Miracle-dz/UniFAR-FTUs huggingface dataset:
The mutational profile and infiltration pattern of murine MLH1-/- tumors: concurrences, disparities and cell line establishment for functional analysis

Mice lines homozygous negative for one of the four DNA mismatch repair (MMR) genes (MLH1, MSH2, PMS2, MSH6) were generated as models for MMR deficient (MMR-D) diseases. Clinically, hereditary forms of MMR-D include Lynch syndrome (characterized by a germline MMR gene defect) and constitutional MMR-D, the biallelic form. MMR-D knockout mice may be representative for both diseases. Here, we aimed at characterizing the MLH1-/- model focusing on tumor-immune microenvironment and identification of coding microsatellite mutations in lymphomas and gastrointestinal tumors (GIT). All tumors showed microsatellite instability (MSI) in non-coding mononucleotide markers. Mutational profiling of 26 coding loci in MSI+ GIT and lymphomas revealed instability in half of the microsatellites, two of them (Rfc3 and Rasal2) shared between both entities. MLH1-/- tumors of both entities displayed a similar phenotype (high CD71, FasL, PD-L1 and CTLA-4 expression). Additional immunofluorescence verified the tumors’ natural immunosuppressive character (marked CD11b/CD200R infiltration). Vice versa, CD3+ T cells as well as immune checkpoints molecules were detectable, indicative for an active immune microenvironment. For functional analysis, a permanent cell line from an MLH1-/- GIT was established. The newly developed MLH1-/- A7450 cells exhibit stable in vitro growth, strong invasive potential and heterogeneous drug response. Moreover, four additional MSI target genes (Nktr1, C8a, Taf1b, and Lig4) not recognized in the primary were identified in this cell line. Summing up, molecular and immunological mechanisms of MLH1-/- driven carcinogenesis correlate well with clinical features of MMR-D. MLH1-/- knockout mice combine characteristics of Lynch syndrome and constitutional MMR-D, making them suitable models for preclinical research aiming at MMR-D related diseases.
Education and Fertility: Evidence from sub-Saharan Africa

This study investigates the eects of dierent levels of education on fertility in 48 sub- Saharan African countries between 1970 and 2010. The results, based on panel data analysis with …xed eects and instrumental variables, show that lower education levels do not have a signi…cant eect on people's fertility decisions. However, the results from the higher education levels suggest otherwise. There is evidence of a child quantity-quality trade-owhich indicates a region that is transitioning from the Malthusian stagnation to a modern growth regime.
Stem Cell Depletion Through Epidermal Deletion of Rac1

Mammalian epidermis is maintained by self-renewal of stem cells, but the underlying mechanisms are unknown. Deletion of Rac1, a Rho guanosine triphosphatase, in adult mouse epidermis stimulated stem cells to divide and undergo terminal differentiation, leading to failure to maintain the interfollicular epidermis, hair follicles, and sebaceous glands. Rac1 exerts its effects in the epidermis by negatively regulating c-Myc through p21-activated kinase 2 (PAK2) phosphorylation. We conclude that a pleiotropic regulator of cell adhesion and the cytoskeleton plays a critical role in controlling exit from the stem cell niche and propose that Rac and Myc represent a global stem cell regulatory axis.
RASPRO: rapid summarization for effective prognosis in wireless remote health monitoring

Consistent power and cost effective health monitoring has become the need of the hour especially for the unstable, chronically and critically ill. Here we present a novel architecture and algorithmic methodology combining the sensing subsystem, symptom summarization, and data transmission. Physiological parameters from multiple sensors feed into a severity quantizer and a subsequent multiplexer, the output of which is processed by the RASPRO engine to rapidly discover and alert any health criticalities. The architecture is optimized for communication and energy performance, and the algorithms result in lucid presentations to physicians. The whole system is the result of close collaboration between engineering and medical teams at one of the best known multidisciplinary universities, building on a multi-terabyte more than a million patient Amrita Hospital Information System (HIS) database, and is being readied for deployment on a large telemedicine network of more than 60 nodes in the Indian subcontinent and parts of Africa.
Gastrointestinal stromal tumors with KIT exon 11 deletions are associated with poor prognosis.

BACKGROUND & AIMS Gain-of-function mutations in the KIT receptor tyrosine kinase gene and rare mutations in the platelet-derived growth factor receptor alpha (PDGFRA) gene are important events in gastrointestinal stromal tumor (GIST) development. Different mutations are reportedly associated with distinctive phenotypes and possibly clinical behavior. We investigated the correlation among mutation type, phenotype, and clinical course in a preimatinib, population-based series of GIST with long-term follow-up. METHODS Genomic DNA from 177 GIST patients was analyzed for KIT exons 9, 11, 13, and 17 and PDGFRA exons 12 and 18 mutations using denaturating high-performance liquid chromatography and bidirectional sequencing. RESULTS KIT exon 11 mutations were detected in 101 of 177 GIST (61 deletions, 23 missense mutations, and 17 duplications); wild-type (WT) KIT and PDGFRA were detected in 63; KIT exon 9 and exon 17 mutations in 6 and 1, respectively; and PDGFRA exons 12 and 18 mutations in 3 each. GIST >5 cm vs GIST </=1 cm had mutations in 73% and 33%, respectively. KIT exon 11 deletions were significantly associated with a higher proportion of high risk or overtly malignant groups compared with WT GIST. KIT exon 11 deletions adversely affected outcome. KIT exon 11 duplications and exon 9 mutations were found exclusively in gastric and small intestinal GIST, respectively. CONCLUSIONS KIT exon 11 deletion is an independent adverse prognostic factor in patients with GIST.
Thermal Impedance Modeling of Si–Ge HBTs From Low-Frequency Small-Signal Measurements

In this letter, the thermal impedance of SiGe heterojunction bipolar transistors has been characterized using low-frequency small-signal measurements. Theoretical works for thermal impedance modeling using different electrothermal networks, developed until date, have been verified with our experimental results. We report for the first time the experimental verification of the electrothermal model for thermal impedance developed by Mnif using a nodal and recursive network. A generalized expression of the frequency-domain thermal impedance has been selected for electrical compact transistor model (HiCuM) improvement, parameter extraction, and electrothermal network verification.
Normal acute behavioral responses to moderate/high dose ethanol in GABAA receptor alpha 4 subunit knockout mice.

BACKGROUND gamma-Aminobutyric acid type A receptors (GABA(A)-Rs) have been implicated in mediating some of the behavioral effects of ethanol (EtOH), but the contribution of specific GABA(A)-R subunits is not yet fully understood. The GABA(A)-R alpha 4 subunit often partners with beta2/3 and delta subunits to form extrasynaptic GABA(A)-Rs that mediate tonic inhibition. Several in vitro studies have suggested that these extrasynaptic GABA(A)-Rs may be particularly relevant to the intoxicating effects of low doses of EtOH. In alpha 4 subunit knockout mice, tonic inhibition was greatly reduced, as were the potentiating effects of EtOH. We therefore hypothesized that those behavioral responses to EtOH that are mediated by alpha 4-containing GABA(A)-Rs would be diminished in alpha 4 knockout mice. METHODS We investigated behavioral responses to acute administration of moderate/high dose EtOH or pentylenetetrazol in alpha 4 subunit knockout mice. We compared behavioral responses to EtOH in alpha 4 knockout and wild-type littermates in the elevated plus maze (0.0, 1.0 g/kg EtOH), screen test (1.5, 2.0 g/kg), hypothermia (1.5, 2.0 g/kg), fixed speed rotarod (1.5, 2.0, 2.5 g/kg), open field (0.0, 1.0, 2.0 g/kg), radiant tail flick (2.0 g/kg), loss of righting reflex (3.5 g/kg), and EtOH metabolism and clearance assays. Sensitivity to pentylenetetrazol-induced seizures was also analyzed. RESULTS No differences were observed between alpha 4 knockout mice and wild-type controls in terms of the baseline behavior in the absence of EtOH treatment or in the behavioral effects of EtOH in the assays tested. In contrast, alpha 4 knockout mice were significantly more sensitive to pentylenetetrazol-induced seizures. CONCLUSIONS We conclude that GABA(A)-Rs containing the alpha 4 subunit are not absolutely required for the acute behavioral responses to moderate/high dose EtOH that were assessed with the elevated plus maze, screen test, hypothermia, fixed speed rotarod, open field, radiant tail flick, and loss of right reflex assays. We further suggest that these findings are complicated by the demonstrated compensatory alterations in synaptic GABA(A)-R EtOH sensitivity and function in alpha 4 knockout mice.
Long‐lasting plasma membrane permeabilization in mammalian cells by nanosecond pulsed electric field (nsPEF)

The barrier function of plasma membrane in nsPEF‐exposed mammalian cells was examined using whole‐cell patch‐clamp techniques. A specialized setup for nsPEF exposure of individual cells in culture was developed and characterized for artifact‐free compatibility with the patch‐clamp method. For the first time, our study provides experimental evidence that even a single 60‐ns pulse at 12 kV/cm can cause a profound and long‐lasting (minutes) reduction of the cell membrane resistance (Rm), accompanied by the loss of the membrane potential. Rm measured in GH3, PC‐12, and Jurkat cells (but not in HeLa cells) in 80–120 s after nsPEF exposure was decreased about threefold, and its gradual recovery could take 15 min. Multiple pulses enhanced permeabilization, for example, Rm in GH3 cells fell about 10‐fold after a train of five pulses. Within studied limits, permeabilization did not depend on the presence of Ca2+, Mg2+, K+, Cs+, Cd2+, EGTA, tetraethylammonium, or 4‐aminopyridine in the pipette or bath solutions. Our results supported theoretical model predictions of plasma membrane poration by nsPEF. However, the extended decrease in Rm, assumed to be related to the life span of the pores, and different nsPEF sensitivity of individual cell lines have yet to be explained. The phenomenon of long‐lived membrane permeabilization provides new insights on the nature of nsPEF‐opened conductance pores and on molecular mechanisms that underlie nsPEF bioeffects. Bioelectromagnetics 28:655–663, 2007. © 2007 Wiley‐Liss, Inc.
Six subthreshold full adder cells characterized in 90 nm CMOS technology

This paper presents a performance analysis and evaluation of six different 1-bit full adder topologies in deep subthreshold operation. The cells are characterized with respect to delay, power consumption, driving capability, power-delay product (PDP), energy-delay product (EDP) and maximum operating frequency. Both traditional CMOS, a specialized low power cell and minority-3 based full adders are simulated and characterized. PDPs of less than 200 aJ are reported, for FA cells operating at frequencies around 2 MHz, for Vdd=200 mV, dissipating less than 100 nW of average power
Second International Workshop on Software Research and Climate Change

This workshop will explore the contributions that software research can make to the challenge of tackling climate change. Software is a critical enabling technology in nearly all aspects of climate change, from the computational models used by climate scientists to improve our understanding of the impact of human activities on earth systems, through to the information and control systems needed to build an effective carbon-neutral society. The intent of the workshop is to explore how software research can contribute to this challenge, to build a community of researchers interested in responding to the challenge, and to map out a research agenda.
On the Energy Efficiency and Performance of Neighbor Discovery Schemes for Low Duty Cycle IoT Devices

Mobile sensing and proximity-based applications require smart devices to find other nodes in vicinity, though it is challenging for a device to find neighbors in an energy efficient manner while running on low duty cycles. Neighbor discovery schemes allow nodes to follow a schedule to become active and send beacons or listen for other active nodes in order to discover each other with a bounded latency. However, a trade-off exists between the energy consumption and the time a node takes to discover neighbors using a given activity schedule. Moreover, energy consumption is not the only bottleneck, as theoretically perfect schedules can result in discovery failures in a real environment. In this paper, we provide an in-depth study on neighbor discovery, by first defining the relation between energy efficiency, discovery latency and the fraction of discovered neighbors. We evaluate existing mechanisms using extensive simulations for up to 100 nodes and testbed implementations for up to 15 nodes, with no synchronization between nodes and using duty cycles as low as 1% and 5%. Moreover, the literature assumes that multiple nodes active simultaneously always result in neighbor discovery, which is not true in practice as this can lead to collisions between the transmitted messages. Our findings reveal such scalability issues in existing schemes, where discovery fails because of collisions between beacons from multiple nodes active at the same time. Therefore, we show that energy efficient discovery schemes do not necessarily result in successful discovery of all neighbors, even when the activity schedules are computed in a deterministic manner.
Assessment of Early Therapeutic Changes to Concurrent Chemoradiotherapy in Uterine Cervical Cancer Using Blood Oxygenation Level–Dependent Magnetic Resonance Imaging

Objective This study aimed to investigate blood oxygenation level–dependent magnetic resonance imaging (MRI) in assessing early therapeutic changes in cervical cancers to concurrent chemoradiotherapy (CCRT). Methods Fifteen consecutive patients with cervical cancer treated with CCRT were evaluated with blood oxygenation level–dependent MRI at 3 T. Magnetic resonance imaging examinations were performed before treatment (preTx), 1 week after treatment (postT1) and 4 weeks after treatment (postT2). At each time, the rate of spin dephasing (R2*) values were measured in tumor and in normal uterus. Results Tumor R2* increased from preTx to postT2 (P < 0.01). In pairwise comparisons of tumor R2*, postT2 was significantly higher than preTx or postT1 (P < 0.01), whereas postT1 was not significantly different from preTx (P > 0.05). A significant difference in R2* was found between the tumors and normal uterus at preTx (P = 0.001), postT1 (P < 0.001), and postT2 (P < 0.001). Conclusions Blood oxygenation level–dependent MRI may demonstrate early therapeutic changes of cervical cancers to CCRT.
Hyperpolarized 13C‐lactate to 13C‐bicarbonate ratio as a biomarker for monitoring the acute response of anti‐vascular endothelial growth factor (anti‐VEGF) treatment

Hyperpolarized [1‐13C]pyruvate MRS provides a unique imaging opportunity to study the reaction kinetics and enzyme activities of in vivo metabolism because of its favorable imaging characteristics and critical position in the cellular metabolic pathway, where it can either be reduced to lactate (reflecting glycolysis) or converted to acetyl‐coenzyme A and bicarbonate (reflecting oxidative phosphorylation). Cancer tissue metabolism is altered in such a way as to result in a relative preponderance of glycolysis relative to oxidative phosphorylation (i.e. Warburg effect). Although there is a strong theoretical basis for presuming that readjustment of the metabolic balance towards normal could alter tumor growth, a robust noninvasive in vivo tool with which to measure the balance between these two metabolic processes has yet to be developed. Until recently, hyperpolarized 13C‐pyruvate imaging studies had focused solely on [1‐13C]lactate production because of its strong signal. However, without a concomitant measure of pyruvate entry into the mitochondria, the lactate signal provides no information on the balance between the glycolytic and oxidative metabolic pathways. Consistent measurement of 13C‐bicarbonate in cancer tissue, which does provide such information, has proven difficult, however. In this study, we report the reliable measurement of 13C‐bicarbonate production in both the healthy brain and a highly glycolytic experimental glioblastoma model using an optimized 13C MRS imaging protocol. With the capacity to obtain signal in all tumors, we also confirm for the first time that the ratio of 13C‐lactate to 13C‐bicarbonate provides a more robust metric relative to 13C‐lactate for the assessment of the metabolic effects of anti‐angiogenic therapy. Our data suggest a potential application of this ratio as an early biomarker to assess therapeutic effectiveness. Furthermore, although further study is needed, the results suggest that anti‐angiogenic treatment results in a rapid normalization in the relative tissue utilization of glycolytic and oxidative phosphorylation by tumor tissue. Copyright © 2016 John Wiley & Sons, Ltd.
Ischemic Stroke Associated with Decrease in Temperature

Background Some studies suggest low temperatures can affect mortality, especially deaths associated with circulatory and respiratory conditions. Methods We investigated the association between ischemic stroke onset and decrease in temperature in 545 patients over a 3-year period (January 1998 to December 2000) in Incheon, Korea. We used a case-crossover study design to assess changes in the risk of ischemic stroke during a brief hazard period after exposure to decrease in temperature. For each subject, the case period was matched to 2 control periods exactly 1 week before and after onset of the ischemic stroke. Results Decreased ambient temperature was associated with risk of acute ischemic stroke. The strongest effect was seen on day after exposure to cold weather. The odds ratio (OR) for an interquartile range decrease in temperature was 2.9 (95% confidence interval [CI] = 1.5–5.3). The risk period was 24-48 hours after cold exposure. Risk estimates associated with decreased temperature were greater in the winter than in the summer. Women, persons greater than 65 years of age, nonobese persons, and those with previous hypertension or hypercholesterolemia were more susceptible to cold-induced ischemic stroke. Conclusions These results suggest that stroke occurrence rises with decreasing temperature, and that even a moderate decrease in temperature can increase the risk of ischemic stroke. Susceptible people should take steps to protect themselves from cold, especially in the winter.
Approval ratings of inpatient coercive interventions in a national sample of mental health service users and staff in England.

OBJECTIVE This study sought to ascertain the degree to which psychiatric inpatients and staff approved of various coercive measures commonly used in acute inpatient care. METHODS A cross-sectional design was adopted. The Attitudes to Containment Measures Questionnaire (ACMQ) was completed by 1,361 service users and 1,226 staff (68% nurses) in acute care mental health services from three regions of England. This provided evaluation of 11 coercive measures (for example, seclusion) on six dimensions of approval (for example, whether the coercive measure is seen as being acceptable or safe to use) in a large national sample. Comparisons between groups were tested with independent-samples t tests, chi square analysis, or Spearman correlations. RESULTS Service users and staff strongly disapproved of net beds and mechanical restraint. The three methods that received the most approval by the service user group were intermittent observation, time out, and PRN (as needed) medication; for the staff group, the three methods that were most approved of were transfer to a psychiatric intensive care unit, PRN medication, and observation. Male staff, older service users, and staff who had been involved in implementing coercion expressed greater approval of coercive measures. CONCLUSIONS There are clear gender differences in how coercive measures that are used in inpatient settings are viewed. Personal involvement in deploying coercive interventions was linked to greater acceptance, suggesting a link between experience and attitudinal changes.
The airway epithelium: Structural and functional properties in health and disease

Abstract: The major function of the respiratory epithelium was once thought to be that of a physical barrier. However, it constitutes the interface between the internal milieu and the external environment as well as being a primary target for inhaled respiratory drugs. It also responds to changes in the external environment by secreting a large number of molecules and mediators that signal to cells of the immune system and underlying mesenchyme. Thus, the epithelium is in a unique position to translate gene–environment interactions. Normally, the epithelium has a tremendous capacity to repair itself following injury. However, evidence is rapidly accumulating to show that the airway epithelium of asthmatics is abnormal and has increased susceptibility to injury compared to normal epithelium. Areas of detachment and fragility are a characteristic feature not observed in other inflammatory diseases such as COPD. In addition to being more susceptible to damage, normal repair processes are also compromised. Failure of appropriate growth and differentiation of airway epithelial cells will cause persistent mucosal injury. The response to traditional therapy such as glucocorticoids may also be compromised. However, whether the differences observed in asthmatic epithelium are a cause of or secondary to the development of the disease remains unanswered. Strategies to address this question include careful examination of the ontogeny of the disease in children and use of gene array technology should provide some important answers, as well as allow a better understanding of the critical role that the epithelium plays under normal conditions and in diseases such as asthma.
Characterization of new mutants in the early part of the yeast secretory pathway isolated by a [3H]mannose suicide selection

We have adapted a [3H]mannose suicide selection to identify mutations in additional genes which function in the early part of the yeast secretory pathway. Thus far this protocol has led to the identification of two new genes which are implicated in this process, as well as additional alleles of previously identified genes. The new mutants, bet1 and bet2, are temperature sensitive for growth and protein transport. Thin section analysis has revealed the accumulation of a network of endoplasmic reticulum (ER) at the restrictive temperature (37 degrees C). Precursors of exported proteins that accumulate in the cell at 37 degrees C are terminally core glycosylated. These observations suggest that the transport of precursors is blocked subsequent to translocation into the ER but before entry into the Golgi apparatus. The bet1 and bet2 mutants define two new complementation groups which have the same properties as previously identified ER- accumulating mutants. This and previous findings (Novick, P., C. Field, and R. Schekman, 1980, Cell, 21:205-215) suggest that protein exit from the ER and entry into the Golgi apparatus is a complex process requiring at least 11 genes.