A tera-electron volt afterglow from a narrow jet in an extremely bright gamma-ray burst.

Some gamma-ray bursts (GRBs) have a tera-electron volt (TeV) afterglow, but the early onset of this has not been observed. We report observations with the Large High Altitude Air Shower Observatory (LHAASO) of the bright GRB 221009A, which serendipitously occurred within the instrument's field of view. More than 64,000 photons >0.2 TeV were detected within the first 3000 seconds. The TeV flux began several minutes after the GRB trigger and then rose to a peak ~10 seconds later. This was followed by a decay phase, which became more rapid ~650 seconds after the peak. We interpret the emission using a model of a relativistic jet with half-opening angle of ~0.8°. This is consistent with the core of a structured jet and could explain the high isotropic energy of this GRB.

Constraints on Heavy Decaying Dark Matter from 570 Days of LHAASO Observations.

The kilometer square array (KM2A) of the large high altitude air shower observatory (LHAASO) aims at surveying the northern γ-ray sky at energies above 10 TeV with unprecedented sensitivity. γ-ray observations have long been one of the most powerful tools for dark matter searches, as, e.g., high-energy γ rays could be produced by the decays of heavy dark matter particles. In this Letter, we present the first dark matter analysis with LHAASO-KM2A, using the first 340 days of data from 1/2-KM2A and 230 days of data from 3/4-KM2A. Several regions of interest are used to search for a signal and account for the residual cosmic-ray background after γ/hadron separation. We find no excess of dark matter signals, and thus place some of the strongest γ-ray constraints on the lifetime of heavy dark matter particles with mass between 10^{5} and 10^{9} GeV. Our results with LHAASO are robust, and have important implications for dark matter interpretations of the diffuse astrophysical high-energy neutrino emission.

[Regulation effect of siRNA on ß-globin in erythrocytes of hemoglobin H disease].

Objective: To investigate the regulatory effect of targeted siRNA on ß-globin in erythroid cells cultured by targeted differentiation in vitro and provide new theoretical support for gene therapy for hemoglobin H (HbH) disease. Methods: Based on the ß-globin gene expression results, the optimal siRNA sequence and its effective action dose were screened in erythroid cells, and the effect of the effective dose of the optimal siRNA on the regulation of ß-globin expression and apoptosis in erythroid cells was examined. The effective dose of the optimal siRNA was applied to erythroid cells with HbH disease. The effects of transfected siRNAs on red line cells with HbH disease were comprehensively evaluated by measuring the expression of ß-globin, reactive oxygen species (ROS) , and apoptosis rates. Results: Within 96 hours after transfection, siRNA2 significantly downregulated ß-globin expression in in vitro cultured erythroid cells, but not α-globin. siRNA silencing effect and duration of effect were dose-dependent. siRNA2 downregulated ß-globin expression, reduced intracellular ROS production, and decreased apoptosis rate in erythroid cells with HbH disease. Conclusion: Targeted siRNAs can downregulate ß-globin expression, reduce intracellular ROS production, and downregulate apoptosis rate in erythroid cells with HbH disease.

A mixed-methods study to explore the supportive care needs of breast cancer survivors.

OBJECTIVE: Needs assessment is the essence of quality cancer survivorship care. The aim of this study was to explore the supportive care needs of breast cancer survivors (BCS) in the first 5 years post treatment. METHODS: A mixed-methods approach was employed. A quantitative study included a Supportive Care Needs Survey, which was completed by 250 BCS to identify the level of their needs for help. The quantitative data informed semistructured qualitative interviews undertaken with 60 BCS to explore in detail their posttreatment needs and experiences. RESULTS: 32.4% and 16.8% reported 1 to 5 and greater than or equal to 6 needs for help, respectively. The regression analyses revealed that women within 2 years posttreatment and with higher educational level had higher levels of Psychological and Health Care System/Information needs. The qualitative data revealed "continuity of care" and "lifestyle advice and self-management" as prominent survivorship concerns. It was shown that determination to continue normal life, social support, and feeling overwhelmed by information were all experienced as important influences on survivors' need for help. CONCLUSIONS: Posttreatment needs vary with BCS characteristics and to the domains concerned. The approach to posttreatment care needs to be personalized and viable.

Comparison of two stroke volume variation-based goal-directed fluid therapies for supratentorial brain tumour resection: a randomized controlled trial.

Background: The optimal volume status for neurosurgery has yet to be determined. We compared two fluid protocols based on different stroke volume variation (SVV) cut-offs for goal-directed fluid therapy (GDFT) during supratentorial brain tumour resection. Methods: A randomized, single-blind, open-label trial was conducted. Eighty adult patients undergoing elective supratentorial brain tumour resection were randomly divided into a low SVV and a high SVV group. The SVV cut-offs were used to determine when to initiate colloid infusion. Clinical outcomes and perioperative changes in serum neuronal biomarkers, including S100ß, neurone-specific enolase (NSE) and glial fibrillary acidic protein (GFAP), were compared. Results: Patients in the low SVV group received a higher volume of colloid [869 (SD 404) vs 569 (453) ml; P=0.0025], had a higher urine output [3.4 (2.4) vs 2.5 (1.7) ml kg-1 h-1; P=0.0416] and a higher average cardiac index [3.2 (0.7) vs 2.8 (0.6) litres min-1 m-2; P=0.0204]. Patients in the low SVV group also had a shorter intensive care unit stay [1.4 (0.7) vs 2.6 (3.3) days, P=0.0326], fewer postoperative neurological events (17.5 vs 40%, P=0.0469), attenuated changes in the NSE and GFAP levels, lower intraoperative serum lactate and a higher Barthel index at discharge (all P<0.05). Conclusions: During GDFT for supratentorial brain tumour resection, fluid boluses targeting a lower SVV are more beneficial than a restrictive protocol. Clinical trial registration: NCT02113358.

Exploring the regulatory role of isocitrate dehydrogenase mutant protein on glioma stem cell proliferation.

OBJECTIVE: Glioma is the most lethal form of cancer that originates mostly from the brain and less frequently from the spine. Glioma is characterized by abnormal regulation of glial cell differentiation. The severity of the glioma was found to be relaxed in isocitrate dehydrogenase 1 (IDH1) mutant. The present study focused on histological discrimination and regulation of cancer stem cell between IDH1 mutant and in non-IDH1 mutant glioma tissue. PATIENTS AND METHODS: Histology, immunohistochemistry and Western blotting techniques are used to analyze the glioma nature and variation in glioma stem cells that differ between IDH1 mutant and in non-IDH1 mutant glioma tissue. RESULTS: The aggressive form of non-IDH1 mutant glioma shows abnormal cellular histological variation with prominent larger nucleus along with abnormal clustering of cells. The longer survival form of IDH1 mutant glioma has a control over glioma stem cell proliferation. Immunohistochemistry with stem cell markers, CD133 and EGFRvIII are used to demonstrate that the IDH1 mutant glioma shows limited dependence on cancer stem cells and it shows marked apoptotic signals in TUNEL assay to regulate abnormal cells. The non-IDH1 mutant glioma failed to regulate misbehaving cells and it promotes cancer stem cell proliferation. CONCLUSIONS: Our finding supports that the IDH1 mutant glioma has a regulatory role in glioma stem cells and their survival.

Chloroquine alleviates etoposide-induced centrosome amplification by inhibiting CDK2 in adrenocortical tumor cells.

The antitumor drug etoposide (ETO) is widely used in treating several cancers, including adrenocortical tumor (ACT). However, when used at sublethal doses, tumor cells still survive and are more susceptible to the recurring tumor due to centrosome amplification. Here, we checked the effect of sublethal dose of ETO in ACT cells. Sublethal dose of ETO treatment did not induce cell death but arrested the ACT cells in G2/M phase. This resulted in centrosome amplification and aberrant mitotic spindle formation leading to genomic instability and cellular senescence. Under such conditions, Chk2, cyclin A/CDK2 and ERK1/2 were aberrantly activated. Pharmacological inactivation of Chk2, CDK2 or ERK1/2 or depletion of CDK2 or Chk2 inhibited the centrosome amplification in ETO-treated ACT cells. In addition, autophagy was activated by ETO and was required for ACT cell survival. Chloroquine, the autophagy inhibitor, reduced ACT cell growth and inhibited ETO-induced centrosome amplification. Chloroquine alleviated CDK2 and ERK, but not Chk2, activation and thus inhibited centrosome amplification in either ETO- or hydroxyurea-treated ACT cells. In addition, chloroquine also inhibited centrosome amplification in osteosarcoma U2OS cell lines when treated with ETO or hydroxyurea. In summary, we have demonstrated that chloroquine inhibited ACT cell growth and alleviated DNA damage-induced centrosome amplification by inhibiting CDK2 and ERK activity, thus preventing genomic instability and recurrence of ACT.

USPIO-related T1 and T2 mapping MRI of cartilage in a rabbit model of blood-induced arthritis: a pilot study.

Ultrasmall paramagnetic iron oxide (USPIO)-enhanced MRI is promising for evaluating inflammation. The aims of this study were to investigate the effect of USPIO on cartilage T1 and T2 mapping, and to evaluate a proposed rapid vs. conventional T2 map method for imaging cartilage in a blood-induced arthritis model. Knees of nine arthritic (induction by intra-articular autologous blood injection) and six control rabbits were imaged over time (baseline, weeks 1, 5, 10) by 1.5 T MRI. All rabbits had USPIO (35-75 µmol Fe/kg)-enhanced MRI at each time point. T1 and T2 (conventional and rapid) maps and signal-to-noise ratios (SNR) were obtained pre- and post-USPIO administration. Cartilage biochemistry and histology were compared with MRI. Excellent correlations were noted between T1 map values and histologic scores at week 10 pre-USPIO (medial, r = 0.93, P = 0.0007; lateral, r = 0.87, P = 0.005) in the arthritic group, but not between T2 map and histology. Marginally and significant differences were observed between pre- and post-USPIO T2 values at weeks 5 (P = 0.06) and 10 (P = 0.02), but only with the administration of high USPIO doses in the arthritic group using the conventional method. No significant differences were noted between pre- and post-USPIO T1 values at any imaging time points. Cartilage T2 maps with short-TR and conventional protocols provided similar T2 values [(decreased trend)] (P > 0.05). Concomitant use of USPIO to T1 and T2 mapping of cartilage would not impair the identification of interval changes of T1 and T2 maps. Rapid T2 map provides similar results compared to conventional method, but its validation warrants further investigation.

A candidate gene approach for identifying differential iron responses in young overweight women to an energy-restricted haem iron-rich diet.

Although iron deficiency is common in women especially during dieting, weight management trials rarely examine the longitudinal impact of genetics on iron. This study examined the associations between the TMPRSS6 rs855791 polymorphism and iron indices at baseline and after a 12-month trial comparing two weight loss diets (higher-protein, higher-haem iron (HPHI) vs lower-protein, lower-haem iron (LPLI)). A total of 76 young overweight women (18-25y; BMI⩾27.5 kg/m(2)) were included at baseline, with 27 (HPHI: n=15; LPLI: n=12) completing the 12-month trial. At baseline, C allele homozygotes exhibited higher serum iron (P=0.047) and lower hepcidin (P=0.023) compared with T allele carriers. After 12 months, no genotypic differences were observed for ferritin and soluble transferrin receptor, although C homozygotes on HPHI showed higher serum iron and transferrin saturation (P<0.05). Results indicate that rs855791 can influence iron metabolism to some extent, but its impact on storage and functional iron status is small relative to dietary protein/iron manipulation.

Higher protein diet for weight management in young overweight women: a 12-month randomized controlled trial.

UNLABELLED: Clinical research on weight management in young women is limited. This randomized controlled trial compared the efficacy of two iso-energetically restricted (5600 kJ) diets [higher protein (HP): 32% protein, 41% carbohydrate, 25% fat or higher carbohydrate (HC): 20, 58, 21%, respectively] in 71 (HP: n = 36; HC: n = 35) young healthy women (18-25 years; body mass index ≥ 27.5 kg/m2) for weight (kg; percent weight loss), body composition, metabolic and iron changes assessed at baseline, 6 and 12 months. DATA: mean (95% CI). In HP completers at 6 months, percent weight loss was higher [HP: 9.3 (5.6-13.1); HC: 5.1 (2.3-7.9)%; p = 0.06]; although, this did not reach statistical significance. Absolute weight [HP: 8.9 (5.3-12.5); HC: 4.6 (2.2-7.0) kg; p = 0.034] and fat loss [HP: 8.0 (4.4-11.5); HC: 3.4 (1.3-5.6) kg; p = 0.022] were significantly greater. No significant between-diet differences were observed at 12 months. Biochemistry remained within normal ranges with HP showing superior preservation of ferritin at 6 months [HP: 53 (40-66); HC: 46 (30-61) µg/l; p = 0.029]. Both diets supported clinically meaningful weight loss with HP tending to be more effective in the medium-term.

Streptococcus agalactiae infective endocarditis with large vegetation in a patient with underlying protein S deficiency.

We present a case of a patient with underlying protein S deficiency who suffered from infective endocarditis with a large anterior mitral leaflet (AML) mass of approximately 4.5 cm in length. Intraoperative transesophageal echocardiography (TEE) revealed the mass at the AML base and a rupture of the posterior mitral leaflet chordae tendinae. The vegetation's large size may have been caused by one or more of three factors: location, underlying disease, and the microorganism causing infection. Patients with protein S deficiency are prone to thromboembolic events during cardiac surgery. Infective endocarditis caused by Streptococcus agalactiae usually has a poor prognosis, and, thus, early surgery is recommended.

The relationship between obesity and hypoferraemia in adults: a systematic review.

A growing number of studies suggest a potential link between obesity and altered iron metabolism. The purpose of this systematic review was to examine existing literature on iron status in obese populations. A comprehensive literature search was conducted. Included studies recruited participants ≥ 18 years with a body mass index ≥ 30 kg m(-2) and provided descriptive statistics for haemoglobin or ferritin at a minimum. There were 25 studies meeting all eligibility criteria, of these 10 examined iron status in free-living obese individuals and 15 reported baseline iron biomarkers from bariatric surgery candidates. Non-obese comparison groups were used by 10 (40%) articles. In these, seven obese groups reported higher mean haemoglobin concentration; six reported significantly higher ferritin concentration; and four significantly lower transferrin saturation. Due to insufficient data, it was not possible to make conclusions regarding mean differences for soluble transferrin receptor (sTfR), hepcidin or C-reactive protein. Existing evidence suggests a tendency for higher haemoglobin and ferritin concentration and lower transferrin saturation in obesity. Alternation of iron biomarkers in obese populations may be a result of obesity-related inflammation and/or related comorbidities. Further research incorporating measurement of inflammatory cytokines, sTfR and hepcidin is required to confirm the impact of obesity on iron status.

Diode-pumped passively mode-locked 1,342 nm Nd:YVO4 laser with an AlGaInAs quantum-well saturable absorber.

We demonstrate what we believe to be the first use of AlGaInAs quantum wells (QWs) as a saturable absorber for a diode-pumped passively mode locked Nd:YVO(4) laser at 1342 nm. The QWs are grown on a Fe-doped InP substrate that is transparent at lasing wavelength. At an incident pump power of 13.5 W an average output power of 1.05 W with a continuous mode-locked pulse duration of 26.4 ps at a repetition rate of 152 MHz was generated.

Antioxidative activities and the total phenolic contents of tonic Chinese medicinal herbs.

Chinese medicated diet is an everyday practice in China. In this study, 16 commonly used soup making tonic Chinese medicinal herbs were selected for antioxidative capacities by 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging activity and ferric reducing antioxidant power (FRAP), and the total phenolic contents of these herbal extracts were measured by the Folin-Ciocalteu method. It confirmed that drinking tonic soups could supplement total antioxidants intake. Amongst the tested herbal extracts, extracts of Canarium album Raeusch., Flos caryophylli and Fructus amomi were found to have the highest antioxidative activities in both DPPH and FRAP assays. Their antioxidative activities were comparable to ascorbic acid and butylated hydroxytoluene. Thus, these herbs are safe and inexpensive sources of natural antioxidants. A significant relationship between the antioxidative effects and total phenolic contents were found, indicating phenolic compounds are the major contributor of antioxidative capacities of these herbs. In addition, a strong correlation between DPPH assay and FRAP assay implied that antioxidants in these herbs were capable of scavenging free radicals and reducing oxidants.

Cholinergic-receptor-independent dysfunction of mitochondrial respiratory chain enzymes, reduced mitochondrial transmembrane potential and ATP depletion underlie necrotic cell death induced by the organophosphate poison mevinphos.

Our current understanding of the nature of cell death that is associated with fatal organophosphate poisoning and the underlying cellular mechanisms is surprisingly limited. Taking advantage of the absence in an in vitro system of acetylcholinesterase, the pharmacological target of organophosphate compounds, the present study evaluated the hypothesis that the repertoire of cholinergic receptor-independent cellular events that underlie fatal organophosphate poisoning entails induction of mitochondrial dysfunction, followed by bioenergetic failure that leads to necrotic cell death because of ATP depletion. Pheochromocytoma PC12 cells incubated with the organophosphate pesticide mevinphos (0.4 or 4mumol) for 1 or 3h underwent a dose-related and time-dependent loss of cell viability that was not reversed by muscarinic (atropine) or nicotinic (mecamylamine) blockade. This was accompanied by depressed NADH cytochrome c reductase, succinate cytochrome c reductase or cytochrome c oxidase activity in the mitochondrial respiratory chain, reduced mitochondrial transmembrane potential, decreased ATP concentration, elevated ADP/ATP ratio, increased lactate dehydrogenase release and necrotic cell death. We conclude that Mev induces cholinergic receptor-independent necrotic cell death by depressing the activity of Complexes I to IV in the mitochondrial respiratory chain, eliciting reduction in mitochondrial transmembrane potential, depleting intracellular ATP contents and damaging cell membrane integrity.

Phytotoxicity of lanthanum in rice in haplic acrisols and cambisols.

Growth and physiological responses of rice to lanthanum were studied to elucidate the function of lanthanum in plants and its critical concentration relative to environmental safety. Shoot La content increased with the increasing added La concentrations. When shoot La content exceeded a toxic value, plant growth and chlorophyll a/b decreased and peroxidase (POD) activity, cell membrane permeability, and content of proline in the leaf increased. Leaf chlorophyll a/b and POD activity might provide useful criteria for early diagnoses of phytotoxicity of soil contaminated by La. In the present study, the critical concentration of La for rice relative to environmental safety was suggested to be 42.03 mg kg(-1) in red soil and 83.33 mg kg(-1) in paddy soil.

Co-expression of RON and MET is a prognostic indicator for patients with transitional-cell carcinoma of the bladder.

Recepteur d'Origine Nantais (RON) is a distinct receptor tyrosine kinase in the c-met proto-oncogene family. We examined the mutational and expression patterns of RON in eight human uroepithelial cell lines. Biological effects of RON overexpression on cancer cells were investigated in vitro, and the prognostic significance of RON and/or c-met protein (MET) expression was analysed in a bladder cancer cohort (n=183). There was no evidence of mutation in the kinase domain of RON. Overexpression of RON using an inducible Tet-off system induced increased cell proliferation, motility, and antiapoptosis. Immunohistochemical analysis showed that RON was overexpressed in 60 cases (32.8%) of primary tumours, with 14 (23.3%) showing a high level of expression. Recepteur d'Origine Nantais expression was positively associated with histological grading, larger size, nonpapillary contour, and tumour stage (all P<0.01). In addition, MET was overexpressed in 82 cases (44.8%). Co-expressed RON and MET was significantly associated with decreased overall survival (P=0.005) or metastasis-free survival (P=0.01) in 35 cases (19.1%). Recepteur d'Origine Nantais-associated signalling may play an important role in the progression of human bladder cancer. Evaluation of RON and MET expression status may identify a subset of bladder-cancer patients who require more intensive treatment.