, and decreased cell death and caspases 3 and 7 activity. PDIA4 knockdown resulted in opposite outcomes. Moreover, results obtained in mice with spontaneous hepatoma indicated that PDIA4 deficiency significantly reduced hepatic tumorigenesis and cyst formation and increased mouse survival, tumor death, and caspases 3 and 7 activity. Mechanistic studies illustrated that PDIA4 negatively regulated tumor cell death by inhibiting degradation and activation of procaspases 3 and 7 via their mutual interaction in a CGHC-dependent manner. Finally, we found that 1,2-dihydroxytrideca-5,7,9,11-tetrayne, a PDIA4 inhibitor, reduced tumor development via enhancement of caspase-mediated cell death in TSA tumor-bearing mice. These findings characterize PDIA4 as a negative regulator of cancer cell apoptosis and suggest that PDIA4 is a potential therapeutic target for cancer.
A planar slab of negative-index material works as a superlens with sub-diffraction-limited resolution, as propagating waves are focused and, moreover, evanescent waves are reconstructed in the image ...plane. Here we demonstrate a superlens for electric evanescent fields with low losses using perovskites in the mid-infrared regime. The combination of near-field microscopy with a tunable free-electron laser allows us to address precisely the polariton modes, which are critical for super-resolution imaging. We spectrally study the lateral and vertical distributions of evanescent waves around the image plane of such a lens, and achieve imaging resolution of λ/14 at the superlensing wavelength. Interestingly, at certain distances between the probe and sample surface, we observe a maximum of these evanescent fields. Comparisons with numerical simulations indicate that this maximum originates from an enhanced coupling between probe and object, which might be applicable for multifunctional circuits, infrared spectroscopy and thermal sensors.
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