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Animals respond to environmental threats, e.g. looming visual stimuli, with innate defensive behaviors such as escape and freezing. The key neural circuits that participate in the generation of such dimorphic defensive behaviors remain unclear. Here we show that the dimorphic behavioral patterns triggered by looming visual stimuli are mediated by parvalbumin-positive (PV + ) projection neurons in mouse superior colliculus (SC). Two distinct groups of SC PV + neurons form divergent pathways to transmit threat-relevant visual signals to neurons in the parabigeminal nucleus (PBGN) and lateral posterior thalamic nucleus (LPTN). Activations of PV + SC-PBGN and SC-LPTN pathways mimic the dimorphic defensive behaviors. The PBGN and LPTN neurons are co-activated by looming visual stimuli. Bilateral inactivation of either nucleus results in the defensive behavior dominated by the other nucleus. Together, these data suggest that the SC orchestrates dimorphic defensive behaviors through two separate tectofugal pathways that may have interactions. In response to environmental threats, such as visual looming stimuli, mice either freeze or escape. Here the authors demonstrate that these two behaviors are mediated by separate tectofugal pathways formed by parvalbumin-positive neurons in the superior colliculus.

Olaparib is a poly(ADP-ribose) polymerase inhibitor and cediranib is an anti-angiogenic agent with activity against VEGF receptor (VEGFR) 1, VEGFR2, and VEGFR3. Both oral agents have antitumour activity in women with recurrent ovarian cancer, and their combination was active and had manageable toxicities in a phase 1 trial. We investigated whether this combination could improve progression-free survival (PFS) compared with olaparib monotherapy in women with recurrent platinum-sensitive ovarian cancer. In our randomised, open-label, phase 2 study, we recruited women (aged ≥18 years) who had measurable platinum-sensitive, relapsed, high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer, or those with deleterious germline BRCA1/2 mutations from nine participating US academic medical centres. We randomly allocated participants (1:1) according to permuted blocks, stratified by germline BRCA status and previous anti-angiogenic therapy, to receive olaparib capsules 400 mg twice daily or the combination at the recommended phase 2 dose of cediranib 30 mg daily and olaparib capsules 200 mg twice daily. The primary endpoint was progression-free survival analysed in the intention-to-treat population. The phase 2 trial is no longer accruing patients. An interim analysis was conducted in November, 2013, after 50% of expected events had occurred and efficacy results were unmasked. The primary analysis was performed on March 31, 2014, after 47 events (66% of those expected). The trial is registered with ClinicalTrials.gov, number NCT01116648. Between Oct 26, 2011, and June 3, 2013, we randomly allocated 46 women to receive olaparib alone and 44 to receive the combination of olaparib and cediranib. Median PFS was 17·7 months (95% CI 14·7–not reached) for the women treated with cediranib plus olaparib compared with 9·0 months (95% CI 5·7–16·5) for those treated with olaparib monotherapy (hazard ratio 0·42, 95% CI 0·23–0·76; p=0·005). Grade 3 and 4 adverse events were more common with combination therapy than with monotherapy, including fatigue (12 patients in the cediranib plus olaparib group vs five patients in the olaparib monotherapy group), diarrhoea (ten vs none), and hypertension (18 vs none). Cediranib plus olaparib seems to improve PFS in women with recurrent platinum-sensitive high-grade serous or endometrioid ovarian cancer, and warrants study in a phase 3 trial. The side-effect profile suggests such investigations should include assessments of quality of life and patient-reported outcomes to understand the effects of a continuing oral regimen with that of intermittent chemotherapy. American Recovery and Reinvestment Act grant from the National Institutes of Health (NIH) (3 U01 CA062490-16S2); Intramural Program of the Center for Cancer Research; and the Division of Cancer Treatment and Diagnosis, National Cancer Institute, NIH.

In recent years, the number of case reports concerning fluid-attenuated inversion recovery (FLAIR) hyperintense cortical lesions in myelin oligodendrocyte glycoprotein (MOG) -associated encephalitis with seizures (FLAMES) has been gradually increasing. However, within the pediatric demographic, there remains a lack of related serial reports. This study was designed to characterize the clinical features and prognosis of FLAMES in pediatric patients. We reviewed the medical records of children diagnosed with FLAMES from January 2019 to July 2024 and retrospectively analyzed their clinical manifestations, brain magnetic resonance imaging (MRI) findings, laboratory results, treatments, and outcomes. Among the 123 children diagnosed with MOG antibody-associated diseases (MOGAD), 9 (7.3%) met the inclusion criteria for FLAMES. The median onset age was 9 years (range: 8-14), and the male-to-female ratio was 5:4. The most common clinical symptoms included seizures (9/9, with 6 experiencing focal seizures), altered mental status (6/9), headache (5/9), fever (4/9), and focal neurological deficits (3/9). Furthermore, three patients presented with status epilepticus, two with cranial nerve involvement (central facial paralysis and lingual paralysis), and two with Todd's palsy. Seven patients had cerebrospinal fluid (CSF) pleocytosis (median count: 58/µL, range: 12-143/µL); two had elevated CSF pressure (range: 240-280 mmH2O); and one had mildly elevated CSF protein levels (0.46 g/L). All patients had normal CSF glucose levels. Abnormal electroencephalogram (EEG) findings were detected in seven patients: epileptic seizures (3/7), interictal discharges (6/7), and slow background activity (3/7). Unilateral cortical hyperintense lesions were observed in all nine cases on FLAIR imaging of brain MRI, affecting the frontal (8/9), parietal (3/9), temporal (2/9), and occipital (1/9) lobes. Five patients exhibited distinct linear enhancement of the corresponding cerebral sulci and/or meninges on gadolinium-enhanced brain MRI. All patients received immunotherapy, and six were administered anti-seizure medicines (ASMs). Each child achieved a satisfactory outcome and remained relapse-free at the final follow-up. FLAMES exhibit an age-dependent pattern. Epileptic seizures are the most common clinical symptom, with focal seizures being the predominant type. FLAIR-hyperintense cortical lesions typically present unilaterally, predominantly affecting the frontal lobes. Enhancement of the corresponding cerebral sulci and/or meninges may be a distinctive feature in children. For children with epilepsy, in the presence of recurrent seizures without identifiable triggers, especially when cortical lesions are detected in cranial MRI, consideration should be given to the possibility of FLAMES.

Idiopathic pulmonary fibrosis (IPF) has attracted considerable attention worldwide and is challenging to diagnose. Cuproptosis is a new form of cell death that seems to be associated with various diseases. However, whether cuproptosis-related genes (CRGs) play a role in regulating IPF disease is unknown. This study aims to analyze the effect of CRGs on the progression of IPF and identify possible biomarkers. Based on the GSE38958 dataset, we systematically evaluated the differentially expressed CRGs and immune characteristics of IPF disease. We then explored the cuproptosis-related molecular clusters, the related immune cell infiltration, and the biological characteristics analysis. Subsequently, a weighted gene co-expression network analysis (WGCNA) was performed to identify cluster-specific differentially expressed genes. Lastly, the eXtreme Gradient Boosting (XGB) machine-learning model was chosen for the analysis of prediction and external datasets validated the predictive efficiency. Nine differentially expressed CRGs were identified between healthy and IPF patients. IPF patients showed higher monocytes and monophages M0 infiltration and lower naive B cells and memory resting T CD4 cells infiltration than healthy individuals. A positive relationship was found between activated dendritic cells and CRGs of LIPT1, LIAS, GLS, and DBT. We also identified cuproptosis subtypes in IPF patients. Go and KEGG pathways analysis demonstrated that cluster-specific differentially expressed genes in Cluster 2 were closely related to monocyte aggregation, ubiquitin ligase complex, and ubiquitin-mediated proteolysis, among others. We also constructed an XGB machine model to diagnose IPF, presenting the best performance with a relatively lower residual and higher area under the curve (AUC= 0.700) and validated by external validation datasets (GSE33566, AUC = 0.700). The analysis of the nomogram model demonstrated that XKR6, MLLT3, CD40LG, and HK3 might be used to diagnose IPF disease. Further analysis revealed that CD40LG was significantly associated with IPF. Our study systematically illustrated the complicated relationship between cuproptosis and IPF disease, and constructed an effective model for the diagnosis of IPF disease patients.

Endoplasmic reticulum (ER) stress, a type of cellular stress, always occurs when unfolded or misfolded proteins accumulating in the ER exceed the protein folding capacity. Because of the demand for rapid viral protein synthesis after viral infection, viral infections become a risk factor for ER stress. The hepatocyte is a cell with large and well-developed ER, and hepatitis virus infection is widespread in the population, indicating the interaction between hepatitis viruses and ER stress may have significance for managing liver diseases. In this paper, we review the process that is initiated by the hepatocyte through ER stress against HBV and HCV infection and explain how this information can be helpful in the treatment of HBV/HCV-related diseases.

Diabetic ketoacidosis (DKA) is rare in pregnancy, especially in pregnant women with normal glucose tolerance examined in early pregnancy. Once DKA occurs in pregnancy, the disease progresses rapidly and can be life-threatening for both mother and fetus. We concluded three cases of DKA in late pregnancy. The clinical manifestations, progression, and prognosis of the three cases are different, but all of the cases have normal glucose tolerance. We summarized the characteristics of pregnant women with DKA and analyzed and discussed them in conjunction with literature for reference by clinical doctors. Keywords: diabetic ketoacidosis, pregnancy, gestational diabetes mellitus

Pulsating heat pipe (PHP) is an efficient heat transfer technology applied in the fields of heat dissipation and energy utilization. There are many factors affecting the heat transfer of PHP, including working fluid, filling ratio, inclination angle, etc. The cooling capacity of the cooling water system at the condensing section to the working fluid is also an important factor affecting the starting and operating of PHP. The research on PHP at different cooling water flow rates is of great significance for enhancing the operating performance. An experimental investigation of starting and running performance is carried out on a closed loop PHP with ultrapure water under different inclination angles of 90°, 60° and 30°. The starting and heat transfer performance of PHP with a filling ratio of 50% is obtained by adjusting the heat input in the range of 30–210 W at different cooling water flow rates of 6.7 g/s, 9.7 g/s and 13.9 g/s. The temperature and heat transfer resistance are used for analyzing the heat transfer performance. The results show that the starting mode, initial pulsating temperature and different heat transfer effects are brought about by different cooling water flow rates. It is observed that the cooling water flow rate has no obvious influence on the starting mode of PHP and that the starting mode of PHP is temperature progressive, starting with the increase in cooling water flow rates at a heating input of about 30 W. The influence of cooling water flow rates on the heat transfer performance of PHP is affected in a different way by inclination angles. The heat transfer performance of PHP with an inclination angle of 90° is similar at 6.7 g/s, 9.7 g/s and 13.9 g/s but, under the condition of 60° and 30°, the heat transfer resistance drops within a certain range effectively with an increasing cooling water flow rate from 6.7 g/s to 9.7 g/s and the heat transfer performance does not change significantly with the cooling water flow rate increasing to 13.9 g/s. Thus, there is an optimal value for the cooling water flow rate during the operating of PHP. The inclination angle also has an important effect on the temperature pulsating, and the temperature of PHP affected by gravity is stable with an inclination angle of 90°. However, the reduced influence of gravity on the backflow of the working fluid drops when the inclination angle decreases from 90° to 30°, and the wall temperature increases due to local overheating when the high heat input occurs.

Based on preclinical work, we found that combination of poly (ADP-ribose) polymerase (PARP) inhibitors with drugs that inhibit the homologous recombination repair (HRR) pathway (such as PI3K inhibitors) might sensitise HRR-proficient epithelial ovarian cancers to PARP inhibitors. We aimed to assess the safety and identify the recommended phase 2 dose of the PARP inhibitor olaparib in combination with the PI3K inhibitor alpelisib in patients with epithelial ovarian cancer and in patients with breast cancer. In this multicentre, open-label, phase 1b trial following a 3 + 3 dose-escalation design, we recruited patients aged 18 years or older with the following key eligibility criteria: confirmed diagnosis of either recurrent ovarian, fallopian tube, or primary peritoneal cancer of high-grade serous histology; confirmed diagnosis of either recurrent ovarian, fallopian tube, or primary peritoneal cancer of any histology with known germline BRCA mutations; confirmed diagnosis of recurrent breast cancer of triple-negative histology; or confirmed diagnosis of recurrent breast cancer of any histology with known germline BRCA mutations. Additional patients with epithelial ovarian cancer were enrolled in a dose-expansion cohort. Four dose levels were planned: the starting dose level of alpelisib 250 mg once a day plus olaparib 100 mg twice a day (dose level 0); alpelisib 250 mg once a day plus olaparib 200 mg twice a day (dose level 1); alpelisib 300 mg once a day plus olaparib 200 mg twice a day (dose level 2); and alpelisib 200 mg once a day plus olaparib 200 mg twice a day (dose level 3). Both drugs were administered orally, in tablet formulation. The primary objective was to identify the maximum tolerated dose and the recommended phase 2 dose of the combination of alpelisib and olaparib for patients with epithelial ovarian cancer and patients with breast cancer. Analyses included all patients who received at least one dose of the study drugs. The trial is active, but closed to enrolment; follow-up for patients who completed treatment is ongoing. This trial is registered with ClinicalTrials.gov, number NCT01623349. Between Oct 3, 2014, and Dec 21, 2016, we enrolled 34 patients (28 in the dose-escalation cohort and six in the dose-expansion cohort); two in the dose-escalation cohort were ineligible at the day of scheduled study initiation. Maximum tolerated dose and recommended phase 2 dose were identified as alpelisib 200 mg once a day plus olaparib 200 mg twice a day (dose level 3). Considering all dose levels, the most common treatment-related grade 3–4 adverse events were hyperglycaemia (five [16%] of 32 patients), nausea (three [9%]), and increased alanine aminotransferase concentrations (three [9%]). No treatment-related deaths occurred. Dose-limiting toxic effects included hyperglycaemia and fever with decreased neutrophil count. Of the 28 patients with epithelial ovarian cancer, ten (36%) achieved a partial response and 14 (50%) had stable disease according to Response Evaluation Criteria in Solid Tumors 1.1. Combining alpelisib and olaparib is feasible with no unexpected toxic effects. The observed activity provides preliminary clinical evidence of synergism between olaparib and alpelisib, particularly in epithelial ovarian cancer, and warrants further investigation. Ovarian Cancer Dream Team (Stand Up To Cancer, Ovarian Cancer Research Alliance, National Ovarian Cancer Coalition), Breast Cancer Research Foundation, Novartis.

Effects of time and height of shading on the sunburn rate, yield and quality of pineapples were investigated in order to provide a theoretical basis for high-quality pineapple production. Golden pineapple was used as the material, and three shading times (30 d, 45 d, and 60 d after flower-fading), and the heights of 0 cm, 20 cm, and 40 cm (the distance from the top of the plant) were set. Golden pineapple's internal and external fruit qualities were measured. The results showed that the incidence of sunburn of pineapple fruits increased with the delay of the shading time, and no differences were found among three heights at 30 d after flower fading. When pineapple plants were shaded at 30 d after flower fading and at height of 0 cm, pineapple fruits showed good external qualities, including larger fruit size, less fruit eyes, less fruit shape index, larger fruit hardness, higher edible rate and good internal qualities, including higher soluble solid content, higher soluble sugar content and lower total acidity. Shading at 30 d after flower fading and at height of 0 cm was suggested in pineapple production.