Tunable and mode-locked Tm,Ho:GdScO3 laser.

A novel, to the best of our knowledge, Tm,Ho:GdScO3 crystal grown using the Czochralski method was investigated for its polarized spectroscopic properties and laser performance in both tunable continuous-wave (CW) and mode-locked regimes. The crystal's multisite structure (Gd3+/Sc3+ site) and Tm3+/Ho3+ dopants contributed to spectral broadening, enabling a tunable laser operation from 1914 to 2125 nm (with a broad range of 215 nm). Additionally, a pulse duration of 72 fs was achieved for E || b polarization. These results demonstrate the potential of the Tm,Ho:GdScO3 perovskite crystal as a promising gain material for ultrafast lasers operating around 2 µm.

The 'Candidatus phytoplasma ziziphi' effectors SJP1 and SJP2 destabilise the bifunctional regulator ZjTCP7 to modulate floral transition and shoot branching.

Phytoplasmic SAP11 effectors alter host plant architecture and flowering time. However, the exact mechanisms have yet to be elucidated. Two SAP11-like effectors, SJP1 and SJP2, from 'Candidatus Phytoplasma ziziphi' induce shoot branching proliferation. Here, the transcription factor ZjTCP7 was identified as a central target of these two effectors to regulate floral transition and shoot branching. Ectopic expression of ZjTCP7 resulted in enhanced bolting and earlier flowering than did the control. Interaction and expression assays demonstrated that ZjTCP7 interacted with the ZjFT-ZjFD module, thereby enhancing the ability of these genes to directly bind to the ZjAP1 promoter. The effectors SJP1 and SJP2 unravelled the florigen activation complex by specifically destabilising ZjTCP7 and ZjFD to delay floral initiation. Moreover, the shoot branching of the ZjTCP7-SRDX transgenic Arabidopsis lines were comparable to those of the SJP1/2 lines, suggesting the involvement of ZjTCP7 in the regulation of shoot branching. ZjTCP7 interacted with the branching repressor ZjBRC1 to enhance suppression of the auxin efflux carrier ZjPIN3 expression. ZjTCP7 also directly bound to and upregulated the auxin biosynthesis gene ZjYUCCA2, thereby promoting auxin accumulation. Our findings confirm that ZjTCP7 serves as a bifunctional regulator destabilised by the effectors SJP1 and SJP2 to modulate plant development.

A two-step method of cyclolinopeptide (linusorb) preparation from flaxseed cake via dry-screening.

Linusorbs (LO), cyclolinopeptides, are a group of cyclic hydrophobic peptides and considered a valuable by-product of flaxseed oil due to numerous health benefits. Currently applied acetone or methanol extraction could contaminate the feedstocks for further food-grade application. Using flaxseed cake as feedstock, this study established a practical method for preparing LO from pressed cake. Firstly, LO composition of 15 flaxseed cultivars was analyzed. Next, cold-pressed cake was milled and screened mechanically. The kernel and hull fractions were separated based on the disparity of their mechanical strength. Monitored by hyperspectral fluorescence, the LO-enriched kernel fraction separated from cold-pressed flaxseed cake was further used as feedstock for LO production. After ethanol extraction, partition, and precipitation, LOs were extracted from cold-pressed flaxseed cake with a purity of 91.4%. The proposed method could serve as feasible flaxseed cake valorization strategy and enable the preparation of other polar compounds such as flax lignan and mucilage.

COL5A1 promotes triple-negative breast cancer progression by activating tumor cell-macrophage crosstalk.

Triple-negative breast cancer (TNBC) is an exceptionally aggressive subtype of breast cancer. Despite the recognized interplay between tumors and tumor-associated macrophages in fostering drug resistance and disease progression, the precise mechanisms leading these interactions remain elusive. Our study revealed that the upregulation of collagen type V alpha 1 (COL5A1) in TNBC tissues, particularly in chemoresistant samples, was closely linked to an unfavorable prognosis. Functional assays unequivocally demonstrated that COL5A1 played a pivotal role in fueling cancer growth, metastasis, and resistance to doxorubicin, both in vitro and in vivo. Furthermore, we found that the cytokine IL-6, produced by COL5A1-overexpressing TNBC cells actively promoted M2 macrophage polarization. In turn, TGFß from M2 macrophages drived TNBC doxorubicin resistance through the TGFß/Smad3/COL5A1 signaling pathway, establishing a feedback loop between TNBC cells and macrophages. Mechanistically, COL5A1 interacted with TGM2, inhibiting its K48-linked ubiquitination-mediated degradation, thereby enhancing chemoresistance and increasing IL-6 secretion. In summary, our findings underscored the significant contribution of COL5A1 upregulation to TNBC progression and chemoresistance, highlighting its potential as a diagnostic and therapeutic biomarker for TNBC.

StMAPKK5 Positively Regulates Response to Drought and Salt Stress in Potato.

MAPKKs, as one of the main members of the mitogen-activated protein kinase (MAPK) cascade pathway, are located in the middle of the cascade and are involved in many physiological processes of plant growth and development, as well as stress tolerance. Previous studies have found that StMAPKK5 is responsive to drought and salt stress. To further investigate the function and regulatory mechanism of StMAPKK5 in potato stress response, potato variety 'Atlantic' was subjected to drought and NaCl treatments, and the expression of the StMAPKK5 gene was detected by qRT-PCR. StMAPKK5 overexpression and RNA interference-mediated StMAPKK5 knockdown potato plants were constructed. The relative water content, superoxide dismutase (SOD), catalase (CAT), and peroxidase (POD) activities, as well as proline (Pro) and malondialdehyde (MDA) contents of plant leaves, were also assayed under drought and NaCl stress. The StMAPKK5 interacting proteins were identified and validated by yeast two-hybrid (Y2H) and bimolecular fluorescence complementation (BiFC). The results showed that the expression of StMAPKK5 was significantly up-regulated under drought and NaCl stress conditions. The StMAPKK5 protein was localized in the nucleus, cytoplasm, and cell membrane. The expression of StMAPKK5 affected the relative water content, the enzymatic activities of SOD, CAT, and POD, and the proline and MDA contents of potatoes under drought and salt stress conditions. These results suggest that StMAPKK5 plays a significant role in regulating drought and salt tolerance in potato crop. Yeast two-hybrid (Y2H) screening identified four interacting proteins: StMYB19, StZFP8, StPUB-like, and StSKIP19. BiFC confirmed the authenticity of the interactions. These findings suggest that StMAPKK5 is crucial for potato growth, development, and response to adversity.

Potential health risks of microplastic fibres release from disposable surgical masks: Impact of repeated wearing and handling.

Disposable surgical masks undeniably provide important personal protection in daily life, but the potential health risks by the release of microplastic fibres from masks should command greater attention. In this study, we conducted a microplastic fibre release simulation experiment by carrying masks in a pocket and reusing them, to reveal the number and morphological changes of microfibres released. Fourier transform infrared spectrometry, scanning electron microscopy, and optical microscopy were employed to analyse the physical and chemical characteristics of the mask fibres. The results indicated that the reuse of disposable masks led to a significant release of microplastic fibres, potentially leading to their migration into the respiratory system. Furthermore, the release of microplastic fibres increased with prolonged external friction, particularly when masks were stored in pockets. The large-scale release of microplastic fibres due to mask reuse raises concerns about potential health risks to the human respiratory system. The reuse of disposable masks should be also strictly avoided in daily life in the future. Furthermore, the current study also established a robust foundation for future research endeavours on health risks associated with microplastic fibres entering the respiratory system through improper mask usage.

Stretchable, antifatigue, and intelligent nanocellulose hydrogel colorimetric film for real-time visual detection of beef freshness.

The use of biopolymers as matrices and anthocyanins as pH-sensing indicators has generated increasing interest in freshness detection. Nevertheless, the weak mechanical properties and color stability of biopolymer-based smart packaging systems restrict their practicality. In this study, a nanocellulose hydrogel colorimetric film with enhanced stretchability, antifatigue properties, and color stability was prepared using soy hull nanocellulose (SHNC), polyvinyl alcohol (PVA), sodium alginate (SA), and anthocyanin (Anth) as raw materials. This hydrogel colorimetric film was used to detect beef freshness. The structure and properties (e.g., mechanical, thermal stability and hydrophobicity) of these hydrogel colorimetric films were characterized using different techniques. Fourier-transform infrared spectroscopy revealed the presence of hydrogen and ester bonds in the hydrogel colorimetric films, whereas scanning electron microscopy revealed the fish scale-like and honeycomb network structure of the hydrogel colorimetric films. Mechanical testing demonstrated that the SHNC/PVA/SA/Anth-2 hydrogel colorimetric film exhibited excellent tensile properties (elongation = 261 %), viscoelasticity (storage modulus of 11.25 kPa), and mechanical strength (tensile strength = 154 kPa), and the hydrogel colorimetric film exhibited excellent mechanical properties after repeated tensile tests. Moreover, the hydrogel colorimetric film had high transparency, excellent anti-UV linearity, thermal stability and hydrophobicity, and had displayed visually discernible color response to pH buffer solution and volatile NH3 by naked eyes, which was highly correlated with the TVB-N and pH values. Notably, the release of anthocyanin in distilled water decreased from 81.23 % to 19.87 %. The designed SHNC/PVA/SA/Anth hydrogel colorimetric films exhibited potential application as smart packaging film or gas-sensing labels in monitoring the freshness of meat products.

A Comparative Study of Removal of Acid Red 27 by Adsorption on Four Different Chitosan Morphologies.

To investigate the relationship between structures and adsorption properties, four different morphologies of chitosan, with hydrogel (CSH), aerogel (CSA), powder (CSP), and electrospinning nanofiber (CSEN) characteristics, were employed as adsorbents for the removal of Acid Red 27. The structures and morphologies of the four chitosan adsorbents were characterized with SEM, XRD, ATR-FTIR, and BET methods. The adsorption behaviors and mechanisms of the four chitosan adsorbents were comparatively studied. All adsorption behaviors exhibited a good fit with the pseudo-second-order kinetic model (R2 > 0.99) and Langmuir isotherm model (R2 > 0.99). Comparing the adsorption rates and the maximum adsorption capacities, the order was CSH > CSA > CSP > CSEN. The maximum adsorption capacities of CSH, CSA, CSP, and CSEN were 2732.2 (4.523), 676.7 (1.119), 534.8 (0.885), and 215.5 (0.357) mg/g (mmol/g) at 20 °C, respectively. The crystallinities of CSH, CSA, CSP, and CSEN were calculated as 0.41%, 6.97%, 8.76%, and 39.77%, respectively. The crystallinity of the four chitosan adsorbents was the main factor impacting the adsorption rates and adsorption capacities, compared with the specific surface area. With the decrease in crystallinity, the adsorption rates and capacities of the four chitosan adsorbents increased gradually under the same experimental conditions. CSH with a low crystallinity and large specific surface area resulted in the highest adsorption rate and capacity.

Successful management of VTE with essential thrombocythemia and cavernous transformation of the portal vein in early pregnancy: a case report.

Due to the thrombohemorrhagic potential of essential thrombocythemia, pregnancy complicated by essential thrombocythemia should be recognized as a risk factor for obstetric complications. Here, we report the case of a patient with essential thrombocythemia with two significantly different pregnancy outcomes. Her first pregnancy (at 30 years of age) ended with an uneventful term delivery. However, the patient progressed to cavernous transformation of the portal vein in the period between her two pregnancies and subsequently experienced deep venous thrombosis during the first trimester of her second pregnancy (at 36 years of age). The patient's platelet count during pregnancy was within the normal range, so she ignored previous instances of essential thrombocytosis (at 26 years of age). The patient's main symptom was unrelieved pain in her leg. After that, she was successfully treated with anticoagulant throughout her entire pregnancy, resulting in a term vaginal delivery. This case highlights the importance of assessing pregnant patients with essential thrombocythemia according to their risk stratification. Specifically, risk assessments for potential pregnancy complications should take into account advanced maternal age and a previous history of thrombosis. Patients with essential thrombocythemia should be encouraged to participate in preconception counseling for risk assessment and to initiate prophylactic anticoagulation as soon as possible.

Safety and efficacy of a low-dose combination of midazolam, alfentanil, and propofol for deep sedation of elderly patients undergoing ERCP.

BACKGROUND: Proper sedation of patients, particularly elderly individuals, who are more susceptible to sedation-related complications, is of significant importance in endoscopic retrograde cholangiopancreatography (ERCP). This study aims to assess the safety and efficacy of a low-dose combination of midazolam, alfentanil, and propofol for deep sedation in elderly patients undergoing ERCP, compared to a group of middle-aged patients. METHODS: The medical records of 610 patients with common bile duct stones who underwent elective ERCP under deep sedation with a three-drug regimen, including midazolam, alfentanil, and propofol at Shandong Provincial Third Hospital from January 2023 to September 2023 were retrospectively reviewed in this study. Patients were categorized into three groups: middle-aged (50-64 years, n = 202), elderly (65-79 years, n = 216), and very elderly (≥ 80 years, n = 192). Intraoperative vital signs and complications were compared among these groups. RESULTS: The three groups showed no significant difference in terms of intraoperative variation of systolic blood pressure (P = 0.291), diastolic blood pressure (P = 0.737), heart rate (P = 0.107), peripheral oxygen saturation (P = 0.188), bispectral index (P = 0.158), and the occurrence of sedation-related adverse events including hypotension (P = 0.170) and hypoxemia (P = 0.423). CONCLUSION: The results suggest that a low-dose three-drug regimen consisting of midazolam, alfentanil, and propofol seems safe and effective for deep sedation of elderly and very elderly patients undergoing ERCP procedures. However, further studies are required to verify these findings and clarify the benefits and risks of this method.

Effective dose of intranasal remimazolam for preoperative sedation in preschool children: a dose-finding study using Dixon's up-and-down method.

Background: Most preschool children are distressed during anesthesia induction. While current pharmacological methods are useful, there is a need for further optimization to an "ideal" standard. Remimazolam is an ultra-short-acting benzodiazepine, and intranasal remimazolam for pre-induction sedation may be promising. Methods: This study included 32 preschool children who underwent short and minor surgery between October 2022 and January 2023. After pretreatment with lidocaine, remimazolam was administered to both nostrils using a mucosal atomizer device. The University of Michigan Sedation Score (UMSS) was assessed for sedation 6, 9, 12, 15, and 20 min after intranasal atomization. We used Dixon's up-and-down method, and probit and isotonic regressions to determine the 50% effective dose (ED50) and 95% effective dose (ED95) of intranasal remimazolam for pre-induction sedation. Results: Twenty-nine pediatric patients were included in the final analysis. The ED50 and ED95 of intranasal remimazolam for successful pre-induction sedation, when processed via probit analysis, were 0.65 (95% confidence interval [CI], 0.59-0.71) and 0.78 mg/kg (95% CI, 0.72-1.07), respectively. In contrast, when processed by isotonic regression, they were 0.65 (95% CI: 0.58-0.72 mg/kg) and 0.78 mg/kg (95% CI: 0.69-1.08 mg/kg), respectively. At 6 min after intranasal remimazolam treatment, 81.2% (13/16) of "positive" participants were successfully sedated with a UMSS ≧ 1. All the "positive" participants were successfully sedated within 9 min. Conclusion: Intranasal remimazolam is feasible for preschool children with a short onset time. For successful pre-induction sedation, the ED50 and ED95 of intranasal remimazolam were 0.65 and 0.78 mg/kg, respectively.

Long-Term Outcome of Photobiomodulation Therapy for Refractory Diabetic Wound After Secretory Carcinoma of the Parotid Gland Surgery: A Case Report.

Objective: To evaluate the efficacy and safety of photobiomodulation therapy (PBMT) in the treatment of diabetic patients with refractory wound. Background: Refractory wound is one of the most challenging clinical complications of diabetes mellitus. Studies have shown that PBMT can promote wound healing in many ways. Methods: We reported a 55-year-old male patient with refractory diabetic wound after secretory carcinoma of the parotid gland surgery responding to 810 nm laser. Results: After PBMT, the refractory diabetic wound healed gradually without adverse events. During follow-up 5-years, the healed wound remained stable and showed no signs of recurrence. Conclusions: PBMT can be potentially considered as a therapeutic method in diabetic patients with refractory diabetic wound.

Enhancing the spatial resolution of time-of-flight based non-line-of-sight imaging via instrument response function deconvolution.

Non-line-of-sight (NLOS) imaging retrieves the hidden scenes by utilizing the signals indirectly reflected by the relay wall. Benefiting from the picosecond-level timing accuracy, time-correlated single photon counting (TCSPC) based NLOS imaging can achieve theoretical spatial resolutions up to millimeter level. However, in practical applications, the total temporal resolution (also known as total time jitter, TTJ) of most current TCSPC systems exceeds hundreds of picoseconds due to the combined effects of multiple electronic devices, which restricts the underlying spatial resolution of NLOS imaging. In this paper, an instrument response function deconvolution (IRF-DC) method is proposed to overcome the constraints of a TCSPC system's TTJ on the spatial resolution of NLOS imaging. Specifically, we model the transient measurements as Poisson convolution process with the normalized IRF as convolution kernel, and solve the inverse problem with iterative deconvolution algorithm, which significantly improves the spatial resolution of NLOS imaging after reconstruction. Numerical simulations show that the IRF-DC facilitates light-cone transform and frequency-wavenumber migration solver to achieve successful reconstruction even when the system's TTJ reaches 1200 ps, which is equivalent to what was previously possible when TTJ was about 200 ps. In addition, the IRF-DC produces satisfactory reconstruction outcomes when the signal-to-noise ratio (SNR) is low. Furthermore, the effectiveness of the proposed method has also been experimentally verified. The proposed IRF-DC method is highly applicable and efficient, which may promote the development of high-resolution NLOS imaging.

Deciphering the intricate linkage between the gut microbiota and Alzheimer's disease: Elucidating mechanistic pathways promising therapeutic strategies.

BACKGROUND: The gut microbiome is composed of various microorganisms such as bacteria, fungi, and protozoa, and constitutes an important part of the human gut. Its composition is closely related to human health and disease. Alzheimer's disease (AD) is a neurodegenerative disease whose underlying mechanism has not been fully elucidated. Recent research has shown that there are significant differences in the gut microbiota between AD patients and healthy individuals. Changes in the composition of gut microbiota may lead to the development of harmful factors associated with AD. In addition, the gut microbiota may play a role in the development and progression of AD through the gut-brain axis. However, the exact nature of this relationship has not been fully understood. AIMS: This review will elucidate the types and functions of gut microbiota and their relationship with AD and explore in depth the potential mechanisms of gut microbiota in the occurrence of AD and the prospects for treatment strategies. METHODS: Reviewed literature from PubMed and Web of Science using key terminologies related to AD and the gut microbiome. RESULTS: Research indicates that the gut microbiota can directly or indirectly influence the occurrence and progression of AD through metabolites, endotoxins, and the vagus nerve. DISCUSSION: This review discusses the future challenges and research directions regarding the gut microbiota in AD. CONCLUSION: While many unresolved issues remain regarding the gut microbiota and AD, the feasibility and immense potential of treating AD by modulating the gut microbiota are evident.

QTL mapping for plant height and ear height using bi-parental immortalized heterozygous populations in maize.

Introduction: Plant height (PH) and ear height (EH) are key plant architectural traits in maize, which will affect the photosynthetic efficiency, high plant density tolerance, suitability for mechanical harvesting. Methods: QTL mapping were conducted for PH and EH using a recombinant inbred line (RIL) population and two corresponding immortalized backcross (IB) populations obtained from crosses between the RIL population and the two parental lines. Results: A total of 17 and 15 QTL were detected in the RIL and IB populations, respectively. Two QTL, qPH1-1 (qEH1-1) and qPH1-2 (qEH1-4) in the RIL, were simultaneously identified for PH and EH. Combing reported genome-wide association and cloned PH-related genes, co-expression network analyses were constructed, then five candidate genes with high confidence in major QTL were identified including Zm00001d011117 and Zm00001d011108, whose homologs have been confirmed to play a role in determining PH in maize and soybean. Discussion: QTL mapping used a immortalized backcross population is a new strategy. These identified genes in this study can provide new insights for improving the plant architecture in maize.

Prognosis and immunotherapy efficacy in dMMR&MSS colorectal cancer patients and an MSI status predicting model.

The inconsistency between mismatch repair (MMR) protein immunohistochemistry (IHC) and microsatellite instability PCR (MSI-PCR) methods has been widely reported. We aim to investigate the prognosis and the effect of immunotherapy in dMMR by IHC but MSS by MSI-PCR (dMMR&MSS) colorectal cancer (CRC) patients. A microsatellite instability (MSI) predicting model was established to help find dMMR&MSS patients. MMR and MSI states were detected by the IHC and MSI-PCR in 1622 CRC patients (ZS6Y-1 cohort). Logistic regression analysis was used to screen clinical features to construct an MSI-predicting nomogram. We propose a new nomogram-based assay to find patients with dMMR&MSS, in which the MSI-PCR assay only detects dMMR patients with MSS predictive results. We applied the new strategy to a random cohort of 248 CRC patients (ZS6Y-2 cohort). The consistency of MMR IHC and MSI-PCR in the ZS6Y-1 cohort was 95.7% (1553/1622). Both pMMR&MSS and dMMR&MSS groups experienced significantly shorter overall survival (OS) than those in dMMR by IHC and MSI-H by MSI-PCR (dMMR&MSI-H) group (hazard ratio [HR] = 2.429, 95% confidence interval [CI]: 1.89-3.116, p < .01; HR = 21.96, 95% CI: 7.24-66.61, p < .01). The dMMR&MSS group experienced shorter OS than the pMMR&MSS group, but the difference did not reach significance (log rank test, p = .0686). In the immunotherapy group, the progression-free survival of dMMR&MSS patients was significantly shorter than that of dMMR&MSI-H patients (HR = 13.83, 95% CI: 1.508-126.8, p < .05). The ZS6Y-MSI-Pre nomogram (C-index = 0.816, 95% CI: 0.792-0.841, already online) found 66% (2/3) dMMR&MSS patients in the ZS6Y-2 cohort. There are significant differences in OS and immunotherapy effect between dMMR&MSI-H and dMMR&MSS patients. Our prediction model provides an economical way to screen dMMR&MSS patients.

Inhibition of USP7 enhances CD8+ T cell activity in liver cancer by suppressing PRDM1-mediated FGL1 upregulation.

Lymphocyte activation gene 3 (LAG3), an immune checkpoint molecule expressed on activated T cells, functions as a negative regulator of immune responses. Persistent antigen exposure in the tumor microenvironment results in sustained LAG3 expression on T cells, contributing to T cell dysfunction. Fibrinogen-like protein 1 (FGL1) has been identified as a major ligand of LAG3, and FGL1/LAG3 interaction forms a novel immune checkpoint pathway that results in tumor immune evasion. In addition, ubiquitin-specific peptidase 7 (USP7) plays a crucial role in cancer development. In this study we investigated the role of USP7 in modulation of FGL1-mediated liver cancer immune evasion. We showed that knockdown of USP7 or treatment with USP7 inhibitor P5091 suppressed liver cancer growth by promoting CD8+ T cell activity in Hepa1-6 xenograft mice and in HepG2 or Huh7 cells co-cultured with T cells, whereas USP7 overexpression produced the opposite effect. We found that USP7 upregulated FGL1 in HepG2 and Huh7 cells by deubiquitination of transcriptional factor PR domain zinc finger protein 1 (PRDM1), which transcriptionally activated FGL1, and attenuated the CD8+ T cell activity, leading to the liver cancer growth. Interestingly, USP7 could be transcriptionally stimulated by PRDM1 as well in a positive feedback loop. P5091, an inhibitor of USP7, was able to downregulate FGL1 expression, thus enhancing CD8+ T cell activity. In an immunocompetent liver cancer mouse model, the dual blockade of USP7 and LAG3 resulted in a superior antitumor activity compared with anti-LAG3 therapy alone. We conclude that USP7 diminishes CD8+ T cell activity by a USP7/PRDM1 positive feedback loop on FGL1 production in liver cancer; USP7 might be a promising target for liver cancer immunotherapy.

Pharmacogenomic profiling of intra-tumor heterogeneity using a large organoid biobank of liver cancer.

Inter- and intra-tumor heterogeneity is a major hurdle in primary liver cancer (PLC) precision therapy. Here, we establish a PLC biobank, consisting of 399 tumor organoids derived from 144 patients, which recapitulates histopathology and genomic landscape of parental tumors, and is reliable for drug sensitivity screening, as evidenced by both in vivo models and patient response. Integrative analysis dissects PLC heterogeneity, regarding genomic/transcriptomic characteristics and sensitivity to seven clinically relevant drugs, as well as clinical associations. Pharmacogenomic analysis identifies and validates multi-gene expression signatures predicting drug response for better patient stratification. Furthermore, we reveal c-Jun as a major mediator of lenvatinib resistance through JNK and ß-catenin signaling. A compound (PKUF-01) comprising moieties of lenvatinib and veratramine (c-Jun inhibitor) is synthesized and screened, exhibiting a marked synergistic effect. Together, our study characterizes the landscape of PLC heterogeneity, develops predictive biomarker panels, and identifies a lenvatinib-resistant mechanism for combination therapy.

Resting-state functional connectivity of amygdala subregions predicts treatment outcome for cognitive behavioral therapy in obsessive-compulsive disorder at a 4-month follow-up.

BACKGROUND: Cognitive behavioral therapy (CBT) is considered as the first-line treatment for obsessive-compulsive disorder (OCD). However, the underlying neural mechanisms through which CBT exerts its effects in OCD remain unclear. This study aims to investigate whether the improvement of clinical symptoms in OCD patients after CBT treatment is associated with changes in resting-state functional connectivity (FC) of the amygdala subregion, and whether these changes can be served as potential predictors of four-months treatment efficacy. METHODS: We collected resting-state functional magnetic resonance imaging (rs-fMRI) data from 57 OCD patients and 50 healthy subjects at baseline. In the patient group, rs-fMRI was also obtained after completion of an 8-week CBT treatment and 4 months post-treatment. A whole-brain rsFC analysis was conducted using the amygdala subregion as the seed point. We analyzed the FC patterns in relation to 4 months clinical outcomes to elucidate the long-term efficacy of CBT in OCD patients. RESULTS: Treatment responseat at pre-treatment was found to be associated with reduced rsFC between the left basolateral amygdala(BLA)and left superior temporal gyrus(STG) at baseline. Lower pre-treatment FC were negatively correlated with the severity of OCD symptoms as measured by the Yale-Brown Obsessive Compulsive Severity Scale (Y-BOCS). Moreover, the area under the receiver operating characteristic (ROC) curve for the FC between the left BLA and STG at the end of treatment was 73.0% and 70.4% for the effective-ineffective and remitted or unremitted groups, respectively. At the 4-month follow-up, the area under the ROC curve for the effective-ineffective and remitted or unremitted groups was 83.9% and 76.5%, respectively. CONCLUSION: These findings suggest that brain functional activity in patients with OCD can predict treatment response to CBT, and longitudinal changes in relevant brain functional activity following CBT treatment are associated with treatment response in OCD.

Inflammation and Connexin 43 profiles in the prefrontal cortex are relevant to stress susceptibility and resilience in mice.

Depression is a major chronic mental illness worldwide, characterized by anhedonia and pessimism. Exposed to the same stressful stimuli, some people behave normally, while others exhibit negative behaviors and psychology. The exact molecular mechanisms linking stress-induced depressive susceptibility and resilience remain unclear. Connexin 43 (Cx43) forms gap junction channels between the astrocytes, acting as a crucial role in the pathogenesis of depression. Cx43 dysfunction could lead to depressive behaviors, and depression down-regulates the expression of Cx43 in the prefrontal cortex (PFC). Besides, accumulating evidence indicates that inflammation is one of the most common pathological features of the central nervous system dysfunction. However, the roles of Cx43 and peripheral inflammation in stress-susceptible and stress-resilient individuals have rarely been investigated. Thus, animals were classified into the chronic unpredictable stress (CUS)-susceptible group and the CUS-resilient group based on the performance of behavioral tests following the CUS protocol in this study. The protein expression of Cx43 in the PFC, the Cx43 functional changes in the PFC, and the expression levels including interleukin (IL)-1ß, tumor necrosis factor-α, IL-6, IL-2, IL-10, and IL-18 in the peripheral serum were detected. Here, we found that stress exposure triggered a significant reduction in Cx43 protein expression in the CUS-susceptible mice but not in the CUS-resilient mice accompanied by various Cx43 phosphorylation expression and the changes of inflammatory signals. Stress resilience is associated with Cx43 in the PFC and fluctuation in inflammatory signaling, showing that therapeutic targeting of these pathways might promote stress resilience.