Miracle-dz/UniFAR-FTUs huggingface dataset:
Insights into autophagosome maturation revealed by the structures of ATG5 with its interacting partners

Autophagy is a bulky catabolic process that responds to nutrient homeostasis and extracellular stress signals and is a conserved mechanism in all eukaryotes. When autophagy is induced, cellular components are sequestered within an autophagosome and finally degraded by subsequent fusion with a lysosome. During this process, the ATG12–ATG5 conjugate requires 2 different binding partners, ATG16L1 for autophagosome elongation and TECPR1 for lysosomal fusion. In our current study, we describe the crystal structures of human ATG5 in complex with an N-terminal domain of ATG16L1 as well as an internal AIR domain of TECPR1. Both binding partners exhibit a similar α-helical structure containing a conserved binding motif termed AFIM. Furthermore, we characterize the critical role of the C-terminal unstructured region of the AIR domain of TECPR1. These findings are further confirmed by biochemical and cell biological analyses. These results provide new insights into the molecular details of the autophagosome maturation process, from its elongation to its fusion with a lysosome.
nanos gene control DNA mediates developmentally regulated transposition in the yellow fever mosquito Aedes aegypti

Transposable elements (TEs) are proposed as a basis for developing drive systems to spread pathogen resistance genes through vector mosquito populations. The use of transcriptional and translational control DNA elements from genes expressed specifically in the insect germ line to mediate transposition offers possibilities for mitigating some of the concerns about transgene behavior in the target vector species and eliminating effects on nontarget organisms. Here, we describe the successful use of the promoter and untranslated regions from the nanos (nos) orthologous gene of the yellow fever mosquito, Aedes aegypti, to control sex- and tissue-specific expression of exogenously derived mariner MosI transposase-encoding DNA. Transgenic mosquitoes expressed transposase mRNA in abundance near or equal to the endogenous nos transcript and exclusively in the female germ cells. In addition, MosI mRNA was deposited in developing oocytes and localized and maintained at the posterior pole during early embryonic development. Importantly, four of five transgenic lines examined were capable of mobilizing a second MosI transgene into the mosquito genome, indicating that functional transposase was being produced. Thus, the nos control sequences show promise as part of a TE-based gene drive system.
The content of placental protein 12 in decidua and fetal membranes is greater than in placenta

Summary. Radioimmunoassay, gel filtration and sodium dodecyl sulphate‐polyacrylamide gel electrophoresis were used to study the content and properties of placental protein 12 (PP12) in the placenta, decidua and fetal membranes. The tissues were obtained from early pregnancy in 12 cases, and after normal term delivery in eight cases in seven of which chorion and amnion laeve were also studied. There was more PP12 in decidua and fetal membranes than in placenta. The decidua/placenta ratio of PP12 content ranged from 2 to 1154 (mean 193, SEM 66). These results suggest that PP12 is a decidual rather than placental protein.
Femural Shaft Fracture in a Newborn Infant Treated With Axial External Fixator: A Case Report

Background: The authors present a case of femural shaft fracture inanewborn infant treated with axial external fixator. Methods: The patient presented at the time of birth with a lumbar myelomeningocele and right femural shaft fracture. The common methods of treatment cannot be used, so 24 hours after birth before neurosurgery, we applied a Mini Penning Orthofix External Fixator for fracture stabilization. Results: The external fixator was maintained for 30 days and removed after taking a radiograph that showed fracture healing. At the last follow-up (2 years), the patient did not present axial or torsional defects of right lower limb. Conclusions: External fixation is not a traditional method for treatment of femural shaft fractures in patients younger than 6 years, but we think that in some cases, when traditional methods (splinting, cast, Pavlik harness) cannot be used, an external fixator is also a good option in patients younger than 2 years and in newborn infants.
Modelling approaches for optimal liquidation under a limit-order book structure

This thesis introduces a selection of models for optimal execution of financial assets at the tactical level. As opposed to optimal scheduling, which defines a trading schedule for the trader, this thesis investigates how the trader should interact with the order book. If a trader is aggressive he will execute his order using market orders, which will negatively feedback on his execution price through market impact. Alternatively, the models we focus on consider a passive trader who places limit orders into the limit-order book and waits for these orders to be filled by market orders from other traders. We assume these models do not exhibit market impact. However, given we await market orders from other participants to fill our limit orders a new risk is borne: execution risk.We begin with an extension of Gu�ant et al. (2012b) who through the use of an exponential utility, standard Brownian motion, and an absolute decay parameter were able to cleverly build symmetry into their model which significantly reduced the complexity. Our model consists of geometric Brownian motion (and mean-reverting processes) for the asset price, a proportional control parameter (the additional amount we ask for the asset), and a proportional decay parameter, implying that the symmetry found in Gu�ant et al. (2012b) no longer exists. This novel combination results in asset-dependent trading strategies, which to our knowledge is a unique concept in this framework of literature. Detailed asymptotic analyses, coupled with advanced numerical techniques (informing the asymptotics) are exploited to extract the relevant dynamics, before looking at further extensions using similar methods.We examine our above mentioned framework, as well as that of Gu�ant et al. (2012), for a trader who has a basket of correlated assets to liquidate. This leads to a higher-dimensional model which increases the complexity of both numerically solving the problem and asymptotically examining it. The solutions we present are of interest, and comparable with Markowitz portfolio theory. We return to our framework of a single underlying and consider four extensions: a stochastic volatility model which results in an added dimension to the problem, a constrained optimisation problem in which the control has an explicit lower bound, changing the exponential intensity to a power intensity which results in a reformulation as a singular stochastic control problem, and allowing the trader to trade using both market orders and limit orders resulting in a free-boundary problem.We complete the study with an empirical analysis using limit-order book data which contains multiple levels of the book. This involves a novel calibration of the intensity functions which represent the limit-order book, before backtesting and analysing the performance of the strategies.
Predicting the biologic behavior of ductal carcinoma in situ: an analysis of molecular markers.

BACKGROUND Ductal carcinoma in situ (DCIS) of the breast encompasses a heterogeneous group of noninvasive cancers that now represents 19% of new breast cancer cases. Optimal treatment remains controversial. We undertook this study to characterize the relationship between angiogenic markers and the biologic behavior of various DCIS phenotypes. METHODS We performed histopathologic review and immunohistochemistry for p53, vascular endothelial growth factor (VEGF), and factor VIII-related antigen on 103 specimens of pure DCIS. RESULTS VEGF expression was seen in 89 tumors (86%) and correlated with microvessel density (MVD). Among VEGF-negative tumors, mean MVD (number of microvessels per square millimeter) was 48 +/- 19, versus 117 +/- 7 for tumors expressing VEGF (P =.001). Strong p53 expression was observed in 28 tumors (27%) and was associated with comedo histology, high tumor grade, necrosis, high MVD, and ipsilateral tumor recurrence (all P < or =.03). Among 8 patients with ipsilateral recurrence, 5 (63%) had tumors with strong p53 expression, whereas only 24% of patients without recurrence had tumors with strong p53 expression (P =.03). Although 7 of 8 patients with ipsilateral recurrence had tumors with VEGF and high MVD, neither parameter achieved statistical significance. CONCLUSIONS These data suggest that molecular alterations may help predict the biologic aggressiveness of DCIS. Mutant p53 expression predisposes the patient toward ipsilateral recurrence, perhaps by promoting angiogenesis. Further investigation may identify clinically useful markers and novel treatment strategies.
Human polyomavirus JC virus genome

The complete DNA sequence of the human JC virus, which was found to consist of 5,130 nucleotide pairs, is presented. The amino acid sequence of six proteins could be deduced: the early, nonstructural proteins, large T and small t antigens; the late capsid proteins, VP1, VP2, and VP3; and the agnogene product encoded within the late leader sequence, called the agnoprotein in simian virus 40. The extent of homology between JC virus DNA and the genomes of simian virus 40 (69%) and BK virus (75%) confirmed the close evolutionary relationship of these three polyomaviruses. The sequences showing the greatest divergence in these viral DNAs occurred within the tandem repeats located to the late side of the replication origins.
The incidence of anastomotic leaks in patients undergoing colorectal surgery

Background There is evolving interest in auditing and credentialling the performance of surgeons. The incidence of anastomotic leakage has been proposed as a measure of performance following colorectal surgery. The aim of this study was to evaluate the incidence and risk factors associated with anastomotic leakage in patients undergoing resections of the colon and rectum.
tTregs, pTregs, and iTregs: similarities and differences

Foxp3+ T‐regulatory cells (Tregs) are primarily generated in the thymus (tTreg), but also may be generated extrathymically at peripheral sites (pTreg), or induced in cell culture (iTreg) in the presence of transforming growth factor β (TGFβ). A major unresolved issue is how these different populations of Tregs exert their suppressive function in vivo. We have developed novel systems in which the function of Tregs can be evaluated in vivo in normal mice. Our studies demonstrate that one prominent mechanism of action of polyclonal tTregs is to inhibit T‐effector cell trafficking to the target organ, while antigen‐specific iTregs primarily prevent T‐cell priming by acting on antigen‐presenting dendritic cells (DCs). Interleukin‐10 (IL‐10) plays an important role in the suppressive function of antigen‐specific iTregs by controlling the expression of MARCH1 and CD83 on the DC. Activated tTregs may mediate infectious tolerance by delivery of cell surface‐expressed TGFβ to naive responder T cells to generate pTregs. Manipulation of Treg function will require the ability to differentiate tTregs from pTregs and iTregs. The expression of the transcription factor Helios has proven to be a useful marker for the identification of stable tTregs in both mouse and human.
Trichloroethylene risk assessment: A review and commentary

Trichloroethylene (TCE) is a widespread environmental contaminant that is carcinogenic when given in high, chronic doses to certain strains of mice and rats. The capacity of TCE to cause cancer in humans is less clear. The current maximum contaminant level (MCL) of 5 ppb (μg/L) is based on an US Environment Protection Agency (USEPA) policy decision rather than the underlying science. In view of major advances in understanding the etiology and mechanisms of chemically induced cancer, USEPA began in the late 1990s to revise its guidelines for cancer risk assessment. TCE was chosen as the pilot chemical. The final guidelines emphasized a “weight-of-evidence” approach with consideration of dose-response relationships, modes of action, and metabolic/toxicokinetic processes. Where adequate data are available to support reversible binding of the carcinogenic moiety to biological receptors as the initiating event (i.e., a threshold exists), a nonlinear approach is to be used. Otherwise, the default assumption of a linear (i.e., nonthreshold) dose-response is utilized. When validated physiologically based pharmacokinetic (PBPK) models are available, they are to be used to predict internal dosimetry as the basis for species and dose extrapolations. The present article reviews pertinent literature and discusses areas where research may resolve some outstanding issues and facilitate the reassessment process. Key research needs are proposed, including role of dichloroacetic acid (DCA) in TCE-induced liver tumorigenesis in humans; extension of current PBPK models to predict target organ deposition of trichloroacetic acid (TCA) and DCA in humans ingesting TCE in drinking water; use of human hepatocytes to ascertain metabolic rate constants for use in PBPK models that incorporate variability in metabolism of TCE by potentially sensitive subpopulations; measurement of the efficiency of first-pass elimination of trace levels of TCE in drinking water; and assessment of exogenous factors’ (e.g., alcohol, drugs) ability to alter metabolic activation and risks at such low-level exposure.
Local Expert Perceptions of Migration as a Climate Change Adaptation in Bangladesh

People have long migrated for many reasons, often with a combination of forced and voluntary reasons combining to push them away from current situations and to pull them towards new situations. Bangladesh is one example where environmental changes have long been amongst the multitude of reasons for migrating, with contemporary climate change suggested as a major impetus towards more migration. This paper examines local expert perceptions of migration as a climate change adaptation strategy for Bangladeshis. Seventeen in-depth interviews were conducted with local experts in Bangladesh and Assam (India) on environmental change and migration to understand the perspectives of those with formal education and expert-related jobs who come from the areas being directly affected by Bangladeshi migration. Findings show that local experts consider that migration is used and will be used for climate change adaptation in Bangladesh, but migration is not solely for climate change adaptation, instead interweaving with all other factors influencing migration-related decisions.
Design and Demonstration of Polarizing Polymer Waveguides Using Birefringent Polymers

TE-pass and TM-pass polarizing waveguides were fabricated by adjusting the birefringence properties of multi-layer stacks. The desired values of indices of refraction and birefringence were obtained by the proper selection and customization of core and cladding materials. The technique developed was used in the fabrication of waveguides in various design configurations such as etched ribs, backfilled trenches and photobleached channels. Both passive and active (electro-optic) core materials were successfully used in demonstrating the polarization extinction ratios as high as 61 dB. To our knowledge, this is the highest extinction ratio reported with polarizing polymer waveguides. In the case of electro-optic polymer waveguides, the designs were modified to enhance the electric field strength in the core without compromising the polarizing extinction ratios of the waveguides.
Individual and Relational Correlates of Pain-related Empathic Accuracy in Spouses of Chronic Pain Patients

ObjectiveThis study aims to investigate correlates of pain-related empathic accuracy in spouses of chronic pain patients. Specifically, analyses addressed: (1) the correlates of pain-related empathic accuracy, (2) the relation between pain-related empathic accuracy, and patient and spouse adaptational outcomes, and (3) the relation between pain-related empathic accuracy and relational outcomes. MethodsFifty-eight chronic pain patients (28 women and 30 men) were filmed while participating in a simulated occupational lifting task. Patients were asked to report their level of pain while lifting canisters partially filled with sand. Spouses were later asked to view the video record of their partner's performance and to estimate their partner's level of pain. Empathic accuracy was defined in terms of the overall discrepancy between patients' pain ratings and spouses' pain estimates, and by the degree of covariation between patients' pain ratings and spouses' pain estimates across trials. ResultsAnalysis revealed that patients' pain severity, catastrophizing, fear of pain, and level of disability were significant correlates of empathic accuracy. Higher levels of pain-related empathic accuracy were associated to negative adaptational outcomes for chronic pain patients. With regard to the spouse, empathic accuracy was associated with the spouses' perceiving that they express less punitive responses when the patient is in pain. Empathic accuracy was not significantly related to relational outcomes. DiscussionThe results of this study suggest that empathic accuracy is associated with negative outcomes for the patient, and might not be an important correlate of marital satisfaction in couples in which one of the partners is suffering from chronic pain.
Tramadol Reduces the Sweating, Vasoconstriction, and Shivering Thresholds

The analgesic tramadol inhibits the neuronal reuptake of norepinephrine and 5-hydroxytryptamine, facilitates 5-hydroxytryptamine release, and activates [micro sign]-opioid receptors. Each of these actions is likely to influence thermoregulatory control. We therefore tested the hypothesis that tramadol inhibits thermoregulatory control. Eight volunteers were evaluated on four study days, on which they received no drugs, tramadol 125 mg, tramadol 250 mg, and tramadol 250 mg with naloxone, respectively. Skin and core temperatures were gradually increased until sweating was observed and then decreased until vasoconstriction and shivering were detected. The core temperature triggering each response defined its threshold. Tramadol decreased the sweating threshold by -1.03 +/- 0.67[degree sign]C[center dot][micro sign]g-1[center dot]mL (r (2) = 0.90 +/- 0.12). Tramadol also decreased the vasoconstriction threshold by -3.0 +/- 4.0[degree sign]C[center dot][micro sign]g-1[center dot]mL (r2 = 0.94 +/- 0.98) and the shivering threshold by -4.2 +/- 4.0[degree sign]C[center dot][micro sign]g-1[center dot]mL (r2 = 0.98 +/- 0.98). The sweating to vasoconstriction interthreshold range nearly doubled from 0.3 +/- 0.4[degree sign]C to 0.7 +/- 0.6[degree sign]C during the administration of large-dose tramadol (P = 0.04). The addition of naloxone only partially reversed the thermoregulatory effects of tramadol. The thermoregulatory effects of tramadol thus most resemble those of midazolam, another drug that slightly decreases the thresholds triggering all three major autonomic thermoregulatory defenses. In this respect, both drugs reduce the "setpoint" rather than produce a generalized impairment of thermoregulatory control. Nonetheless, tramadol nearly doubled the interthreshold range at a concentration near 200 ng/mL. This indicates that tramadol slightly decreases the precision of thermoregulatory control in addition to reducing the setpoint. Implications: The authors evaluated the effects of the analgesic tramadol on the three major thermoregulatory responses: sweating, vasoconstriction, and shivering. Tramadol had only slight thermoregulatory effects. Its use is thus unlikely to provoke hypothermia or to facilitate fever. (Anesth Analg 1998;87:173-9)
Current treatment of nontuberculous mycobacteriosis: an update

Introduction: Nontuberculous mycobacteria (NTM) are becoming increasingly important. A growing number of patients with underlying conditions that make them prone to diseases caused by NTM. These diseases include the appearance of new syndromes, such as mesotherapy and other cosmetic-related infections, or diseases that affect patients who are being treated with tumor necrosis factor. Areas covered: A literature search has been performed for each mycobacterium species. An introduction to the different aspects of the species and the diseases is provided, along with a review of the current therapeutic options; special emphasis is put on new research and discoveries. Expert opinion: Recognition of the current role of NTM isolates remains the key step in the management of NTM infections. After recognition, treatment must be guided by attending to the isolated species, the specific syndromes, clinical experience and – for some species – the results of in-vitro susceptibility tests. Surgical therapy is also important for some species (Mycobacterium ulcerans, Mycobacterium scrofulaceum) and for localized infections. The treatment of uncommon species is not yet well defined and recent research on resistance mechanisms has described their importance. The role of biofilms is currently of special concern for various specific infections.
Stress‐inducible protein 1 is a cell surface ligand for cellular prion that triggers neuroprotection

Prions are composed of an isoform of a normal sialoglycoprotein called PrPc, whose physiological role has been under investigation, with focus on the screening for ligands. Our group described a membrane 66 kDa PrPc‐binding protein with the aid of antibodies against a peptide deduced by complementary hydropathy. Using these antibodies in western blots from two‐dimensional protein gels followed by sequencing the specific spot, we have now identified the molecule as stress‐inducible protein 1 (STI1). We show that this protein is also found at the cell membrane besides the cytoplasm. Both proteins interact in a specific and high affinity manner with a Kd of 10−7 M. The interaction sites were mapped to amino acids 113–128 from PrPc and 230–245 from STI1. Cell surface binding and pull‐down experiments showed that recombinant PrPc binds to cellular STI1, and co‐immunoprecipitation assays strongly suggest that both proteins are associated in vivo. Moreover, PrPc interaction with either STI1 or with the peptide we found that represents the binding domain in STI1 induce neuropro tective signals that rescue cells from apoptosis.
What's in a Name? “Negritos” in the Context of the Human Prehistory of Southeast Asia

Abstract The “negrito”hypothesis posits that various indigenous groups throughout Island and Mainland Southeast Asia have a shared phenotype due to common descent from a putative ancestral population, representing a preagricultural substrate of humanity in the region. This has been examined and tested many times in the past, with no clear resolution. With many new resources to hand, the articles in this volume reexamine this hypothesis in a range of different ways. The evidence presented in this double issue of Human Biology speaks more against the category of “negrito” than for it. While populations with the negrito phenotype form a small proportion of all contemporary populations in this region, they have remained a persistent presence. And without a fascination about their origins, there would not be such a depth of knowledge about the human biology of this region more broadly as there is now.
The Ethics of Defining Quality of Life

The concept of quality of life is a popular, confusing taxonomy of definitions that lacks consensus for practice applications in healthcare disciplines. Usage of the term is infused with diverse and inconsistent meanings in contemporary healthcare literature. This article begins a discussion regarding the ethical implications for current usage of the concept in professional healthcare literature. Potential opportunities-limitations in professional nurse practice are discussed. The theoretical lens of the humanbecoming ethical tenets shall undergird the exploration and articulation of potential meanings of the concept.