Peripheral cranio-spinal nerve communication for trapezius muscle control using axonal profiling through immunostaining.

Accessory nerve (CNXI) has been known to be the primary conduit for motor control of the trapezius, while the supplementary cervical nerves (C3 and C4) are responsible for processing sensory information from muscle. However, the lack of substantial direct evidence has led to these conclusions being regarded as mere speculation. This study used immunostaining (using antibodies against neurofilament 200 for all axons, choline acetyltransferase for cholinergic axons, tyrosine hydroxylase for sympathetic axons, and alpha 3 sodium potassium ATPase for proprioceptive afferent axons) of human samples to verify the functional contributions of nerves. Study highlights the pivotal role of C3 and C4 in regulating precise movements of trapezius, contributing to motor control, proprioceptive feedback, and sympathetic modulation. CNXI is composed primarily of somatic efferent fibers, with significant numbers of sympathetic or sensory fibers. Furthermore, C3-4 have both cholinergic and non-cholinergic axons, suggesting their involvement in proprioceptive feedback and somatic efferent functions. Although less common, mechanosensors such as nociceptive sensor and sympathetic fibers are also supplied by these cervical nerves. The study demonstrated that these nerves contain motor fibers and significant proprioceptive and sympathetic axons, challenging the long-held notion that CNXI are motor and upper spinal nerves are sensory.

Discovery of Dual TRPA1 and TRPV1 Antagonists as Novel Therapeutic Agents for Pain.

Pain management remains a major challenge in medicine, highlighting the need for the development of new therapeutic agents. The transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) are ion channels that play key roles in pain perception. Targeting both TRPA1 and TRPV1 simultaneously with dual antagonists offers a promising approach to pain relief. In this study, we investigated a series of hybrid analogs of TRPA1 and TRPV1 antagonists to discover novel therapeutic agents for pain. Among these compounds synthesized by a condensation reaction forming 1,2,4-oxadiazole between the A- and C-regions, compound 50 exhibited substantial dual-acting antagonism to TRPA1 and TRPV1 with IC50 values of 1.42, 2.84, 2.13, and 5.02 µM for hTRPA1, mTRPA1, hTRPV1, and rTRPV1, respectively. In the formalin test, compound 50 demonstrated dose-dependent analgesic activity with an ED50 of 85.9 mg/kg in phase 1 and 21.6 mg/kg in phase 2, respectively, and was able to inhibit pain behavior completely at a dose of 100 mg/kg. This study presents the discovery and characterization of a novel dual TRPA1/TRPV1 antagonist, highlighting its potential as a therapeutic agent for pain management.

How do multidimensional energy justices work?: Specifying the role of anthropocentric and ecological justice in the acceptance of solar energy.

This study analyzed the acceptance of solar energy in terms of energy justice. The critical issue of energy supply, demand, and transition is a process of social redistribution of risks from old to new energy systems. The question of the appropriate distribution of risks for the energy system is closely related to energy justice. Previous studies are limited in empirically testing whether or not energy justice can contribute to the acceptance of new energy system. In addition, previous studies have heavily depended on energy justice in terms of anthropocentric type. Anthropocentric definitions of energy justice have focused primarily on the benefits and costs allocated only to humans. Such an anthropocentric view of justice lacks consideration of the value of various ecological beings. Therefore, this study aims to shed light on the role of not only four anthropocentric types of energy justices but also on for four ecological ones in the acceptance of solar energy. The analysis reveals that recognitive justice, generational justice, deep ecological justice, social ecological justice, and distributional justice positively influence the acceptance of solar energy, whereas procedural justice, restorative justice, and eco-socialist justice have no effect on it. In particular, this study found that recognitive justice moderates the effect of personal norms on acceptance of solar energy, whereas restorative justice moderates the effect of knowledge on it.

The surgical management of third ventricle region tumors.

OBJECTIVES: The goal of this study was to characterize the largest known cohort of patients presenting with different tumor pathologies in the third ventricle region to better understand outcomes of surgical management. METHODS: All patients undergoing surgical intervention on tumors in or encroaching upon the third ventricle at Loyola University Medical Center between the years 1986-2021 were reviewed. Information recorded included presenting symptoms, pre- and post-operative interventions, tumor pathology, operative technique, extent of resection (EOR), and approach of operation. The primary clinical outcome was Karnofsky Performance Status (KPS) score. RESULTS: Ninety-seven patients underwent 123 operations. Forty-six (47.4 %) patients were female, and the median age at operation was 39 years. Eighty-seven (70.7 %) operations were open, and 36 (29.3 %) were endoscopic. Gross total resection (GTR) was achieved in 34.4 % of operations, near-total resection (NTR) in 31.5 %, subtotal resection in 25.0 %, and biopsy alone in 9.3 %. Median KPS increased pre- to postoperatively, regardless of surgical technique. Adjusting for preoperative KPS, age, and operation number, regression analysis demonstrated a trend that lesser EOR is associated with lower KPS at most recent follow-up (p=0.031 for NTR vs GTR, p=0.022 for biopsy vs GTR). There was no statistically significant association between the most recent KPS and either open or endoscopic surgical technique, with or without adjusting for the previously stated factors (p=0.26). There was no association between postoperative complication rates or age with either surgical technique. CONCLUSIONS: Here, we characterize a large cohort of patients presenting for neurosurgical evaluation of tumors in the region of the third ventricle. Our results demonstrate a trend that a more aggressive resection may yield better KPS outcomes. Additionally, both open and endoscopic techniques lead to a similar improvement in clinical outcome and rates of complication. While ultimate surgical approach and technique is determined by individual tumor characteristics, patient health status, and surgeon expertise, ability to resect the tumor in its entirety should be taken into consideration.

Reconsidering Neurogenetic Indication in the Human Brain: Broad Expression of Doublecortin Transcript in the Hippocampal and Cortical Cell Populations.

INTRODUCTION: Neurogenesis in the adult brain may play an important role in memory and cognition; however, knowledge of neurogenic markers in the human brain remains limited. We compared the single-nucleus transcriptome of the hippocampus with that of other cortical regions to identify hippocampus-specific neurogenic markers. METHODS: We analyzed 26,189 nuclei from four human brains collected within 16 h of death. Clustering and annotation were performed to examine differential expression, gene ontology, and intercellular communication. DCX expression was validated by ddPCR. RESULTS: Immature markers such as DCX, CALB2, NES, SOX2, PAX6, DPYSL3, and TUBB3 were expressed in both hippocampus and prefrontal cortex, with higher levels in the prefrontal cortex. ddPCR confirmed higher expression of DCX in the prefrontal cortex. DCX was involved in both neurogenesis and neuroprotection pathways. CONCLUSION: Neurogenic markers are not definitive indicators of adult neurogenesis as their roles are more complex than previously understood.

In vivo neural regeneration via AAV-NeuroD1 gene delivery to astrocytes in neonatal hypoxic-ischemic brain injury.

BACKGROUND: Neonatal hypoxic-ischemic brain injury (HIBI) is a significant contributor to neonatal mortality and long-term neurodevelopmental disability, characterized by massive neuronal loss and reactive astrogliosis. Current therapeutic approaches for neonatal HIBI have been limited to general supportive therapy because of the lack of methods to compensate for irreversible neuronal loss. This study aimed to establish a feasible regenerative therapy for neonatal HIBI utilizing in vivo direct neuronal reprogramming technology. METHODS: Neonatal HIBI was induced in ICR mice at postnatal day 7 by permanent right common carotid artery occlusion and exposure to hypoxia with 8% oxygen and 92% nitrogen for 90 min. Three days after the injury, NeuroD1 was delivered to reactive astrocytes of the injury site using the astrocyte-tropic adeno-associated viral (AAV) vector AAVShH19. AAVShH19 was engineered with the Cre-FLEX system for long-term tracking of infected cells. RESULTS: AAVShH19-mediated ectopic NeuroD1 expression effectively converted astrocytes into GABAergic neurons, and the converted cells exhibited electrophysiological properties and synaptic transmitters. Additionally, we found that NeuroD1-mediated in vivo direct neuronal reprogramming protected injured host neurons and altered the host environment, i.e., decreased the numbers of activated microglia, reactive astrocytes, and toxic A1-type astrocytes, and decreased the expression of pro-inflammatory factors. Furthermore, NeuroD1-treated mice exhibited significantly improved motor functions. CONCLUSIONS: This study demonstrates that NeuroD1-mediated in vivo direct neuronal reprogramming technology through AAV gene delivery can be a novel regenerative therapy for neonatal HIBI.

Pharmacologic inhibition of Il6st/gp130 improves dermatological inflammation and pruritus.

Chronic dermatitis is a disease with large unmet need for pharmacological improvement. Dermatitis conditions are maintained and exacerbated by various cytokine actions in the context of inflammation. Interleukin 6 signal transducer (Il6st), also known as glycoprotein 130 (Gp130), is a key component for surface reception of a multitude of cytokines and transduction and amplification of their pro-inflammatory signals. We hypothesized accordingly that pharmacological inhibition of Il6st can alter dermatitis pathology. Treatment with SC-144 and bazedoxifene, two representative small molecule Il6st inhibitors with different binding modes led to moderate but significant improvement of skin conditions in a 1-chloro-2,4-dinitrobenzene animal model. Part of cytokine expressions indicating the dermatological index were normalized particularly when treated with SC-144. Pruritic behaviors were blunted, also possibly giving limited contribution to disease improvement. In psoriatic skin and itch of an imiquimod animal model, those two treatments appeared to be relatively moderate. Collectively, pharmacological inhibition of Il6st seems to lessen pathological irritation. Inversely, this experimental attempt newly implies that Il6st participates in pathological mechanisms. In conclusion, we suggest Il6st as a novel target for improving dermatitis, and that agents with suitable efficacy and safety for its modulation are translatable.

Development of a Convenient and Quantitative Method for Evaluating Photosensitizing Activity Using Thiazolyl Blue Formazan Dye.

Photosensitizers cause oxidative damages in various biological systems under light. In this study, the method for analyzing photosensitizing activity of various dietary and medicinal sources was developed using 1-(4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan (thiazolyl blue formazan; MTT-F) as a probe. Significant and quantitative decolorization of MTT-F was observed in the presence of photosensitizers used in this study under light but not under dark conditions. The decolorization of MTT-F occurred irradiation time-, light intensity-, and photosensitizer concentration-dependently. The decolorized MTT-F was reversibly reduced by living cells; the LC-MS/MS results indicated the formation of oxidized products with -1 m/z of base peak from MTT-F, suggesting that MTT-F decolorized by photosensitizers was its corresponding tetrazolium. The present results indicate that MTT-F is a reliable probe for the quantitative analysis of photosensitizing activities, and the MTT-F-based method can be an useful tool for screening and evaluating photosensitizing properties of various compounds used in many industrial purposes.

Evaporation-Driven Energy Generation Using an Electrospun Polyacrylonitrile Nanofiber Mat with Different Support Substrates.

Water evaporation-driven energy harvesting is an emerging mechanism for contributing to green energy production with low cost. Herein, we developed polyacrylonitrile (PAN) nanofiber-based evaporation-driven electricity generators (PEEGs) to confirm the feasibility of utilizing electrospun PAN nanofiber mats in an evaporation-driven energy harvesting system. However, PAN nanofiber mats require a support substrate to enhance its durability and stability when it is applied to an evaporation-driven energy generator, which could have additional effects on generation performance. Accordingly, various support substrates, including fiberglass, copper, stainless mesh, and fabric screen, were applied to PEEGs and examined to understand their potential impacts on electrical generation outputs. As a result, the PAN nanofiber mats were successfully converted to a hydrophilic material for an evaporation-driven generator by dip-coating them in nanocarbon black (NCB) solution. Furthermore, specific electrokinetic performance trends were investigated and the peak electricity outputs of Voc were recorded to be 150.8, 6.5, 2.4, and 215.9 mV, and Isc outputs were recorded to be 143.8, 60.5, 103.8, and 121.4 µA, from PEEGs with fiberglass, copper, stainless mesh, and fabric screen substrates, respectively. Therefore, the implications of this study would provide further perspectives on the developing evaporation-induced electricity devices based on nanofiber materials.

Age-stratified comorbid and pharmacologic analysis of patients with glioblastoma.

Background: Increased age is a strong and unfavorable prognostic factor for patients with glioblastoma (GBM). However, the relationships between stratified patient age, comorbidities, and medications have yet to be explored in GBM patient survival analyses. Objective: To evaluate co-morbid conditions, tumor-related symptoms, medication prescriptions, and subject age for patients with GBM and to establish potential targets for prospective studies. Methods: Electronic health records for 565 patients with IDHwt GBM were evaluated at a single center between January 1, 2000 and August 9, 2021 were retrospectively assessed. Data were stratified by MGMT promoter methylation status when available and were used to construct multivariable time-dependent cox models and intra-cohort hazards. Results: Younger (<65 years of age) but not older (≥65 years) GBM patients demonstrated a worse prognosis with movement related disabilities (P < 0.0001), gait/balance difficulty (P = 0.04) and weakness (P = 0.007), as well as psychiatric conditions, mental health disorders (P = 0.002) and anxiety (P = 0.001). In contrast, older but not younger GBM patients demonstrated a worse prognosis with epilepsy (P = 0.039). Both groups had worse survival with confusion/altered mental status (P = 0.023 vs < 0.000) and an improved survival with a Temozolomide prescription. Older but not younger GBM patients experienced an improved hazard with a prescription of ace-inhibitor medications (P = 0.048). Conclusion: Age-dependent novel associations between clinical symptoms and medications prescribed for co-morbid conditions were demonstrated in patients with GBM. The results of the current work support future mechanistic studies that investigate the negative relationship(s) between increased age, comorbidities, and drug therapies for differential clinical decision-making across the lifespan of patients with GBM.

Efficient bioproduction of poly(3-hydroxypropionate) homopolymer using engineered Escherichia coli strains.

This study focuses on the development of a scalable method for producing poly(3-hydroxypropionate), a homopolymer with significant physico-mechanical properties, through the use of metabolically-engineered Escherichia coli K12 (MG1655) and externally supplied 3-hydroxypropionate. The polymer synthesis pathway was established and optimized through synthetic biology techniques, including the effects of overexpressing phasin and cell division proteins. The optimized strain achieved unprecedented production titers of 9.5 g/L in flask cultures and 80 g/L in fed-batch bioreactors within 45 h. The analysis of poly(3-hydroxypropionate) polymer properties revealed it possesses excellent elasticity (Young's modulus < 6 MPa) and tensile strength (∼80 MPa), positioning it within the category of elastomers or flexible plastics. These findings suggest a viable path for the sustainable, large-scale production of the poly(3-hydroxypropionate) biopolymer.

Rapid response of nail psoriasis to secukinumab in patients with moderate to severe psoriasis after 12 weeks of treatment with a total of 24 weeks of follow-up.

BACKGROUND/OBJECTIVES: Nail psoriasis, a subtype of psoriasis, can cause significant pain, disability, and reduced quality of life. Despite the established efficacy of anti-IL17 secukinumab in improving skin psoriasis, there is a lack of clinical trials focusing on nail psoriasis as primary endpoint. This study aims to investigate the efficacy of secukinumab in treating nail psoriasis in patients with moderate to severe psoriasis. METHODS: We prospectively recruited patients newly diagnosed with moderate to severe psoriasis in single centre from January 2021 to January 2022 who were treated with secukinumab. RESULTS: A total of 16 patients consisting of 9 males and 7 females were included. Their mean age was 38.88 ± 10.29 years. They had an average initial Nail Psoriasis Severity Index (NAPSI) score of 45.06 ± 20.39 and an average NAPSI score at 12 weeks of 8.94 ± 13.50, showing a significant (p < 0.05) decrease of NAPSI score after 12 weeks of secukinumab treatment. After 24 weeks of treatment, NAPSI score was decreased to 5.12 ± 8.52. CONCLUSION: Secukinumab rapidly improved nail psoriasis after 12 weeks of treatment, with further enhancement at 24 weeks, suggesting its potential as a potent therapeutic option for nail psoriasis.

Anatomical study of the sacrotuberous ligament and the hamstring muscles: A histomorphological analysis.

The sacrotuberous ligament (STL) and the hamstrings are important structures that are mutually connected and influenced by the pelvis. However, the anatomical connectivity and histological characteristics of these structures remain unclear. The present study aimed to comprehensively investigate the relationship between the STL and the proximal hamstrings through histological analysis. Sixteen specimens were obtained from eight fresh cadavers (mean age at death, 73.4 years). Verhoeff Van Gieson, Masson's trichrome, and immunohistochemical staining were used to analyze the connectivity between the STL and the hamstrings and to verify the ratios of collagen and elastic fibers. Dense connective tissue that overlapped tightly between the STL and hamstrings was observed. The relative ratios of collagen and elastic fibers between the STL and hamstrings characteristically identified regional differences. The ratio of elastic fibers to collagen in the biceps femoris (BF) was ~38.6 ± 4.7%, and the lowest ratio was 5.9 ± 2.6% observed in the semimembranosus (SM). In the case of the BF, contractibility is well-regulated due to a high content of elastic fibers; however, the muscular structure of the BF is relatively fragile due to the low content of collagen. In the SM, collagen content is higher than that in the STL. This ratio of elastic fibers in the collagen analysis could provide crucial information for understanding the differences in hamstring contractility and maintaining the morphology of these structures.

Microenvironmental network of clonal CXCL13+CD4+ T cells and Tregs in pemphigus chronic blisters.

BACKGROUNDPemphigus, a rare autoimmune bullous disease mediated by antidesmoglein autoantibodies, can be controlled with systemic medication like rituximab and high-dose systemic corticosteroids combined with immunosuppressants. However, some patients continue to experience chronically recurrent blisters in a specific area and require long-term maintenance systemic therapy.METHODSSkin with chronic blisters was obtained from patients with pemphigus. Immunologic properties of the skin were analyzed by immunofluorescence staining, bulk and single-cell RNA and TCR sequencing, and a highly multiplex imaging technique known as CO-Detection by indEXing (CODEX). Functional analyses were performed by flow cytometry and bulk RNA-Seq using peripheral blood from healthy donors. Intralesional corticosteroid was injected into patient skin, and changes in chronically recurrent blisters were observed.RESULTSWe demonstrated the presence of skin tertiary lymphoid structures (TLSs) with desmoglein-specific B cells in chronic blisters from patients with pemphigus. In the skin TLSs, CD4+ T cells predominantly produced CXCL13. These clonally expanded CXCL13+CD4+ T cells exhibited features of activated Th1-like cells and downregulated genes associated with T cell receptor-mediated signaling. Tregs are in direct contact with CXCL13+CD4+ memory T cells and increased CXCL13 production of CD4+ T cells through IL-2 consumption and TGF-ß stimulation. Finally, intralesional corticosteroid injection improved chronic blisters and reduced skin TLSs in patients with pemphigus.CONCLUSIONThrough this study we conclude that skin TLSs are associated with the persistence of chronically recurrent blisters in patients with pemphigus, and the microenvironmental network involving CXCL13+CD4+ T cells and Tregs within these structures plays an important role in CXCL13 production.TRIAL REGISTRATIONClinicalTrials.gov NCT04509570.FUNDINGThis work was supported by National Research Foundation of South Korea (NRF-2021R1C1C1007179) and Korea Drug Development Fund, which is funded by Ministry of Science and ICT; Ministry of Trade, Industry, and Energy; and Ministry of Health and Welfare (grant RS-2022-00165917).

Cytotoxicity and genotoxicity of various types of endodontic sealers in Chinese hamster ovary (CHO-K1) cells.

This study aimed to evaluate the cytotoxicity and genotoxicity of five endodontic sealers (AH Plus, MTA Fillapex, Endoseal MTA, Sealapex, and Zinc oxide eugenol) in Chinese hamster ovary cells. Cytotoxicity was evaluated by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay to check cell viability at 1, 3, and 7 days. Genotoxicity was assessed by cytokinesis-block micronucleus, single-cell gel electrophoresis, and γH2AX immunofluorescence assays. Cell viability of all endodontic sealers, except Endoseal MTA, on day 1 was less than 100%. Endoseal MTA showed the highest cell viability on day 7. AH Plus and Endoseal MTA showed less DNA damage than other sealers. After complete setting, AH Plus and Endoseal MTA showed low genotoxicity, which could reduce DNA damage in periapical cells, making them suitable as endodontic sealers.

Challenges and Future Trends in the Treatment of Psoriasis.

Psoriasis is a chronic inflammatory skin disorder, and current treatments include topical therapies, phototherapy, systemic immune modulators, and biologics, aiming to alleviate symptoms and improve quality of life. However, challenges persist, such as adverse effects, treatment resistance, high costs, and variability in response among individuals. The future of psoriasis treatment shows promising emerging trends. New biologic agents targeting novel pathways, such as interleukin 23 inhibitors like mirikizumab, offer enhanced efficacy. Small molecule inhibitors like RORγt inhibitors and ROCK2 inhibitors provide additional treatment options. Combination therapies, including biologics with methotrexate, may improve treatment response. Advancements in topical treatments utilizing microneedles and nanoparticle-based carriers can enhance drug delivery and improve therapeutic outcomes. Biomarkers and multi-omics technologies hold potential for personalized treatment approaches, thus aiding in diagnosis, predicting treatment response, and guiding therapeutic decisions. Collaboration among researchers, clinicians, and industry stakeholders is crucial to translating these scientific breakthroughs into clinical practice. By addressing current challenges and exploring these promising trends, we can optimize psoriasis management and improve the lives of those affected by this chronic condition.

Advanced Age in Humans and Mouse Models of Glioblastoma Show Decreased Survival from Extratumoral Influence.

PURPOSE: Glioblastoma (GBM) is the most common aggressive primary malignant brain tumor in adults with a median age of onset of 68 to 70 years old. Although advanced age is often associated with poorer GBM patient survival, the predominant source(s) of maladaptive aging effects remains to be established. Here, we studied intratumoral and extratumoral relationships between adult patients with GBM and mice with brain tumors across the lifespan. EXPERIMENTAL DESIGN: Electronic health records at Northwestern Medicine and the NCI SEER databases were evaluated for GBM patient age and overall survival. The commercial Tempus and Caris databases, as well as The Cancer Genome Atlas were profiled for gene expression, DNA methylation, and mutational changes with varying GBM patient age. In addition, gene expression analysis was performed on the extratumoral brain of younger and older adult mice with or without a brain tumor. The survival of young and old wild-type or transgenic (INK-ATTAC) mice with a brain tumor was evaluated after treatment with or without senolytics and/or immunotherapy. RESULTS: Human patients with GBM ≥65 years of age had a significantly decreased survival compared with their younger counterparts. While the intra-GBM molecular profiles were similar between younger and older patients with GBM, non-tumor brain tissue had a significantly different gene expression profile between young and old mice with a brain tumor and the eradication of senescent cells improved immunotherapy-dependent survival of old but not young mice. CONCLUSIONS: This work suggests a potential benefit for combining senolytics with immunotherapy in older patients with GBM.

Pamoic acid-induced peripheral GPR35 activation improves pruritus and dermatitis.

BACKGROUND AND PURPOSE: Pruritic dermatitis is a disease with a considerable unmet need for treatment and appears to present with not only epidermal but also peripheral neuronal complications. Here, we propose a novel pharmacological modulation targeting both peripheral dorsal root ganglion (DRG) sensory neurons and skin keratinocytes. GPR35 is an orphan G-protein-coupled receptor expressed in DRG neurons and has been predicted to downregulate neuronal excitability when activated. Modulator information is currently increasing for GPR35, and pamoic acid (PA), a salt-forming agent for drugs, has been shown to be an activator solely specific for GPR35. Here, we investigated its effects on dermatitic pathology. EXPERIMENTAL APPROACH: We confirmed GPR35 expression in peripheral neurons and tissues. The effect of PA treatment was pharmacologically evaluated in cultured cells in vitro and in in vivo animal models for acute and chronic pruritus. KEY RESULTS: Local PA application mitigated acute non-histaminergic itch and, consistently, obstructed DRG neuronal responses. Keratinocyte fragmentation under dermatitic simulation was also dampened following PA incubation. Chronic pruritus in 1-chloro-2,4-dinitrobenzene and psoriasis models were also moderately but significantly reversed by the repeated applications of PA. Dermatitic scores in the 1-chloro-2,4-dinitrobenzene and psoriatic models were also improved by its application, indicating that it is beneficial for mitigating disease pathology. CONCLUSION AND IMPLICATIONS: Our findings suggest that pamoic acid activation of peripheral GPR35 can contribute to the improvement of pruritus and its associated diseases.