Miracle-dz/UniFAR-FTUs huggingface dataset:
Panitumumab interaction with TAS‐102 leads to combinational anticancer effects via blocking of EGFR‐mediated tumor response to trifluridine

Panitumumab is a monoclonal antibody developed against the human epidermal growth factor receptor (EGFR). TAS‐102 is a novel chemotherapeutic agent containing trifluridine (FTD) as the active cytotoxic component. Both panitumumab and TAS‐102 have been approved for the treatment of metastatic colorectal cancer. In this study, we revealed the mechanism underlying the anticancer effects of panitumumab/TAS‐102 combination using preclinical models. Panitumumab/FTD cotreatment showed additive antiproliferative effects in LIM1215 and synergistic antiproliferative effects in SW48 colon cancer cells. Consistent with the in vitro effects, panitumumab/TAS‐102 combination caused tumor regression in LIM1215 and COL‐01‐JCK colon cancer patient‐derived xenograft models. In LIM1215 cells, FTD induced extracellular signal‐regulated kinase (ERK)/protein kinase B (AKT)/signal transducer and activator of transcription 3 (STAT3) phosphorylation and subsequent serine/threonine phosphorylation of EGFR, while it had no effects on EGFR tyrosine phosphorylation. Panitumumab and the tyrosine kinase inhibitor erlotinib reduced the basal level of EGFR tyrosine phosphorylation and reversed FTD‐induced ERK/AKT/STAT3 and EGFR serine/threonine phosphorylation. These results suggested that FTD in combination with the basal activity of EGFR tyrosine kinase induced downstream prosurvival signaling through ERK/AKT/STAT3 phosphorylation. Collectively, we propose that panitumumab interacts with FTD by targeting EGFR‐mediated adaptive responses, thereby exerting anticancer effects when used in combination with TAS‐102. These preclinical findings provide a compelling rationale for evaluating the combination of anti‐EGFR antibodies with TAS‐102 against metastatic colorectal cancer.
Neogene Epeirogeny of Iberia

The origin of Iberia's topography is examined by combining gravity, magmatic, topographic, and seismological observations with geomorphic considerations. We have four principal results. First, the highest coherence between free‐air gravity and topography is at wavelengths ≲ 250 km where admittance indicates that elastic thickness of Iberia's plate is 20 ± 3 km. These results imply that flexural and subplate support of Iberian topography could be expressed at wavelengths of O(100) km. Second, P‐to‐S receiver functions and simple isostatic calculations indicate that while crustal thickness variations and flexural loading (e.g., as a result of plate shortening) partially explain the elevation of Pyrenean, Betics, Cantabrian, Spanish Central System, and Iberian Chain topography, they fail to explain the elevation of large parts of Iberia. Third, a new full waveform shear wave tomographic model and velocity to temperature conversions suggest that the asthenosphere beneath Iberia is anomalously slow and has excess temperatures of up to 162 ± 14 °C. Simple isostatic calculations indicate asthenospheric support of topography of up to 1 km. Neogene‐Recent (∼23–0 Ma) extrusive magmatism (e.g., Calatrava, Catalan) sit atop many of the slow shear wave velocity anomalies. Finally, biostratigraphic data, combined with inversion of 3,217 river profiles, show that most of Iberia's topography grew during the last ∼30 Ma at rates of up to 0.3 mm/year. Best‐fitting theoretical rivers have a low residual root‐mean‐square misfit (=0.96) and calculated uplift is consistent with an independent inventory of stratigraphic and biostratigraphic observations. We suggest that Neogene‐Recent growth of most of central Iberia's topography was a result of asthenospheric support.
Fermi-LAT Observations of Markarian 421: the Missing Piece of its Spectral Energy Distribution

We report on the gamma-ray activity of the high-synchrotron-peaked BL Lacertae object Mrk 421 during the first 1.5 years of Fermi operation, from 2008 August 5 to 2010 March 12. We find that the Large Area Telescope (LAT) gamma-ray spectrum above 0.3 GeV can be well-described by a power-law function with photon index Gamma=1.78 +/- 0.02 and average photon flux F(>0.3 GeV)=(7.23 +/- 0.16) x 10^{-8} ph cm^{-2} s^{-1}. Over this time period, the Fermi-LAT spectrum above 0.3 GeV was evaluated on 7-day-long time intervals, showing significant variations in the photon flux (up to a factor ~3 from the minimum to the maximum flux), but mild spectral variations. The variability amplitude at X-ray frequencies measured by RXTE/ASM and Swift/BAT is substantially larger than that in gamma-rays measured by Fermi-LAT, and these two energy ranges are not significantly correlated. We also present the first results from the 4.5-month-long multifrequency campaign on Mrk 421, which included the VLBA, Swift, RXTE, MAGIC, the F-GAMMA, GASP-WEBT, and other collaborations and instruments which provided excellent temporal and energy coverage of the source throughout the entire campaign (2009 January 19 to 2009 June 1). During this campaign, Mrk 421 showed a low activity at all wavebands. The extensive multi-instrument (radio to TeV) data set provides an unprecedented, complete look at the quiescent spectral energy distribution (SED) for this source. The broad band SED was reproduced with a leptonic (one-zone Synchrotron Self-Compton) and a hadronic model (Synchrotron Proton Blazar). Both frameworks are able to describe the average SED reasonably well, implying comparable jet powers but very different characteristics for the blazar emission site.
Nanosecond pulsed electric fields: Microdosimetry on single cells

A microdosimetric study on nanosecond pulsed electric fields (nsPEF) including cell compartments dispersivity through Debye equation has been detailed in this paper. A quasi-static solution properly adapted for a wide band analysis and coupled with an asymptotic electroporation model has been used to face the problem. Main paper results highlight the relevance of Debye modeling for nsPEF microdosimetry, evidencing that both the trans-membrane potential (TMP) and the pore density are strongly influenced by such a modeling choice. Particularly, an electric (E) field variability up to 70 % has been observed during the pulse rise time, when the high frequency components of the nsPEF prevail, inducing consequently strong pore density alterations within the cell membrane. Furthermore the influence of the use of different membrane dielectric models has been analyzed. The presented results have demonstrated the crucial role of the dielectric membrane characteristics and the importance of their accurate and reliable determination.
Pharmacodynamics of Oral Ganciclovir and Valganciclovir in Solid Organ Transplant Recipients

Background. A randomized, double-blind study was conducted to evaluate the pharmacokinetics of ganciclovir following oral administration of ganciclovir or valganciclovir for prophylaxis of cytomegalovirus (CMV) disease in solid organ transplant recipients (n = 240/372). Methods. The correlations between individual exposure to ganciclovir during prophylaxis, with CMV viremia incidence during and after treatment, CMV disease up to 12 months posttransplant, and hematological toxicity were assessed. Results. Mean daily areas under the curve (AUCs) of ganciclovir from valganciclovir and oral ganciclovir were 46.3 ± 15.2 and 28.0 ± 10.9 &mgr;g·h/ml (mean ± SD), respectively. Viremia was suppressed during prophylaxis when exposure to ganciclovir was 40–50 &mgr;g·h/ml, AUCs typical of those achieved in valganciclovir-treated patients. The development of viremia 1 month after ending prophylaxis was also reduced with higher ganciclovir AUC (median predicted incidence, 20% and 10% at AUCs of 33 and 50 &mgr;g h/ml, respectively). The development of CMV disease within 1 year of transplant was 17.6% and independent of prophylactic exposure to ganciclovir. There was only a weak tendency to increased neutropenia and leukopenia with higher ganciclovir exposure. Conclusions. The greater systemic exposure to ganciclovir delivered by valganciclovir was associated with delayed development of viremia. There was only a weak association between AUC and hematological toxicity.
Spatiotemporal Dynamics of Word Processing in the Human Brain

We examined the spatiotemporal dynamics of word processing by recording the electrocorticogram (ECoG) from the lateral frontotemporal cortex of neurosurgical patients chronically implanted with subdural electrode grids. Subjects engaged in a target detection task where proper names served as infrequent targets embedded in a stream of task-irrelevant verbs and nonwords. Verbs described actions related to the hand (e.g, throw) or mouth (e.g., blow), while unintelligible nonwords were sounds which matched the verbs in duration, intensity, temporal modulation, and power spectrum. Complex oscillatory dynamics were observed in the delta, theta, alpha, beta, low, and high gamma (HG) bands in response to presentation of all stimulus types. HG activity (80–200 Hz) in the ECoG tracked the spatiotemporal dynamics of word processing and identified a network of cortical structures involved in early word processing. HG was used to determine the relative onset, peak, and offset times of local cortical activation during word processing. Listening to verbs compared to nonwords sequentially activates first the posterior superior temporal gyrus (post-STG), then the middle superior temporal gyrus (mid-STG), followed by the superior temporal sulcus (STS). We also observed strong phase-locking between pairs of electrodes in the theta band, with weaker phase-locking occurring in the delta, alpha, and beta frequency ranges. These results provide details on the first few hundred milliseconds of the spatiotemporal evolution of cortical activity during word processing and provide evidence consistent with the hypothesis that an oscillatory hierarchy coordinates the flow of information between distinct cortical regions during goal-directed behavior.
Distributed Sparse Cut Approximation

We study the problem of computing a sparse cut in an undirected network graph G=(V,E). We measure the sparsity of a cut (S,V\S) by its conductance phi(S), i.e., by the ratio of the number of edges crossing the cut and the sum of the degrees on the smaller of the two sides. We present an efficient distributed algorithm to compute a cut of low conductance. Specifically, given two parameters b and phi, if there exists a cut of balance at least b and conductance at most phi, our algorithm outputs a cut of balance at least b/2 and conductance at most ~O(sqrt{phi}), where ~O(.) hides polylogarithmic factors in the number of nodes n. Our distributed algorithm works in the \congest model, i.e., it only requires to send messages of size at most O(log(n)) bits. The time complexity of the algorithm is ~O(D + 1/b*phi), where D is the diameter of G. This is a significant improvement over a result by Das Sarma et al. [ICDCN 2015], where it is shown that a cut of the same quality can be computed in time ~O(n + 1/b*phi). The improved running time is in particular achieved by devising and applying an efficient distributed algorithm for the all-prefix-sums problem in a distributed search tree. This algorithm, which is based on the classic parallel all-prefix-sums algorithm, might be of independent interest.
Hemicastration induced spermatogenesis-related DNA methylation and gene expression changes in mice testis

Objective Hemicastration is a unilateral orchiectomy to remove an injured testis, which can induce hormonal changes and compensatory hypertrophy of the remaining testis, and may influence spermatogenesis. However, the underlying molecular mechanisms are poorly understood. Here, we investigated the impact of hemicastration on remaining testicular function. Methods Prepubertal mice (age 24 days) were hemicastrated, and their growth was monitored until they reached physical maturity (age 72 days). Subsequently, we determined testis DNA methylation patterns using reduced representation bisulfite sequencing of normal and hemicastrated mice. Moreover, we profiled the testicular gene expression patterns by RNA sequencing (RNA-seq) to examine whether methylation changes affected gene expression in hemicastrated mice. Results Hemicastration did not significantly affect growth or testosterone (p>0.05) compared with control. The genome-wide DNA methylation pattern of remaining testis suggested that substantial genes harbored differentially methylated regions (1,139) in gene bodies, which were enriched in process of protein binding and cell adhesion. Moreover, RNA-seq results indicated that 46 differentially expressed genes (DEGs) involved in meiotic cell cycle, synaptonemal complex assembly and spermatogenesis were upregulated in the hemicastration group, while 197 DEGs were downregulated, which were related to arachidonic acid metabolism. Integrative analysis revealed that proteasome 26S subunit ATPase 3 interacting protein gene, which encodes a protein crucial for homologous recombination in spermatocytes, exhibited promoter hypomethylation and higher expression level in hemicastrated mice. Conclusion Global profiling of DNA methylation and gene expression demonstrated that hemicastration-induced compensatory response maintained normal growth and testicular morphological structure in mice.
Community evolution increases ecosystem functioning and stability

In grassland biodiversity experiments the positive biodiversity– ecosystem functioning relationship generally increases over time. However, there is still a large gap in our understanding of the underlying short-term evolutionary processes. Research has shown that differential selection in monoculture vs. mixedspecies communities can lead to rapid evolution. We assessed whether selection history altered productivity, biodiversity effects and species complementarity within newly assembled monocultures and 2-species mixtures using five plant species selected for twelve years in such a biodiversity experiment in mixture or monoculture and plants without such a selection history. Plants without past community selection history produced the lowest community biomass and showed the weakest biodiversity effects. Furthermore, we found that twelve years of selection history in monocultures or species mixtures differentiated plants into monocultureand mixture-types within species. In newly assembled mixtures, plants with a selection history in mixtures performed better than plants with a monoculture selection history. Biodiversity effects were generally positive but, contrary to expectation, not stronger for mixture types. In addition, biodiversity effects were both influenced by trait differences among plants and community-weighted means, but these relationships were largely independent of selection history. Our findings indicate possible mechanisms underlying the rapid evolution of adapted subtypes within a species in grasslands. Uncovering these mechanisms contributes to our understanding of the biodiversity–ecosystem functioning relationship, which has the potential to influence species conservation practice.
Numb directs the subcellular localization of EAAT3 through binding the YxNxxF motif

ABSTRACT Excitatory amino acid transporter type 3 (EAAT3, also known as SLC1A1) is a high-affinity, Na+-dependent glutamate carrier that localizes primarily within the cell and at the apical plasma membrane. Although previous studies have reported proteins and sequence regions involved in EAAT3 trafficking, the detailed molecular mechanism by which EAAT3 is distributed to the correct location still remains elusive. Here, we identify that the YVNGGF sequence in the C-terminus of EAAT3 is responsible for its intracellular localization and apical sorting in rat hepatoma cells CRL1601 and Madin–Darby canine kidney (MDCK) cells, respectively. We further demonstrate that Numb, a clathrin adaptor protein, directly binds the YVNGGF motif and regulates the localization of EAAT3. Mutation of Y503, N505 and F508 within the YVNGGF motif to alanine residues or silencing Numb by use of small interfering RNA (siRNA) results in the aberrant localization of EAAT3. Moreover, both Numb and the YVNGGF motif mediate EAAT3 endocytosis in CRL1601 cells. In summary, our study suggests that Numb is a pivotal adaptor protein that mediates the subcellular localization of EAAT3 through binding the YxNxxF (where x stands for any amino acid) motif. Summary: Numb binds the YxNxxF motif in the cytoplasmic C-terminus of EAAT3 and drives its endocytosis in non-polarized cells and its apical sorting in polarized cells.
On the Development of Shear Surface Roughness

From deformed quartzites in the Singhbhum Shear Zone, eastern India, we report shear fractures of varying surface roughness: very smooth, containing no lineation to strongly rough with prominent slickenlines. We reproduced them in analogue laboratory experiments, which suggest that the modes of shear failure (brittle versus ductile) and the fracture orientation are potential factors to control the fracture roughness. The experiments were conducted on cohesive sand‐talc models with varying sand:talc volume ratio. Pure sand models underwent Coulomb failure in the brittle regime; this failure mode switched to plastic yielding in the ductile regime with increasing talc content. Such a transition in failure behavior resulted in a remarkable variation in the fracture roughness characteristics. Shear fractures produced by Coulomb failure are smooth, and devoid of any slickenlines, whereas those produced by plastic yielding display strongly linear roughness, defined by cylindrical ridges along the slip direction. Such linear irregularities become more prominent with increasing fracture orientation (θ) to the compression direction (θ = 30 to 60°). We develop a new computational technique, based on controlled optical images to map the shear surface geometry from field casts and laboratory samples. Binarization of the irregular surface images (cantor set) provides 1‐D fractal dimension (D), which is used to quantify the roughness variability, and the degree of their anisotropy in terms of ΔD (difference in D across and along the slip direction). From numerical models, we finally show onset of wave instability in the mechanically distinct rupture zone as an alternative mechanism for slickenline formation.
A Weighted and Directed Interareal Connectivity Matrix for Macaque Cerebral Cortex

Retrograde tracer injections in 29 of the 91 areas of the macaque cerebral cortex revealed 1,615 interareal pathways, a third of which have not previously been reported. A weight index (extrinsic fraction of labeled neurons [FLNe]) was determined for each area-to-area pathway. Newly found projections were weaker on average compared with the known projections; nevertheless, the 2 sets of pathways had extensively overlapping weight distributions. Repeat injections across individuals revealed modest FLNe variability given the range of FLNe values (standard deviation <1 log unit, range 5 log units). The connectivity profile for each area conformed to a lognormal distribution, where a majority of projections are moderate or weak in strength. In the G29 × 29 interareal subgraph, two-thirds of the connections that can exist do exist. Analysis of the smallest set of areas that collects links from all 91 nodes of the G29 × 91 subgraph (dominating set analysis) confirms the dense (66%) structure of the cortical matrix. The G29 × 29 subgraph suggests an unexpectedly high incidence of unidirectional links. The directed and weighted G29 × 91 connectivity matrix for the macaque will be valuable for comparison with connectivity analyses in other species, including humans. It will also inform future modeling studies that explore the regularities of cortical networks.
Sex differences in susceptibility to etiologic factors for peripheral atherosclerosis. Importance of plasma fibrinogen and blood viscosity.

Cardiovascular risk factors in men, such as cigarette smoking, hypercholesterolemia, and hypertension, also increase risk in women, but the relative susceptibility to risk factors between the sexes is not established. Our aim was to investigate a wide range of possible etiologic factors in a single population study and identify those that were more strongly related to peripheral atherosclerosis in men or women. We studied personal factors (age and social class), lifestyle factors (smoking, exercise, alcohol intake, and dietary nutrients), and intermediary factors (obesity, diabetes, serum lipids, coagulation, and rheological factors). In the Edinburgh Artery Study in 1988 we measured cardiovascular risk factors in a random population sample of 1592 men and women aged 55 to 74 years. The ankle-brachial pressure index (ABPI), which is inversely related to the degree of peripheral atherosclerosis, was assessed in each subject. Lifetime cigarette smoking was correlated with a lower ABPI equally in men and women (r = -.27, P < .001). Dietary nutrients and alcohol intake were not related differently between the sexes with ABPI. However, recall of strenuous and moderate leisure time exercise during the age range of 35 to 45 years was related more strongly to a higher ABPI in men than in women (P < .05). Plasma fibrinogen, plasma viscosity, and blood viscosity were the only intermediary factors that had stronger univariate correlations with lower ABPI in men than in women. On multivariate analysis, the sex differences persisted for plasma fibrinogen (P < .05) and blood viscosity (P < .001); high-density lipoprotein cholesterol was related to ABPI in men only (sex difference, P < .1). (ABSTRACT TRUNCATED AT 250 WORDS)
Switching treatments in haemophilia: is there a risk of inhibitor development?

Patients with haemophilia A (and their physicians) may be reluctant to switch factor VIII (FVIII) concentrates, often due to concerns about increasing the risk of inhibitors; this reluctance to switch may contribute to patients missing the clinical benefits provided by the arrival of new factor VIII products. This topic was explored at the Eleventh Zürich Haemophilia Forum. Clinical scenarios for which product switching may be cause for concern were discussed; when there is a clinical need, there are no absolute contraindications to switching, but some patients (e.g. previously untreated patients and those undergoing elective surgery) may require more careful consideration. Both patient and physician surveys indicate that the reluctance to switch, and the fear of inhibitor development, does not appear to be evidence based. The evaluation of more recent data did not support previous studies suggesting that particular products (e.g. recombinant vs. plasma‐derived and full length vs. B‐domain modified) may be associated with increased risk. In addition, data from three national product switches showed that switching was not associated with increased inhibitor risk, but highlighted the need for regular inhibitor testing and for a centralised, unbiased database of inhibitor incidence. To conclude, current evidence does not suggest that switching products significantly influences inhibitor development.