Miracle-dz/UniFAR-FTUs huggingface dataset:
Cation-π interaction regulates ligand-binding affinity and signaling of integrin α4β7

Integrin α4β7 mediates rolling and firm adhesion of leucocytes, two of the critical steps in leukocyte migration and tissue specific homing. Affinity of α4β7 for ligand is dynamically regulated by three interlinked metal ion-binding sites in β7-subunit I domain. In this study, we found that Phe185 (F185), a highly conserved aromatic residue in β7-subunit, links the specificity-determining loop and the synergistic metal ion-binding site (SyMBS) through cation-π interaction. Mutations of F185 that disrupted the SyMBS cation-F185 interaction led to deficient firm cell adhesion mediated by high affinity α4β7, and only slightly affected rolling adhesion mediated by low affinity α4β7. Disruption of SyMBS cation-F185 interaction induced partial extension of integrin ectodomain and separation of cytoplasmic tails, and impaired α4β7-mediated bidirectional signaling. In addition, loss of SyMBS cation-F185 interaction increased paxillin expression and promoted paxillin-integrin binding, leading to deficient cell spreading. Furthermore, integrin α4β7-mediated cell migration was decreased by the abolishment of SyMBS cation-F185 interaction. Thus, these findings reveal a cation-π interaction playing vital roles in the regulation of integrin affinity, signaling, and biological functions.
The Nexus between Contract Duration and the Use of Formal and Informal Incentive Pay

We investigate a firm's choice of formal and informal effort incentives in a repeated game setting with undistorted signaling and liquidity‐constrained agents. The model allows for a simple geometric representation of credibility and incentive‐feasibility effects on optimal contract design. If credibility constitutes a binding constraint, explicit, i.e. enforceable, performance pay and discretionary salary promises are unambiguous substitutes and higher employee performance is associated with lower‐powered bonus pay. Using personnel data from an insurance company, we show that the model's predictions regarding the mediating role of expected contract duration on these relationships are consistent with remuneration practices.
Novel Electrode Design for Potentially Painless Internal Defibrillation Also Allows for Successful External Defibrillation

Background: Implantable cardioverter defibrillators (ICDs) save lives, but the defibrillation shocks delivered by these devices produce substantial pain, presumably due to skeletal muscle activation. In this study, we tested an electrode system composed of epicardial panels designed to shield skeletal muscles from internal defibrillation, but allow penetration of an external electric field to enable external defibrillation when required.
Mutations that affect neural cell lineages and cell fates during the development of the nematode Caenorhabditis elegans.

We have described 19 genes that affect neural cell lineages and cell fates during the development of C. elegans. These genes differ markedly in the nature, breadth, and specificity of their effects. Their only obvious common characteristic is that they all lack specificity for the nervous system, affecting both neural and nonneural development. For some of these genes (lin-5, lin-6, unc-59, unc-85), this nonspecificity probably reflects a general utilization of their products in cellular replication. In contrast, most of these genes appear to be highly specific in their effects, but their specificity is not on the basis of cell type but rather on the basis of some particular aspect of development. Specifically, unc-83 and unc-84 mutations affect certain precursor cells that generate both neural and nonneural descendants; lin-22 and lin-26 mutants lead to the generation of supernumerary neural cells with a concomitant loss of nonneural cells; lin-4, lin-14, lin-28, and lin-29 mutants perturb global aspects of developmental timing, altering the time of appearance (or preventing the appearance) of both neural and nonneural cells; lin-1, lin-8, lin-9, and lin-15 mutations affect the cell lineages of certain nonneuron -producing ectoblasts in hermaphrodites and of homologous neuron-producing ectoblasts in males; lin-12 mutations affect many sets of nonidentical homologs (cells of similar lineage history that express different fates), only some of which are neural; ced-3 mutations prevent all programmed cell deaths, again only some of which are neural. Of these 19 genes, only unc-86 is specific for neural as opposed to nonneural cell lineages. However, some unc-86 mutants are abnormal in chromosome segregation at meiosis, indicating that this gene also may affect nonneural aspects of development. One implication of these observations is that genes (and molecules) involved in neural development are likely to function in nonneural development as well. The genes lin-22, lin-12, unc-86, and ced-3 may play decision-making roles during C. elegans neurogenesis, as mutations in each of these genes cause specific transformations in the fates of particular cells. These genes and others like them may act within a hierarchy to effect decisions at different levels within cell lineages. For example, lin-22 animals display transformations affecting entire postembryonic cell lineages, unc-86 animals are altered at an intermediate level of certain cell lineages, and ced-3 animals are affected only in the ultimate fates of cells produced by terminal cell divisions. (ABSTRACT TRUNCATED AT 400 WORDS)
Current role, techniques and outcomes of percutaneous biopsy of renal tumors

The use of percutaneous biopsy of renal masses has not been traditionally widely used because of concerns about safety, accuracy and sampling errors. The current gold standard of treatment for localized renal tumors is partial or radical nephrectomy. However, many small masses are benign tumors or low-grade renal cell carcinomas (RCCs). In selected cases, RCCs can be managed with active surveillance or with minimally invasive ablative technologies. In the setting of metastatic disease, the histological characterization of a renal tumor may also be helpful to select the most suitable targeted treatment. With the development of new and improved techniques and increasing expertise, percutaneous needle core biopsy of renal masses is a safe and accurate diagnostic procedure. Clinically significant bleeding is very rare and no case of RCC seeding along the needle tract has been observed in the last decade. Percutaneous biopsy should have an increasing role in the diagnostic management of renal masses, particularly in elderly or unfit patients diagnosed with small incidental masses or in patients with metastatic disease being considered for cytoreductive surgery and/or therapy with biological modifiers.
Towards a miniature atomic scalar magnetometer using liquid crystal polarization rotator

CEA-LETI and CNES have successfully realized a helium-4 isotropic space-qualified magnetometer for the SWARM mission. The present paper reviews the progress made in the miniaturization of this isotropic optically pumped magnetometer. Sensor isotropy is provided by a liquid crystal polarization rotator that sets the pumping beam polarization at 90° with respect to the ambient magnetic field. It allows a continuous polarization rotation from 0° to more than 300° with response times sufficient for mobile or space applications. This rotator is non-magnetic and can be easily integrated close to the gas cell. The miniature sensor reaches a sensitivity of 10 pT/√Hz in a bandwidth from DC to 100 Hz.
Dynamic secretion during meiotic reentry integrates the function of the oocyte and cumulus cells

Significance Oocyte fitness to support embryo development and pregnancy is dependent on an elaborate cross-talk with the surrounding environment of the ovarian follicle. Here, we show that this cross-talk continues during the periovulatory period when a new set of bioactive molecules is secreted by the oocyte in mice and humans. This shift in pattern of secretion is dependent on oocyte maturation and on paracrine factors secreted by somatic cells at the time of ovulation. These changes in pattern of secretion may be used to assess oocyte quality. The differentiation of the female gamete into a developmentally competent oocyte relies on the protected environment of the ovarian follicle. The oocyte plays a key role in establishing this microenvironment by releasing paracrine factors that control the functions of surrounding somatic cells. Growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) are secreted during follicle growth and play pivotal roles in this local regulation. The current view is that the function of these secreted factors declines in the periovulatory period when the oocyte reenters the meiotic cell cycle. Here, we provide evidence that oocyte reentry into meiosis is instead associated with a shift in the pattern of secretion with a new set of bioactive molecules synthesized before ovulation. Using interleukin 7 (IL7) as a prototypic secreted factor, we show that its secretion is dependent on activation of mRNA translation in synchrony with the cell cycle and that its translation is under the control of somatic cells. IL7 is part of a local feedback loop with the soma because it regulates cumulus cell replication. Similar conclusions are reached when IL7 secretion is measured in human follicular fluid during in vitro fertilization cycles. IL7 concentration in the follicular fluid correlates with the oocyte ability to reach the MII stage of maturation. These findings are consistent with the hypothesis that a new set of local factors is secreted by the oocyte during ovulation. These dynamic secretions are likely critical for promoting the final stages of maturation and oocyte developmental competence.
PAK6 Phosphorylates 14-3-3γ to Regulate Steady State Phosphorylation of LRRK2

Mutations in Leucine-rich repeat kinase 2 (LRRK2) are associated with Parkinson's disease (PD) and, as such, LRRK2 is considered a promising therapeutic target for age-related neurodegeneration. Although the cellular functions of LRRK2 in health and disease are incompletely understood, robust evidence indicates that PD-associated mutations alter LRRK2 kinase and GTPase activities with consequent deregulation of the downstream signaling pathways. We have previously demonstrated that one LRRK2 binding partner is P21 (RAC1) Activated Kinase 6 (PAK6). Here, we interrogate the PAK6 interactome and find that PAK6 binds a subset of 14-3-3 proteins in a kinase dependent manner. Furthermore, PAK6 efficiently phosphorylates 14-3-3γ at Ser59 and this phosphorylation serves as a switch to dissociate the chaperone from client proteins including LRRK2, a well-established 14-3-3 binding partner. We found that 14-3-3γ phosphorylated by PAK6 is no longer competent to bind LRRK2 at phospho-Ser935, causing LRRK2 dephosphorylation. To address whether these interactions are relevant in a neuronal context, we demonstrate that a constitutively active form of PAK6 rescues the G2019S LRRK2-associated neurite shortening through phosphorylation of 14-3-3γ. Our results identify PAK6 as the kinase for 14-3-3γ and reveal a novel regulatory mechanism of 14-3-3/LRRK2 complex in the brain.
In vitro binding of the Salmonella dublin virulence plasmid regulatory protein SpvR to the promoter regions of spvA and spvR

The spv regulon of Salmonella dublin is essential for virulence in mice. SpvR, a LysR-type regulator, induces the expression of the spvABCD operon and its own expression in the stationary phase of bacterial growth and in macrophages. We constructed fusion proteins to the maltose-binding protein (MBP) and a His tag peptide (His) to overcome the insolubility and to facilitate purification of SpvR. We demonstrated that both fusion proteins, MBP-SpvR and His-SpvR, were able to induce spvA expression in vivo. MBP-SpvR was produced as soluble protein, whereas His-SpvR was only marginally present in the soluble cell fraction. Affinity chromatography resulted in at least 95% pure MBP-SpvR protein and in an enrichment of His-SpvR. Gel mobility shift assay revealed that the SpvR fusion proteins were able to bind to 125-and 147-bp DNA fragments of the spvA and spvR promoter regions, respectively. DNase I footprint experiments showed that the fusion proteins protected DNA regions of 54 and 50 bp within the spvA and spvR promoter regions, respectively.
Use of physical restraints and psychotropic medications in Alzheimer special care units in nursing homes.

OBJECTIVES This study analyzed the use of mechanical restraints and psychotropic medication in Alzheimer special care units (SCUs) in nursing homes. METHODS We analyzed 1993 data for more than 71,000 nursing home residents in 4 states, including more than 1,100 residents in 48 SCUs. The dependent variable in multinomial logistic regression was use of physical restraints or psychotropic medication. Models contained covariates representing facility and resident characteristics, and multivariate matching strategies were used to protect against selection bias. RESULTS Residents in SCUs did not differ from similar residents in traditional units in their likelihood of being physically restrained. Residents in SCUs were more likely to receive psychotropic medication. CONCLUSIONS With regard to the measures used in this research, the findings indicate that residents in the SCUs in the 4 study states did not receive quality of care superior to that provided to similar residents in traditional units. In fact, the results related to drug use raise the question of whether some may have received poorer care.
VH and VL region structure of antibodies that recognize the (NANP)3 dodecapeptide sequence in the circumsporozoite protein of Plasmodium falciparum

The sporozoite form of Plasmodium falciparum displays on its surface the circumsporozoite (CS) protein. The central domain of this protein possesses a reiterated tetrapeptide sequence Asn‐Ala‐Asn‐Pro (NANP), and > 90% of the sporozoite‐specific antibodies obtained from individuals living in malaria endemic areas recognize epitopes within this repeat sequence. Considering the highly repetitive structure of this naturally occurring antigen and its immunodominance, we were interested in analyzing the structural diversity of antibodies that bind to the (NANP)3 sequence. Molecular characterization of immunoglobulin heavy and light chain mRNA was performed for five hybridomas that produce antibodies with binding specificity for the dodecapeptide (NANP)3. These hybridomas were produced in BALB/c mice by inoculation with whole P. falciparum sporozoites. Sequence analysis and Northern blotting showed that for heavy chain, three hybridomas used VH elements that belong to the VHIX family and two to the VHJ558 family. Four different Vχ subgroups were represented among the light chains. Different D and Jχ segments are also utilized, while four heavy chain gene rearrangements involved the JH4 segment. These results indicated that multiple VH‐VL gene combinations can code for reactivity to the (NANP)3 sequence, demonstrating that the murine antibody response to this immunodominant region is structurally heterogeneous.
Cyclic AMP Signaling Functions as a Bimodal Switch in Sympathoadrenal Cell Development in Cultured Primary Neural Crest Cells

ABSTRACT Cells of the vertebrate neural crest (crest cells) are an invaluable model system to address cell fate specification. Crest cells are amenable to tissue culture, and they differentiate to a variety of neuronal and nonneuronal cell types. Earlier studies have determined that bone morphogenetic proteins (BMP-2, -4, and -7) and agents that elevate intracellular cyclic AMP (cAMP) stimulate the development of the sympathoadrenal (SA, adrenergic) lineage in neural crest cultures. To investigate whether interactive mechanisms between signaling pathways influence crest cell differentiation, we characterized the combinatorial effects of BMP-2 and cAMP-elevating agents on the development of quail trunk neural crest cells in primary culture. We report that the cAMP signaling pathway modulates both positive and negative signals influencing the development of SA cells. Specifically, we show that moderate activation of cAMP signaling promotes, in synergy with BMP-2, SA cell development and the expression of the SA lineage-determining gene Phox2a. By contrast, robust activation of cAMP signaling opposes, even in the presence of BMP-2, SA cell development and the expression of the SA lineage-determining ASH-1 and Phox2 genes. We conclude that cAMP signaling acts as a bimodal regulator of SA cell development in neural crest cultures.
Perceptual Knots and Black Identity Politics: Linked Fate, American Heritage, and Support for Trump Era Immigration Policy

Since the 2016 U.S. presidential election, much ado has been made about how racial anxiety fueled White vote choice for Donald Trump. Far less empirical attention has been paid to whether the 2016 election cycle triggered black anxieties and if those anxieties led blacks to reevaluate their communities’ standing relative to Latinos and immigrants. Employing data from the 2016 Collaborative Multiracial Post-Election Survey, we examine the extent to which race consciousness both coexists with black perceptions of Latinos and shapes black support for anti-immigrant legislation. Our results address how the conflation of Latino with undocumented immigrant may have activated a perceptional and policy backlash amongst black voters.
A dose escalation study of paclitaxel and carboplatin in untreated Japanese patients with advanced non-small cell lung cancer.

BACKGROUND The combination of paclitaxel (225 mg/m(2), 3-h infusion) and carboplatin (area under the curve 6) is widely used for non-small cell lung cancer in the USA. In Japan, however, the recommended dose for single-use paclitaxel in 3-h infusion is 210 mg/m(2) and the optimal dose of this agent in combination with carboplatin has not been established. This dose escalation study was designed to determine the maximum tolerated dose of paclitaxel in 3-h infusion plus carboplatin at a fixed dose of area under the curve 6 for Japanese patients with advanced, untreated non-small cell lung cancer. METHODS Between October 1999 and May 2000, 19 patients were enrolled and 18 of these patients were evaluable for toxicity. Chemotherapy consisted of carboplatin area under the curve 6 and an escalated dose of paclitaxel on day 1 every 3-4 weeks. The initial dose of paclitaxel was 175 mg/m(2) and was increased by 25 mg/m(2) at each dose level. RESULTS Neutropenia was the major toxicity observed, but was not dose related. Febrile neutropenia was not observed. No grade 3 or more peripheral neuropathy, myalgia or arthralgia was reported. The maximum tolerated dose was not determined even at the highest paclitaxel dose level (225 mg/m(2)) in this study. Partial responses were observed in six of the 19 patients (31.6%). CONCLUSION We conclude that paclitaxel at 225 mg/m(2) in 3-h infusion and carboplatin area under the curve 6 can safely be given to Japanese patients with non-small cell lung cancer.
Development of specimen-specific finite element models of human vertebrae for the analysis of vertebroplasty

Abstract The aim of this study was to determine the accuracy of specimen-specific finite element models of untreated and cement-augmented vertebrae by direct comparison with experimental results. Eleven single cadaveric vertebrae were imaged using micro computed tomography (mCT) and tested to failure in axial compression in the laboratory. Four of the specimens were first augmented with PMMA cement to simulate a prophylactic vertebroplasty. Specimen-specific finite element models were then generated using semi-automated methods. An initial set of three untreated models was used to determine the optimum conversion factors from the image data to the bone material properties. Using these factors, the predicted stiffness and strength were determined for the remaining specimens (four untreated, four augmented). The model predictions were compared with the corresponding experimental data. Good agreement was found with the non-augmented specimens in terms of stiffness (root-mean-square (r.m.s.) error 12.9 per cent) and strength (r.m.s. error 14.4 per cent). With the augmented specimens, the models consistently overestimated both stiffness and strength (r.m.s. errors 65 and 68 per cent). The results indicate that this method has the potential to provide accurate predictions of vertebral behaviour prior to augmentation. However, modelling the augmented bone with bulk material properties is inadequate, and more detailed modelling of the cement region is required to capture the bone—cement interactions if the models are to be used to predict the behaviour following vertebroplasty.
Panning for science.

Scientists are using a powerful tool for teaching and public engagement with science and the natural world for projects as diverse as analyzing Middle Eastern petroglyphs, monitoring an urban forest, archiving a museum insect collection, studying a collapsed honey bee colony, keeping tabs on glaciers, examining erosion in a jaguar reserve, and viewing Galapagos fish clustered into a bait ball. Users of the GigaPan system punch numbers into a keypad on a robotic mount for a digital camera, specifying how expansive they want their panorama to be. A microprocessor calculates the size and number of exposures needed for the pan and moves the camera accordingly. A small robotic finger pushes the shutter button for each exposure. These are stitched together to form a panorama with a resolution 1000 times that of HDTV. The largest GigaPan has 100 gigapixels. The final image contains more data than most personal computers can handle, so the system9s developers created a massive server system and Web site for storing and accessing GigaPans. When viewers zoom in on an area of an image, they seem to fly into the image itself. The result is an immersive, interactive experience that can reveal surprising details––an ant on a leaf in a forest, or a hummingbird sipping nectar from a flower in a backyard. It9s like viewing nature through a huge magnifying glass. * Karen A. Frenkel is a science writer in New York City.
Roles of individual prolyl‐4‐hydroxylase isoforms in the first 24 hours following transient focal cerebral ischaemia: insights from genetically modified mice

• Cerebral ischaemia results in the activation of multiple pathways that can independently lead to neuronal death. Agents targeting a number of processes at one time are likely to be translated into stroke therapy. • Hypoxia‐inducible factor (HIF) is a transcription complex which responds to changes in oxygen. HIF levels are tightly regulated by a group of prolyl hydroxylases (PHDs). • In this study, we investigated the function of each of the HIF‐PHDs in the first 24 hours following transient focal cerebral ischaemia by using mice with each isoform genetically suppressed. • We found that the PHD1−/−, PHD2+/−, PHD3−/− mice had different outcomes after inducing ischaemia. In particular, the PHD2+/− mice had an improved rCBF response post‐reperfusion with better behavioural scores. The PHD3−/− mice have worse rCBF but no behavioural change. • The information gained enhances understanding of the biological processes involved and informs strategies for therapeutic targeting of the PHD enzymes.