Miracle-dz/UniFAR-FTUs huggingface dataset:
Inhibition of CD4/CDK6 enhances radiosensitivity of HPV negative head and neck squamous cell carcinomas Palbociclib radiosensitises HPV- HNSCC

Purpose: Human papillomavirus negative (HPV-ve) head and neck squamous cell carcinomas (HNSCC) have a poor prognosis compared to HPV+ve HNSCCs. Expression of p16 in HPV+ve HNSCC is thought to mediate radiosensitivity via inhibition of cyclin-dependent kinase (CDK) 4/6. We used a clinically approved CDK4/CDK6 inhibitor, palbociclib, and assessed its effect on radiosensitivity in HNSCC. Methods and Materials: The effect of palbociclib on radiosensitivity was determined in HPV-ve and +ve HNSCC cell lines using colony survival assays, immunofluorescent staining of repair proteins, homologous recombination (HR) assays, cell cycle and metaphase spread analyses. Results: Only HPV-ve HNSCC cells were radiosensitized by palbociclib, which also occurred at hypoxic levels associated with radioresistance. Palbociclib led to a decreased induction of BRCA1 and RAD51 after irradiation. HR was diminished and repair of radiation-induced DNA damage was delayed in the presence of palbociclib leading to increased chromosomal damage. Failure to repair radiation-induced damage led to cell death as a result of mitotic catastrophe. Conclusions: Here, we highlight a therapeutic strategy to improve the radiosensitivity of HPV-ve HNSCC, a patient group that has an unmet and urgent need for improved radiotherapy efficacy. G1 and G2 phases, and therefore present as a static population. As there was no observed decrease in S- of G2-phase, we concluded that the palbociclib-induced deficiency in HR was not cell cycle dependent. The finding that pre-incubation with palbociclib fails to radiosensitize HPV-ve HNSCC cells also indicates that the effect of palbociclib is independent of its effect on cell cycle. For future in vivo experiments, it will be important to address the dependency on phosphorylated RB for palbociclib-mediated radiosentivity, as we have shown that the timing of palbociclib and irradiation treatment is critical. Together, our data demonstrate that the combination of IR and palbociclib is extremely effective and leads to loss of cell viability and a failure to repair IR-induced DNA damage and subsequent mitotic catastrophe. Most importantly, we show that HPV status predicts the sensitivity to the combination of palbociclib and IR. The combination therapy described here could be relatively easily tested for the treatment of HPV-ve HNSCC, which currently urgently needs novel therapeutic strategies to improve patient prognosis.
Mineralogía magnética y registros de susceptibilidad en sedimentos cuaternarios de polaridad normal (Brunhes) y reversa (Matuyama) de la cantera de Juárez, provincia de Buenos Aires

Magnetic mineralogy and susceptibility records in Quaternary sediments of normal (Brunhes) and reverse (Matuyama) polarity in the Juarez quarry, Buenos Aires Province. Sediments exposed in the Juárez quarry of Buenos Aires Province (34o57’10’’S and 57o53’00’’ W), belong to the Pleistocene and Holocene. The sedimentary units are those of the Ensenada and Buenos Aires formations and the so-called Post-Pampean. The Ensenada Formation has reversed polarity (Matuyama) at the bottom of the exposed sequence and normal polarity (Brunhes) at the upper part, while the Buenos Aires Formation and Post-pampean sediments are of normal polarity (Brunhes). The highest susceptibility values were obtained in loess of the Ensenada Formation (189 x 10-8 m3/kg), and the lowest in sediments belonging to the Buenos Aires Formation (11 x 10-8 m3/kg) and in hydromorphic paleosols of the Ensenada Formation (30 to 50 x 10-8 m3/kg), both associated with climatic conditions of higher relative humidity. An increase in magnetic values in the coarseto medium-silt fractions reflects the dominance of vigorous winds as the main carrier of ferromagnetic minerals during arid periods (glacial periods). The frequency-dependent susceptibility (F factor) varies between 0 % and 6,45 %. The highest values, obtained in intensively weathered horizons (interglacial periods), are, however, intermediate compared with those of Siberia and China. This property allows us to suggest the existence of a third model of susceptibility behaviour related to changes of Quaternary paleoclimate: that of strong winds modified by pedological processes at middle latitudes.
Establishing Environmental Water Requirements for the Murray–Darling Basin, Australia's Largest Developed River System

There is a global need for management of river flows to be informed by science to protect and restore biodiversity and ecological function while maintaining water supply for human needs. However, a lack of data at large scales presents a substantial challenge to developing a scientifically robust approach to flow management that can be applied at a basin and valley scale. In most large systems, only a small number of aquatic ecosystems have been well enough studied to reliably describe their environmental water requirements. The umbrella environmental asset (UEA) approach uses environmental water requirements developed for information‐rich areas to represent the water requirements of a broader river reach or valley. We illustrate this approach in the Murray–Darling Basin (MDB) in eastern Australia, which was recently subject to a substantial revision of water management arrangements. The MDB is more than 1 million km2 with 18 main river valleys and many thousands of aquatic ecosystems. Detailed eco‐hydrologic assessments of environmental water requirements that focused on the overbank, bankfull and fresh components of the flow regime were undertaken at a total of 24 UEA sites across the MDB. Flow needs (e.g. flow magnitude, duration, frequency and timing) were established for each UEA to meet the needs of key ecosystem components (e.g. vegetation, birds and fish). Those flow needs were then combined with other analyses to determine sustainable diversion limits across the basin. The UEA approach to identifying environmental water requirements is a robust, science‐based and fit‐for‐purpose approach to determining water requirements for large river basins in the absence of complete ecological knowledge. © 2015 The Authors. River Research and Applications published by John Wiley & Sons, Ltd.
Regulation of p53 Family Member Isoform Δ Np63 α by the Nuclear Factor- κ B Targeting Kinase I κ B Kinase β

The p53 family gene p63 plays an instrumental role in cellular stress responses including responses to DNA damage. In addition to encoding a full-length transcriptional activator, p63 also encodes several dominant inhibitory isoforms including the isoform Δ Np63 α , the function of which is not fully understood. Δ Np63 α is degraded in response to DNA damage, thereby enabling an effective cellular response to genotoxic agents. Here, we identify a key molecular mechanism underlying regulation of Δ Np63 α expression in response to chemotherapeutic agents or tumor necrosis factor- α . We found that Δ Np63 α interacts with I κ B kinase (IKK), a multisubunit protein kinase that consists of two catalytic subunits, IKK α and IKK β , and a regulatory subunit, IKK γ . The IKK β kinase promotes ubiquitin-mediated proteasomal degradation of Δ Np63 α , whereas a kinase-deficient mutant IKK β -K44A fails to do so. Cytokine- or chemotherapy-induced stimulation of IKK β caused degradation of Δ Np63 α and augmented transactivation of p53 family – induced genes involved in the cellular response to DNA damage. Conversely, IKK β inhibition attenuated cytokine- or chemotherapy-induced degradation of Δ Np63 α . Our findings show that IKK β plays an essential role in regulating Δ Np63 α in response to extrinsic stimuli. IKK activation represents one mechanism by which levels of Δ Np63 α can be reduced, thereby rendering cells susceptible to cell death in the face of cellular stress or DNA damage. Res; 70(4); 1419 are stabilized and upregulated in response to genotoxic insults (UV radiation and chemotherapeutic agents), Δ Np63 α is degraded in response to these agents (11 – 13). This degradation of Δ Np63 α could augment the function of transactivating p53 family members and enable an effective cellular response to genotoxic agents (14). In this study, we identify a key molecular mechanism underlying the regulation of Δ Np63 α expressioninresponsetoex-trinsic stimuli, such as chemotherapeutic agents or tumor necrosis factor- α (TNF- α ). We show that Δ Np63 α interacts with I κ B kinase (IKK), a multisubunit protein kinase that consists of two catalytic subunits, IKK α and IKK β and a regulatory IKK γ κ B essential modifier We find that IKK β kinase promotes ubiquitin-mediated degradation of Δ Np63 α (17). Cytokine- or chemotherapy-induced stimulation of IKK leads to degradation of Δ Np63 α and aug-ments transactivation of p53 family – induced genes involved in the cellular response to DNA damage. Conversely, inhibition of IKK β with a NEMO-binding peptide or small interfering RNA (siRNA) – mediated silencing IKK β expression attenuates cytokine- or chemotherapy-induced degradation of Δ Np63 α . These data show that IKK β plays an essential role in regulating Δ Np63 α in response to extrinsic stimuli. Our findings suggest that the activation of IKK may be a mechanism by which levels of Δ Np63 α are reduced, thereby rendering the cells susceptible to cell death in the face of cellular stress or DNA damage.
Regulation of p53 Family Member Isoform Δ Np63 α by the Nuclear Factor- κ B Targeting Kinase I κ B Kinase β

The p53 family gene p63 plays an instrumental role in cellular stress responses including responses to DNA damage. In addition to encoding a full-length transcriptional activator, p63 also encodes several dominant inhibitory isoforms including the isoform Δ Np63 α , the function of which is not fully understood. Δ Np63 α is degraded in response to DNA damage, thereby enabling an effective cellular response to genotoxic agents. Here, we identify a key molecular mechanism underlying regulation of Δ Np63 α expression in response to chemotherapeutic agents or tumor necrosis factor- α . We found that Δ Np63 α interacts with I κ B kinase (IKK), a multisubunit protein kinase that consists of two catalytic subunits, IKK α and IKK β , and a regulatory subunit, IKK γ . The IKK β kinase promotes ubiquitin-mediated proteasomal degradation of Δ Np63 α , whereas a kinase-deficient mutant IKK β -K44A fails to do so. Cytokine- or chemotherapy-induced stimulation of IKK β caused degradation of Δ Np63 α and augmented transactivation of p53 family – induced genes involved in the cellular response to DNA damage. Conversely, IKK β inhibition attenuated cytokine- or chemotherapy-induced degradation of Δ Np63 α . Our findings show that IKK β plays an essential role in regulating Δ Np63 α in response to extrinsic stimuli. IKK activation represents one mechanism by which levels of Δ Np63 α can be reduced, thereby rendering cells susceptible to cell death in the face of cellular stress or DNA damage. Res; 70(4); 1419 are stabilized and upregulated in response to genotoxic insults (UV radiation and chemotherapeutic agents), Δ Np63 α is degraded in response to these agents (11 – 13). This degradation of Δ Np63 α could augment the function of transactivating p53 family members and enable an effective cellular response to genotoxic agents (14). In this study, we identify a key molecular mechanism underlying the regulation of Δ Np63 α expressioninresponsetoex-trinsic stimuli, such as chemotherapeutic agents or tumor necrosis factor- α (TNF- α ). We show that Δ Np63 α interacts with I κ B kinase (IKK), a multisubunit protein kinase that consists of two catalytic subunits, IKK α and IKK β , and a regulatory IKK γ κ B essential modifier We find that IKK β kinase promotes ubiquitin-mediated degradation of Δ Np63 α (17). Cytokine- or chemotherapy-induced stimulation of IKK leads to degradation of Δ Np63 α and aug-ments transactivation of p53 family – induced genes involved in the cellular response to DNA damage. Conversely, inhibition of IKK β with a NEMO-binding peptide or small interfering RNA (siRNA) – mediated silencing IKK β expression attenuates cytokine- or chemotherapy-induced degradation of Δ Np63 α . These data show that IKK β plays an essential role in regulating Δ Np63 α in response to extrinsic stimuli. Our findings suggest that the activation of IKK may be a mechanism by which levels of Δ Np63 α are reduced, thereby rendering the cells susceptible to cell death in the face of cellular stress or DNA damage.
How Big? The Impact of Approved Destination Status on Mainland Chinese Travel Abroad

China’s Approved Destination Status (ADS) policy governs foreign leisure travel by citizens to ADS-designated countries. To model the effects of ADS on Chinese visitor arrivals, we specify a model of demand for a representative Chinese consumer who values trips to n differentiated foreign destinations. Using panel data for Chinese visitor arrivals for 61 countries from 1985 to 2005, we estimate fixed effects models accounting for selection effects and a semiparametric matched difference-in-differences (DID) model. The semiparametric matched DID estimates indicate that ADS increased Chinese visitor arrivals annually by 10.5 to 15.7 percent in the three-year period following ADS designation.
Space‐time variability of ozone over the Indian region for the period 1981–1998

[1] The space-time variability of monthly mean total column ozone (TCO) over India has been studied for the period of 18 years from 1981 to 1998. TCO data at four stations, New Delhi (28.31°N, 77.12°E), Varanasi (25.20°N, 83.00°E), Pune (18.31°N, 73.55°E), and Kodaikanal (10.13°N, 77.36°E), Quasi-Biennial Oscillation (QBO) index data of 30 hPa at Singapore (1°N, 103°E), and F10.7 cm solar flux and Southern Oscillation index data for the above period are used in the study. The effects of the Quasi-Biennial Oscillation, solar cycle, and volcanic eruptions (El Chichon of 1982, Mount Pinatubo of 1991) on ozone variations have been examined. The multiple regression analysis and singular spectrum analysis of ozone time series (1981–1998) for four stations showed good association between ozone and global forcing parameters, namely QBO and solar cycle. TCO and QBO showed significant negative correlations for New Delhi, Varanasi, and Pune and positive correlation for Kodaikanal. All the stations showed significant positive correlations between TCO and solar flux.
A crack model of afterslip events on shallow faults

SUMMARY Post-seismic evolution of surface displacement on a strike slip fault is studied employing a linear viscous rheology for the shallow fault zone. A mathematical model is built in which the singular integral equation governing the equilibrium of cracks is transformed in an infinite-dimensional linear symmetric system whose positive eigenvalues define a sequence of characteristic relaxation times. The model lends to model vertical heterogeneities in the rheological parameters and the equations can be efficiently solved by truncation. Several specific problems are then considered in order to assess which parameters may govern the fast early relaxation observed in afterslip events in California. Neither stress heterogeneities, nor the spectral distribution of characteristic relaxation times have significant effects on surface displacement if a uniform effective viscosity is employed. Viscosity heterogeneities however, can provide fast early afterslip and, perhaps, precursory events. Post-seismic creep data following the 1966 Parkfield, the 1979 Imperial Valley and the 1987 Superstition Hill earthquakes can be fitted well with this model without resorting necessarily to non-linear rheological relations.
Kinetics and structural features of dimeric glutamine-dependent bacterial NAD (cid:2) synthetases suggest evolutionary adaptation to available metabolites

NADH (NAD (cid:2) ) and its reduced form NADH serve as cofac-tors for a variety of oxidoreductases that participate in many metabolic pathways. NAD (cid:2) also is used as substrate by ADP-ribosyl transferases and by sirtuins. NAD (cid:2) biosynthesis is one of the most fundamental biochemical pathways in nature, and the ubiquitous NAD (cid:2) synthetase (NadE) catalyzes the final step in this biosynthetic route. Two different classes of NadE have been described to date: dimeric single-domain ammonium-depen-dent NadE NH3 and octameric glutamine-dependent NadE Gln , and the presence of multiple NadE isoforms is relatively com-moninprokaryotes.Here,weidentifiedanoveldimericgroupof NadE Gln in bacteria. Substrate preferences and structural anal-yses suggested that dimeric NadE Gln enzymes may constitute evolutionaryintermediatesbetweendimericNadE NH3 andocta-meric NadE Gln . The characterization of additional NadE isoforms in the diazotrophic bacterium Azospirillum brasilense along with the determination of intracellular glutamine levels
Do subfossil Cladocera and chydorid ephippia disentangle Holocene climate trends?

We used sedimentary records of Cladocera and chydorid (Chydoridae) ephippia to reconstruct Holocene climate trends from Lake Arapisto in southern Finland. The quantitative temperature record (TJulyCla) inferred from subfossil Cladocera was compared with a previously published pollen-based mean annual temperature reconstruction (TAnn) from the same lake. Furthermore, proportions of total chydorid ephippia (TCE), indicating proportions of asexual and sexual reproduction, were examined from the sediment core to provide supplementary data. The TJulyCla record showed a consistent trend of slowly rising July temperatures (from 12–13°C to ~15°C) during the early Holocene until ~9500 cal. BP and indicated slightly higher temperatures than prior (~16°C) during the Holocene thermal maximum (HTM) at ~7000–4000 cal. BP. The TCE record was strongly similar to the TJulyCla reconstruction during the Holocene. It suggested that chydorids would have reproduced predominantly sexually (higher TCE) under environmentally unfavorable periods (early Holocene) and some other occasions, and used mainly asexual reproduction mode under periods of stable environmental conditions (HTM). The monotony of the Cladocera-based reconstruction, when compared with the previously available pollen-based TAnn record and other reference material from the adjacent region, suggests that it was partly hampered by other forcing factors more important than temperature, such as major food-web changes or adaptation ability of cladoceran species.
Semiparametric Accelerated Failure Time Models for Censored Data

An accelerated failure time (AFT) semiparametric regression model for censored data is analyzed as an alternative to the widely used proportional hazards survival model.The statistical inference is based on a nonparametric Bayesian approach that uses a Dirichlet process prior for the mixing distribution.Consistency of the posterior distribution of the regression parameters in the Euclidean metric is established under certain conditions.Finite sample parameter estimates along with associated measure of un-certainties can be computed by a MCMC method. Simulation studies are presented to provide empirical validation of the new method.Analysis of data from two studies are provided to show the easy applicability of the proposed method.
Melting upon cooling and freezing upon heating: Fluid-solid phase diagram for Svejk-Hasek model of dimerizing hard spheres

A simple model of dimerizing hard spheres with highly nontrivial fluid-solid phase behaviour is proposed. The model is studied using the recently proposed resummed thermodynamic perturbation theory for central force (RTPT-CF) associating potentials. The phase diagram has the fluid branch of the fluid-solid coexistence curve located at a temperatures lower than those of the solid branch. This unusual behaviour is related to the strong dependence of the system excluded volume on the temperature, which for the model at hand decreases with increasing temperature. This effect can be also seen for a wide family of fluid models with an effective interaction that combines short range attraction and repulsion at a larger distance. We expect that for sufficiently high repulsive barrier, such systems may show similar phase behaviour.
VU Research Portal Dimerization and signaling of the chemokine receptors CXCR3 and CCX-CKR

The chemokine receptor CXCR3 is a G-protein-coupled receptor that signals through the Gα i class of heterotrimeric G proteins. CXCR3 is highly expressed on activated T cells and has been proposed to be a therapeutic target in autoimmune disease. CXCR3 is activated by the chemokines CXCL9, CXCL10 and CXCL11. CXCR3 signaling properties in response to CXCL10, CXCL11 and the synthetic agonist VUF10661 have previously been evaluated using conventional endpoint assays. In the present study, label-free impedance measurements were used to characterize holistic responses of CXCR3-expressing cells to stimulation with chemokines and VUF10661 in real time and to compare these responses with both G protein and non-G protein (β-arrestin2) mediated responses. Differences in response kinetics were apparent between the chemokines and VUF10661. Moreover, CXCR3-independent effects could be distinguished from CXCR3-specific responses with the use of the selective CXCR3 antagonist NBI-74330 and the Gα i inhibitor pertussis toxin. By comparing the various responses, we observed that CXCL9 is a biased CXCR3 agonist, stimulating solely G-protein-dependent pathways. Moreover, CXCR3-mediated changes in cellular impedance correlated with G protein signaling, but not β-arrestin2 recruitment.
VU Research Portal Dimerization and signaling of the chemokine receptors CXCR3 and CCX-CKR

The chemokine receptors CXCR3 and CXCR4 are involved in various autoimmune diseases and cancers. Small antagonists have previously been shown to cross-inhibit chemokine binding to CCR2, CCR5, and CXCR4 heteromers. We investigated whether CXCR3 and CXCR4 can form heteromeric complexes and the binding characteristics of chemokines and small ligand compounds to these chemokine receptor heteromers. CXCR3-CXCR4 heteromers were identified in HEK293T cells using co-immunoprecipitation, time-resolved fluorescence resonance energy transfer, saturation bioluminescence resonance energy transfer, and the GPCR-HIT approach. Equilibrium competition binding and dissociation experiments were performed to detect negative binding co-operativity. We provide evidence that chemokine receptors CXCR3 and CXCR4 form heteromeric complexes in HEK293T cells. Chemokine binding was mutually exclusive on membranes co-expressing CXCR3 and CXCR4 as revealed by equilibrium competition binding and dissociation experiments. The small CXCR3 agonist VUF10661 impaired binding of CXCL12 to CXCR4, whereas small antagonists were unable to cross-inhibit chemokine binding to the other chemokine receptor. In contrast, negative binding co-operativity between CXCR3 and CXCR4 chemokines was not observed in intact cells. However, using the GPCR-HIT approach we have evidence for specific β-arrestin2 recruitment to CXCR3-CXCR4 heteromers in response to agonist stimulation. This study indicates that heteromeric CXCR3-CXCR4 complexes may act as functional units in living cells, which potentially open up novel therapeutic opportunities. GPCR results in a ligand-induced BRET signal indicates β-arrestin binding specifically to a heteromer complex. 19 Data analysis. Statistical analysis as well as nonlinear regression analysis of saturation BRET and radioligand binding data was performed using Prism 4.03 (GraphPad Software Inc, San Diego, CA). -conjugated anti-HA XL665-conjugated anti-FLAG