Miracle-dz/UniFAR-FTUs huggingface dataset:
Health benefits of cultured and culture-containing milks

Summary Although cultured milk products have an image of ‘healthiness’, the scientific basis for many of the claims made is insubstantial. The published evidence that the lactose in yoghurt is tolerated better by lactase-deficient people than an equivalent amount of lactose in milk is consistent, although the mechanism remains to be demonstrated. There is little convincing evidence that cultured milks have any different effect on plasma cholesterol than unfermented milk but current research on products cultured with specific cholesterol metabolizing strains of lactic acid bacteria may cause this conclusion to be revised. Despite long-standing assertions that cultured products have therapeutic properties for diarrhoea and constipation, the data are not convincing. Stimulatory effects on the immune system and antitumour properties are current areas of active research which may yield interesting results. Notwithstanding these reservations, cultured milk products are nutritious foods adding interest, variety and palatability to the diet.
The definition and computation of trajectory and subtrajectory similarity

Trajectory data is becoming more and more available, opening up possibilities to subject whole sets of trajectories to data mining. The techniques for trajectory mining are only partly developed. This paper discusses new problems and solutions in the analysis of the similarity of two trajectories. Contrary to most previous research, similarity is not considered to be only shape-dependent but also time-dependent. The emphasis is on computing the most similar subtrajectories of two trajectories of some specified duration. We give polynomial time algorithms for exact or approximately most similar subtrajectories for various versions of this problem.
Slp2-a controls renal epithelial cell size through regulation of Rap–ezrin signaling independently of Rab27

ABSTRACT Synaptotagmin-like protein 2 (Slp2-a/Sytl2) is a Rab27 effector protein that regulates transport of Rab27-bearing vesicles and organelles through its N-terminal Rab27-binding domain and a phospholipid-binding C2A domain. Here we demonstrate a Rab27-independent function of Slp2-a in the control of renal cell size through a previously uncharacterized C2B domain. We found that by recruiting Rap1 GAPs to the plasma membrane of MDCK II cells through the C2B domain, Slp2-a inactivates Rap signaling and modulates the size of the cells. Functional ablation of Slp2-a resulted in an increase in the size of MDCK II cells. Drosophila Slp Bitesize was found to compensate for the function of Slp2-a in MDCK II cells, thereby indicating that the mechanism of the cell size control by Slp proteins has been evolutionarily conserved. Interestingly, blockade of the activity of ezrin, a downstream target of Rap, with the glucosylceramide synthase inhibitor, miglustat, effectively inhibited cell spreading of Slp2-a-knockdown cells. We also discovered aberrant expression of Slp2-a and increased activity of ezrin in pcy (Nphp3pcy) mice, a model of polycystic kidney disease that is characterized by renal cell spreading. Our findings indicate that Slp2-a controls renal cell size through regulation of Rap–ezrin signaling independently of Rab27.
Interphase phosphorylation of lamin A

ABSTRACT Nuclear lamins form the major structural elements that comprise the nuclear lamina. Loss of nuclear structural integrity has been implicated as a key factor in the lamin A/C gene mutations that cause laminopathies, whereas the normal regulation of lamin A assembly and organization in interphase cells is still undefined. We assumed phosphorylation to be a major determinant, identifying 20 prime interphase phosphorylation sites, of which eight were high-turnover sites. We examined the roles of these latter sites by site-directed mutagenesis, followed by detailed microscopic analysis – including fluorescence recovery after photobleaching, fluorescence correlation spectroscopy and nuclear extraction techniques. The results reveal three phosphorylation regions, each with dominant sites, together controlling lamin A structure and dynamics. Interestingly, two of these interphase sites are hyper-phosphorylated in mitotic cells and one of these sites is within the sequence that is missing in progerin of the Hutchinson-Gilford progeria syndrome. We present a model where different phosphorylation combinations yield markedly different effects on the assembly, subunit turnover and the mobility of lamin A between, and within, the lamina, the nucleoplasm and the cytoplasm of interphase cells.
A distributed topology-aware overlays construction algorithm

Peer-to-Peer (P2P) computing systems are rapidly growing in importance as the medium of choice for the mass storage. Peers in the most P2P systems randomly choose logical neighbors without any knowledge about underlying physical topology. This mechanism can cause a serious topology mismatch between the P2P overlay network and the underlying network. It greatly limits the performance gain from various search or routing techniques. In this paper, a distributed topology-aware overlays construction algorithm Taonet is proposed, in which the overlay network construction is based on the location information of underlying topology. The nodes that are close in the logical network are also close in terms of network latency. This leads to low latency stretch of the overlay network. This algorithm is scalable and distributed. Simulation results indicate that the latency of data location in these topology-aware P2P systems that are constructed with Taonet can be significantly decreased.
Hypothermia and Neonatal Encephalopathy

Data from large randomized clinical trials indicate that therapeutic hypothermia, using either selective head cooling or systemic cooling, is an effective therapy for neonatal encephalopathy. Infants selected for cooling must meet the criteria outlined in published clinical trials. The implementation of cooling needs to be performed at centers that have the capability to manage medically complex infants. Because the majority of infants who have neonatal encephalopathy are born at community hospitals, centers that perform cooling should work with their referring hospitals to implement education programs focused on increasing the awareness and identification of infants at risk for encephalopathy, and the initial clinical management of affected infants.
The A&bgr;1-42 peptide regulates microtubule stability independently of tau

ABSTRACT Interference with microtubule stability by beta-amyloid peptide (A&bgr;) has been shown to disrupt dendritic function and axonal trafficking, both early events in Alzheimer's disease. However, it is unclear whether A&bgr; regulation of microtubule dynamics can occur independently of its action on tau. RhoA has been implicated in neurotoxicity by A&bgr; but the mechanism by which this activation generates cytoskeletal changes is also unclear. We found that oligomeric A&bgr;1-42 induced the formation of stable detyrosinated microtubules in NIH3T3 cells and this function resulted from the activation of a RhoA-dependent microtubule stabilization pathway regulated by integrin signaling and the formin mDia1. Induction of microtubule stability by A&bgr; was also initiated by dimerization of APP and required caspase activity, two previously characterized regulators of neurotoxicity downstream of A&bgr;. Finally, we found that this function was conserved in primary neurons and abolished by Rho inactivation, reinforcing a link between induction of stable detyrosinated microtubules and neuropathogenesis by A&bgr;. Our study reveals a novel activity of A&bgr; on the microtubule cytoskeleton that is independent of tau and associated with pathways linked to microtubule stabilization and A&bgr;-mediated neurotoxicity.
The E3 SUMO ligase Nse2 regulates sumoylation and nuclear-to-cytoplasmic translocation of skNAC–Smyd1 in myogenesis

ABSTRACT Skeletal and heart muscle-specific variant of the &agr; subunit of nascent polypeptide associated complex (skNAC; encoded by NACA) is exclusively found in striated muscle cells. Its function, however, is largely unknown. Previous reports have demonstrated that skNAC binds to m-Bop/Smyd1, a multi-functional protein that regulates myogenesis both through the control of transcription and the modulation of sarcomerogenesis, and that both proteins undergo nuclear-to-cytoplasmic translocation at the later stages of myogenic differentiation. Here, we show that skNAC binds to the E3 SUMO ligase mammalian Mms21/Nse2 and that knockdown of Nse2 expression inhibits specific aspects of myogenic differentiation, accompanied by a partial blockade of the nuclear-to-cytoplasmic translocation of the skNAC–Smyd1 complex, retention of the complex in promyelocytic leukemia (PML)-like nuclear bodies and disturbed sarcomerogenesis. In addition, we show that the skNAC interaction partner Smyd1 contains a putative sumoylation motif and is sumoylated in muscle cells, with depletion of Mms21/Nse2 leading to reduced concentrations of sumoylated Smyd1. Taken together, our data suggest that the function, specifically the balance between the nuclear and cytosolic roles, of the skNAC–Smyd1 complex might be regulated by sumoylation.
A new approach to text searching

We introduce a family of simple and fast algorithms for solving the classical string matching problem, string matching with don't care symbols and complement symbols, and multiple patterns. In addition we solve the same problems allowing up to k mismatches. Among the features of these algorithms are that they are real time algorithms, they don't need to buffer the input, and they are suitable to be implemented in hardware.
The selective inhibition of protein phosphatase-1 results in mitotic catastrophe and impaired tumor growth

ABSTRACT The serine/threonine protein phosphatase-1 (PP1) complex is a key regulator of the cell cycle. However, the redundancy of PP1 isoforms and the lack of specific inhibitors have hampered studies on the global role of PP1 in cell cycle progression in vertebrates. Here, we show that the overexpression of nuclear inhibitor of PP1 (NIPP1; also known as PPP1R8) in HeLa cells culminated in a prometaphase arrest, associated with severe spindle-formation and chromosome-congression defects. In addition, the spindle assembly checkpoint was activated and checkpoint silencing was hampered. Eventually, most cells either died by apoptosis or formed binucleated cells. The NIPP1-induced mitotic arrest could be explained by the inhibition of PP1 that was titrated away from other mitotic PP1 interactors. Consistent with this notion, the mitotic-arrest phenotype could be rescued by the overexpression of PP1 or the inhibition of the Aurora B kinase, which acts antagonistically to PP1. Finally, we demonstrate that the overexpression of NIPP1 also hampered colony formation and tumor growth in xenograft assays in a PP1-dependent manner. Our data show that the selective inhibition of PP1 can be used to induce cancer cell death through mitotic catastrophe. Highlighted Article: Mitosis is an established target for cancer chemotherapy. We show that the inhibition of protein phosphatase PP1 causes an arrest in mid-mitosis that often culminates in cell death.
Probabilistic ranked queries in uncertain databases

Recently, many new applications, such as sensor data monitoring and mobile device tracking, raise up the issue of uncertain data management. Compared to "certain" data, the data in the uncertain database are not exact points, which, instead, often locate within a region. In this paper, we study the ranked queries over uncertain data. In fact, ranked queries have been studied extensively in traditional database literature due to their popularity in many applications, such as decision making, recommendation raising, and data mining tasks. Many proposals have been made in order to improve the efficiency in answering ranked queries. However, the existing approaches are all based on the assumption that the underlying data are exact (or certain). Due to the intrinsic differences between uncertain and certain data, these methods are designed only for ranked queries in certain databases and cannot be applied to uncertain case directly. Motivated by this, we propose novel solutions to speed up the probabilistic ranked query (PRank) over the uncertain database. Specifically, we introduce two effective pruning methods, spatial and probabilistic, to help reduce the PRank search space. Then, we seamlessly integrate these pruning heuristics into the PRank query procedure. Extensive experiments have demonstrated the efficiency and effectiveness of our proposed approach in answering PRank queries, in terms of both wall clock time and the number of candidates to be refined.
FGF2 inhibits endothelial–mesenchymal transition through microRNA-20a-mediated repression of canonical TGF-β signaling

ABSTRACT Endothelial-to-mesenchymal transition (EndMT) is characterized by the loss of endothelial cell markers and functions, and coincides with de novo expression of mesenchymal markers. EndMT is induced by TGFβ1 and changes endothelial microRNA expression. We found that miR-20a is decreased during EndMT, and that ectopic expression of miR-20a inhibits EndMT induction. TGFβ1 induces cellular hypertrophy in human umbilical vein endothelial cells and abrogates VE-cadherin expression, reduces endothelial sprouting capacity and induces the expression of the mesenchymal marker SM22α (also known as TAGLN). We identified ALK5 (also known as TGFBR1), TGFBR2 and SARA (also known as ZFYVE9) as direct miR-20a targets. Expression of miR-20a mimics abrogate the endothelial responsiveness to TGFβ1, by decreasing ALK5, TGFBR2 and SARA, and inhibit EndMT, as indicated by the maintenance of VE-cadherin expression, the ability of the cells to sprout and the absence of SM22α expression. FGF2 increases miR-20a expression and inhibits EndMT in TGFβ1-stimulated endothelial cells. In summary, FGF2 controls endothelial TGFβ1 signaling by regulating ALK5, TGFBR2 and SARA expression through miR-20a. Loss of FGF2 signaling combined with a TGFβ1 challenge reduces miR-20a levels and increases endothelial responsiveness to TGFβ1 through elevated receptor complex levels and activation of Smad2 and Smad3, which culminates in EndMT. Summary: FGF2 induces the expression of miR-20a, which targets the TGFβ receptor complex and abolishes endothelial–mesenchymal transition, a process that has a major role in fibroproliferative diseases.
Sub-tenon Anaesthesia versus Intracameral Anaesthesia in Patients Undergoing cataract extraction: A Comparative Study of the Level of Pain, Visual Perception and Anxiety

Background: Phacoemulsification is a modern method of cataract extraction. Sub-tenon anaesthesia used to be the preferred anaesthetic technique for this procedure before intracameral anaesthesia gained its popularity in recent years. Nevertheless, many surgeons still believe that sub-tenon anaesthesia is better than topical anaesthesia. This study aimed to evaluate and compare the experiences of patients who were treated for cataract by phacoemulsification surgery using either sub-tenon or intracameral anaesthesia. Methods: Cross-sectional study conducted at Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia. Participants were asked to complete a questionnaire within 1-2 hours following surgery. The questionnaires were designed to gather information on the patient’s level of anxiety, visual perception and amount of pain experienced during cataract surgery. Results: A total of 62 patients were included in the study. Thirty-one patients received anaesthesia by sub-tenon injection, whereas another 31 patients received anaesthesia by intracameral injection. There were no significant differences in the level of pain experienced by the two groups of patients during instillation of anaesthesia and during surgery (p=0.205 and p=0.592, respectively). There were also no significant differences in terms of visual perception and anxiety levels during surgery between the two groups (p=0.178 and p=0.731, respectively). Conclusion: Intracameral anaesthesia obviates the need for an injection during cataract surgery and is as comfortable for patients as sub-tenon anaesthesia in terms of visual perception, level of pain, and anxiety.
PP1 initiates the dephosphorylation of MASTL, triggering mitotic exit and bistability in human cells

ABSTRACT Entry into mitosis is driven by the phosphorylation of thousands of substrates, under the master control of Cdk1. During entry into mitosis, Cdk1, in collaboration with MASTL kinase, represses the activity of the major mitotic protein phosphatases, PP1 and PP2A, thereby ensuring mitotic substrates remain phosphorylated. For cells to complete and exit mitosis, these phosphorylation events must be removed, and hence, phosphatase activity must be reactivated. This reactivation of phosphatase activity presumably requires the inhibition of MASTL; however, it is not currently understood what deactivates MASTL and how this is achieved. In this study, we identified that PP1 is associated with, and capable of partially dephosphorylating and deactivating, MASTL during mitotic exit. Using mathematical modelling, we were able to confirm that deactivation of MASTL is essential for mitotic exit. Furthermore, small decreases in Cdk1 activity during metaphase are sufficient to initiate the reactivation of PP1, which in turn partially deactivates MASTL to release inhibition of PP2A and, hence, create a feedback loop. This feedback loop drives complete deactivation of MASTL, ensuring a strong switch-like activation of phosphatase activity during mitotic exit. Highlighted Article: Our results show that loss of Cdk1 activity allows PP1 to partially dephosphorylate MASTL, activating PP2A, which completes the dephosphorylation and deactivation of MASTL, thereby promoting mitotic exit.
TrkA mediates retrograde semaphorin 3A signaling through plexin A4 to regulate dendritic branching

ABSTRACT Semaphorin 3A (Sema3A), a secretory semaphorin, exerts various biological actions through a complex between neuropilin-1 and plexin-As (PlexAs). Sema3A induces retrograde signaling, which is involved in regulating dendritic localization of GluA2 (also known as GRIA2), an AMPA receptor subunit. Here, we investigated a possible interaction between retrograde signaling pathways for Sema3A and nerve growth factor (NGF). Sema3A induces colocalization of PlexA4 (also known as PLXNA4) signals with those of tropomyosin-related kinase A (TrkA, also known as NTRK1) in growth cones, and these colocalized signals were then observed along the axons. The time-lapse imaging of PlexA4 and several TrkA mutants showed that the kinase and dynein-binding activity of TrkA were required for Sema3A-induced retrograde transport of the PlexA4–TrkA complex along the axons. The inhibition of the phosphoinositide 3-kinase (PI3K)–Akt signal, a downstream signaling pathway of TrkA, in the distal axon suppressed Sema3A-induced dendritic localization of GluA2. The knockdown of TrkA suppressed Sema3A-induced dendritic localization of GluA2 and that suppressed Sema3A-regulated dendritic branching both in vitro and in vivo. These findings suggest that by interacting with PlexA4, TrkA plays a crucial role in redirecting local Sema3A signaling to retrograde axonal transport, thereby regulating dendritic GluA2 localization and patterning. Highlighted Article: By interacting with PlexA4, TrkA plays a crucial role in redirecting local Sema3A signaling to retrograde axonal transport, thereby regulating dendritic GluA2 localization and patterning.
Exploitation of the host cell ubiquitin machinery by microbial effector proteins

ABSTRACT Pathogenic bacteria are in a constant battle for survival with their host. In order to gain a competitive edge, they employ a variety of sophisticated strategies that allow them to modify conserved host cell processes in ways that favor bacterial survival and growth. Ubiquitylation, the covalent attachment of the small modifier ubiquitin to target proteins, is such a pathway. Ubiquitylation profoundly alters the fate of a myriad of cellular proteins by inducing changes in their stability or function, subcellular localization or interaction with other proteins. Given the importance of ubiquitylation in cell development, protein homeostasis and innate immunity, it is not surprising that this post-translational modification is exploited by a variety of effector proteins from microbial pathogens. Here, we highlight recent advances in our understanding of the many ways microbes take advantage of host ubiquitylation, along with some surprising deviations from the canonical theme. The lessons learned from the in-depth analyses of these host–pathogen interactions provide a fresh perspective on an ancient post-translational modification that we thought was well understood. This article is part of a Minifocus on Ubiquitin Regulation and Function. For further reading, please see related articles: ‘Mechanisms of regulation and diversification of deubiquitylating enzyme function’ by Pawel Leznicki and Yogesh Kulathu (J. Cell Sci. 130, 1997–2006). ‘Cell scientist to watch – Mads Gyrd-Hansen' (J. Cell Sci. 130, 1981–1983). Summary: Microbial pathogens have developed a variety of strategies, both conventional and unconventional, to exploit and interfere with the ubiquitylation machinery of infected host cells.
Common NOS1AP Variants Are Associated With a Prolonged QTc Interval in the Rotterdam Study

Background— QT prolongation is an important risk factor for sudden cardiac death. About 35% of QT-interval variation is heritable. In a recent genome-wide association study, a common variant (rs10494366) in the nitric oxide synthase 1 adaptor protein (NOS1AP) gene was found to be associated with QT-interval variation. We tested for association of 2 NOS1AP variants with QT duration and sudden cardiac death. Methods and Results— The Rotterdam Study is a population-based, prospective cohort study of individuals ≥55 years of age. The NOS1AP variants rs10494366 T>G and rs10918594 C>G were genotyped in 6571 individuals. Heart rate–corrected QT interval (QTc) was determined with ECG analysis software on up to 3 digital ECGs per individual (total, 11108 ECGs from 5374 individuals). The association with QTc duration was estimated with repeated-measures analyses, and the association with sudden cardiac death was estimated by Cox proportional-hazards analyses. The rs10494366 G allele (36% frequency) was associated with a 3.8-ms (95% confidence interval, 3.0 to 4.6; P=7.8×10−20) increase in QTc interval duration for each additional allele copy, and the rs10918594 G allele (31% frequency) was associated with a 3.6-ms (95% confidence interval, 2.7 to 4.4; P=6.9×10−17) increase per additional allele copy. None of the inferred NOS1AP haplotypes showed a stronger effect than the individual single-nucleotide polymorphisms. There were 233 sudden cardiac deaths over 11.9 median years of follow-up. No significant association was observed with sudden cardiac death risk. Conclusions— Common variants in NOS1AP are strongly associated with QT-interval duration in an elderly population. Larger sample sizes are needed to confirm or exclude an effect on sudden cardiac death risk.