bluuebunny/crossref_metadata_2025 huggingface dataset:
Treatment of Congenital Gastric Outlet Obstruction due to a Web: A Retrospective Single-center Review
Authors: Gehwolf Philipp , Hechenleitner Paul , Sanal Murat , Profanter Christoph , Häussler Beatrice , Härter Bettina
Published: March 2019

Background:

Congenital gastric antral web and congenital pyloric atresia are rare reasons of congenital gastric outlet obstruction (CGOO). Depending on the different forms, the symptoms vary from unspecific epigastric pain to nonbilious “projectile” vomiting, ileus and failure to thrive. Throughout the years, many different treatment options are described, like simple surgical dilatation, incision or excision of the membrane, possibly combined with a pyloroplasty.

Patients and Methods:

In this retrospective single-center observation study, we present 9 cases with different kinds of webs leading to CGOO. In a time period of 45 years (1970 to 2015) different treatment strategies and limitations of minimal invasive endoscopic treatment on the basis of complications and outcome are discussed.

Results:

Six patients had an incomplete antrum web. One patient suffered from a complete antrum web. In addition, in 2 patients a complete pyloric web, as well as an incomplete pyloric web was found. During the past 45 years, the treatment options for CGOO due to webs changed, and with the development of smaller and more flexible video endoscopes an endoscopic treatment has become feasible. The treatment strategy and follow-up examination was specific to every patient.

Conclusion:

On the basis of our review, minimal endoscopic procedures in small newborns and toddlers require a high level of experience. They are technically challenging and need suitable equipment. Overall, endoscopists and pediatric surgeons should equally be prepared for all possible complications in every treatment step. The endoscopic approach to managing this unusual disease may require multiple interventions and is associated with a risk of perforation. Therefore, we are convinced that centers undertaking this treatment modality should be equipped with the proper instrumentation, prepared to perform multiple endoscopic interventions, and supported with an ability to emergently convert to surgery if required.
Dynamics of acute respiratory distress syndrome development due to smoke inhalation injury: Implications for prolonged field care
Authors: Batchinsky Andriy I. , Wyckoff Ruth , Choi Jae-Hyek , Burmeister David , Jordan Bryan S. , Necsoiu Corina , Burkett Samuel E. , Morris Michael J. , Chung Kevin K. , Cancio Leopoldo C.
Published: March 2019

BACKGROUND

Smoke inhalation injury (SII) causes 30% to 40% mortality and will increase as a cause of death during prolonged field care. We used a combat relevant model of acute respiratory distress syndrome due to SII to study temporal changes in ventilation-perfusion (V/Q) matching, computed tomography (CT) scan data, and histopathology and hypothesized that SII leads to increase in shunt (Qshunt), V/Q mismatch, lung consolidation, and diffuse alveolar damage.

METHODS

Swine received severe SII and airway pressure release ventilation (APRV, n = 6), or conventional ARDSNet mechanical ventilation (MV) (CMV, n = 8). A control group without injury received volume controlled MV (CTRL, n = 6), The multiple inert gas elimination technique and CT were performed at baseline (BL), 0.5 hours, 1 hours, 2 hours, 24 hours, and 48 hours after injury. Diffuse alveolar damage scoring was performed post mortem. Significance at p less than 0.05: APRV versus CTRL‡; CMV versus CTRL†; APRV versus CMV*; & denotes changes versus BL.

RESULTS

(1) SII caused increases in Qshunt more so in APRV than CMV group. Qshunt did not change in CTRL. (2) Pao
2-to-FIO2 ratio (PFR) was lower in APRV versus CTRL at 2 hours (375 ± 62‡ vs. 549 ± 40) and 24 hours (126 ± 34‡*& vs. 445 ± 5) and 48 hours (120 ± 41‡& vs. 430 ± 13). In CMV animals, PFR was lower versus CTRL and BL at 24 hours (238 ± 33†&) and 48 hours (98 ± 27†&). Qshunt correlated with PFR (r = 0.75, p < 0.0001, APRV and (r = 0.65, p < 0.0001, CMV). CT showed decrease in normally aerated lung, while poorly and nonaerated lung increased.

CONCLUSION

Smoke inhalation injury leads to early development of shunt, V/Q mismatch, lung consolidation, and diffuse alveolar damage. These data substantiate the need for new point of injury interventions in the prolonged field care setting.

LEVEL OF EVIDENCE

Animal research.
Low-value clinical practices in injury care: A scoping review and expert consultation survey
Authors: Moore Lynne , Lauzier François , Tardif Pier-Alexandre , Boukar Khadidja Malloum , Farhat Imen , Archambault Patrick , Mercier Éric , Lamontagne François , Chassé Michael , Stelfox Henry T. , Berthelot Simon , Gabbe Belinda , Lecky Fiona , Yanchar Natalie , Champion Howard , Kortbeek John , Cameron Peter , Bonaventure Paule Lessard , Paquet Jérôme , Truchon Catherine , Turgeon Alexis F.
Published: March 2019

BACKGROUND

Tests and treatments that are not supported by evidence and could expose patients to unnecessary harm, referred to here as low-value clinical practices, consume up to 30% of health care resources. Choosing Wisely and other organizations have published lists of clinical practices to be avoided. However, few apply to injury and most are based uniquely on expert consensus. We aimed to identify low-value clinical practices in acute injury care.

METHODS

We conducted a scoping review targeting articles, reviews and guidelines that identified low-value clinical practices specific to injury populations. Thirty-six experts rated clinical practices on a five-point Likert scale from clearly low value to clearly beneficial. Clinical practices reported as low value by at least one level I, II, or III study and considered clearly or potentially low-value by at least 75% of experts were retained as candidates for low-value injury care.

RESULTS

Of 50,695 citations, 815 studies were included and led to the identification of 150 clinical practices. Of these, 63 were considered candidates for low-value injury care; 33 in the emergency room, 9 in trauma surgery, 15 in the intensive care unit, and 5 in orthopedics. We also identified 87 “gray zone” practices, which did not meet our criteria for low-value care.

CONCLUSION

We identified 63 low-value clinical practices in acute injury care that are supported by empirical evidence and expert opinion. Conditional on future research, they represent potential targets for guidelines, overuse metrics and de-implementation interventions. We also identified 87 “gray zone” practices, which may be interesting targets for value-based decision-making. Our study represents an important step toward the deimplementation of low-value clinical practices in injury care.

LEVEL OF EVIDENCE

Systematic Review, Level IV.
Transient non-integrative nuclear reprogramming promotes multifaceted reversal of aging in human cells
Authors: Sarkar Tapash Jay , Quarta Marco , Mukherjee Shravani , Colville Alex , Paine Patrick , Doan Linda , Tran Christopher M. , Chu Constance R. , Horvath Steve , Bhutani Nidhi , Rando Thomas A. , Sebastiano Vittorio
Published: March 2019

Aging is characterized by a gradual loss of function occurring at the molecular, cellular, tissue and organismal levels1-3. At the chromatin level, aging is associated with the progressive accumulation of epigenetic errors that eventually lead to aberrant gene regulation, stem cell exhaustion, senescence, and deregulated cell/tissue homeostasis3. The technology of nuclear reprogramming to pluripotency, through over-expression of a small number of transcription factors, can revert both the age and the identity of any cell to that of an embryonic cell by driving epigenetic reprogramming2,4,5. Recent evidence has shown that transient transgenic reprogramming can ameliorate age-associated hallmarks and extend lifespan in progeroid mice6. However, it is unknown how this form of ‘epigenetic rejuvenation’ would apply to physiologically aged cells and, importantly, how it might translate to human cells. Here we show that transient reprogramming, mediated by transient expression of mRNAs, promotes a rapid reversal of both cellular aging and of epigenetic clock in human fibroblasts and endothelial cells, reduces the inflammatory profile in human chondrocytes, and restores youthful regenerative response to aged, human muscle stem cells, in each case without abolishing cellular identity. Our method, that we named Epigenetic Reprogramming of Aging (ERA), paves the way to a novel, potentially translatable strategy for ex vivo cell rejuvenation treatment. In addition, ERA holds promise for in vivo tissue rejuvenation therapies to reverse the physiological manifestations of aging and the risk for the development of age-related diseases.
Pan-GWAS of Streptococcus agalactiae highlights lineage-specific genes associated with virulence and niche adaptation
Authors: Gori Andrea , Harrison Odile , Mlia Ethwako , Nishihara Yo , Chinkwita-Phiri Jacquline , Mallewa Macpherson , Dube Queen , Swarthout Todd D , Nobbs Angela H , Maiden Martin , French Neil , Heyderman Robert S
Published: March 2019

Streptococcus agalactiae (Group B streptococcus, GBS) is a coloniser of the gastrointestinal and urogenital tracts, and an opportunistic pathogen of infants and adults. The worldwide population of GBS is characterised by Clonal Complexes (CCs) with different invasive potentials. CC17 for example, is a hypervirulent lineage commonly associated with neonatal sepsis and meningitis, while CC1 is less invasive in neonates and more commonly causes invasive disease in adults with co-morbidities. The genetic basis of GBS virulence and to what extent different CCs have adapted to different host environments remain uncertain. We have therefore applied a pan-genome wide association study approach to 1988 GBS strains isolated from different hosts and countries. Our analysis identified 279 CC-specific genes associated with virulence, disease, metabolism and regulation of cellular mechanisms that may explain the differential virulence potential of particular CCs. In CC17 and CC23 for example, we have identified genes encoding for pilus, quorum sensing proteins, and proteins for the uptake of ions and micronutrients which are absent in less invasive lineages. Moreover, in CC17, carriage and disease strains were distinguished by the allelic variants of 21 of these CC-specific genes. Together our data highlight the lineage-specific basis of GBS niche adaptation and virulence, and suggest that human-associated GBS CCs have largely evolved in animal hosts before crossing to the humans and then spreading clonally.
Growth Mode and Carbon Source Impact the Surfaceome Dynamics ofLactobacillus rhamnosusGG
Authors: Savijoki Kirsi , Nyman Tuula A. , Kainulainen Veera , Miettinen Ilkka , Siljamäki Pia , Fallarero Adyary , Sandholm Jouko , Satokari Reetta , Varmanen Pekka
Published: March 2019

Bacterial biofilms have clear implications in disease and in food applications involving probiotics. Here, we show that switching the carbohydrate source from glucose to fructose increased the biofilm formation and the total surface-antigenicity of a well-known probiotic,Lactobacillus rhamnosusGG. Surfaceomes (all cell surface-associated proteins) of GG cells grown with glucose and fructose in planktonic and biofilm cultures were identified and compared, which indicated carbohydrate source-dependent variations, especially during biofilm growth. The most distinctive differences under these conditions were detected with several surface adhesins (e.g., MBF, SpaC/A pilus and penicillin-binding proteins), enzymes (glycoside hydrolases, PrsA, PrtP, PrtR and HtrA) and moonlighting proteins (glycolytic, transcription/translation and stress-associated proteins, r-proteins, tRNA synthetases, Clp family proteins, PepC, PepN and PepA). The abundance of several known adhesins and novel moonlighters, including enzymes acting on casein-derived peptides (ClpP, PepC and PepN), increased in the biofilm cells grown on fructose, from which the surface-associated aminopeptidase activity mediated by PepC and PepN was further confirmed by an enzymatic assay. The classical surface adhesins were predicted to be more abundant on planktonic cells growing either on fructose (MBF and SpaA) or glucose (SpaC). An additional indirect ELISA indicated both growth mode- and carbohydrate-dependent differences in abundance of SpaC, whereas the overall adherence of GG assessed with porcine mucus indicated that the carbon source and the growth mode affected mucus adhesion. The adherence of GG cells to mucus was almost completely inhibited by anti-SpaC antibodies regardless of growth mode and/or carbohydrate source, indicating the key role of the SpaCBA pilus in adherence under the tested conditions. Altogether, our results suggest that carbon source and growth mode coordinate classical and nonclassical protein export in GG, which ensures the presence of an integral and coordinated system that contributes to resistance, nutrient acquisition and cell-cell interactions under different conditions. In conclusion, the present study shows that different growth regimes and conditions can have a profound impact on the adherent and antigenic features of GG, thereby providing new information on how to gain additional benefits from this probiotic.
Direct visualization of single nuclear pore complex proteins using genetically-encoded probes for DNA-PAINT
Authors: Schlichthaerle Thomas , Strauss Maximilian T. , Schueder Florian , Auer Alexander , Nijmeijer Bianca , Kueblbeck Moritz , Sabinina Vilma Jimenez , Thevathasan Jervis V. , Ries Jonas , Ellenberg Jan , Jungmann Ralf
Published: March 2019

The Nuclear Pore Complex (NPC) is one of the largest and most complex protein assemblies in the cell and – among other functions – serves as the gatekeeper of nucleocytoplasmic transport. Unraveling its molecular architecture and functioning has been an active research topic for decades with recent cryogenic electron microscopy and superresolution studies advancing our understanding of the NPC's complex architecture. However, the specific and direct visualization of single copies of NPC proteins and thus the ability to observe single-molecule heterogeneities of these complex structures is thus far elusive. Here, we combine genetically-encoded self-labeling enzymes such as SNAP-tag and HaloTag with DNA-PAINT microscopy. We employ the high localization precision in DNA-PAINT and molecular contrast of these protein tags to optically resolve single copies of nucleoporins in the human Y-complex in three dimensions with a precision of ~3 nm. This technological advancement now enables structural studies of multicomponent complexes on the level of single proteins in cells using optical fluorescence microscopy.
Exceptional subgenome stability and functional divergence in allotetraploid teff, the primary cereal crop in Ethiopia
Authors: VanBuren Robert , Wai Ching Man , Pardo Jeremy , Yocca Alan E. , Wang Xuewen , Wang Hao , Chaluvadi Srinivasa R. , Bryant Doug , Edger Patrick P. , Bennetzen Jeffrey L. , Mockler Todd C. , Michael Todd P.
Published: March 2019

Teff (Eragrostis tef) is a cornerstone of food security in the Horn of Africa, where it is prized for stress resilience, grain nutrition, and market value. Despite its overall importance to small-scale farmers and communities in Africa, teff suffers from low production compared to other cereals because of limited intensive selection and molecular breeding. Here we report a chromosome-scale genome assembly of allotetraploid teff (variety ‘Dabbi’) and patterns of subgenome dynamics. The teff genome contains two complete sets of homoeologous chromosomes, with most genes maintained as syntenic gene pairs. Through analyzing the history of transposable element activity, we estimate the teff polyploidy event occurred ∼1.1 million years ago (mya) and the two subgenomes diverged ∼5.0 mya. Despite this divergence, we detected no large-scale structural rearrangements, homoeologous exchanges, or bias gene loss, contrasting most other allopolyploid plant systems. The exceptional subgenome stability observed in teff may enable the ubiquitous and recurrent polyploidy within Chloridoideae, possibly contributing to the increased resilience and diversification of these grasses. The two teff subgenomes have partitioned their ancestral functions based on divergent expression patterns among homoeologous gene pairs across a diverse expression atlas. The most striking differences in homoeolog expression bias are observed during seed development and under abiotic stress, and thus may be related to agronomic traits. Together these genomic resources will be useful for accelerating breeding efforts of this underutilized grain crop and for acquiring fundamental insights into polyploid genome evolution.
Bacterial endosymbionts influence fungal transcriptional profiles with implications for host response in the human fungal pathogensRhizopus microsporusandRhizopus delemar
Authors: Sephton-Clark Poppy , Muñoz José F , Itabangi Herbert , Voelz Kerstin , Cuomo Christina A , Ballou Elizabeth R
Published: March 2019

Mucorales spores, the causative agents of mucormycosis, interact with the innate immune system to cause acute, chronic, or resolving infection. Understanding the factors that influence disease initiation and progression is key to understanding mucormycosis and developing new treatments. Complicating this, mucormycosis can be caused by a number of species that span the Mucorales order and may be host to bacterial endosymbionts. This study sets out to examine the differences between two species in the Mucorales order by characterising their differential interactions with the innate immune system, and their interactions with environmental bacterial endosymbionts. Through a holistic approach, this study examines the transcriptional responses ofRhizopus delemarandRhizopus microsporus, two of the most commonly diagnosed species, to innate immune cells. This study also examines the immune cell response and assesses the variation in these responses, given the presence or absence of bacterial endosymbionts within the fungi. We see that the fungal response is driven by interaction with innate immune cells. Moreover, the effect of the bacterial endosymbiont on the fungus is species-specific and strongly influences fungal transcription during phagocyte stress. The macrophage response varies depending on the infecting fungal species, and depending on endosymbiont status. Macrophages are better able to survive when germination is inhibited, or upon a pro-inflammatory response. This work reveals species-specific host responses to related Mucorales spores and shows that bacterial endosymbionts have an important role to play by impacting both innate immune cell response, and fungal response when under stress.
ZapA stabilizes FtsZ filament bundles without slowing down treadmilling dynamics
Authors: Caldas Paulo , López-Pelegrín Mar , Pearce Daniel J.G. , Budanur Nazmi B. , Brugués Jan , Loose Martin
Published: March 2019

For bacterial cell division, treadmilling filaments of FtsZ organize into a ring-like structure at the center of the cell. What governs the architecture and stability of this dynamic Z-ring is currently unknown, but FtsZ-associated proteins have been suggested to play an important role. Here, we used anin vitroreconstitution approach combined with fluorescence microscopy to study the influence of the well-conserved protein ZapA on the organization and dynamics of FtsZ filaments recruited to a supported membrane. We found that ZapA increases the spatial order and stabilizes the steady-state architecture of the FtsZ filament network in a highly cooperative manner. Despite its strong influence on their large-scale organization, ZapA binds only transiently to FtsZ filaments and has no effect on their treadmilling velocity. Together, our data explains how FtsZ-associated proteins can contribute to the precision and stability of the Z-ring without compromising treadmilling dynamics.
Analysis of Genetically Regulated Gene Expression identifies a trauma type specific PTSD gene, SNRNP35
Authors: Huckins Laura M , Breen Michael S , Chatzinakos Chris , Hartmann Jakob , Klengel Torsten , da Silva Almeida Ana C , Dobbyn Amanda , Girdhar Kiran , Hoffman Gabriel E , Klengel Claudia , Logue Mark W , Lori Adriana , Morrison Filomene G , Nguyen Hoang T , Park Yongjin , Ruderfer Douglas , Sloofman Laura G , van Rooij Sanne JH ,   PTSD Working Group of Psychiatric Genomics Consortium, Baker Dewleen G , Chen Chia-Yen , Cox Nancy , Duncan Laramie E , Geyer Mark A , Glatt Stephen J. , Im Hae Kyung , Maihofer Adam X , Risbrough Victoria B , Smoller Jordan W , Stein Dan J , Yehuda Rachel , Liberzon Israel , Koenen Karestan C , Jovanovic Tanja , Kellis Manolis , Miller Mark W , Bacanu Silviu-Alin , Nievergelt Caroline M , Buxbaum Joseph D , Sklar Pamela , Ressler Kerry J , Stahl Eli A , Daskalakis Nikolaos P
Published: March 2019

PTSD has significant genetic heritability; however, it is unclear how genetic risk influences tissue-specific gene expression. We used brain and non-brain transcriptomic imputation models to impute genetically regulated gene expression (GReX) in 9,087 PTSD-cases and 23,811 controls and identified thirteen significant GReX-PTSD associations. The results suggest substantial genetic heterogeneity between civilian and military PTSD cohorts. The top study-wide significant PTSD-association was with predicted downregulation of the Small Nuclear Ribonucleoprotein U11/U12 Subunit 35 (SNRNP35) in the BA9 region of the prefrontal cortex (PFC) in military cohorts. In peripheral leukocytes from 175 U.S. Marines, the observed PTSD differential gene expression correlated with the predicted blood GReX differences for these individuals, and deployment stress downregulatedSNRNP35expression, primarily in Marines with post-deployment PTSD. SNRNP35 is a subunit of the minor spliceosome complex andSNRNP35knockdown in cells validated its functional importance in U12-intron splicing. Finally, mimicking acute activation of the endogenous stress axis in mice downregulated PFCSnrnp35expression.
Large-scale correlations between eight key double strand break related data sets over the whole human genome
Authors: Brahme Anders , Hultén Maj , Bengtsson Carin , Hultgren Andreas , Zetterberg Anders
Published: March 2019

Eight different data sets, covering the whole human genome are compared with regard to their genomic distribution. A close correlation between cytological detected chiasma and MLH1 immunofluorescence sites with the recombination density distribution from the HapMap project was found. Sites with a high probability of chromatid breakage after exposure to low and high ionization density radiations are often located inside common and rare Fragile Sites (FSs) indicating that the common Radiation-Induced Breakpoint sites (RIBs) may be a new kind of more local fragility. Furthermore, Oncogenes and other cancer-related genes are commonly located in regions with an increased probability of rearrangements during genomic recombination, or in regions with high probability of copy number changes, possibly since these processes may be involved in oncogene activation and cancer induction. An increased CpG density is linked to regions of high gene density to secure high fidelity reproduction and survival. To minimize cancer induction these genes are often located in regions of decreased recombination density and/or higher than average CpG density. Interestingly, copy number changes occur predominantly at common RIBs and/or FSs at least for breast cancers with poor prognosis and they decrease weakly but significantly in regions with increasing recombination density and CpG density. It is compelling that all these datasets are influenced by the cells handling of double strand breaks and more generally DNA damage on its genome. In fact, the DNA repair genes are systematically avoiding regions with a high recombination density. This may be a consequence of natural selection, as they need to be intact to accurately handle repairable DNA lesions.
Crystal structure of the LRR ectodomain of the plant immune receptor kinase SOBIR1
Authors: Hohmann Ulrich , Hothorn Michael
Published: March 2019

Plant unique membrane receptor kinases with leucine-rich repeat (LRR) extracellular domains are key regulators of development and immune responses. Here we present the 1.55 Å resolution crystal structure of the immune receptor kinase SOBIR1 from Arabidopsis. The ectodomain structure reveals the presence of 5 LRRs sandwiched between non-canonical capping domains. The disulphide bond-stabilized N-terminal cap harbors an unusual β-hairpin structure. The C-terminal cap features a highly positively charged linear motif which we find largely disordered in our structure. Size-exclusion chromatography and right-angle light scattering experiments suggest that SOBIR1 is a monomer in solution. The protruding β-hairpin, a set of highly conserved basic residues at the inner surface of the SOBIR LRR domain and the presence of a genetic missense allele in LRR2, together suggest that the SOBIR1 ectodomain may mediate protein – protein interaction in plant immune signalling.

Synopsis

The ectodomain structure of a novel plant membrane receptor kinase with unusual capping domains is reported.
Predicting the effects of SNPs on transcription factor binding affinity
Authors: Nishizaki Sierra S , Ng Natalie , Dong Shengcheng , Morterud Cody , Williams Colten , Boyle Alan P
Published: March 2019

GWAS have revealed that 88% of disease associated SNPs reside in noncoding regions. However, noncoding SNPs remain understudied, partly because they are challenging to prioritize for experimental validation. To address this deficiency, we developed the SNP effect matrix pipeline (SEMpl). SEMpl estimates transcription factor binding affinity by observing differences in ChIP-seq signal intensity for SNPs within functional transcription factor binding sites genome-wide. By cataloging the effects of every possible mutation within the transcription factor binding site motif, SEMpl can predict the consequences of SNPs to transcription factor binding. This knowledge can be used to identify potential disease-causing regulatory loci.
Neural signals to violations of abstract rules using speech-like stimuli
Authors: Vidal Yamil , Brusini Perrine , Bonfieni Michela , Mehler Jacques , Bekinschtein Tristan
Published: March 2019

As the evidence of predictive processes playing a role in a wide variety of cognitive domains increases, the brain as a predictive machine becomes a central idea in neuroscience. In auditory processing a considerable amount of progress has been made using variations of the Oddball design, but most of the existing work seems restricted to predictions based on physical features or conditional rules linking successive stimuli. To characterise the predictive capacity of the brain to abstract rules, we present here two experiments that use speech-like stimuli to overcome limitations and avoid common confounds. Pseudowords were presented in isolation, intermixed with infrequent deviants that contained unexpected phoneme sequences. As hypothesized, the occurrence of unexpected sequences of phonemes reliably elicited an early prediction error signal. These prediction error signals do not seemed to be modulated by attentional manipulations due to different task instructions, suggesting that the predictions are deployed even when the task at hand does not volitionally involve error detection. In contrast, the amount of syllables congruent with a standard pseudoword presented before the point of deviance exerted a strong modulation. Prediction error’s amplitude doubled when two congruent syllables were presented instead of one, despite keeping local transitional probabilities constant. This suggest that auditory predictions can be built integrating information beyond the immediate past. In sum, the results presented here further contribute to the understanding of the predictive capabilities of the human auditory system when facing complex stimuli and abstract rules.

Significance Statement

The generation of predictions seem to be a prevalent brain computation. In the case of auditory processing this information is intrinsically temporal. The study of auditory predictions has been largely circumscribed to unexpected physical stimuli features or rules connecting consecutive stimuli. In contrast, our everyday experience suggest that the human auditory system is capable of more sophisticated predictions. This becomes evident in the case of speech processing, where abstract rules with long range dependencies are universal. In this article, we present two electroencephalography experiments that use speech-like stimuli to explore the predictive capabilities of the human auditory system. The results presented here increase the understanding of the ability of our auditory system to implement predictions using information beyond the immediate past.
Overlapping transcriptional expression response of wheat zinc-induced facilitator-like transporters emphasize important role during Fe and Zn stress
Authors: Sharma Shivani , Kaur Gazaldeep , Kumar Anil , Kaur Jaspreet , Pandey Ajay Kumar
Published: March 2019

Background

Hexaploid wheat is an important cereal crop that has been targeted to enhance grain micronutrient content including zinc and iron. In this direction, modulating the expression of plant transporters involved in Fe and Zn homeostasis could be one of the promising approaches. Therefore, the present work was undertaken to identify bread wheatZinc–InducedFacilitator-Like (ZIFL) family of transporters and study their transcriptional expression response during micronutrient fluctuations and exposure to multiple heavy metals.

Results

The genome-wide analyses resulted in identification of thirty-five putativeTaZIFLgenes, which were distributed only on Chromosome 3, 4 and 5. Wheat ZIFL proteins subjected to the phylogenetic analysis showed the uniform distribution along with rice,Arabidopsisand maize.In-silicoanalysis of the promoters of the wheat ZIFL genes suggested the presence of multiple metal binding sites including those which are involved in Fe homeostasis. QRT-PCR analysis of wheatZIFLgenes suggested the differential regulation of the transcripts in roots and shoots under surplus Zn and also during Fe starvation. Specifically, in roots,TaZIFL2.3, TaZIFL4.1, TaZIFL4.2, TaZIFL5, TaZIFL6.1andTaZIFL6.2were significantly up-regulated by both Zn and Fe. This suggested that ZIFL could possibly be regulated by both the nutrient stress in a tissue specific manner. Interestingly, upon exposure to heavy metals,TaZIFL4.2andTaZIFL7.1showed significant up-regulation, whereasTaZIFL5andTaZIFL6.2remained almost unaffected.

Conclusion

This is the first report with detailed analysis of wheat ZIFL genes. Our study also identifies closest ortholog for transporter of mugineic acid, a chelator required for Fe uptake. Comprehensive transcript expression pattern during development of wheat seedlings and against various abiotic/biotic stresses resulted in tissue specific responses. Overall, this work addresses the role of wheatZIFLduring the interplay between micronutrient and heavy metal stress in a tissue specific manner.
Coronary atherosclerosis: Un-altered physiology
Authors: de Groot Paul , Veldhuizen Roel W
Published: March 2019

Background

End-stage coronary artery atherosclerosis has been studied extensively but the exact mechanisms of initiation and progression have not been defined fully. The aim of this study was to mathematically describe luminal change in relation to coronary vessel wall thickness in its progression from normal to atherosclerotic to establish whether these explain the pathophysiology.

Methods

One hundred coronary artery sections were graded histologically as ‘normal’ to ‘highly atherosclerotic’. Random systemic sampling by image analysis yielded 32 measurements (lumen radius and intima, medial, and adventitial thickness) from each section along 32 evenly spaced radii.

Results

The raw data follow an undulating course in relation to successive segments in all sections analyzed, pointing to a dynamic and well-ordered system. The calculated values, studied in triplets, followed a non-synchronized parabolic course, which was converted to linearity by taking the change in numbers (n-(n-1)=Δ) into account. The course and sign of ‘Δvessel wall’ (resulting from summed Δintima, Δmedia, Δadventitia) and ‘Δlumen radius’ values were unique for each triplet. Triplets order according to ‘Δlumen radius minus Δvessel wall’ and its course given by the trendline a-value presented stages in which increased Δvessel wall resulted in increased Δlumen radius in stages 1 and 3 and decreased Δlumen radius in stage 2. This phenomenon was found in all sections regardless of histological indication and independent of vessel wall constituent parts (intima, media, adventitia).

Conclusions

Similar basic processes are defined in all sections regardless of histological rating, indicating un-altered physiology. As such, coronary atherosclerosis can only be defined by a large to small shift of the triplets Δvessel wall trendline a-value. Consequently, no parameter of vessel wall pathology exists in absolute terms. Vessel wall composition has no importance for Δlumen radius.
Transitions in brain-network level information processing dynamics are driven by alterations in neural gain
Authors: Li Mike , Han Yinuo , Aburn Matthew J. , Breakspear Michael , Poldrack Russell A. , Shine James M. , Lizier Joseph T.
Published: March 2019

A key component of the flexibility and complexity of the brain is its ability to dynamically adapt its functional network structure between integrated and segregated brain states depending on the demands of different cognitive tasks. Integrated states are prevalent when performing tasks of high complexity, such as maintaining items in working memory, consistent with models of a global workspace architecture. Recent work has suggested that the balance between integration and segregation is under the control of ascending neuromodulatory systems, such as the noradrenergic system. In a previous large-scale nonlinear oscillator model of neuronal network dynamics, we showed that manipulating neural gain led to a ‘critical’ transition in phase synchrony that was associated with a shift from segregated to integrated topology, thus confirming our original prediction. In this study, we advance these results by demonstrating that the gain-mediated phase transition is characterized by a shift in the underlying dynamics of neural information processing. Specifically, the dynamics of the subcritical (segregated) regime are dominated by information storage, whereas the supercritical (integrated) regime is associated with increased information transfer (measured via transfer entropy). Operating near to the critical regime with respect to modulating neural gain would thus appear to provide computational advantages, offering flexibility in the information processing that can be performed with only subtle changes in gain control. Our results thus link studies of whole-brain network topology and the ascending arousal system with information processing dynamics, and suggest that the constraints imposed by the ascending arousal system constrain low-dimensional modes of information processing within the brain.

Author summary

Higher brain function relies on a dynamic balance between functional integration and segregation. Previous work has shown that this balance is mediated in part by alterations in neural gain, which are thought to relate to projections from ascending neuromodulatory nuclei, such as the locus coeruleus. Here, we extend this work by demonstrating that the modulation of neural gain alters the information processing dynamics of the neural components of a biophysical neural model. Specifically, we find that low levels of neural gain are characterized by high Active Information Storage, whereas higher levels of neural gain are associated with an increase in inter-regional Transfer Entropy. Our results suggest that the modulation of neural gain via the ascending arousal system may fundamentally alter the information processing mode of the brain, which in turn has important implications for understanding the biophysical basis of cognition.
A game theoretic approach to deciphering the dynamics of amyloid-β aggregation along competing pathways
Authors: Ghosh Preetam , Rana Pratip , Rangachari Vijayaraghavan , Saha Jhinuk , Steen Edward , Vaidya Ashwin
Published: March 2019

Aggregation of amyloidβ(Aβ) peptides is a significant event that underpins Alzheimer disease (AD). Aβaggregates, especially the low-molecular weight oligomers, are the primary toxic agents in AD pathogenesis. Therefore, there is increasing interest in understanding their formation and behavior. In this paper, we use our previously established investigations on heterotypic interactions between Aβand fatty acids (FAs) that adopt off-fibril formation pathway under the control ofFAconcentrations, to develop a mathematical framework in defining this complex mechanism. We bring forth the use of novel game theoretic framework based on the principles of Nash equilibria to define and simulate the competing on- and off-pathways of Aβaggregation. Together with detailed simulations and biophysical experiments, our mathematical models define the dynamics involved in the mechanisms of Aβaggregation in the presence ofFAs to adopt multiple pathways. Specifically, our game theoretic model indicates that the emergence of off- or on-pathway aggregates are tightly controlled by a narrow set of rate constant parameters, and one could alter such parameters to populate a particular oligomeric species. These models agree with the detailed simulations and experimental data on usingFAas a heterotypic partner to modulate temporal parameters. Predicting spatiotemporal landscape along competing pathways for a given heterotypic partner such as biological lipids is a first step towards simulating physiological scenarios in which the generation of specific conformeric strains of Aβcould be predicted. Such an approach could be profoundly significant in deciphering the biophysics of amyloid aggregation and oligomer generation, which is ubiquitously observed in many neurodegenerative diseases.
The structural evolution of host-pathogen protein interactions: an integrative approach
Authors: Brito Anderson F. , Pinney John W.
Published: March 2019

The evolution of protein-protein interactions (PPIs) is directly influenced by the evolutionary histories of the genes and the species encoding the interacting proteins. When it comes to PPIs of host-pathogen systems, the complexity of their evolution is much higher, as two independent, but biologically associated entities, are involved. In this work, an integrative approach combining phylogenetics, tree reconciliations, ancestral sequence reconstructions, and homology modelling is proposed for studying the evolution of host-pathogen PPIs. As a case study, we analysed the evolution of interactions between herpesviral glycoproteins gD/gG and the cell membrane proteins nectins. By modelling the structures of more than 12,000 ancestral states of these virus-host complexes it was found that in early times of their evolution, these proteins were unable to interact, most probably due to electrostatic incompatibilities between their interfaces. After the event of gene duplication that gave rise to a paralog of gD (known as gG), both protein lineages evolved following distinct functional constraints, with most gD reaching high binding affinities towards nectins, while gG lost such ability, most probably due to a process of neofunctionalization. Based on their favourable interaction energies (negative ΔG), it is possible to hypothesize that apart from nectins 1 and 2, some alphaherpesviruses might also use nectins 3 and 4 as cell receptors. These findings show that the proposed integrative method is suitable for modelling the evolution of host-pathogen protein interactions, and useful for raising new hypotheses that broaden our understanding about the evolutionary history of PPIs, and their molecular functioning.
Ring canals permit extensive cytoplasm sharing among germline cells independent of fusomes inDrosophilatestes
Authors: Kaufman Ronit S. , Price Kari L. , Mannix Katelynn M. , Ayers Kathleen , Hudson Andrew M. , Cooley Lynn
Published: March 2019

Intercellular bridges, also called ring canals (RCs), connect germline cells during gametogenesis in males and females. They form as a consequence of incomplete cytokinesis during cell division leaving groups of daughter cells connected in syncytia. InDrosophilafemales, RCs are required for oocyte growth but little is known about the role of RCs during spermatogenesis. Using live imaging, we document extensive intercellular movement of GFP and a subset of endogenous proteins through RCs during spermatogenesis from two-cell diploid spermatogonia to clusters of 64 post-meiotic haploid spermatids. Loss of the fusome, a large cytoplasmic structure extending through RCs that is known to be important during oogenesis, has minimal impact on RC development or intercellular protein movement during spermatogenesis. Our results reveal that male germline RCs remain persistently open and mediate extensive sharing of cytoplasmic information, supporting multiple roles for RCs throughout sperm development.
Macrophage Activation by a Substituted Pyrimido[5,4-b]Indole Increases Anti-Cancer Activity
Authors: Hardie Joseph , Mas-Rosario Javier A. , Ha Siyoung , Rizzo Erik M. , Farkas Michelle E.
Published: March 2019

Immunotherapy has become a promising new approach for cancer treatment due to the immune system’s ability to remove tumors in a safe and specific manner. Many tumors express anti-inflammatory factors that deactivate the local immune response or recruit peripheral macrophages into pro-tumor roles. Because of this, effective and specific ways of activating macrophages into anti-tumor phenotypes is highly desirable for immunotherapy purposes. Here, the use of a small molecule TLR agonist as a macrophage activator for anti-cancer therapy is reported. This compound, referred to as PBI1, demonstrated unique activation characteristics and expression patterns compared to treatment with LPS, through activation of TLR4. Furthermore, PBI1 treatment resulted in anti-tumor immune behavior, enhancing macrophage phagocytic efficiency five-fold versus non-treated macrophages. Additive effects were observed via use of a complementary strategy (anti-CD47 antibody), resulting in ∼10-fold enhancement of phagocytosis, suggesting this small molecule approach could be used in conjunction with other therapeutics.
De novo Identification of Essential Protein Domains from CRISPR/Cas9 Tiling-sgRNA Knockout Screens
Authors: He Wei , Zhang Liang , Villarreal Oscar D. , Fu Rongjie , Bedford Ella , Dou Jingzhuang , Bedford Mark T. , Shi Xiaobing , Chen Taiping , Bartholomew Blaine , Xu Han
Published: March 2019

High-throughput CRISPR/Cas9 knockout screens using a tiling-sgRNA design permit in situ evaluation of protein domain function. To facilitate de novo identification of essential protein domains from such screens, we developed ProTiler, a computational method for the robust mapping of CRISPR knockout hyper-sensitive (CKHS) regions, which refers to the protein regions that are associated with strong sgRNA dropout effect in the screens. We used ProTiler to analyze a published CRISPR tiling screen dataset, and identified 175 CKHS regions in 83 proteins. Of these CKHS regions, more than 80% overlapped with annotated Pfam domains, including all of the 15 known drug targets in the dataset. ProTiler also revealed unannotated essential domains, including the N-terminus of the SWI/SNF subunit SMARCB1, which we validated experimentally. Surprisingly, the CKHS regions were negatively correlated with phosphorylation and acetylation sites, suggesting that protein domains and post-translational modification sites have distinct sensitivities to CRISPR/Cas9 mediated amino acids loss.
KHNYN is essential for ZAP-mediated restriction of HIV-1 containing clustered CpG dinucleotides
Authors: Ficarelli Mattia , Wilson Harry , Galão Rui Pedro , Neil Stuart J D , Swanson Chad M
Published: March 2019

CpG dinucleotides are suppressed in most vertebrate RNA viruses, including HIV-1, and introducing CpGs into RNA virus genomes inhibits their replication. The zinc-finger antiviral protein (ZAP) binds regions of viral RNA containing CpGs and targets them for degradation. ZAP does not have enzymatic activity and recruits other cellular proteins to inhibit viral replication. Here we show that KHNYN, a protein with no previously known function, interacts with ZAP. KHNYN overexpression selectively inhibits HIV-1 containing clustered CpG dinucleotides and this requires ZAP and its cofactor TRIM25. KHNYN requires both its KH-like domain and NYN endonuclease domain for antiviral activity. Crucially, depletion of KHNYN eliminated the deleterious effect of CpG dinucleotides on HIV-1 RNA abundance and infectious virus production indicating that KHNYN is required for this antiviral pathway. Overall, we have identified KHNYN as a novel ZAP cofactor that is essential for innate immune destruction of CpG containing viral RNA.
Stag1 and Stag2 regulate cell fate decisions in hematopoiesis through non-redundant topological control
Authors: Viny Aaron D. , Bowman Robert L. , Liu Yu , Lavallée Vincent-Philippe , Eisman Shira E. , Xiao Wenbin , Durham Benjamin H. , Navitski Anastasia , Park Jane , Braunstein Stephanie , Azizi Elham , Witkin Matthew , Baslan Timour , Ott Christopher J. , Pe’er Dana , Dekker Job , Koche Richard , Levine Ross L.
Published: March 2019

Transcriptional regulators, including the cohesin complex member STAG2, are recurrently mutated in cancer. The role of STAG2 in gene regulation, hematopoiesis, and tumor suppression remains unresolved. We show Stag2 deletion in hematopoietic stem/progenitor cells (HSPC) results in altered hematopoietic function, increased self-renewal, and impaired differentiation. ChIP-sequencing revealed that while Stag2 and Stag1 can bind the same loci, a component of Stag2 binding sites are unoccupied by Stag1 even in Stag2-deficient HSPCs. While concurrent loss of Stag2 and Stag1 abrogated hematopoiesis, Stag2 loss alone decreased chromatin accessibility and transcription of lineage-specification genes, including Ebf1 and Pax5, leading to blunted HSPC commitment to the B-cell lineage. Our data illustrate a role for Stag2 in transformation and transcriptional dysregulation distinct from its shared role with Stag1 in chromosomal segregation.

One Sentence Summary

Stag1 rescues topologically associated domains in the absence of Stag2, but cannot restore chromatin architecture required for hematopoietic lineage commitment