bluuebunny/crossref_metadata_2025 huggingface dataset:
Accelerometer Detects Pump Thrombosis and Thromboembolic Events in an In vitro HVAD Circuit
Authors: Schalit Itai , Espinoza Andreas , Pettersen Fred-Johan , Thiara Amrit P. S. , Karlsen Hilde , Sørensen Gro , Fosse Erik , Fiane Arnt E. , Halvorsen Per S.
Published: October 2017

Pump thrombosis and stroke are serious complications of left ventricular assist device (LVAD) support. The aim of this study was to test the ability of an accelerometer to detect pump thrombosis and thromboembolic events (TEs) using real-time analysis of pump vibrations. An accelerometer sensor was attached to a HeartWare HVAD and tested in three in vitro experiments using different pumps for each experiment. Each experiment included thrombi injections sized 0.2–1.0 mL and control interventions: pump speed change, afterload increase, preload decrease, and saline bolus injections. A spectrogram was calculated from the accelerometer signal, and the third harmonic amplitude was used to test the sensitivity and specificity of the method. The third harmonic amplitude was compared with the pump energy consumption. The acceleration signals were of high quality. A significant change was identified in the accelerometer third harmonic during the thromboembolic interventions. The third harmonic detected thromboembolic events with higher sensitivity/specificity than LVAD energy consumption: 92%/94% vs. 72%/58%, respectively. A total of 60% of thromboembolic events led to a prolonged third harmonic amplitude change, which is indicative of thrombus mass residue on the impeller. We concluded that there is strong evidence to support the feasibility of real-time continuous LVAD monitoring for thromboembolic events and pump thrombosis using an accelerometer. Further in vivo studies are needed to confirm these promising findings.
Charcot-Marie-Tooth Disease 1X Simulating Paraparetic Guillain-Barre Syndrome
Authors: Parissis Dimitrios , Ioannidis Panagiotis , Papadopoulos Georgios , Karacostas Dimitrios
Published: October 2017

X-linked Charcot-Marie-Tooth disease (CMT 1X) is the second most common form of inherited demyelinating neuropathy. It is established that patients suffering from CMT 1X can have episodes of hemiparesis, paraparesis, quadriparesis, ataxia, aphasia, and dysarthria, which can be fully reversible, and ‘trigger’ factors for these episodes are usually febrile illness, high altitudes, hyperventilation, and physical activity. We describe a 22-year-old patient with a history of viral infection and sleep deprivation who presented to our department because of acute difficulty in walking and neurophysiological findings suggesting Guillain-Barre syndrome. The patient’s phenotype was compatible with CMT disease and within hours he showed remarkable improvement of his muscle strength without receiving any medical treatment. Any other metabolic, infectious, vasculitic, hematological, paraneoplastic, or infiltrative cause of polyneuropathy was excluded with laboratory work-up. Diagnosis of CMT 1X was confirmed with repeated neurophysiological study and genetic testing of his and his mother’s blood, demonstrating the Arg75Trp [CGG to TGG,(R75W)] mutation on exon2 of gap junction protein beta 1. CMT 1X should be considered in patients with a phenotype compatible with the disease, rapid improvement of their clinical manifestations, and neurophysiological findings consistent with a hereditary, demyelinating neuropathy.
Bismuth Subgallate Toxicity in the Age of Online Supplement Use
Authors: Sampognaro Paul , Vo Kathy T. , Richie Megan , Blanc Paul D. , Keenan Kevin
Published: October 2017

Introduction:

Bismuth salts have been used to treat gastroenterological disorders and are readily available over-the-counter and via the internet. Even though generally considered safe, bismuth compounds can cause a syndrome of subacute, progressive encephalopathy when taken in large quantities.

Case Report:

We present the case of woman who developed progressive encephalopathy, aphasia, myoclonus, and gait instability after chronically ingesting large amounts of bismuth subgallate purchased from a major online marketing website to control symptoms of irritable bowel syndrome. After extensive neurological work-up, elevated bismuth levels in her blood, urine, and cerebrospinal fluid confirmed the diagnosis of bismuth-related neurotoxicity. She improved slowly following cessation of exposure.

Conclusion:

This case highlights bismuth subgallate as a neurotoxic bismuth formulation and reminds providers of the potential for safety misconceptions of positively reviewed online supplements.
Thrombolytic Therapy in Acute Ischemic Stroke in Patients Not Fulfilling Conventional Criteria
Authors: Chi Man Sum , Chan Lok Yiu
Published: October 2017

Introduction:

There are many exclusion criteria in early randomized control trials for intravenous recombinant tissue plasminogen activator use in acute ischemic stroke, thus, many patients were not eligible for the treatment.

Objective:

This study aimed to compare the safety and short-term treatment outcome between those who fulfilled the criteria and those who did not.

Methods:

All acute ischemic stroke patients treated with intravenous thrombolysis from 2004 to 2015 in Tuen Mun hospital were recruited. They were divided into an on-label group if they did not have any of the contraindications and an off-label group if contraindication existed. Primary outcome of symptomatic hemorrhage, and secondary outcome of early neurological change, 3-month mortality and functional outcome were measured. Multivariate analysis with logistic regression with adjustment of baseline characteristics was done.

Results:

Totally, 323 patients received intravenous thrombolysis and 162 (50.2%) had at least one contraindication. None of the contraindications were associated with symptomatic intracranial hemorrhage. Patients with previous stroke and diabetes mellitus performed similarly in all outcome measures. Patients with minor stroke had less early neurological deterioration and better functional outcome. Old age and high blood pressure were shown to have less early neurological improvement and less good functional outcome. Severe stroke was related to increased mortality and none had a good functional outcome.

Conclusions:

This study demonstrated that the off-label group had comparable symptomatic intracranial hemorrhagic risk which gave ground for further study into its safety. However, some subgroups had less favorable outcome, including high blood pressure, severe stroke, and old age. This may be due to underlying comorbidities and limited rehabilitation potential rather than thrombolysis per se.
Longitudinal Analysis of Particulate Air Pollutants and Adolescent Delinquent Behavior in Southern California
Authors: Younan Diana , Tuvblad Catherine , Franklin Meredith , Lurmann Fred , Li Lianfa , Wu Jun , Berhane Kiros , Baker Laura A. , Chen Jiu-Chiuan
Published: October 2017

Animal experiments and cross-sectional human studies have linked particulate matter (PM) with increased behavioral problems. We conducted a longitudinal study to examine whether the trajectories of delinquent behavior are affected by PM2.5(PM with aerodynamic diameter ≤2.5 m) exposures before and during adolescence. We used the parent-reported Child Behavior Checklist at age 9-18 with repeated measures every ~2-3 years (up to 4 behavioral assessments) on 682 children from the Risk Factors for Antisocial Behavior Study conducted in a multi-ethnic cohort of twins born in 1990-1995. Based on prospectively-collected residential addresses and a spatiotemporal model of ambient air concentrations in Southern California, monthly PM2.5estimates were aggregated to represent long-term (1-, 2-, 3-year average) exposures preceding baseline and cumulative average exposure until the last assessment. Multilevel mixed-effects models were used to examine the association between PM2.5exposure and individual trajectories of delinquent behavior, adjusting for within-family/within-individual correlations and potential confounders. We also examined whether psychosocial factors modified this association. The results suggest that PM2.5exposure at baseline and cumulative exposure during follow-up was significantly associated (p<0.05) with increased delinquent behavior. The estimated effect sizes (per interquartile increase of PM2.5by 3.12-5.18 µg/m3) were equivalent to the difference in delinquency scores between adolescents who are 3.5-4 years apart in age. The adverse effect was stronger in families with unfavorable parent-to-child relationships, increased parental stress or maternal depressive symptoms. Overall, these findings suggest long-term PM2.5exposure may increase delinquent behavior of urban-dwelling adolescents, with the resulting neurotoxic effect aggravated by psychosocial adversities.
A modeling of a Diphtheria epidemic in the refugees camps
Authors: Torrea María , Torrea José Luis , Ortega Daniel
Published: October 2017

Background

Diphtheria has a big mortality rate. Vaccination practically eradicated it in industrialized countries. A decrease in vaccine coverage and public health deterioration cause a reemergence in the Soviet Union in 1990. These circumstances seem to be being reproduced in refugee camps with a potential risk of new outbreak.

Methods

We constructed a mathematical model that describes the evolution of the Soviet Union epidemic outbreak. We use it to evaluate how the epidemic would be modified by changing the rate of vaccination, and improving public health conditions.

Results

We observe that a small decrease of 15% in vaccine coverage, translates an ascent of 47% in infected people. A coverage increase of 15% and 25% decreases a 44% and 66% respectively of infected people. Just improving health care measures a 5%, infected people decreases a 11.31%. Combining high coverage with public health measures produces a bigger reduction in the amount of infected people compare to amelioration of coverage rate or health measures alone.

Conclusions

Our model estimates the evolution of a diphtheria epidemic outbreak. Small increases in vaccination rates and in public health measures can translate into large differences in the evolution of a possible epidemic. These estimates can be helpful in socioeconomic instability, to prevent and control a disease spread.
Sensory Detection of Aversive and Appetitive Stimuli by CRF neurons
Authors: Kim Jineun , Fang Yi-Ya , Bhat Shreelatha , Shin Anna , Hashikawa Koichi , Kim Daesoo , Sohn Jong-woo , Lin Dayu , Suh Greg S. B.
Published: October 2017

Corticotropin-releasing factor (CRF), which is released from the paraventricular nucleus (PVN) of the hypothalamus, is essential for mediating stress response by activating the hypothalamic-pituitary-adrenal (HPA) axis. CRF-releasing PVN neurons receive inputs from multiple brain regions that convey stressful events, but their rapid neuronal dynamics on the timescale of behavior remain unknown. Here, our optical recordings of PVN CRF neuronal activity in freely behaving mice revealed that PVN CRF neurons are activated immediately by a range of stress-inducing aversive stimuli, including predator odor. By contrast, CRF neuronal activity starts to drop within a second of exposure to appetitive stimuli, such as food. These findings suggest that PVN CRF neurons receive real-time information about aversive and appetitive stimuli. Their role in mediating the sensory detection and regulating the neuroendocrine axis resembles those of AgRP/NPY neurons and SFO neurons that regulate neurophysiology responses and mediate sensory detection of food and water.
Beyond Bilingualism: multilingual experience correlates with caudate volume
Authors: Hervais-Adelman Alexis , Egorova Natalia , Golestani Narly
Published: October 2017

The multilingual brain implements mechanisms that serve to select the appropriate language as a function of the communicative environment. Engaging these mechanisms on a regular basis appears to have consequences for brain structure and function. Studies have implicated the caudate nuclei as important nodes in polyglot language control processes, and have also shown structural differences in the caudate nuclei in bilingual compared to monolingual populations. However, the majority of published work has focused on the categorical differences between monolingual and bilingual individuals, and little is known about whether these findings extend to multilingual individuals, who have even greater language control demands. In the present paper, we present an analysis of the volume and morphology of the caudate nuclei, putamen, pallidum and thalami in 75 multilingual individuals who speak three or more languages. Volumetric analyses revealed a significant relationship between multilingual experience and right caudate volume, as well as a marginally-significant relationship with left caudate volume. Vertex-wise analyses revealed a significant enlargement of dorsal and anterior portions of the left caudate nucleus, known to have connectivity with executive brain regions, as a function of multilingual expertise. These results suggest that multilingual expertise might exercise a continuous impact on brain structure, and that as additional languages beyond a second are acquired, the additional demands for linguistic and cognitive control result in modifications to brain structures associated with language management processes.
Multi-modal brain fingerprinting: a manifold approximation based framework
Authors: Kumar Kuldeep , Chauvin Laurent , Toews Matthew , Colliot Olivier , Desrosiers Christian
Published: October 2017

This work presents an efficient framework, based on manifold approximation, for generating brain fingerprints from multi-modal data. The proposed framework represents images as bags of local features, which are used to build a subject proximity graph. Compact fingerprints are obtained by projecting this graph in a low-dimensional manifold, using spectral embedding. Experiments using the T1/T2-weighted MRI, diffusion MRI, and resting state fMRI data of 945 Human Connectome Project subjects demonstrate the benefit of combining multiple modalities, with multi-modal fingerprints more discriminative than those generated from individual modalities. Results also highlight the link between fingerprint similarity and genetic proximity, monozygotic twins having more similar fingerprints than dizygotic or non-twin siblings. This link is also reflected in the differences of feature correspondences between twin/sibling pairs, occurring in major brain structures and across hemispheres. The robustness of the proposed framework to factors like image alignment and scan resolution, as well as the reproducibility of results on retest scans, suggest the potential of multi-modal brain fingerprinting for characterizing individuals in a large cohort analysis. In addition, taking inspiration from the computer vision community, the proposed rank retrieval evaluation based on the task of twin/sibling identification and using Mean Average Precision (MAP) can be used for a standardized comparison of future brain fingerprints.
Molecular basis for the recognition of the human AAUAAA polyadenylation signal
Authors: Sun Yadong , Zhang Yixiao , Hamilton Keith , Manley James L. , Shi Yongsheng , Walz Thomas , Tong Liang
Published: October 2017

Nearly all eukaryotic messenger RNA precursors must undergo cleavage and polyadenylation at their 3′-end for maturation. A crucial step in this process is the recognition of the AAUAAA polyadenylation signal (PAS), and the molecular mechanism of this recognition has been a long-standing problem. Here we report the cryo-electron microscopy structure of a quaternary complex of human CPSF-160, WDR33, CPSF-30 and an AAUAAA RNA at 3.4 Å resolution. Strikingly, the AAUAAA PAS assumes an unusual conformation that allows this short motif to be bound directly by both CPSF-30 and WDR33. The A1 and A2 bases are recognized specifically by zinc finger 2 (ZF2) of CPSF-30 and the A4 and A5 bases by ZF3. Interestingly, the U3 and A6 bases form an intramolecular Hoogsteen base pair and directly contact WDR33. CPSF-160 functions as an essential scaffold and pre-organizes CPSF-30 and WDR33 for high-affinity binding to AAUAAA. Our findings provide an elegant molecular explanation for how PAS sequences are recognized for mRNA 3′-end formation.
Simultaneous CRISPR/Cas9-mediated editing of cassavaeIF4EisoformsnCBP-1andnCBP-2reduces cassava brown streak disease symptom severity and incidence
Authors: Gomez Michael A. , Lin Z. Daniel , Moll Theodore , Chauhan Raj Deepika , Renninger Kelley , Beyene Getu , Taylor Nigel J. , Carrington J. , Staskawicz B. , Bart R.
Published: October 2017

Cassavabrownstreakdisease (CBSD) is a major constraint on cassava yields in East and Central Africa and threatens production in West Africa. CBSD is caused by two species of positive sense RNA viruses belonging to the familyPotyviridae, genusIpomovirus:Cassavabrownstreakvirus(CBSV) andUgandancassavabrownstreakvirus(UCBSV). Diseases caused by the familyPotyviridaerequire the interaction of viral genome-linked protein (VPg) and hosteukaryotic translationinitiationfactor4E(eIF4E) isoforms. Cassava encodes five eIF4E proteins: eIF4E, eIF(iso)4E-1, eIF(iso)4E-2,novelcap-bindingprotein-1(nCBP-1), and nCBP-2. Protein-protein interaction experiments consistently found that VPg proteins associate with cassava nCBPs. CRISPR/Cas9-mediated genome editing was employed to generatencbp-1, ncbp-2, andncbp-1/ncbp-2mutants in cassava cultivar 60444. Challenge with CBSV showed thatncbp-1/ncbp-2mutants displayed delayed and attenuated CBSD aerial symptoms, as well as reduced severity and incidence of storage root necrosis. Suppressed disease symptoms were correlated with reduced virus titer in storage roots relative to wild-type controls. Our results demonstrate the ability to modify multiple genes simultaneously in cassava to achieve tolerance to CBSD. Future studies will investigate the contribution of remaining eIF4E isoforms on CBSD and translate this knowledge into an optimized strategy for protecting cassava from disease.
Robustness encoded across essential and accessory replicons in an ecologically versatile bacterium
Authors: diCenzo George C , Benedict Alex B , Fondi Marco , Walker Graham C , Finan Turlough M , Mengoni Alessio , Griffitts Joel S
Published: October 2017

Bacterial genome evolution is characterized by gains, losses, and rearrangements of functional genetic segments. The extent to which genotype-phenotype relationships are influenced by large-scale genomic alterations has not been investigated in a high-throughput manner. In the symbiotic soil bacteriumSinorhizobium meliloti,the genome is composed of a chromosome and two large extrachromosomal replicons (pSymA and pSymB, which together constitute 45% of the genome). Massively parallel transposon insertion sequencing (Tn-seq) was employed to evaluate contributions of chromosomal genes to fitness in both the presence and absence of these extrachromosomal replicons. Ten percent of chromosomal genes from diverse functional categories are shown to genetically interact with pSymA and pSymB. These results demonstrate the pervasive robustness provided by the extrachromosomal replicons, which is further supported by constraint-based metabolic modelling. A comprehensive picture of coreS. melilotimetabolism was generated through a Tn-seq-guidedin silicometabolic network reconstruction, producing a core network encompassing 726 genes. This integrated approach facilitated functional assignments for previously uncharacterized genes, while also revealing that Tn-seq alone misses over a quarter of wild type metabolism. This work highlights the strong functional dependencies and epistatic relationships that may arise between bacterial replicons and across a genome, while also demonstrating how Tn-seq and metabolic modelling can be used together to yield insights not obtainable by either method alone.
Subsurface Zircons with Presumptive “Biogenic” Inclusions as Potentially Useful Proxies for Studying Precambrian Bygone Biospheres in Goa
Authors: Sujata Dabolkar , Nandkumar Kamat
Published: October 2017

This work was inspired by recent report by Bell et al., 2015 who studied potentially biogenic carbon preserved in a 4.1 billion-year-old Zircon and need to assess the potential of Zircons found in Goa. Zircons (ZrSiO4) are naturally occurring silicate minerals which show radioactivity and high ductility and contain traces of Thorium and Uranium useful in Uranium–Thorium /Thorium −230 dating techniques. Zircons can be found in igneous, metamorphic rocks, sedimentary deposits and occurs as a detrital minerals in river and beach sands. Previous reports show that the Zircons can occur in different shapes such as round, elongated and with surface characteristics (Gartner et al.,2013). U-Pb Zircon dating methods had been used to study the continental growth in the western Dharwar craton of southern India (Jayananda et al., 2015). The present study was aimed at detection of subsurface Zircons with biogenic inclusions and assess their use as proxies for studying bygone Precambrium biospheres in Goa. Deep tubewell drilled Cores (60 and 65 m deep from surface) in island of Tiswadi at Taleigao were analyzed by light microscopy, Phase contrast microscopy and SEM to detect and classify the Zircons. In rapid preliminary sampling, total 50 Zircons were identified and 98% indicated the presence of interesting inclusions. These could be bubbles or kerogens or unidentified biological material. Zircons were classified as elongated, slightly rounded with sharp edges and showed widespread variety of surface characteristics like fracturing, cracks, scratches, striations and impact pits which may occur during transport processes. It is suggested that Zircons with presumptive biogenic inclusions can be further studied using techniques such as Raman Spectroscopy, Carbon Isotopic Measurements, X-Ray Microscopy, Trace Element Measurement consistent with Bell et al., 2015. More exhaustive studies have been undertaken to create a detail image database of Zircons from various other local samples to pinpoint those specifically useful for advanced work based on image analysis of the presumptive bioinclusions. Further attempts would be made to develop specific harvesting techniques to select potentially useful Zircons. International collaborations would be sought for applications of advanced techniques to local Zircons. Such studies would shed light on nature of bygone Precambrian biospheres in Goa and help in understanding evolution of life and the impact of plate tectonics and cataclysmic events shaping life on this planet.
Probabilistic Graphical Models Relate Immune Status with Response to Neoadjuvant Chemo-Therapy in Breast Cancer
Authors: Zapater-Moros Andrea , Gámez-Pozo Angelo , Prado-Vázquez Guillermo , Trilla-Fuertes Lucía , Arevalillo Jorge M , Díaz-Almirón Mariana , Navarro Hilario , Maín Paloma , Feliú Jaime , Zamora Pilar , Espinosa Enrique , Fresno Vara Juan Ángel
Published: October 2017

Breast cancer is the most frequent tumor in women and its incidence is increasing. Neoadjuvant chemotherapy has become standard of care as a complement to surgery in locally advanced or poor-prognosis early stage disease. The achievement of a complete response to neoadjuvant chemotherapy correlates with prognosis but it is not possible to predict who will obtain an excellent response. The molecular analysis of the tumor offers a unique opportunity to unveil predictive factors. In this work, gene expression profiling in 279 tumor samples from patients receiving neoadjuvant chemotherapy was performed and probabilistic graphical models were used. This approach enables addressing biological and clinical questions from a Systems Biology perspective, allowing to deal with large gene expression data and their interactions. Tumors presenting complete response to neoadjuvant chemotherapy had a higher activity of immune related functions compared to resistant tumors. Similarly, samples from complete responders presented higher expression of lymphocyte cell lineage markers, immune-activating and immune-suppressive markers, which may correlate with tumor infiltration by lymphocytes (TILs). These results suggest that the patient’s immune system plays a key role in tumor response to neoadjuvant treatment. However, future studies with larger cohorts are necessary to validate these hypotheses.
Prediction and interpretation of deleterious coding variants in terms of protein structural stability
Authors: Ancien F. , Pucci F. , Godfroid M. , Rooman M.
Published: October 2017

The classification of human genetic variants into deleterious and neutral is a challenging issue, whose complexity is rooted in the large variety of biophysical mechanisms that can be responsible for disease conditions. For non-synonymous mutations in structured proteins, one of these is the protein stability change, which can lead to functionality loss. We developed a stability-driven knowledge-based classifier that uses protein structure, artificial neural networks and solvent accessibility-dependent combinations of statistical potentials to predict whether destabilizing or stabilizing mutations are disease-causing. Our predictor yields a balanced accuracy of 71% in cross validation. As expected, it has a very high positive predictive value of 89%: it predicts with high accuracy the subset of mutations that are deleterious because of stability issues, but is by construction unable of classifying variants that are deleterious for other reasons. Its combination with an evolutionary-based predictor increases the balanced accuracy up to 75%, and allowed predicting more than 1/4 of the deleterious variants with 95% positive predictive value. Our method, called SNPMuSiC, can be used with both experimental and structural models and compares favorably with other prediction tools on several independent test sets. It constitutes a step towards interpreting variant effects at the molecular scale.
The self-organization of plant microtubules in three dimensions enable stable cortical localization and sensitivity to external cues
Authors: Mirabet Vincent , Krupinski Pawel , Hamant Olivier , Meyerowitz Elliot M , Jönsson Henrik , Boudaoud Arezki
Published: October 2017

Many cell functions rely on the ability of microtubules to self-organize as complex networks. In plants, cortical microtubules are essential to determine cell shape as they guide the deposition of cellulose microfibrils, and thus control mechanical anisotropy in the cell wall. Here we analyze how, in turn, cell shape may influence microtubule behavior. Using a computational model of microtubules enclosed in a three-dimensional space, We show that the microtubule network has spontaneous configurations that could explain many experimental observations without resorting to specific regulation. In particular, we find that the preferred localization of microtubules at the cortex emerges from directional persistence of the microtubules, combined with their growth mode. We identified microtubule parameters that seem relatively insensitive to cell shape, such as length or number. In contrast, microtubule array anisotropy depends strongly on local curvature of the cell surface and global orientation follows robustly the longest axis of the cell. Lastly, we found that the network is capable of reorienting toward weak external directional cues. Altogether our simulations show that the microtubule network is a good transducer of weak external polarity, while at the same time, it easily reaches stable global configurations.

Author summary

Plants exhibit an astonishing diversity in architecture and shape. A key to such diversity is the ability of their cells to coordinate and grow to reach a broad spectrum of sizes and shapes. Cell growth in plants is guided by the microtubule cytoskeleton. Here, we seek to understand how microtubules self-organize close to the cell surface. We build upon previous two-dimensional models and we consider microtubules as lines growing in three dimensions, accounting for interactions between microtubules or between microtubules and the cell surface. We show that microtubule arrays are able to adapt to various cell shapes and to reorient in response to factors such as signals or environment. Altogether, our results help to understand how the microtubule cytoskeleton contributes to the diversity of plant shapes and to how these shapes adapt to environment.
Restriction of dietary protein leads to conditioned protein preference and elevated palatability of protein-containing food in rats
Authors: Murphy Michelle , Peters Kate Z. , Denton Bethany S. , Lee Kathryn A. , Chadchankar Heramb , McCutcheon James E.
Published: October 2017

The mechanisms by which intake of dietary protein is regulated are poorly understood despite their potential involvement in determining food choice and appetite. In particular, it is unclear whether protein deficiency results in a specific appetite for protein and whether influences on diet are immediate or develop over time. To determine the effects of protein restriction on consumption, preference, and palatability for protein we assessed patterns of intake for casein (protein) and maltodextrin (carbohydrate) solutions in adult rats. To induce a state of protein restriction, rats were maintained on a low protein diet (5% casein) and compared to control rats on non-restricted diet (20% casein). Under these dietary conditions, relative to control rats, protein-restricted rats exhibited hyperphagia without weight gain. After two weeks, on alternate conditioning days, rats were given access to either isocaloric casein or maltodextrin solutions that were saccharin-sweetened and distinctly flavoured whilst consumption and licking patterns were recorded. This allowed rats to learn about the post-ingestive nutritional consequences of the two different solutions. Subsequently, during a preference test when rats had access to both solutions, we found that protein-restricted rats exhibited a preference for casein over carbohydrate whereas non-restricted rats did not. Analysis of lick microstructure revealed that this preference was associated with an increase in cluster size and number, reflective of an increase in palatability. In conclusion, protein-restriction induced a conditioned preference for protein, relative to carbohydrate, and this was associated with increased palatability.
Deep-RBPPred: Predicting RNA binding proteins in the proteome scale based on deep learning
Authors: Zheng Jinfang , Zhang Xiaoli , Zhao Xunyi , Tong Xiaoxue , Hong Xu , Xie Juan , Liu Shiyong
Published: October 2017

RNA binding protein (RBP) plays an important role in cell processes. Identifying RBPs by computation and experiment are both essential. Recently, RBPPred is proposed in our group to predict RBP with a high performance. However, RBPPred is too slow for that it will generate PSSM matrix as its feature. Herein, we develop a deep learning model called Deep-RBPPred. The model has three advantages comparing to previous models. 1. Deep-RBPPred only needs few physicochemical properties. 2. Deep-RBPPred runs much faster. 3. Deep-RBPPred has a good generalization ability. In the meantime, the performance is still as good as the stats-of-the-art method. In the testing in A. thaliana, S. cerevisiae and H. sapiens proteomics, MCC (AUC) are 0.6077 (0.9421), 0.573 (0.9034) and 0.8141(0.9515) respectively when the score cutoff is set to 0.5. In the verifying in Gerstberger-1538, the SN of our model is 90.38%. The running times are 9s, 7s, 8s and 10s, respectively, for H.sapiens, A.thaliana, S.cerevisiae and Gerstberger-1538 when it is tested in GPU. Deep-RBPPred forecasts 94.65% of 299 new RBP and about 8% higher sensitivity than RBPPred. We also apply deep-RBPPred in 19 eukaryotes proteomics and 11 bacteria proteomics downloaded from Uniprot. The result shows that rate of RBPs in eukaryotes proteome are much higher than bacteria proteome. Testing in 6 proteomics shows the many RBPs may be still undiscovered so far.
In vivoRNA targeting of point mutations via suppressor tRNAs and adenosine deaminases
Authors: Katrekar Dhruva , Mali Prashant
Published: October 2017

Point mutations underlie many genetic diseases. In this regard, while programmable DNA nucleases have been used to repair mutations, their use for gene therapy poses multiple challenges: one, efficiency of homologous recombination is typically low in cells; two, an active nuclease presents a risk of introducing permanent off-target mutations; and three, prevalent programmable nucleases typically comprise elements of non-human origin raising the potential ofin vivoimmunogenicity. In light of these, approaches to instead directly target RNA, and use of molecular machinery native to the host would be highly desirable. Towards this, we engineered and optimized two complementary approaches, referred together hereon astRiAD, based on the use oftRNAsin codon suppression andadenosinedeaminases in RNA editing. Specifically, by delivering modified endogenous tRNAs and/or the RNA editing enzyme ADAR2 and an associated guiding RNA (adRNA) via adeno-associated viruses, we enabled premature stop codon read-through and correction in themdxmouse model of muscular dystrophy that harbors a nonsense mutation in the dystrophin gene. We further demonstrated inducible restoration of dystrophin expression by pyrolysyl-tRNA mediated incorporation of unnatural amino acids (UAAs) at the stop codon. Additionally, we also engineered ADAR2 mediated correction of a point mutation in liver RNA of thespfashmouse model of ornithine transcarbamylase (OTC) deficiency. Taken together, our results establish the use of suppressor tRNAs and ADAR2 forin vivoRNA targeting, and this integrated tRiAD approach is robust, genomically scarless, and potentially non-immunogenic as it utilizes effector RNAs and human proteins.
Large-scale phenome-wide association study of PCSK9 loss-of-function variants demonstrates protection against ischemic stroke
Authors: Rao Abhiram S. , Lindholm Daniel , Rivas Manuel A. , Knowles Joshua W. , Montgomery Stephen B. , Ingelsson Erik
Published: October 2017

PCSK9 inhibitors are a potent new therapy for hypercholesterolemia and have been shown to decrease risk of coronary heart disease. Although short-term clinical trial results have not demonstrated major adverse effects, long-term data will not be available for some time. Genetic studies in large well-phenotyped biobanks offer a unique opportunity to predict drug effects and provide context for the evaluation of future clinical trial outcomes. We tested association of the PCSK9 loss-of-function variant rsll591147 (R46L) in a hypothesis-driven 11 phenotype set and a hypothesis-generating 278 phenotype set in 337,536 individuals of British ancestry in the United Kingdom Biobank (UKB), with independent discovery (n = 225K) and replication (n = 112K). In addition to the known association with lipid levels (OR 0.63) and coronary heart disease (OR 0.73), the T allele of rs11591147 showed a protective effect on ischemic stroke (OR 0.61, p = 0.002) but not hemorrhagic stroke in the hypothesis-driven screen. We did not observe an association with type 2 diabetes, cataracts, heart failure, atrial fibrillation, and cognitive dysfunction. In the phenome-wide screen, the variant was associated with a reduction in metabolic disorders, ischemic heart disease, coronary artery bypass graft operations, percutaneous coronary interventions and history of angina. A single variant analysis of UKB data using TreeWAS, a Bayesian analysis framework to study genetic associations leveraging phenotype correlations, also showed evidence of association with cerebral infarction and vascular occlusion. This result represents the first genetic evidence in a large cohort for the protective effect of PCSK9 inhibition on ischemic stroke, and corroborates exploratory evidence from clinical trials. PCSK9 inhibition was not associated with variables other than those related to low density lipoprotein cholesterol and atherosclerosis, suggesting that other effects are either small or absent.
Accounting for Apparent Deviations between Calorimetric and van’t Hoff Enthalpies
Authors: Kantonen Samuel A. , Henriksen Niel M. , Gilson Michael K.
Published: October 2017

Background

In theory, binding enthalpies directly obtained from calorimetry (such as ITC) and the temperature dependence of the binding free energy (van’t Hoff method) should agree. However, previous studies have often found them to be discrepant.

Methods

Experimental binding enthalpies (both calorimetric and van’t Hoff) are obtained for two host-guest pairs using ITC, and the discrepancy between the two enthalpies is examined. Modeling of artificial ITC data is also used to examine how different sources of error propagate to both types of binding enthalpies.

Results

For the host-guest pairs examined here, good agreement, to within about 0.4 kcal/mol, is obtained between the two enthalpies. Additionally, using artificial data, we find that different sources of error propagate to either enthalpy uniquely, with concentration error and heat error propagating primarily to calorimetric and van’t Hoff enthalpies, respectively.

Conclusions

With modern calorimeters, good agreement between van’t Hoff and calorimetric enthalpies should be achievable, barring issues due to non-ideality or unanticipated measurement pathologies. Indeed, disagreement between the two can serve as a flag for error-prone datasets. A review of the underlying theory supports the expectation that these two quantities should be in agreement.

General Significance

We address and arguably resolve long-standing questions regarding the relationship between calorimetric and van’t Hoff enthalpies. In addition, we show that comparison of these two quantities can be used as an internal consistency check of a calorimetry study.

Highlights

Agreement within ~0.4 kcal/mol between calorimetric and van’t Hoff enthalpies can be achieved for systems with typical heat and concentration errors, if solution non-ideality is not an issue.

Concentration error chiefly affects calorimetric enthalpies, while error in measured heat chiefly affects van’t Hoff enthalpies.

Large discrepancies between calorimetric and van’t Hoff enthalpies can be used to flag experimental error.

There is no theoretical basis to expect discrepancies between these two methods of determining the binding enthalpy.
Redundancy principle for optimal random search in biology
Authors: Schuss Z. , Basnayake K. , Holcman D.
Published: October 2017

Chemical activation rate is traditionally determined by the diffusion flux into an absorbing ball, as computed by Smoluchowski in 1916. Thus the rate is set by the mean first passage time (MFPT) of a Brownian particle to a small target. This paradigm is shifted in this manuscript to set the time scale of activation in cellular biology to the mean time of the first among many arrivals of particles at the activation site. This rate is very different from the MFPT and depends on different geometrical parameters. The shift calls for the reconsideration of physical modeling such as deterministic and stochastic chemical reactions based on the traditional forward rate, especially for fast activation processes occurring in living cells. Consequently, the biological activation time is not necessarily exponential. The new paradigm clarifies the role of population redundancy in accelerating search processes and in defining cellular-activation time scales. This is the case, for example, in cellular transduction or in the nonlinear dependence of fertilization rate on the number of spermatozoa. We conclude that statistics of the extreme set the new laws of biology, which can be very different from the physical laws derived for individuals.
Unsupervised discovery of demixed, low-dimensional neural dynamics across multiple timescales through tensor components analysis
Authors: Williams Alex H. , Kim Tony Hyun , Wang Forea , Vyas Saurabh , Ryu Stephen I. , Shenoy Krishna V. , Schnitzer Mark , Kolda Tamara G. , Ganguli Surya
Published: October 2017

Perceptions, thoughts and actions unfold over millisecond timescales, while learned behaviors can require many days to mature. While recent experimental advances enable large-scale and long-term neural recordings with high temporal fidelity, it remains a formidable challenge to extract unbiased and interpretable descriptions of how rapid single-trial circuit dynamics change slowly over many trials to mediate learning. We demonstrate a simple tensor components analysis (TCA) can meet this challenge by extracting three interconnected low dimensional descriptions of neural data: neuron factors, reflecting cell assemblies; temporal factors, reflecting rapid circuit dynamics mediating perceptions, thoughts, and actions within each trial; and trial factors, describing both long-term learning and trial-to-trial changes in cognitive state. We demonstrate the broad applicability of TCA by revealing insights into diverse datasets derived from artificial neural networks, large-scale calcium imaging of rodent prefrontal cortex during maze navigation, and multielectrode recordings of macaque motor cortex during brain machine interface learning.
Dark selection for JAK/STAT-inhibitor resistance in chronic myelomonocytic leukemia
Authors: Kaznatcheev Artem , Grimes David Robert , Velde Robert Vander , Cannataro Vincent , Baratchart Etienne , Dhawan Andrew , Liu Lin , Myroshnychenko Daria , Taylor-King Jake P. , Yoon Nara , Padron Eric , Marusyk Andriy , Basanta David
Published: October 2017

Acquired therapy resistance to cancer treatment is a common and serious clinical problem. The classic U-shape model for the emergence of resistance supposes that: (1) treatment changes the selective pressure on the treatment-naive tumour; (2) this shifting pressure creates a proliferative or survival difference between sensitive cancer cells and either an existing or de novo mutant; (3) the resistant cells then out-compete the sensitive cells and – if further interventions (like drug holidays or new drugs or dosage changes) are not pursued – take over the tumour: returning it to a state dangerous to the patient. The emergence of ruxolitinib resistance in chronic myelomonocytic leukemia (CMML) seems to challenge the classic model: we see the global properties of resistance, but not the drastic change in clonal architecture expected with the selection bottleneck. To study this, we explore three population-level models as alternatives to the classic model of resistance. These three effective models are designed in such a way that they are distinguishable based on limited experimental data on the time-progression of resistance in CMML. We also propose a candidate reductive implementation of the proximal cause of resistance to ground these effective theories. With these reductive implementations in mind, we also explore the impact of oxygen diffusion and spatial structure more generally on the dynamics of CMML in the bone marrow concluding that, even small fluctuations in oxygen availability can seriously impact the efficacy of ruxolitinib. Finally, we look at the ability of spatially distributed cytokine signaling feedback loops to produce a relapse in symptoms similar to what we observe in the clinic.
A novel high accuracy bandgap reference voltage source
Authors: Wang Songlin , Feng Shuang , Wang Hui , Yao Yu , Mao Jinhua , Lai Xinquan
Published: October 2017

Purpose

This paper aims to design a new bandgap reference circuit with complementary metal–oxide–semiconductor (CMOS) technology.

Design/methodology/approach

Different from the conventional bandgap reference circuit with operational amplifiers, this design directly connects the two bases of the transistors with both the ends of the resistor. The transistor acts as an amplifier to amplify the change of voltage, which is convenient for the feedback regulation of low dropout regulator (LDO) regulator circuit, at last to realize the temperature control. In addition, introducing the depletion-type metal–oxide–semiconductor transistor and the transistor operating in the saturation region through the connection of the novel circuit structure makes a further improvement on the performance of the whole circuit.

Findings

This design is base on the 0.18?m process of BCD, and the new bandgap reference circuit is verified. The results show that the circuit design not only is simple and novel but also can effectively improve the performance of the circuit. Bandgap voltage reference is an important module in integrated circuits and electronic systems. To improve the stability and performance of the whole circuit, simple structure of the bandgap reference voltage source is essential for a chip.

Originality/value

This paper adopts a new circuit structure, which directly connects the two base voltages of the transistors with the resistor. And the transistor acts as an amplifier to amplify the change of voltage, which is convenient for the feedback regulation of LDO regulator circuit, at last to realize the temperature control.
Static failure load predictions in notched steel components using a combined experimental-numerical approach
Authors: Smolnicki Michal Jan , Ptak Michal , Lesiuk Grzegorz
Published: October 2017

Purpose

The combined numerical-experimental approach has been presented. The purpose of this paper is to determine the critical rupture load of the notched components based on the cohesive zone modeling (CZM).

Design/methodology/approach

The 42CrMo4 steel (in normalized state) state has been tested and modeled using an eXtended finite element method (xFEM) philosophy with the CZM approach. In order to validate the numerically obtained critical load forces the experimental verification was performed.

Findings

The critical loads were determined for various notch configurations. The numerical and experimental values were compared. Based on this, a good agreement between experimental and numerical data is achieved. The relative error does not exceed 7 percent.

Practical implications

The presented procedure and approach is effective and simple for engineering applications. It is worth to underline that the obtained critical load values for notched components require only the static tensile test results and implementation of the presented route in numerical FEM, xFEM environment.

Originality/value

The presented methodology is actual and still developed. The scientific and engineering value of the presented numerical procedure is high.
Iteratively re‐weighted and refined least squares algorithm for robust inversion of geophysical data
Authors: Gholami Ali , Aghamiry Hossein S.
Published: October 2017

A robust metric of data misfit such as the ℓ1‐norm is required for geophysical parameter estimation when the data are contaminated by erratic noise. Recently, the iteratively re‐weighted and refined least‐squares algorithm was introduced for efficient solution of geophysical inverse problems in the presence of additive Gaussian noise in the data. We extend the algorithm in two practically important directions to make it applicable to data with non‐Gaussian noise and to make its regularisation parameter tuning more efficient and automatic. The regularisation parameter in iteratively reweighted and refined least‐squares algorithm varies with iteration, allowing the efficient solution of constrained problems. A technique is proposed based on the secant method for root finding to concentrate on finding a solution that satisfies the constraint, either fitting to a target misfit (if a bound on the noise is available) or having a target size (if a bound on the solution is available). This technique leads to an automatic update of the regularisation parameter at each and every iteration. We further propose a simple and efficient scheme that tunes the regularisation parameter without requiring target bounds. This is of great importance for the field data inversion where there is no information about the size of the noise and the solution. Numerical examples from non‐stationary seismic deconvolution and velocity‐stack inversion show that the proposed algorithm is efficient, stable, and robust and outperforms the conventional and state‐of‐the‐art methods.