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For surveilling human health, industries, and the environment, pH monitoring is important. Numerous studies on fluorescent probes have been conducted to monitor various pH ranges. However, fluorescent probes that are capable of sensing alkaline regions are rare. In this study, we propose turn-on-type fluorescent probes for detecting alkaline pHs using bis[2-(2′-hydroxyphenyl)benzazole] (bis(HBX)) derivatives. These probes have high pKa values (from 9.7 to 10.8) and exhibit strong fluorescence intensity and color changes at alkaline pHs. Probes derived from bis(HBX) exhibit good photostability, reversibility, and anti-interference toward pH variations, which can be identified as a certain fluorescence change toward a basic pH. Therefore, compounds would be advantageous to use fluorescent probes for monitoring alkaline pH changes.

Repeated exposure to traumatic experiences may put professional firefighters at increased risk of developing posttraumatic stress disorder (PTSD). To date, however, the rate of PTSD symptoms, unmet need for mental health treatment, and barriers to treatment have only been investigated in subsamples rather than the total population of firefighters. We conducted a nationwide, total population-based survey of all currently employed South Korean firefighters (n = 39,562). The overall response rate was 93.8% (n = 37,093), with 68.0% (n = 26,887) complete responses for all variables. The rate of current probable PTSD was estimated as 5.4%. Among those with current probable PTSD (n = 1,995), only a small proportion (9.7%) had received mental health treatment during the past month. For those who had not received treatment, perceived barriers of accessibility to treatment (29.3%) and concerns about potential stigma (33.8%) were reasons for not receiving treatment. Although those with higher PTSD symptom severity and functional impairment were more likely to seek treatment, greater symptom severity and functional impairment were most strongly associated with increased concerns about potential stigma. This nationwide study points to the need for new approaches to promote access to mental health treatment in professional firefighters.

Post-traumatic stress disorder (PTSD) is a chronic condition characterized by symptoms of physiological and psychosocial burden. While growing research demonstrated signs of inflammation in PTSD, specific biomarkers that may be representative of PTSD such as the detailed neural correlates underlying the inflammatory responses in relation to trauma exposure are seldom discussed. Here, we review recent studies that explored alterations in key inflammatory markers in PTSD, as well as neuroimaging-based studies that further investigated signs of inflammation within the brain in PTSD, as to provide a comprehensive summary of recent literature with a neurological perspective. A search was conducted on studies published from 2009 through 2019 in PubMed and Web of Science. Fifty original articles were selected. Major findings included elevated levels of serum proinflammatory cytokines in individuals with PTSD across various trauma types, as compared with those without PTSD. Furthermore, neuroimaging-based studies demonstrated that altered inflammatory markers are associated with structural and functional alterations in brain regions that are responsible for the regulation of stress and emotion, including the amygdala, hippocampus, and frontal cortex. Future studies that utilize both central and peripheral inflammatory markers are warranted to elucidate the underlying neurological pathway of the pathophysiology of PTSD.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes the coronavirus disease (COVID-19), is currently infecting millions of people worldwide and is causing drastic changes in people’s lives. Recent studies have shown that neurological symptoms are a major issue for people infected with SARS-CoV-2. However, the mechanism through which the pathological effects emerge is still unclear. Brain endothelial cells (ECs), one of the components of the blood–brain barrier, are a major hurdle for the entry of pathogenic or infectious agents into the brain. They strongly express angiotensin converting enzyme 2 (ACE2) for its normal physiological function, which is also well-known to be an opportunistic receptor for SARS-CoV-2 spike protein, facilitating their entry into host cells. First, we identified rapid internalization of the receptor-binding domain (RBD) S1 domain (S1) and active trimer (Trimer) of SARS-CoV-2 spike protein through ACE2 in brain ECs. Moreover, internalized S1 increased Rab5, an early endosomal marker while Trimer decreased Rab5 in the brain ECs. Similarly, the permeability of transferrin and dextran was increased in S1 treatment but decreased in Trimer, respectively. Furthermore, S1 and Trimer both induced mitochondrial damage including functional deficits in mitochondrial respiration. Overall, this study shows that SARS-CoV-2 itself has toxic effects on the brain ECs including defective molecular delivery and metabolic function, suggesting a potential pathological mechanism to induce neurological signs in the brain.

Assessing shoulder joint range of motion (ROM) is essential for diagnosing musculoskeletal disorders and optimizing treatments. This single-center pilot study evaluated the reliability and validity of iBalance, a single-camera markerless motion capture system, for measuring shoulder ROM. Forty participants (30 healthy individuals and 10 patients with adhesive capsulitis) underwent measurements of seven shoulder joint movements. Each movement was assessed three times by two raters using both iBalance and a goniometer, with measurements repeated after 1 week. The iBalance demonstrated excellent inter- and intra-rater reliability for flexion (ICC = 0.93 [0.91–0.95], 0.91 [0.88–0.94]), abduction (ICC = 0.97 [0.95–0.98], 0.93 [0.91–0.95]), and passive abduction (ICC = 0.97 [0.96–0.98], 0.98 [0.97–0.98]). The system also showed strong validity compared to the goniometer for flexion (ICC = 0.85 [0.68–0.92]), abduction (ICC = 0.95 [0.94–0.96]), and passive abduction (ICC = 0.97 [0.96–0.98]). Bland–Altman plots showed high consistency between the two devices for flexion, abduction, and passive abduction, with most data points falling within the limits of agreement. Patients with adhesive capsulitis exhibited greater variability than healthy individuals. No adverse events were reported, supporting the safety of the system. This study highlights the potential of a single-camera markerless motion capture system for diagnosing and treating shoulder joint disorders. The iBalance showed clinical applicability for measuring flexion, abduction, and passive abduction. Future enhancements to the algorithm and the incorporation of advanced metrics could improve its performance, facilitating broader clinical applications for diagnosing complex shoulder conditions.

Firefighters are routinely exposed to various traumatic events and often experience a range of trauma-related symptoms. Although these repeated traumatic exposures rarely progress to the development of post-traumatic stress disorder, firefighters are still considered to be a vulnerable population with regard to trauma.AimsTo investigate how the human brain responds to or compensates for the repeated experience of traumatic stress. We included 98 healthy firefighters with repeated traumatic experiences but without any diagnosis of mental illness and 98 non-firefighter healthy individuals without any history of trauma. Functional connectivity within the fear circuitry, which consists of the dorsal anterior cingulate cortex, insula, amygdala, hippocampus and ventromedial prefrontal cortex (vmPFC), was examined using resting-state functional magnetic resonance imaging. Trauma-related symptoms were evaluated using the Impact of Event Scale - Revised. The firefighter group had greater functional connectivity between the insula and several regions of the fear circuitry including the bilateral amygdalae, bilateral hippocampi and vmPFC as compared with healthy individuals. In the firefighter group, stronger insula-amygdala connectivity was associated with greater severity of trauma-related symptoms (β = 0.36, P = 0.005), whereas higher insula-vmPFC connectivity was related to milder symptoms in response to repeated trauma (β = -0.28, P = 0.01). The current findings suggest an active involvement of insular functional connectivity in response to repeated traumatic stress. Functional connectivity of the insula in relation to the amygdala and vmPFC may be potential pathways that underlie the risk for and resilience to repeated traumatic stress, respectively.Declaration of interestNone.

Growing evidence indicates a reciprocal relationship between low-grade systemic inflammation and stress exposure towards increased vulnerability to neuropsychiatric disorders, including posttraumatic stress disorder (PTSD). However, the neural correlates of this reciprocity and their influence on the subsequent development of PTSD are largely unknown. Here we investigated alterations in functional connectivity among brain networks related to low-grade inflammation and stress exposure using two large independent data sets. Functional couplings among the higher-order cognitive network system including the salience, default mode, and central executive networks were reduced in association with low-grade inflammation and stress exposure. This reduced functional coupling may also be related to subsequent posttraumatic stress symptom severity. The current findings propose functional couplings among the higher-order cognitive network system as neural correlates of low-grade inflammation and stress exposure, and suggest that low-grade inflammation, alongside with stress, may render individuals more vulnerable to PTSD. Low-grade systemic inflammation and stress increase vulnerability to neuropsychiatric disorders. Here, the authors show that inflammation and stress-induced changes in higher order cognitive networks increase vulnerability to posttraumatic stress disorder.

Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder of the central nervous system (CNS) that is defined by a CAG expansion in exon 1 of the huntingtin gene leading to the production of mutant huntingtin (mHtt). To date, the disease pathophysiology has been thought to be primarily driven by cell-autonomous mechanisms, but, here, we demonstrate that fibroblasts derived from HD patients carrying either 72, 143 and 180 CAG repeats as well as induced pluripotent stem cells (iPSCs) also characterized by 143 CAG repeats can transmit protein aggregates to genetically unrelated and healthy host tissue following implantation into the cerebral ventricles of neonatal mice in a non-cell-autonomous fashion. Transmitted mHtt aggregates gave rise to both motor and cognitive impairments, loss of striatal medium spiny neurons, increased inflammation and gliosis in associated brain regions, thereby recapitulating the behavioural and pathological phenotypes which characterizes HD. In addition, both in vitro work using co-cultures of mouse neural stem cells with 143 CAG fibroblasts and the SH-SY5Y human neuroblastoma cell line as well as in vivo experiments conducted in newborn wild-type mice suggest that exosomes can cargo mHtt between cells triggering the manifestation of HD-related behaviour and pathology. This is the first evidence of human-to-mouse prion-like propagation of mHtt in the mammalian brain; a finding which will help unravel the molecular bases of HD pathology as well as to lead to the development of a whole new range of therapies for neurodegenerative diseases of the CNS.

We previously reported that CD133, as a putative cancer stem cell marker, plays an important role in cell proliferation and invasion in colon cancer. To understand the role of CD133 expression in colon cancer, we evaluated the inhibitory effect of CD133 in colon cancer cells. In this study, we generated CD133knockout colon cancer cells (LoVo) using the CRISPR-Cas9 gene editing system. CD133+ colon cancer cells (LoVo) were infected with the lentiviral vector carrying CD133 gRNA and purified cell by culturing single cell colonies. CD133knockout cells was validated by western blot and flow cytometry analysis. In functional study, we observed a significant reduction in cell proliferation and colony formation in CRISPR-Cas9 mediated CD133 knockout cells in compare with control (P < 0.001). We also found the anticancer effect of stattic was dependent on CD133 expression in colon cancer cells. Although CD133knockout cells could not completely block the tumorigenic property, they showed remarkable inhibitory effects on the ability of cell migration and invasion (P < 0.001). In addition, we examined the epithelial mesenchymal transition (EMT)-related protein expression by western blot. The result clearly showed a loss of vimentin expression in CD133knockout cells. Therefore, CRISPR-Cas9 mediated CD133knockout can be an effective treatment modality for CD133+ colon cancer through reducing the characteristics of cancer stem cells.

Translational modulation based on RNA-binding proteins can be used to construct artificial gene circuits, but RNA-binding proteins capable of regulating translation efficiently and orthogonally remain scarce. Here we report CARTRIDGE (Cas-Responsive Translational Regulation Integratable into Diverse Gene control) to repurpose Cas proteins as translational modulators in mammalian cells. We demonstrate that a set of Cas proteins efficiently and orthogonally repress or activate the translation of designed mRNAs that contain a Cas-binding RNA motif in the 5’-UTR. By linking multiple Cas-mediated translational modulators, we designed and built artificial circuits like logic gates, cascades, and half-subtractor circuits. Moreover, we show that various CRISPR-related technologies like anti-CRISPR and split-Cas9 platforms could be similarly repurposed to control translation. Coupling Cas-mediated translational and transcriptional regulation enhanced the complexity of synthetic circuits built by only introducing a few additional elements. Collectively, CARTRIDGE has enormous potential as a versatile molecular toolkit for mammalian synthetic biology. The scarcity of qualified RNA-binding proteins hinders the development of artificial translational regulators and synthetic gene circuits. Here, the authors repurposed CRISPR-Cas proteins as translational regulators to build synthetic circuits.