Miracle-dz/UniFAR-FTUs huggingface dataset:
Kinetic traps in the folding/unfolding of procaspase‐1 CARD domain

We have examined the folding and unfolding of the caspase recruitment domain of procaspase‐1 (CP1‐CARD), a member of the α‐helical Greek key protein family. The equilibrium folding/unfolding of CP1‐CARD is described by a two‐state mechanism, and the results show CP1‐CARD is marginally stable with a ΔG H 2O of 1.1 ± 0.2 kcal/mole and an m‐value of 0.65 ± 0.06 kcal/mole/M (10 mM Tris‐HCl at pH 8.0, 1 mM DTT, 25°C). Consistent with the equilibrium folding data, CP1‐CARD is a monomer in solution when examined by size exclusion chromatography. Single‐mixing stopped‐flow refolding and unfolding studies show that CP1‐CARD folds and unfolds rapidly, with no detectable slow phases, and the reactions appear to reach equilibrium within 10 msec. However, double jump kinetic experiments demonstrate the presence of an unfolded‐like intermediate during unfolding. The intermediate converts to the fully unfolded conformation with a half‐time of 10 sec. Interrupted refolding studies demonstrate the presence of one or more nativelike intermediates during refolding, which convert to the native conformation with a half‐time of about 60 sec. Overall, the data show that both unfolding and refolding processes are slow, and the pathways contain kinetically trapped species.
Model for homologous recombination during transfer of DNA into mouse L cells: role for DNA ends in the recombination process

We have constructed phage lambda and plasmid DNA substrates (lambda tk2 and ptk2) that contain two defective herpesvirus thymidine kinase (tk) genes that can be used to detect homologous recombination during the transfer of DNA into mouse L cells deficient in thymidine kinase activity. The recombination event reconstructs a wild-type tk gene and is scored because it converts Tk- cells to Tk+. Using this system, we have shown that (i) both intramolecular and intermolecular homologous recombination can be detected after gene transfer; (ii) the degree of recombination decreases with decreasing tk gene homology; and (iii) the efficiency of recombination can be stimulated 10- to 100-fold by cutting the tk2 DNA with restriction enzymes at appropriate sites relative to the recombining sequences. Based on the substrate requirements for these recombination events, we propose a model to explain how recombination might occur in mammalian cells. The essential features of the model are that the cut restriction site ends are substrates for cellular exonucleases that degrade DNA strands. This process exposes complementary strands of the two defective tk genes, which then pair. Removal of unpaired DNA at the junction between the paired and unpaired regions permits a gap repair process to reconstruct an intact gene.
Selecting Patients for Treatment with Epidermal Growth Factor Tyrosine Kinase Inhibitors

Identification of objective tumor regressions with epidermal growth factor receptor tyrosine kinases (EGFR TKI) in non–small cell lung cancer (NSCLC) patients has resulted in intense, worldwide clinical and basic research directed toward finding the optimal use of EGFR TKIs in NSCLC. EGFR TKI clinical trials have shown that higher response rates and longer survival are associated with specific patient characteristics and that using conventional chemotherapy simultaneously with EGFR TKIs in unselected patients does not increase survival. Molecular studies have revealed that EGFR-activating mutations and high EGFR gene copy number are frequently found in patients who have the best outcomes with EGFR TKIs. More recent studies suggest that KRAS mutations may identify the subset of patients who have the worst outcome with the EGFR TKI treatment. Currently, investigators are trying to determine the optimal approach to selecting patients for treatment with EGFR TKIs. Studies that have evaluated the potential predictive value of clinical features and/or molecular profiles in EGFR TKI-treated NSCLC patients are discussed in this review.
Residual γH2AX foci induced by low dose x-ray radiation in bone marrow mesenchymal stem cells do not cause accelerated senescence in the progeny of irradiated cells

Mechanisms underlying the effects of low-dose ionizing radiation (IR) exposure (10-100 mGy) remain unknown. Here we present a comparative study of early (less than 24h) and delayed (up to 11 post-irradiation passages) radiation effects caused by low (80 mGy) vs intermediate (1000 mGy) dose X-ray exposure in cultured human bone marrow mesenchymal stem cells (MSCs). We show that γН2АХ foci induced by an intermediate dose returned back to the control value by 24 h post-irradiation. In contrast, low-dose irradiation resulted in residual γН2АХ foci still present at 24 h. Notably, these low dose induced residual γН2АХ foci were not co-localized with рАТМ foci and were observed predominantly in the proliferating Кi67 positive (Кi67+) cells. The number of γН2АХ foci and the fraction of nonproliferating (Кi67-) and senescent (SA-β-gal+) cells measured at passage 11 were increased in cultures exposed to an intermediate dose compared to unirradiated controls. These delayed effects were not seen in the progeny of cells that were irradiated with low-dose X-rays, although such exposure resulted in residual γН2АХ foci in directly irradiated cells. Taken together, our results support the hypothesis that the low-dose IR induced residual γH2AХ foci do not play a role in delayed irradiation consequences, associated with cellular senescence in cultured MSCs.
ENDOSCOPIC SUBMUCOSAL DISSECTION IN THE UPPER GASTROINTESTINAL TRACT: PRESENT AND FUTURE VIEW OF EUROPE

In Western countries endoscopic mucosal resection (EMR) has been widely accepted for treatment of early Barrett`s neoplasia and flat or depressed colorectal adenomas. In contrast endoscopic submucosal dissection (ESD) is infrequently performed for several reasons. It seems to be difficult to overcome the learning curve of this difficult technique because of the low case volume of early gastric cancer. On the other hand ESD of esophageal or colorectal lesions is even more challenging and is considered to be inappropriate for learning. In addition the indication for esophageal or colorectal ESD is controversial in view of excellent results of the well established EMR technique which is less time‐consuming and safer than ESD. A recent survey of leading Western endoscopy centers indicated the limited experience with ESD with a low number of cases for all potential indications. Only a few training courses have been established and the number of ongoing clinical studies is limited. Only 12 out of 340 published articles on “endoscopic mucosal dissection” were reported from Western countries.
Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey.

BACKGROUND This study presents estimates of lifetime and 12-month prevalence of 14 DSM-III-R psychiatric disorders from the National Comorbidity Survey, the first survey to administer a structured psychiatric interview to a national probability sample in the United States. METHODS The DSM-III-R psychiatric disorders among persons aged 15 to 54 years in the noninstitutionalized civilian population of the United States were assessed with data collected by lay interviewers using a revised version of the Composite International Diagnostic Interview. RESULTS Nearly 50% of respondents reported at least one lifetime disorder, and close to 30% reported at least one 12-month disorder. The most common disorders were major depressive episode, alcohol dependence, social phobia, and simple phobia. More than half of all lifetime disorders occurred in the 14% of the population who had a history of three or more comorbid disorders. These highly comorbid people also included the vast majority of people with severe disorders. Less than 40% of those with a lifetime disorder had ever received professional treatment, and less than 20% of those with a recent disorder had been in treatment during the past 12 months. Consistent with previous risk factor research, it was found that women had elevated rates of affective disorders and anxiety disorders, that men had elevated rates of substance use disorders and antisocial personality disorder, and that most disorders declined with age and with higher socioeconomic status. CONCLUSIONS The prevalence of psychiatric disorders is greater than previously thought to be the case. Furthermore, this morbidity is more highly concentrated than previously recognized in roughly one sixth of the population who have a history of three or more comorbid disorders. This suggests that the causes and consequences of high comorbidity should be the focus of research attention. The majority of people with psychiatric disorders fail to obtain professional treatment. Even among people with a lifetime history of three or more comorbid disorders, the proportion who ever obtain specialty sector mental health treatment is less than 50%. These results argue for the importance of more outreach and more research on barriers to professional help-seeking.
The Challenge of Moving from Welfare to Work

Despite overall low unemployment rates in 1996, various subgroups of the population had rates much higher than the average. This brief article considers the labor market profile of welfare recipients and examines the unemployment and underemployment rates of groups with similar demographic characteristics. In some cases, such rates are three and four times the overall national average.
Delay Tolerant Networking for smart city through drones

Sensors in future smart cities will continuously monitor the environment in order to prevent critical situations and waste of resources or to offer new services to end users. Likely, the existing networks will not be able to sustain such a traffic without huge investments in the telecommunication infrastructure. One possible solution to overcome these problems is to apply the Delay Tolerant Network (DTN) paradigm, that is to exploit the movement of objects, possibly carrying data toward the final destination. Depending on location of data sources in the area and on paths followed by moving objects some sources could be isolated. In order to fix this issue, we use a drone, flying at proper instant of time over the isolated sources to deliver their data to the final destination. The impact of the presence of a drone as relay of the DTN is investigated accounting for realistic constraints, such as limited drone flight duration.
Gravity Cues Embedded in the Kinematics of Human Motion Are Detected in Form-from-Motion Areas of the Visual System and in Motor-Related Areas

The present study investigated the cortical areas engaged in the perception of graviceptive information embedded in biological motion (BM). To this end, functional magnetic resonance imaging was used to assess the cortical areas active during the observation of human movements performed under normogravity and microgravity (parabolic flight). Movements were defined by motion cues alone using point-light displays. We found that gravity modulated the activation of a restricted set of regions of the network subtending BM perception, including form-from-motion areas of the visual system (kinetic occipital region, lingual gyrus, cuneus) and motor-related areas (primary motor and somatosensory cortices). These findings suggest that compliance of observed movements with normal gravity was carried out by mapping them onto the observer’s motor system and by extracting their overall form from local motion of the moving light points. We propose that judgment on graviceptive information embedded in BM can be established based on motor resonance and visual familiarity mechanisms and not necessarily by accessing the internal model of gravitational motion stored in the vestibular cortex.
The influence of crossbite on the coordinated electromyographic activity of human masticatory muscles during mastication.

The analysis of the masticatory muscle activity in subjects with altered occlusal relationships could provide useful data of the functional impact of morphological discrepancies. Thirty subjects aged 16-18 years, with a sound, full permanent dentition, bilateral angle class I, and an overjet and overbite between 2 and 5 mm, were examined. The control group (10 male, 10 female) had no crossbite, while the crossbite group (four male, six female) had a posterior unilateral crossbite (five on the left side, five on the right side). The electromyographic activity of the left and right masseter and temporalis anterior muscles was recorded during 15 s of unilateral (left and right) chewing of gum, and expressed as a percentage of the maximum voluntary clench on cotton rolls. For each subject, the masticatory frequency, the confidence ellipse of the simultaneous differential left-right masseter and temporal activity (Lissajous figure), and an index of muscular symmetry, were computed to assess muscular coordination. In the crossbite subjects, the four analysed muscles appeared to contract with altered and asymmetric patterns. A large variability was found, and the confidence ellipses calculated for the chewing tests performed on the crossed sides were not significant, while the confidence ellipses of the uncrossed side chewing were different from the ellipses computed in the normal occlusion group. The altered occlusal relationship influenced the coordination of the masticatory muscles during chewing on both sides. The functional alteration was more apparent when the side with the altered morphology was directly involved, i.e. when chewing was performed on the crossbite side.
Profit-sharing investment accounts in islamic banks or mutualization, accounting perspective

Purpose Islamic banks use Mudarabah contract to replace the interest-bearing deposits with profit-sharing investment accounts. The purpose of this paper is to explore the challenges and problems associated with the employment of Mudarabah contract by Islamic banks. Design/methodology/approach The study critically analyzes the Mudarabah contract used by Islamic banks. It reviews the evolution of the contract from its traditional type to more complicated types such as compound, unrestricted, commingled and continuous Mudarabah. The paper investigates the problems that have emerged from implementing such types in current business settings. Findings The paper proves that implementing the Mudarabah contract by banks imposes several problems among which are the following: difficulty in the determination of total profit resulting from Mudarabah and in allocating this profit to the multiple parties involved in Mudarabah; usage of reserves to cater against future losses may undermine the concept of Mudarabah profit-loss sharing and lead to earnings management; corporate governance is also a major problem in Mudarabah contract, as the depositors are exposed to risks but have no governance rights; and Mudarabah may also lessen the fair presentation of financial reporting. Research limitations/implications The paper examines the evolving Mudarabah contract and its implementation challenges, based on available literature (no empirical analysis was conducted). Practical implications The implications are significant for the future development of Islamic contracts and Islamic accounting treatments. Originality/value Many studies explored the Mudarabah contract from a Shariah or law perspective. However, this paper investigates the Mudarabah contract with a focus on the implication on accounting and financial reporting because of the lack of studies in this area. Furthermore, it demonstrates the persistent flaws in the Mudarabah contract, and it proposes a new model for mobilizing funds, i.e. mutual fund.
CD28 Costimulation Mediates T Cell Expansion Via IL-2-Independent and IL-2-Dependent Regulation of Cell Cycle Progression1

In the presence of TCR ligation by Ag, CD28 pathway mediates the most potent costimulatory signal for T cell activation, cytokine secretion, and T cell expansion. Although CD28 costimulation promotes T cell expansion due to IL-2 secretion and subsequent signaling via the IL-2 receptor, recent studies indicate that the dramatic T cell expansion mediated through the unopposed CD28 stimulation in CTLA4-deficient mice is IL-2 independent. Therefore, we sought to dissect the effects of CD28 and IL-2 receptor pathways on cell cycle progression and determine the molecular mechanisms by which the CD28 pathway regulates T cell expansion. Here we show that CD28 costimulation directly regulates T cell cycle entry and progression through the G1 phase in an IL-2-independent manner resulting in activation of cyclin D2-associated cdk4/cdk6 and cyclin E-associated cdk2. Subsequent progression into the S phase is mediated via both IL-2-dependent and IL-2-independent mechanisms and, although in the absence of IL-2 the majority of T cells are arrested at the G1/S transition, a significant fraction of them progresses into the S phase. The key regulatory mechanism for the activation of cyclin-cdk complexes and cell cycle progression is the down-regulation of p27kip1 cdk inhibitor, which is mediated at the posttranscriptional level by its ubiquitin-dependent degradation in the proteasome pathway. Therefore, CD28 costimulation mediates T cell expansion in an IL-2-independent and IL-2 dependent manner and regulates cell cycle progression at two distinct points: at the early G1 phase and at the G1/S transition.
Human mast cells, bacteria, and intestinal immunity

Summary: Mast cells are versatile tissue regulator cells controlling major intestinal functions such as epithelial secretion, epithelial permeability, blood flow, neuroimmune interactions, and peristalsis. Most importantly, mast cells are key regulators of the integrity and function of the gastrointestinal barrier. At the same time, they can act as immunomodulatory cells by reacting to various exogenous signals from bacteria, viruses, and parasites through innate recognition receptors, such as Toll‐like receptors (TLRs) or through receptors of the specific immune system, such as immunoglobulins (Igs) bound to their cell surface. This mast cell function is enhanced by an intensive cross talk of mast cells with other cells of the innate or adaptive immune systems. Finally, mast cells act as inflammatory cells mediating diseases such as allergy, once they become dysregulated because of excess of allergen, allergen‐specific IgE and cytokines, or invading microbes. The present article focuses on the human mast cell functions in the intestine and compares the data with those derived from animal experiments. In particular, the role of bacteria and TLRs expression by mast cells for allergic reactions are discussed.
QUANTITATIVE CONVERSION OF THE (6–4) PHOTOPRODUCT OF TpdC TO ITS DEWAR VALENCE ISOMER UPON EXPOSURE TO SIMULATED SUNLIGHT

Abstract— It has been found that the (6‐4) photoproduct of thymidylyl‐(3→ 5')‐deoxycytidine (TpdC) is converted quantitatively to a further photoproduct upon exposure to Pyrex‐filtered medium pressure mercury arc light. Infrared UV, FAB MS, 'H NMR, 13C NMR and “P” NMR spectra were obtained for both the (6–4) product and its photolysis product. 'H NMR assignments were made on the basis of proton decoupling and homonuclear shift correlated experiments and 13C NMR assignments were made on the basis of proton‐detected heteronuclear shift correlated experiments. The Dewar pyrimidi‐none structure was assigned to the photolysis product by analysis of the spectral data in comparison to those of the Dewar photoproduct of TpT and other Dewar pyrimidinones. The (6–4) product of TpdC is the second member of the class of (6–4) photoproducts that has been found to photoisomerize to its Dewar valence isomer upon exposure to wavelengths > 280 nm, the first being that of TpT (Taylor and Cohrs. 1987,J. Am. Chem. Soc.109,2834–2835). These results further support the proposal that all members of the (6–4) photoproduct class are converted to their Dewar valence isomers upon exposure to sunlight.
Image identification from brain activity using the population receptive field model

A goal of computational models is not only to explain experimental data but also to make new predictions. A current focus of computational neuroimaging is to predict features of the presented stimulus from measured brain signals. These computational neuroimaging approaches may be agnostic about the underlying neural processes or may be biologically inspired. Here, we use the biologically inspired population receptive field (pRF) approach to identify presented images from fMRI recordings of the visual cortex, using an explicit model of the underlying neural response selectivity. The advantage of the pRF-model is its simplicity: it is defined by a handful of parameters, which can be estimated from fMRI data that was collected within half an hour. Using 7T MRI, we measured responses elicited by different visual stimuli: (i) conventional pRF mapping stimuli, (ii) semi-random synthetic images and (iii) natural images. The pRF mapping stimuli were used to estimate the pRF-properties of each cortical location in early visual cortex. Next, we used these pRFs to identify which synthetic or natural images was presented to the subject from the fMRI responses. We show that image identification using V1 responses is far above chance, both for the synthetic and natural images. Thus, we can identify visual images, including natural images, using the most fundamental low-parameter pRF model estimated from conventional pRF mapping stimuli. This allows broader application of image identification.
Long-term photoreceptor transplants in dystrophic and normal mouse retina.

PURPOSE To determine the long-term status of transgenic photoreceptors transplanted to the subretinal space of both rd mutant (receptorless) and normal mouse retina. METHODS Microaggregates of neural retina from transgenic mice containing lacZ-labeled photoreceptors were transplanted to the subretinal space of adult rd mutant and normal mice. The transplant site was examined by light and electron microscopy at monthly intervals up to 9 months after transplantation surgery. RESULTS Photoreceptors develop and survive well if transplanted with the proper orientation to the retinal pigment epithelium (RPE). The status of the photoreceptors, including outer segments and synaptic terminals, appear normal for at least 9 months after transplantation; they continue to express the lacZ reporter gene. Cones survive as well as rods. Transplants to the normal mouse develop normally, whereas the host photoreceptors displaced from the RPE degenerate. A barrier, formed by Müller cell processes, develops after photoreceptor degeneration in both normal and rd mouse retina and demarcates host from transplant tissue. Areas can be found in which neural processes have penetrated this barrier. There is no evidence of host-graft rejection. CONCLUSION Transplanted progenitor photoreceptors develop and survive well for long periods of time in either the rd mutant or normal retina if they are properly positioned. In the former, they reconstitute a photoreceptor layer; in the latter, they replace the host photoreceptor layer, which degenerates after being displaced from the RPE. Areas of potential contact between donor and host neurons exist in these transplants.
Apaf-1/Cytochrome c-independent and Smac-dependent Induction of Apoptosis in Multiple Myeloma (MM) Cells*

Smac, a second mitochondria-derived activator of caspases, promotes caspase activation in the cytochrome c(cyto-c)/Apaf-1/caspase-9 pathway. Here, we show that treatment of multiple myeloma (MM) cells with dexamethasone (Dex) triggers the release of Smac from mitochondria to cytosol and activates caspase-9 without concurrent release of cyto-c and Apaf-1 oligomerization. Smac binds to XIAP (an inhibitor of apoptosis protein) and thereby, at least in part, eliminates its inhibitory effect on caspase-9. Interleukin-6, a growth factor for MM, blocks Dex-induced apoptosis and prevents release of Smac. Taken together, these findings demonstrate that Smac plays a functional role in mediating Dex-induced caspase-9 activation and apoptosis in MM cells.