Low Response Research Articles

Visual Field Asymmetries in Responses to ON and OFF Pathway Biasing Stimuli.

Recent reports suggest the ON and OFF pathways are differentially susceptible to selective vision loss in glaucoma. Thus, perimetric assessment of ON- and OFF-pathway function may serve as a useful diagnostic. However, this necessitates a developed understanding of normal ON/OFF pathway function around the visual field and as a function of input intensity. Here, using electroencephalography, we measured ON- and OFF-pathway biased contrast response functions in the upper and lower visual fields. Using the steady-state visually evoked potential paradigm, we flickered achromatic luminance probes according to a saw-tooth waveform, the fast phase of which biased responses towards the ON or OFF pathways. Neural responses from the upper and lower visual fields were simultaneously measured using frequency tagging - probes in the upper visual field modulated at 3.75Hz, while those in the lower visual field modulated at 3Hz. We find that responses to OFF/decrements are larger than ON/increments, especially in the lower visual field. In the lower visual field, both ON and OFF responses were well described by a sigmoidal non-linearity. In the upper visual field, the ON pathway function was very similar to that of the lower, but the OFF pathway function showed reduced saturation and more cross-subject variability. Overall, this demonstrates that the relationship between the ON and OFF pathways depends on the visual field location and contrast level, potentially reflective of natural scene statistics.

Digoxigenin activates autophagy in hepatocellular carcinoma cells by regulating the PI3K/AKT/mTOR pathway

Hepatocellular carcinoma (HCC) is recognized as a highly malignant tumor. Targeted combination immunotherapy, the initially approved regimen, is compromised by adverse side effects and low response rates during clinical treatment. Traditional Chinese medicine and its derived natural compounds, known for their anticancer effects, offer advantages of low toxicity and cost. In this study, we performed high-throughput phenotypic screening in vitro to identify promising anti-HCC drugs. Among 1,444 bioactive compounds, digoxigenin (DIG) was found to significantly impede HCC cell progression. We validated DIG’s therapeutic effects through assays such as cell counting by CCK8, lactate dehydrogenase, and colony formation. Analyses including transmission electron microscopy, western blotting, and immunofluorescence demonstrated that DIG inhibits HCC cell proliferation via autophagy. Network pharmacology and molecular docking studies suggest that DIG targets the PI3K/AKT/mTOR signaling pathway. Comparative treatments of Hep3B and Huh7 cells with DIG or mTOR inhibitors revealed similar inhibitory impacts, indicating that DIG induces autophagy by inhibiting the PI3K/AKT/mTOR pathway. In vivo studies confirmed that DIG halts the growth of subcutaneous xenograft tumors. In conclusion, DIG represents a potential HCC treatment by modulating the PI3K/AKT/mTOR pathway to induce autophagy. This research, via phenotypic screening, accelerates drug discovery and the development of novel therapies targeting the underlying mechanisms of liver cancer.

Outpatient subcutaneous alemtuzumab is feasible and safe for aplastic anemia and associated with high response rates.

Immunosuppressive therapy (IST) using horse antithymocyte globulin (h-ATG) combined with cyclosporine (CsA) and eltrombopag is the standard care for aplastic anemia (AA) in patients without a suitable matched donor. However, in many countries, h-ATG use has been discontinued, leaving rabbit ATG (r-ATG), which has a lower response rates and poorer survival, as the only alternative. In previous studies, alemtuzumab (ALZ), a humanized monoclonal antibody targeting CD52, combined with CsA resulted in an adequate ORR in AA patients. This study describes a multicenter, international retrospective analysis of ALZ for treating AA. We analyzed a series of patients who received subcutaneous ALZ for AA in four centers in Brazil and the United Kingdom from March 2009 to January 2024. We analyzed 64 ALZ treatments in 61 AA adult patients, 76% with SAA or very severe aplastic anemia (VSAA). Overall response rate (ORR) was 59.4% at 12 months (complete: 21.9%, partial: 37.5%). Cumulative incidence (CI) of response was 54.7% at 6 months, and 59.4% at 12 months. Younger patients (under 65) had higher CI of response (67% vs. 31%, P=0.03), as well as patients treated with a total dose of 103 mg (70% vs. 38%, P=0.02). Overall survival (OS) was 86% at 1 year, 78% at 2 years, and 70% at 4 years, significantly higher in responders (90% vs. 44%, P<0.0001). Adverse events were of low grade, and infectious events were infrequent. Subcutaneous ALZ is a feasible, effective, and safe alternative to r-ATG for AA patients requiring immunosuppressive treatment where h-ATG access is limited.

Enhanced Insulin Production From Porcine Islets: More Insulin, Less Islets

Clinical pancreatic islet xenotransplantation will most probably rely on genetically modified pigs as donors. Several lines of transgenic pigs carrying one and more often, multiple modifications already exist. The vast majority of these modifications aim to mitigate the host immune response by suppressing major xeno-antigens, or expressing immunomodulatory molecules that act locally at the graft site. While these modifications are essential and have proven beneficial in preclinical trials, ensuring good intrinsic islet secretory function is equally important to achieve normoglycemia in recipients. Neonatal and even adult porcine islets are known for their low secretory response to physiological stimulation, a shortcoming that is often overcome by implanting extremely large numbers of such islets to compensate for insulin requirement incompatibilities between donor pigs and rodent, non-human primate or human recipients. Recent studies have revealed the existence of secretory amplifying pathways in porcine beta-cells previously identified in murine and human cells. Building upon these findings, a new line of transgenic pigs where these pathways are activated specifically in beta-cells has been created. Compared to their wild-type counterparts, islets from these transgenic pigs have proven to be better insulin secretors in their native pancreas environment, in vitro after isolation and most importantly in vivo after transplantation to diabetic mice.

Efficacy of HBV booster dose administration in Italian medical students in relation to health determinants

ABSTRACT We evaluated the efficacy of a booster dose of HBV in Italian medical students. We conducted a prospective observational study in students who had received a full course of anti-HBV vaccination for at least 15 y. Those with an anti-HBs titer <10 mIU/mL were offered a booster dose of the HBV vaccine and the antibody titer was reevaluated after 1 month. The participants were classified into three categories: with anti-HBs titer >100 mIU/mL, between 10 and 100 mIU/mL and <10 mIU/mL. The study population was n. 625 medical student and 355 (56.8%) with anti HBs titer <10 mIU/mL were offered a booster dose. A total of 166 of them received the booster dose and 92.77% (38 + 116/166) achieved an anti-HBs titer ≥10 mIU/mL. The post-booster anti-HBs titer response was higher, i.e. >100 mIU/mL, in subjects who had a pre-booster anti-HBs titer between 1.00 and 9.99 mIU/mL (84.38%, 81/96), compared to those with titer <1 mIU/mL (50.00%, 35/70). Subjects with a titer <1.00 mIU/mL at enrollment showed no anamnestic response (post-booster anti-HBs <10 mIU/mL, RRR 0.23, 95% CI 0.06–0.84) and to a low anamnestic response (post-booster anti-HBs 10–100 mIU/mL, RRR 0.16, 95% CI 0.07–0.38). Physical activity was linked to a better antibody response to vaccination (post-booster anti-HBs 10–100 mIU/mL: RRR 2.39, 95% CI 1.05–5.59). Immune protection following primary vaccination against HBV tends to wane over time. Booster dose induces anamnestic responses, especially in individuals who maintain titer HBsAg >1 mIU/mL and do physical activity.

Modifying reaction time tasks parameters in the automated IntelliCage identifies heightened impulsivity and impaired attention in the 3xTg-AD model of Alzheimer’s disease

BackgroundThe 3xTg-AD transgenic mouse model of Alzheimer’s disease (AD) is an important tool to investigate the relationship between development of pathological amyloid-β (Aβ) and tau, neuroinflammation, and cognitive impairments. Traditional behavioral tasks assessing aspects of learning and memory, such as mazes requiring spatial navigation, unfortunately suffer from several shortcomings, including the stress of human handling and not probing species-typical behavior. The automated IntelliCage system was developed to circumvent such issues by testing mice in a social environment while measuring multiple aspects of cognition. Water consumption can serve as a primary motivator for task engagement. Once animals adapt to the cage and can access water, mice can be subjected to operant tasks. Each of the four corners of a cage contains doors to manipulate access to water, visual LED cues, and a valve allowing administration of an air puff. Previously, we detected significant impairments in 3xTg-AD mice in the IntelliCage, however a high failure rate and genotypical differences in water motivation were observed.MethodsHere, we implemented an IntelliCage paradigm where mice underwent progressively more difficult reaction time tasks to assess attention and impulsivity, behaviors mediated by the prefrontal cortex. Mice were placed in the IntelliCage at 11.5 months of age, which corresponds with the presence of widespread pathology.ResultsAs the difficulty of the reaction time tasks increased, 3xTg-AD mice exhibited lower percent Correct Responses than NonTg. When implementing varying pre-cue durations, where animals are required to wait between the initiation of the trial and the LED turning on (which then requires a nose-poke to access water), 3xTg-AD mice prematurely nose-poked on trials requiring a longer delay before a second nose poke would allow water access, demonstrating heightened impulsivity. The presence of soluble and insoluble fractions of cortical Aβ40 and 42, and phosphorylated tau epitopes threonine 181 and serine 396 confirmed the presence of neuropathological hallmarks in 3xTg-AD mice.ConclusionTogether, this study describes a novel protocol that overcomes motivational differences and detects attention and impulsivity deficits in 3xTg-AD mice utilizing the IntelliCage.

Immunogenicity and safety of the fourth dose of quadrivalent human papillomavirus (HPV) vaccine in immunosuppressed women who did not seroconvert after three doses

IntroductionImmunocompromised persons have high risk of persistent human papillomavirus (HPV) infection and HPV-related diseases, and lower immune response to vaccines. This study evaluated the immunogenicity and safety of administering a fourth dose of quadrivalent (4v)HPV vaccine in immunosuppressed women who did not seroconvert after three doses.MethodsAn open-label, not-controlled trial included immunosuppressed women (solid organ transplant patients and women receiving treatment for SLE) who did not seroconvert to at least one of the four HPV vaccine types after three 4vHPV vaccine doses. All participants received a fourth 4vHPV vaccine dose (median 27 months after third dose). Immunogenicity was evaluated a month after the fourth dose, by measuring seroconversion rates and antibody geometric mean concentration (GMC).ResultsTwenty-three women were included. Among women who did not seroconvert for each vaccine type after three doses, 2/10 seroconverted to HPV6, 3/10 to HPV11, 3/10 to HPV16 and 6/18 to HPV18, after the fourth 4vHPV dose. There was an increase in antibody GMC for HPV 6, 16, 18, with highest increase for HPV16 (from 6.02 to 44.63 International Units). There was no increase of anti-HPV-11. Within seven days after vaccination, only three of the 23 vaccinees reported any adverse event, none of which were classified as serious.ConclusionsAlthough safe, the fourth 4vHPV vaccine dose led to seroconversion in only few immunosuppressed women who had not seroconverted after three doses.

Workplace interpersonal relationships and turnover intentions among care workers working in older adult care facilities in Japan: a mediation analysis comparing direct and mediated effects via psychological distress

BackgroundThis study aimed to investigate the relationship between workplace interpersonal relationships, psychological distress, and turnover intentions among care workers working in older adult care facilities.MethodsAn anonymous online survey among 811 care workers in Tottori Prefecture, Japan, was conducted between November and December 2023. The data were collected using the Workplace Interpersonal Problems Scale for care workers (WIPS), the K6 scale to assess psychological distress, the Turnover Intention Scale and basic attributes. Responses were obtained from 254 participants with a response rate of 31.3%. The low response rate suggests that selection bias may have affected the results of this study.ResultsThe results of the mediation analysis for the WIPS subscale which was adjusted for basic attributes show that the direct effects of insufficient communication and a sense of unfair workload were stronger than the mediating effects of psychological distress (Insufficient communication: direct effect: β = 0.319 [95% CI = 0.192, 0.459]; mediation effect: β = 0.194 [95% CI = 0.105, 0.285]), sense of unfair workload: direct effect: β = 0.314 [95% CI = 0.187, 0.443]; mediation effect: β = 0.190 [95% CI = 0.113, 0.268]). In these other four WIPS subscales, psychological distress was partially mediated (bullying: direct effect: β = 0.207 [95% CI = 0.091, 0.322]; mediation effect: β = 0.204 [95% CI = 0.135, 0.290], different attitudes to care work: direct effect: β = 0.278 [95% CI = 0.140, 0.401]; mediation effect: β = 0.204 [95% CI = 0.128, 0.293], difficulty in guidance for subordinates/new staff: direct effect: β = 0.207 [95% CI = 0.072, 0.329]; mediation effect: β = 0.219[95% CI = 0.141, 0.313], labeling: direct effect: β = 0.198 [95% CI = 0.073, 0.330]; mediation effect: β = 0.211 [95% CI = 0.143, 0.287]).ConclusionsThis study revealed that some workplace interpersonal problems have a stronger direct effect on turnover intentions, whereas others have a stronger mediating effect on turnover intentions through psychological distress. Workplace interpersonal problems are predictors of turnover intentions among care workers working in elderly care facilities, and different workplace interpersonal problems may be targeted for intervention to reduce turnover intentions.

Technique imagination guided to decline painful response on patient fracture at dr. central general hospital Wahidin Sudirohusodo Makassar

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The relationship between inclusive leadership, organizational justice, work engagement and organizational citizenship behavior in healthcare workers.

Based on social exchange theory, this study aims to determine the relationship between inclusive leadership in their managers and organizational justice perceived by healthcare workers and work engagement and organizational citizenship behavior. A cross-sectional and correlational study was performed by healthcare workers (n = 330) working in a city hospital for at least six months in Türkiye. Descriptive statistics, correlation and regression analysis were used in data analysis. The hypotheses were tested using Hayes' PROCESS macro (v4.1). It was determined that inclusive leadership had a positive significant effect on organizational justice, work engagement and organizational citizenship behavior; and organizational justice had a positive significant effect on work engagement and organizational citizenship behavior. In addition, it was found that work engagement also had a significant effect on organizational citizenship behavior. It was found that organizational justice had a partial mediating role between inclusive leadership and work engagement, while its mediating role between inclusive leadership and organizational citizenship behavior was not statistically significant. In addition, work engagement was found to have a partial mediating role in the effect of inclusive leadership on organizational citizenship behavior. The limitations of this study can be summarized as follows: First, the data were collected from the employees in a hospital based on the self-reports of the participants. The fact that the study used a cross-sectional design limited the establishment of a causal relationship between variables. Since the study was planned during the COVID-19 period, the participants were reached through convenience sampling. Isolation measures due to the pandemic led to a lower response rate than expected. To reveal more generalizable results, it may be recommended to collect the data at different periods in future studies and to include different types of healthcare institutions. Inclusive leadership of the healthcare managers will lead to positive employee outcomes by preventing the disadvantages brought by internal conflict in the work environment. This study indicates that managers' inclusive leadership style will improve perceived organizational justice and work engagement and will lead employees to exhibit the desired extra-role behavior, such as organizational citizenship behavior.

Adaptive evolution of extensive drug resistance and persistence in epidemic ST11 KPC-producing Klebsiella pneumoniae during antimicrobial chemotherapy.

The global rise of carbapenem-resistant Klebsiella pneumoniae, including strains producing K. pneumoniae carbapenemase (KPC) types, poses a significant public health challenge due to their resistance to critical antibiotics. Treatment options for infections caused by KPC-producing K. pneumoniae (KPC-KP) are increasingly limited, particularly as these strains develop resistance to last-line antibiotics such as ceftazidime/avibactam and colistin. This study investigates the evolution of antibiotic resistance and persistence in a series of clonally related ST11 KPC-KP strains isolated from a single patient undergoing extended antimicrobial treatment. The patient, a 47-year-old male with a history of kidney transplantation, developed multiple KPC-KP lung infections during his hospital stay. Resistance to colistin and ceftazidime/avibactam emerged during treatment with these antibiotics. Key resistance mechanisms identified included the integration of ISKpn26 into mgrB gene, leading to mgrB inactivation and colistin resistance, and the emergence of novel blaKPC-2 variants (blaKPC-71 and blaKPC-179) that confer resistance to ceftazidime/avibactam. Despite the development of colistin resistance in a ceftazidime/avibactam-resistant KPC-KP strain following combination therapy, the patient's clinical condition significantly improved. Phenotypic assays showed that mgrB disruption in KPC-KP resulted in increased biofilm formation and higher susceptibility to phagocytosis. In mouse models, KPC-KP strains with mgrB disruption showed reduced virulence, increased lung colonization and persistence, and a lower inflammatory response, suggesting that mgrB disruption facilitates the transition from acute infection to colonization. This study highlights the complex interplay between antibiotic resistance and bacterial fitness, offering insights into why some patients experience clinical improvement despite severe drug resistance and incomplete bacterial clearance.

Biomass production of hairy vetch and Egyptian clover as affected by sowing dates under warm and hot semi-arid conditions

Abstract In Southern Africa, feed gaps towards the end of the cool–dry season are a challenge that needs addressing by the timely growth of suitable forage species. Therefore, we assessed the adaptation of the species vetch (Vicia villosa Roth) and Egyptian clover (Trifolium alexandrinum L.) with one cultivar of each. A fully irrigated experiment consisting of a factorial combination of species, sowing dates (early, late) and sites (warm and hot environments) was conducted across two separate cool–dry seasons. Data were collected at successive harvest dates (hd1, hd2 and hd3) i.e. about 50, 70 and 90 days after sowing, respectively. The accumulated aboveground biomass was affected by the effect of site × sowing date irrespective of harvest date. At hd3, aboveground biomass was further affected by the effect of site × species. Site-specific sensitivity to temperature, photoperiod and soil type influenced the vegetative development of the selected species. Early sowing compared to late sowing achieved about 60% higher biomass accumulation. The species effect was major with higher vetch biomass than clover (2943 v. 961 DM kg/ha), and (1459 v. 1066 DM kg/ha) at the warm and hot sites, respectively. Moreover, clover showed a lower DM response to irrigated water (4.7 against 13.5 kg DM/ha/mm) as compared to vetch. Thus, vetch was the better-adapted crop providing adequate biomass across harvest dates and under different environments. Adoption of these species to alleviate feed gaps is possible when irrigated; however, implementation of the genetic variability of cultivars should also be assessed.

The effects of different hormone combinations on the growth of Panax notoginseng anther callus based on metabolome analysis

Panax notoginseng saponins (PNS), the primary active components of Panax notoginseng (Burk.) F.H.Chen, a traditional and precious Chinese medicinal herb, are mainly derived from the roots of the plant. However, due to the long cultivation period and specific environmental requirements, the PNS supply is often limited. And, callus cultures of P. notoginseng, which grow rapidly, have short production cycles, and can be cultured under controlled conditions, provide a more efficient source for the quick acquisition of saponins. In this study, anthers of P. notoginseng were used as explants, and twelve hormone combinations were tested to induce callus formation. Eight kinds of hormone combinations successfully induced P. notoginseng anther callus. Among these, callus induced by combinations 5 and 7 had the highest saponin content, while those induced by combinations 1 and 3 exhibited the highest relative growth rates. Metabolomic analysis of these four callus types revealed that there were a total of 99 differential metabolites between combinations 5 and 7, 30 between combinations 1 and 3, 123 between combinations 3 and 7, and 116 between combinations 1 and 5. Further analysis showed that the tricarboxylic acid (TCA) cycle metabolites in callus induced by combinations 1 and 3 were significantly upregulated, with corresponding genes showing high expression levels, increased ATP accumulation, and low responses of the auxin response factor PnARF-3 and cytokinin response factor PnCRF-3. The abundance of metabolites in the PNS biosynthesis pathway in callus induced by combinations 5 and 7 increased significantly, with related genes showing high expression levels, increased IPP accumulation, and high responses of PnARF-3 and PnCRF-3. Overexpression of PnARF-3 and PnCRF-3 in callus induced by combination 3 promoted the production of IPP and saponins while reducing ATP production. In conclusion, different hormone combinations affect the distribution of Acetyl-CoA through PnARF-3 and PnCRF-3, resulting in the relative growth rate and saponin of P. notoginseng anther callus differences.

Design and Control of Radial Electromagnetic Bearing for Flywheel Battery

Abstract High rotational speed is the key to increasing energy storage capacity of flywheel battery. Non-contact bearing ensures reliable operation of high-speed flywheel battery. To design an electromagnetic bearing that meets the requirement of high-speed flywheel battery, firstly, a multi-parameters and multi-objectives optimization model for radial electromagnetic bearing is established. The optimization aims at the smallest spatial volume while ensuring electromagnetic force. A 16.58% reduction of the spatial volume is obtained. Furthermore, the influence of bias current and control current on the electromagnetic force and rotor displacement of radial magnetic bearing are analyzed. The bias current and control current that meet the requirements of current stiffness and displacement stiffness are determined. Based on this, a differential control model for radial magnetic bearing is constructed. Then, a controller based on adaptive discrete sliding mode control is designed. Finally, performance test and data analysis are completed. Results indicate that the designed radial electromagnetic bearing is able to achieve low response error, low system jitter and high robust under different test conditions. Compared with traditional sliding mode control method, under stochastic excitation, the maximum and average tracking errors of bearing displacement are reduced by 62.31% and 42.74%. The energy consumption is decreased by 49.32%.

Loss of AXIN1 regulates response to lenvatinib through a WNT/KDM5B/p15 signalling axis in hepatocellular carcinoma.

As a highly heterogeneous cancer, hepatocellular carcinoma (HCC) shows different response rates to the multi-kinase inhibitor lenvatinib. Thus, it is important to explore genetic biomarkers for precision lenvatinib therapy in HCC. The effect and mechanism of AXIN1 mutation on HCC were revealed by cell proliferation assay, long-term clone formation assay, sphere formation assay and small molecule inhibitor library screening. A new therapeutic strategy targeting HCC with AXIN1 mutation was evaluated in humanized models (patient-derived xenograft [PDX] and patient-derived organoid [PDO]). Based on The Cancer Genome Atlas (TCGA) data, we screened 6 most frequently lost tumour suppressor genes in HCC (TP53, ARID1A, AXIN1, CDKN2A, ARID2 and PTEN) and identified AXIN1 as the most crucial gene for lenvatinib sensitivity. Further study showed that AXIN1-knockout HCC cells had a more malignant phenotype and lower sensitivity to lenvatinib in vitro and in vivo. Mechanistically, the WNT pathway and its target gene c-Myc were activated when AXIN1 was missing, and the expression of tumour suppressor p15 was inhibited by transcription co-repressors c-Myc and Miz-1, resulting in the exacerbation of the resistant phenotype. Screening of a library of epigenetic-related enzyme inhibitors showed that a KDM5B inhibitor up-regulated p15 expression, leading to increased sensitivity to lenvatinib in vitro and in vivo. AXIN1-deficient patients have a lower response to lenvatinib, which may be associated with suppression of p15 mediated by WNT pathway activation. KDM5B inhibitors can restore p15 levels, resulting in efficient killing of resistant cells in HCC.

IDCNNPred: an interpretable deep learning model for virtual screening and identification of PI3Ka inhibitors against triple-negative breast cancer.

Triple-negative breast cancer (TNBC) lacks estrogen, progesterone, and HER2 expression, accounting for 15-20% of breast cancer cases. It is challenging due to low therapeutic response, heterogeneity, and aggressiveness. The PI3Ka isoform is a promising therapeutic target, often hyperactivated in TNBC, contributing to uncontrolled growth and cancer cell formation. We have proposed an interpretable deep convolutional neural network prediction (iDCNNPred) system using 2D molecular images to classify bioactivity and identify potential PI3Ka inhibitors. We built Custom-DCNN models and pre-trained models such as AlexNet, SqueezeNet, and VGG19 by using the Bayesian optimization algorithm, and found that our Custom-DCNN model performed better than a pre-trained model with lower complexity and memory usage. All top-performed models were screened with the Maybridge Chemical library to find predictive hit molecules. The screened molecules were further evaluated for protein-ligand interaction with molecular docking and finally 12 promising hits were shortlisted for biological validation using in-vitro PI3K inhibition studies. After biological evaluation, 4 potent molecules with different structural moieties were identified, and these molecules present new starting scaffolds for further improvement in terms of their potency and selectivity as PI3K inhibitors with the help of medicinal chemistry efforts. Furthermore, we also showed the significance of the interpretation and visualization of the model's predictions by the Grad-CAM technique, enhancing the robustness, transparency, and interpretability of the model's predictions. The data and script files and prediction run of models used for this study to reproduce the experiment are available in the GitHub repository at https://github.com/ravishankar1307/iDCNNPred.git .

The role of existential concerns in borderline personality disorder and their responsiveness to dialectical behaviour therapy

ABSTRACT Objectives Existential concerns (i.e. death anxiety, isolation, identity, meaninglessness, and guilt) have increasingly been linked to various mental health conditions. Two studies were conducted to examine whether these are relevant to borderline personality disorder (BPD) and whether they are ameliorated through dialectical behaviour therapy (DBT). Methods In Study 1, 175 people reporting a BPD diagnosis were administered measures of existential concerns and mental health difficulties. Correlational analyses were conducted to examine relationships between existential concerns and measures of mental health. In Study 2, these measures were completed at baseline and post-treatment by 22 outpatients undertaking a standalone 16-week DBT skills training (DBT-ST) group program. The percentage of participants who made a clinically reliable change on each existential concern was then calculated. Results Study 1 indicated that all five existential concerns were above community norms, and were significantly correlated with mental health outcomes in BPD (i.e. depression, anxiety, stress, emotion regulation difficulties). In Study 2, only 33.3% (4/12) of participants made a clinically reliable improvement in their overall existential concerns following a 16-week DBT-ST group intervention. Conclusions These findings suggest that existential issues are pronounced in BPD, but show low responsiveness to the DBT-ST group intervention examined in the current study. Further research should examine whether existentially-informed treatments may be more efficacious.

Study on vibration characteristics of anisotropic vehicle rubber bushings by conformal contact force analysis

For ride comfort and handling performance design of vehicles, anisotropic rubber bushings are used as the connection between lower arms and body frames. The nonlinear vibration performance with the deformation amplitude is advantageous to minimise vibration transmission at low magnitude responses and to reduce deformation at large excitations. During transient deformation, the area under the force-deformation curve serves as an indicator for evaluating vibration reduction and isolation performance. The elastomer geometric variables such as the relative radius between the inner and outer contact surfaces are effective design parameters for controlling bushing dynamic behaviour. This study presents a dynamic model to understand the nonlinear stiffness by the contact theory after addressing the actions between elastomer surfaces. The proposed model was confirmed by the measured dynamics stiffness and damping performance. Their influence on the vehicle ride comfort was investigated.

Intensity and volume of physical exercise influence DOMS and skin temperature differently in healthy adults

It remains unclear whether exercises leading to different outcomes of delayed onset muscle soreness (DOMS) may also elicit different skin temperature responses. The aim of this study was to determine whether different intensities and volumes of a single-joint exercise influence the DOMS and skin temperature measurements differently in healthy adults. Thirty-nine men and women were randomly assigned to three groups performing different exercise of different intensities and volumes (Exhaustion, Fatigue, Submaximal) to induce DOMS in the biceps brachii. DOMS (numeric pain rate scale, NPRS), pressure pain threshold (PPT) and skin temperature (infrared thermography, IRT) were measured on exercise day and 48 h later. The different exercises resulted in lower PPT responses 48 h after exercise and different DOMS reported across the different groups. Skin temperature outcomes did not differ following the different protocols. We found an increased minimum skin temperature 48 h after exercise in groups performing more intense exercises, but such differences were found in both exercised and non-exercised arms. Differently of PPT outcomes, pain reported depended on exercise intensity, and skin temperature 48 h after exercise could not show acute exercise adaptations. Skin temperature responses are contingent upon the characteristics of the participants rather than exercise intensity.

TIP60 enhances cisplatin resistance via regulating ΔNp63α acetylation in SCC

Non-melanoma skin cancer, including basal and squamous cell carcinoma, is the most common form of cancer worldwide, with approximately 5.4 million new cases diagnosed each year in the United States. While the chemotherapeutic drug cisplatin is often used to treat squamous cell carcinoma (SCC) patients, low response rates and disease recurrence are common. In this study, we show that TIP60 and ΔNp63α levels correlate with cisplatin resistance in SCC cell lines, suggesting that TIP60 contributes to the failure of platinum-based drugs in SCC by regulating the stability and transcriptional activity of ΔNp63α. Depletion of endogenous TIP60 or pharmacological inhibition of TIP60 led to a decrease in ΔNp63α protein and acetylation levels in multiple SCC cell lines. We showed that TIP60 upregulates ΔNp63α protein levels in cisplatin-resistant SCC cell lines by protecting it from cisplatin-mediated degradation and increasing its protein stability. Stable expression of TIP60 or ΔNp63α individually promoted resistance to cisplatin and reduced cell death, while loss of either TIP60 or ΔNp63α induced G2/M arrest, increased cell death, and sensitized cells to cisplatin. Moreover, pharmacological inhibition of TIP60 reduced acetylation of ΔNp63α and sensitized resistant cells to cisplatin. Taken together, our study indicates that TIP60-mediated stabilization of ΔNp63α increases cisplatin resistance and provides critical insights into the mechanisms by which ΔNp63α confers cisplatin resistance by promoting cell proliferation and inhibiting apoptosis. Furthermore, our data suggests that inhibition of TIP60 may be therapeutically advantageous in overcoming cisplatin resistance in SCC and other epithelial cancers.