bluuebunny/crossref_metadata_2025 huggingface dataset:
Giant Cell Tumor of Tendon Sheath Revealed on 68Ga-DOTA-TATE PET/CT in a Patient With Suspicious Tumor-Induced Osteomalacia
Authors: Jia Chaoyi , Shao Fuqiang , Yang Ming , Qin Chunxia , Lan Xiaoli
Published: April 2019

Giant cell tumor of tendon sheath (GCTTS) is benign mesenchymal neoplasm, and it rarely induces hypophosphatemia. We report a 49-year-old woman with suspicious tumor-induced osteomalacia underwent 68Ga-DOTA-TATE PET/CT to identify potential causative tumor, which showed a hypermetabolic soft tissue nodule in the right foot. Pathology confirmed it as GCTTS following surgical resection. The patient's symptoms improved rapidly, and the serum phosphate normalized after surgery, which supports the diagnosis of tumor-induced osteomalacia. Our case showed GCTTS can be rich of somatostatin receptor and cause osteomalacia.
Prostate-Specific Membrane Antigen Accumulation in Lower Extremity Lymphedema
Authors: Zhang Jingjing , Kulkarni Harshad R. , Singh Aviral , Baum Richard P.
Published: April 2019

Prostate-specific membrane antigen (PSMA) is overexpressed in a majority of prostate cancer cells, which has led to the development of radiolabeled small-molecule inhibitors of PSMA for molecular imaging and targeted radioligand therapy. 177Lu-labeled PSMA, with therapeutic β-emission and concomitant γ radiation, permits posttherapy imaging for the assessment of biodistribution and uptake in tumors and normal organs, as well as dosimetry. We report a patient with prostate cancer and metastatic lymph nodes–related lower extremity lymphedema, who presented with dermal backflow and soft-tissue uptake in the lower extremity on posttherapeutic whole body scan after intravenous 177Lu-PSMA treatment.
Hibernoma Demonstrated on 68Ga-DOTATATE PET/CT
Authors: Woodford Hannah , Le Ken , Bui Chuong , Mansberg Robert
Published: April 2019

A 60-year-old woman with recently diagnosed neuroendocrine tumors underwent staging 68Ga-DOTATATE PET/CT, which revealed focal uptake within the right sacral ala. Histopathology of the right sacral ala confirmed hibernoma. This case illustrates that hibernoma can be a cause of false-positive intraosseous accumulation of 68Ga-DOTATATE.
Promoting Wellness on College Campuses
Authors: Christianson Jenna , Kattelmann Kendra , Riggsbee Kristin , Moret Lauren , Vilaro Melissa J. , Olfert Melissa D. , Mathews Anne E. W. , Barr Makenzie , Colby Sarah
Published: April 2019

The objective of this study was to explore the health-related knowledge, beliefs, and attitudes of college students. An online and in-class course was offered at 4 universities. As part of the course, focus groups consisting of 102 students met virtually for 5 sessions to answer questions aimed at addressing students' wellness issues. Students indicated that college campuses need to offer more services centered on student health while addressing the barriers to student wellness overall. Students also indicated that universities better met their needs when communicating about various health-related services and facilities that were available to students.
Nutrition Management of Major Burn Injuries
Authors: Lowe Jessica M. , Brody Rebecca A.
Published: April 2019

Burn injuries are characterized by hypermetabolic and catabolic states. Despite aggressive intervention, optimizing nutrition support to match the increased metabolic demands remains challenging. Enteral feeding intolerance, found in 35% of these patients, exacerbates caloric and protein debt. In theory, early enteral nutrition could minimize nutrition deficits, but it has not been heavily explored. Ensuring nutritional adequacy is not the only intervention shown to improve outcomes in patients with major burn injuries. Additional strategies include blood glucose management and glutamine supplementation. A case is presented to demonstrate challenges and opportunities for maximizing nutrition support for patients with major burn injuries.
The Effect of a Family-Based Dietary Intervention on Dietary Fiber Density in Children Aged 6 to 11 Years
Authors: Nobles Jennifer , McNamara Jade , Tovar Alison , Marchand Stephanie , Xu Furong , Greene Geoffrey
Published: April 2019

Dietary fiber plays an important role for weight management; yet, few interventions have explored changes in fiber intake pre- and postintervention. This study determined whether a family-based weight management intervention had an effect on energy-adjusted dietary fiber intake. Sixty children aged 6 to 11 years and their caregivers participated in a 16-week nutrition and physical activity intervention that included completing a Food Frequency Questionnaire. Children increased fiber intake from 8.62 ± 2.02 to 9.45 ± 2.25 g/1000 kcal (P < .001). Energy intake decreased from 2141.88 ± 480.81 to 1913.36 ± 435.96 kcal (P < .001). The intervention was associated with an increase in fiber density intake and a reduction in energy intake.
The measurement of ultrafast electronic and structural dynamics with X-rays
Authors: Marangos J. P.
Published: April 2019

In this theme issue, leading researchers discuss recent work on the measurement of ultrafast electronic and structural dynamics in matter using a new generation of short duration X-ray photon sources. These photon sources, based upon high harmonic generation from lasers and X-ray free-electron lasers, look set to have a high impact on ultrafast science.

This article is part of the theme issue ‘Measurement of ultrafast electronic and structural dynamics with X-rays’.
Environmental light is required for maintenance of long-term memory in Drosophila
Authors: Inami Show , Sato Shoma , Kondo Shu , Tanimoto Hiromu , Kitamoto Toshihiro , Sakai Takaomi
Published: April 2019

Long-term memory (LTM) is stored as functional modifications of relevant neural circuits in the brain. A large body of evidence indicates that the initial establishment of such modifications through the process known as memory consolidation requires learning-dependent transcriptional activation and de novo protein synthesis. However, it remains poorly understood how the consolidated memory is maintained for a long period in the brain, despite constant turnover of molecular substrates. Using the Drosophila courtship-conditioning assay of adult males as a memory paradigm, here, we show that in Drosophila, environmental light plays a critical role in LTM maintenance. LTM is impaired when flies are kept in constant darkness (DD) during the memory maintenance phase. Because light activates the brain neurons expressing the neuropeptide Pigment-dispersing factor (Pdf), we examined the possible involvement of Pdf neurons in LTM maintenance. Temporal activation of Pdf neurons compensated for the DD-dependent LTM impairment, whereas temporal knockdown of Pdf during the memory maintenance phase impaired LTM in light–dark cycles. Furthermore, we demonstrated that the transcription factor cAMP response element-binding protein (CREB) is required in the memory center, mushroom bodies (MBs), for LTM maintenance, and Pdf signaling regulates light-dependent transcription via CREB. Our results demonstrate for the first time that universally available environmental light plays a critical role in LTM maintenance by activating the evolutionarily conserved memory modulator CREB in MBs via the Pdf signaling pathway.

Significant Statement

Temporary memory can be consolidated into long-term memory (LTM) through de novo protein synthesis and functional modifications of neuronal circuits in the brain. Once established, LTM requires continual maintenance so that it is kept for an extended period against molecular turnover and cellular reorganization that may disrupt memory traces. How is LTM maintained mechanistically? Despite its critical importance, the molecular and cellular underpinnings of LTM maintenance remain elusive. This study using Drosophila is significant because it revealed for the first time in any organism that universally available environmental light plays an essential role in LTM maintenance. Interestingly, light does so by activating the evolutionarily conserved transcription factor cAMP response element-binding protein via peptidergic signaling.
StanDep: capturing transcriptomic variability improves context-specific metabolic models
Authors: Joshi Chintan J. , Schinn Song-Min , Richelle Anne , Shamie Isaac , O’Rourke Eyleen J. , Lewis Nathan E.
Published: April 2019

Diverse algorithms can integrate transcriptomics with genome-scale metabolic models (GEMs) to build context-specific metabolic models. These algorithms require identification of a list of high confidence (core) reactions from transcriptomics, but parameters related to identification of core reactions, such as thresholding of expression profiles, can significantly change model content. Importantly, current thresholding approaches are burdened with setting singular arbitrary thresholds for all genes; thus, resulting in removal of enzymes needed in small amounts and even many housekeeping genes. Here, we describe StanDep, a novel heuristic method for using transcriptomics to identify core reactions prior to building context-specific metabolic models. StanDep clusters gene expression data based on their expression pattern across different contexts and determines thresholds for each cluster using data-dependent statistics, specifically standard deviation and mean. To demonstrate the use of StanDep, we built hundreds of models for the NCI-60 cancer cell lines. These models successfully increased the inclusion of housekeeping reactions, which are often lost in models built using standard thresholding approaches. Further, StanDep also provided a transcriptomic explanation for inclusion of lowly expressed reactions that were otherwise only supported by model extraction methods. Our study also provides novel insights into how cells may deal with context-specific and ubiquitous functions. StanDep, as a MATLAB toolbox, is available athttps://github.com/LewisLabUCSD/StanDep
Homomeric Q/R edited AMPA receptors conduct when desensitized
Authors: Coombs Ian D. , Soto David , McGee Thomas P. , Gold Matthew G. , Farrant Mark , Cull-Candy Stuart G.
Published: April 2019

Desensitization is a canonical property of ligand-gated ion channels, causing progressive current decline in the continued presence of agonist. AMPA-type glutamate receptors, which mediate fast excitatory signaling throughout the brain, exhibit profound desensitization. Recent cryo-EM studies of AMPAR assemblies show their ion channels to be closed in the desensitized state. Here we report the surprising finding that homomeric Q/R edited AMPARs still allow ions to flow when the receptors are desensitized. GluA2(R) expressed alone, or with auxiliary subunits (γ-2, γ-8 or GSG1L), generates large steady-state currents and anomalous current-variance relationships. Using fluctuation analysis, single-channel recording, and kinetic modeling we demonstrate that the steady-state current is mediated predominantly by ‘conducting desensitized’ receptors. When combined with crystallography this unique functional readout of a hith-erto silent state enabled us to examine cross-linked cysteine mutants to probe the conformation of the desensitized ligand binding domain of functioning AMPAR complexes within the plasma membrane.
mRNA Degradation Rates Are Coupled to Metabolic Status in Mycobacteria
Authors: Vargas-Blanco Diego A. , Zhou Ying , Zamalloa Luis Gutierrez , Antonelli Tim , Shell Scarlet S.
Published: April 2019

The success ofMycobacterium tuberculosis(Mtb) as a human pathogen is due in part to its ability to survive stress conditions, such as hypoxia or nutrient deprivation, by entering non-growing states. In these low-metabolic states, Mtb can tolerate antibiotics and develop genetically encoded antibiotic resistance, making its metabolic adaptation to stress crucial for survival. Numerous bacteria, including Mtb, have been shown to reduce their rates of mRNA degradation under growth limitation and stress. While the existence of this response appears to be conserved across species, the underlying bacterial mRNA stabilization mechanisms remains unknown. To better understand the biology of non-growing mycobacteria, we sought to identify the mechanisms by which mRNA stabilization occurs using the non-pathogenic modelMycobacterium smegmatis. We found that mRNA half-life was responsive to energy stress, with carbon starvation and hypoxia causing global mRNA stabilization. This global mRNA stabilization was rapidly reversed when hypoxia-adapted cultures were re-exposed to oxygen, even in the absence of new transcription. The stringent response and RNase protein levels did not explain mRNA stabilization, nor did transcript abundance. This led us to hypothesize that metabolic changes during growth cessation impact the activity of degradation proteins, increasing mRNA stability. Indeed, bedaquiline and isoniazid, two drugs with opposing effects on cellular energy status, had opposite effects on mRNA half-lives in growth-arrested cells. Taken together, our results indicate that mRNA stability in mycobacteria is not directly regulated by growth status, but rather seems to be dependent on the status of energy metabolism.

IMPORTANCE

The logistics of treating tuberculosis are difficult, requiring multiple drugs for at least six months. Mtb is able to survive within the human host in part by entering non-growing states in which it is metabolically less active, thus rendering it less susceptible to antibiotics. Basic knowledge on how Mtb survives during these low-metabolic states is incomplete, and we postulate that optimized energy resource management –such as transcriptome stabilization—is important for survival. Here we report that mRNA stabilization (increased mRNA half-lives) is a common feature of mycobacteria under stress (e.g. hypoxia and nutrient deprivation) but is not dependent on the mechanisms that have been most often postulated in the literature. Finally, we found that mRNA stability and growth status can be decoupled by a drug that causes growth arrest but increases metabolic activity, indicating that mRNA stability responds to metabolic status rather than to growth rate changes per se. Our findings suggest a need to re-orient the study of global mRNA stabilization to identify novel mechanisms that are presumably responsible.
Use of human iPSCs and kidney organoids to develop a cysteamine/mTOR inhibition combination therapy to treat cystinosis
Authors: Hollywood Jennifer A. , Przepiorski Aneta , Harrison Patrick T. , Wolvetang Ernst J. , Davidson Alan J. , Holm Teresa M.
Published: April 2019

Cystinosis is a lysosomal storage disease caused by mutations inCTNS, encoding a cystine transporter, and in its severest form is characterized by cystine accumulation, renal proximal tubule dysfunction and kidney failure. Cystinosis is treated with the cystine-depleting drug cysteamine, however this only slows progression of the disease and there is an urgent need for better treatments. Here, we have generated and characterized the first human induced pluripotent stem cell (iPSC) and kidney organoid models of cystinosis. These models exhibit elevated cystine and cysteine levels, enlarged lysosomes and a block in basal autophagy flux. Cysteamine treatment ameliorates this phenotype except for the basal autophagy flux defect. We found that treatment with Everolimus, an inhibitor of the mTOR pathway, reduces the number of large lysosomes and activates autophagy but does not rescue the cystine/cysteine loading defect. However, dual treatment of cystinotic iPSCs or kidney organoids with cysteamine and Everolimus corrects all of the observed phenotypes indicating that a combination therapy has therapeutic potential to improve the treatment of cystinosis.
FilTar: Using RNA-Seq data to improve microRNA target prediction accuracy in animals
Authors: Bradley Thomas , Moxon Simon
Published: April 2019

MicroRNAs (miRNAs) are a class of small non-coding RNA molecule, approximately 22nt in length, which guide the repression of mRNA transcripts. A number of tools have been developed to predict miRNA targets in animals which do not account for the effects of a specific cellular context on miRNA targeting. We present FilTar (Filtering of predicted miRNATargets), a method which utilises available RNA-Seq information to filter non- or lowly expressed transcripts and refine existing 3’UTR annotations for a given cellular context, to increase miRNA target prediction accuracy in animals.

The FilTar tool is available athttps://github.com/TBradley27/FilTar.
Nixconfers heritable sex-conversion inAedes aegyptiandmyo-sexis needed for male flight
Authors: Aryan Azadeh , Anderson Michelle , Biedler James K. , Qi Yumin , Overcash Justin M. , Naumenko Anastasia N. , Sharakhova Maria V. , Mao Chunhong , Adelman Zach N. , Tu Zhijian
Published: April 2019

A dominant and hemizygous male-determining locus (M locus) establishes the male sex (M/m) in the yellow fever mosquito,Aedes aegypti.Nixis a male-determining factor (M factor) in the M locus and its transient expression in females (m/m) results in partial masculinization. Here, we show that theNixtransgene alone was sufficient to convert females into fertile males, which continued to produce sex-converted progeny in subsequent generations. However, assisted mating with wild-type females was necessary, as the converted m/m males could not fly. Knockout ofmyo-sex, a myosin heavy chain gene and the only other protein-coding gene reported in the M locus, rendered wild-type males flightless. Thus,Nixalone converts femaleAe. aegyptito fertile males andmyo-sexis required for male flight. Only femaleAe. aegyptimosquitoes bite and transmit disease-causing viruses.Nix-mediated female-to-male conversion is 100% penetrant and stable over many generations, indicating great potential for mosquito control.
Pitfalls and Remedies for Cross Validation with Multi-trait Genomic Prediction Methods
Authors: Runcie Daniel , Cheng Hao
Published: April 2019

Incorporating measurements on correlated traits into genomic prediction models can increase prediction accuracy and selection gain. However, multi-trait genomic prediction models are complex and prone to overfitting which may result in a loss of prediction accuracy relative to single-trait genomic prediction. Cross-validation is considered the gold standard method for selecting and tuning models for genomic prediction in both plant and animal breeding. When used appropriately, cross-validation gives an accurate estimate of the prediction accuracy of a genomic prediction model, and can effectively choose among disparate models based on their expected performance in real data. However, we show that a naive cross-validation strategy applied to the multi-trait prediction problem can be severely biased and lead to sub-optimal choices between single and multi-trait models when secondary traits are used to aid in the prediction of focal traits and these secondary traits are measured on the individuals to be tested. We use simulations to demonstrate the extent of the problem and propose three partial solutions: 1) a parametric solution from selection index theory, 2) a semi-parametric method for correcting the cross-validation estimates of prediction accuracy, and 3) a fully non-parametric method which we call CV2*: validating model predictions against focal trait measurements from genetically related individuals. The current excitement over high-throughput phenotyping suggests that more comprehensive phenotype measurements will be useful for accelerating breeding programs. Using an appropriate cross-validation strategy should more reliably determine if and when combining information across multiple traits is useful.
Generation of Temperature Sensitive Mutations with Error-Prone PCR in a Gene Encoding a Component of the Spindle Pole Body in Fission Yeast
Authors: Tang Ngang Heok , Fong Chii Shyang , Masuda Hirohisa , Jourdain Isabelle , Yukawa Masashi , Toda Takashi
Published: April 2019

Temperature-sensitive (ts) mutants provide powerful tools, thereby investigating cellular functions of essential genes. We report here a simple procedure to generate ts mutations using error-prone PCR in pcp1 that encodes a spindle pole body (SPB) component in Schizosaccharomyces pombe. This manipulation is not restricted to analysis of Pcp1, and can be suited to any essential genes involved in other processes.
Brain dysfunction in chronic pain patients assessed by resting-state electroencephalography
Authors: Dinh Son Ta , Nickel Moritz M. , Tiemann Laura , May Elisabeth S. , Heitmann Henrik , Hohn Vanessa D. , Edenharter Günther , Utpadel-Fischler Daniel , Tölle Thomas R. , Sauseng Paul , Gross Joachim , Ploner Markus
Published: April 2019

Chronic pain is a common and severely disabling disease whose treatment is often unsatisfactory. Insights into the brain mechanisms of chronic pain promise to advance the understanding of the underlying pathophysiology and might help to develop disease markers and novel treatments. Here, we systematically and comprehensively exploited the potential of electroencephalography (EEG) to determine abnormalities of brain function during the resting state in chronic pain. To this end, we performed state-of-the-art analyses of oscillatory brain activity, brain connectivity and brain networks in 101 patients of either sex suffering from chronic pain. The results show that global and local measures of brain activity did not differ between chronic pain patients and a healthy control group. However, we observed significantly increased connectivity at theta (4 – 8 Hz) and gamma (> 60 Hz) frequencies in frontal brain areas as well as global network reorganization at gamma frequencies in chronic pain patients. Furthermore, a machine learning algorithm could differentiate between patients and healthy controls with an above-chance accuracy of 57%, mostly based on frontal connectivity. These results implicate increased theta and gamma synchrony in frontal brain areas in the pathophysiology of chronic pain. While substantial challenges concerning accuracy, specificity and validity of potential EEG-based disease markers remain to be overcome, our study identifies abnormal frontal synchrony at theta and gamma frequencies as promising targets for non-invasive brain stimulation and/or neurofeedback approaches.
Neighborhood-statistics reveal complex dynamics of song acquisition in the zebra finch
Authors: Kollmorgen Sepp , Hahnloser Richard , Mante Valerio
Published: April 2019

Motor behaviors are continually shaped by a variety of processes such as environmental influences, development, and learning1,2. The resulting behavioral changes are commonly quantified based on hand-picked features3–10(e.g. syllable pitch11) and assuming discrete classes of behaviors (e.g. distinct syllables)3–5,9,10,12–17. Such methods may generalize poorly across behaviors and species and are necessarily biased. Here we present an account of behavioral change based on nearest-neighbor statistics18–23that avoids such biases and apply it to song development in the juvenile zebra finch3. First, we introduce the concept ofrepertoire dating, whereby each syllable rendition isdatedwith a “pseudo” production-day corresponding to the day when similar renditions were typical in the behavioral repertoire. Differences in pseudo production-day across renditions isolate the components of vocal variability congruent with the long-term changes due to vocal learning and development. This variability is large, as about 10% of renditions have pseudo production-days falling more than 10 days into the future (anticipations) or into the past (regressions) relative to their actual production time. Second, we obtain a holistic, yet low-dimensional, description of vocal change in terms of abehavioral trajectory, which reproduces the pairwise similarities between renditions grouped by production time and pseudo production-day24. The behavioral trajectory reveals multiple, previously unrecognized components of behavioral change operating at distinct time-scales. These components interact differently across the behavioral repertoire—diurnal change in regressions undergoes only weak overnight consolidation4,5, whereas anticipations and typical renditions consolidate fully2,6,25. Our nearest-neighbor methods yield model-free descriptions of how behavior evolves relative to itself, rather than relative to a potentially arbitrary, experimenter-defined, goal3–5,11. Because of their generality, our methods appear well-suited to comparing learning across behaviors and species1,26–32, and between biological and artificial systems.
Spatial and temporal structure of choice representations in primate prefrontal cortex
Authors: Kollmorgen Sepp , Newsome William T , Mante Valerio
Published: April 2019

Divergent accounts of how choices are represented by neural populations have led to conflicting explanations of the underlying mechanisms of decision-making, ranging from persistent, attractor-based dynamics to transient, sequence-based dynamics. To evaluate these mechanisms, we characterize the spatial and temporal structure of choice representations in large neural populations in prefrontal cortex. We find that the pronounced diversity of choice responses across neurons reflects only a few, mostly persistent population patterns recruited at progressively later times before and after a choice. Brief sequential activity occurs during a saccadic choice, but is entirely absent in a delay preceding it. The diversity of choice responses, which could result from almost-random connectivity in the underlying circuits, instead largely reflects the topographical arrangement of response-field properties across the cortical surface. This spatial organization appears to form a fixed scaffold upon which the context-dependent representations of task-specific variables often observed in prefrontal cortex can be learned.
HDX-MS reveals nucleotide-regulated, anti-correlated opening and closure of SecA and SecY channels of the bacterial translocon
Authors: Ahdash Zainab , Pyle Euan , Allen William J. , Corey Robin A. , Collinson Ian , Politis Argyris
Published: April 2019

The bacterial Sec translocon is a multi-component protein complex responsible for translocating diverse proteins across the plasma membrane. For post-translational protein translocation, the Sec-channel – SecYEG – associates with the motor protein SecA to mediate the ATP-dependent transport of unfolded pre-proteins across the membrane. Based on the structure of the machinery, combined with ensemble and single molecule analysis, a diffusional based Brownian ratchet mechanism for protein secretion has been proposed [Allen et al. eLife 2016;5:e15598]. However, the conformational dynamics required to facilitate this mechanism have not yet been fully resolved. Here, we employ hydrogen-deuterium exchange mass spectrometry (HDX-MS) to reveal striking nucleotide-dependent conformational changes in the Sec protein-channel. In addition to the ATP-dependent opening of SecY, reported previously, we observe a counteracting, also ATP-dependent, constriction of SecA around the mature regions of the pre-protein. Thus, ATP binding causes SecY to open and SecA to close, while ATP hydrolysis has the opposite effect. This alternating behaviour could help impose the directionality of the Brownian ratchet for protein transport through the Sec machinery, and possibly in translocation systems elsewhere. The results highlight the power of HDX-MS for interrogating the dynamic mechanisms of diverse membrane proteins; including their interactions with small molecules such as nucleotides (ATPases and GTPases) and inhibitors (e.g. antibiotics).
Tissue specific vulnerability to mitotic defects caused by mutations in theDrosophilaASPM homologue, Asp
Authors: Borgal Lori , Quiniou Margaux , Wakefield James
Published: April 2019

Misregulation of candidate stem cell marker ASPM, and itsDrosophilahomologue Asp, leads to either tumour formation or microcephaly, but the functional roles contributing to each are not understood. We reverse-engineered flies to express a version of Asp (AspLIE), predicted to have lost its ability to bind the phosphatase PP2A-B’. Although AspLIEflies were viable, they exhibited splayed neural stem cell spindle poles under stress, and development was substantially delayed. A tissue-level analysis of microcephaly and midgut abnormalities in Asp mutants with a compromised spindle assembly checkpoint (SAC) demonstrates tissue-specific vulnerability to mitotic defects.
Relative distances between homology groups to assess persistent defects in time series
Authors: Diaz Ochoa Juan G.
Published: April 2019

It is common to consider a data-intensive strategy to be an appropriate way to develop systemic analyses in biology and physiology. Therefore, options for data collection, sampling, standardization, visualization, and interpretation determine how causes are identified in time series to build mathematical models. However, there are often biases in the collected data that can affect the validity of the model: while collecting enough large datasets seems to be a good strategy for reducing the bias of the collected data, persistent and dynamical anomalies in the data structure can affect the overall validity of the model. In this work we present a methodology based on the definition of homological groups to evaluate persistent anomalies in the structure of the sampled time series. In this evaluation relevant patterns in the combination of different time series are clustered and grouped to customize the identification of causal relationships between parameters. We test this methodology on data collected from patients using mobile sensors to test the response to physical exercise in real-world conditions and outside the lab. With this methodology we plan to obtain a patient stratification of the time series to customize models in medicine.
Volumetric and microstructural regional changes of the hippocampus underlying development of extended delay long-term memory
Authors: Fjell Anders M , Sneve Markus H. , Sederevicius Donatas , Sørensen Øystein , Krogsrud Stine K , Mowinckel Athanasia M , Walhovd Kristine B
Published: April 2019

Episodic memory function improves through childhood and adolescence, in part due to structural maturation of the medial temporal cortex. Although partly different processes support long-term memory over shorter vs. longer intervals, memory is usually assessed after less than an hour. The aim of the present study was to test whether there are unique developmental changes in extended memory, and whether these are related to structural maturation of sub-regions of the hippocampus. 650 children and adolescents from 4.1 to 24.8 years were assessed in total 962 times (mean interval ≈ 1.8 years). Memory was assessed by the California Verbal Learning Test (CVLT) and the Rey Complex Figure Test (CFT). In addition to 30 min recall, an extended delay recall condition was administered ≈ 10 days after encoding. We found unique developmental effects on extended delay memory independently of 30 min recall performance. For visuo-constructive memory, this could be accounted for by visuo-constructive ability levels. Performance was modestly related to anterior and posterior hippocampal volume and mean diffusion. The relationships did not show an anterior-posterior hippocampal axis difference. In conclusion, extended delay memory shows unique development, likely due to changes in encoding depth or efficacy, or improvements of long-term consolidation processes.

Highlights

Unique developmental effects on episodic memories over days rather than minutes

Development of visuoconstructive recall explainable by visuoconstructive abilitity

Development of verbal recall cannot be explained by verbal ability

Modest relationships between memory and hippocampal structural features
The generality of post-antimicrobial treatment persistence of replicatively-attenuatedBorrelia burgdorferiin a mouse model
Authors: Hodzic Emir , Imai Denise M. , Escobar Edlin
Published: April 2019

A basic feature of infection caused byBorrelia burgdorferi, the etiological agent of Lyme borreliosis, is that persistent infection is the rule, not the norm, in its many hosts. The ability to persist and evade host immune clearance poses a challenge to effective antimicrobial treatment. A link between therapy failure and the presence of persister cells has started to emerge. There is growing experimental evidence that viable, but non-cultivable spirochetes persist following treatment with several different antimicrobial agents, then resurge after 12 months. The current study utilized the mouse model to evaluate if persistence and resurgence occur following antimicrobial treatment in a disease-susceptible (C3H/HeN) and disease-resistant (C57BL/6) mouse strain infected withB. burgdorferistrains N40 and B31, to confirm the generality of these phenomena. The status of infection was evaluated at 12 and 18-months after treatment. The results demonstrated that persistent spirochetes remain viable for up to 18 months following treatment, but divide slowly, thereby being tolerant to the effects of antimicrobial agents, as well as being non-cultivable. The phenomenon of persistence and resurgence in disease-susceptible C3H mice is equally evident in disease-resistant B6 mice, and not unique to any particularB. burgdorferistrain. The results also demonstrate that following antimicrobial treatment, both strains ofB. burgdorferi, N40 and B31, lose one or more small plasmids, resulting in attenuation. The biological relevance of attenuatedB. burgdorferispirochetes is probably inconsequential. The study demonstrated that non-cultivable spirochetes can persist in a host following antimicrobial treatment for a long time but did not demonstrate their clinical relevance in a mouse model of chronic infection.
Spontaneous back-pain alters randomness in functional connections in large scale brain networks
Authors: Matharoo Gurpreet S. , Hashmi Javeria A.
Published: April 2019

We use randomness as a measure to assess the impact of evoked pain on brain networks. Randomness is defined here as the intrinsic correlations that exist between different brain regions when the brain is in a task-free state. We use fMRI data of three brain states in a set of back pain patients monitored over a period of 6 months. We find that randomness in the task-free state closely follows the predictions of Gaussian orthogonal ensemble of random matrices. However, the randomness decreases when the brain is engaged in attending to painful inputs in patients suffering with early stages of back pain. A persistence of this pattern is observed in the patients that develop chronic back pain, while the patients who recover from pain after 6 months, the randomness reverts back to a normal level.

Author Summary

Back-pain is a salient percept known to affect brain regions. We studied random correlations in brain networks using random matrix theory. The brain networks were generated by fMRI scans obtained from a longitudinal back-pain study. Without modelling the neuronal interactions, we studied universal and subject-independent properties of brain networks in resting state and two distinct task states. Specifically, we hypothesized that relative to the resting state, random correlations would decrease when the brain is engaged in a task and found that the random correlations showed a maximum decrease when the brain is engaged in detecting back pain than performing a visual task.
Pharmacogenomic considerations for antiplatelet agents: the era of precision medicine in stroke prevention and neurointerventional practice
Authors: Bonney Phillip A. , Yim Benjamin , Brinjikji Waleed , Walcott Brian P.
Published: April 2019

Antiplatelet drugs are widely utilized in the setting of primary stroke prevention, secondary stroke prevention, and neuroendovascular device-related stroke prevention. These medications are effective in general, although significant variability in drug activity exists between patients. Although this variation may be related in part to a multitude of factors, a growing body of evidence suggests that individual genotypes are a main contributor. The PharmGKB database was mined to prioritize genetic variants with potential clinical relevance for response to aspirin, clopidogrel, prasugrel, and ticagrelor. Although variants were reported for all drugs, the highest level of evidence was found in cytochrome P450 (CYP450) genotype variation related to clopidogrel response. Individual genetic influences have an impact on the pharmacodynamics of antiplatelet agents. Current clinical practice for stroke prevention is primarily empiric or guided by functional assays; however, there now exists a third potential pathway to base treatment decisions: genotype-guided treatment.
Identification of a secondary RET mutation in a pediatric patient with relapsed acute myeloid leukemia leads to the diagnosis and treatment of asymptomatic metastatic medullary thyroid cancer in a parent: a case for sequencing the germline
Authors: Pendrick Danielle M. , Oberg Jennifer A. , Hsiao Susan J. , Chung Wendy K. , Koval Carrie , Sireci Anthony , Kuo Jennifer H. , Satwani Prakash , Glasser Chana L. , Sulis Maria Luisa , Mansukhani Mahesh M. , Glade Bender Julia L.
Published: April 2019

The incorporation of tumor-normal genomic testing into oncology can identify somatic mutations that inform therapeutic measures but also germline variants associated with unsuspected cancer predisposition. We describe a case in which a RET variant was identified in a 3-yr-old male with relapsed leukemia. Sanger sequencing revealed the patient's father and three siblings carried the same variant, associated with multiple endocrine neoplasia 2A (MEN2A). Evaluation of the father led to the diagnosis and treatment of metastatic medullary thyroid carcinoma. Detection of RET mutations in families with hereditary MTC allows for genetic risk stratification and disease surveillance to reduce morbidity and mortality.
Preparation of siRNA Duplexes
Authors: Li Chengjian , Zamore Phillip D.
Published: April 2019

This protocol describes how to anneal synthetic sense and antisense siRNAs to form siRNA duplexes, as well as the analysis of siRNA duplexes using nondenaturing polyacrylamide gel electrophoresis.
RNAi in Mammalian Cells by siRNA Duplex Transfection
Authors: Li Chengjian , Zamore Phillip D.
Published: April 2019

Long dsRNA cannot be used in most cultured mammalian cells because it triggers the interferon response, causing widespread changes in gene expression and apoptosis. This protocol describes a method for delivering into mammalian cells siRNA duplexes that are too short to elicit the sequence-nonspecific responses associated with long dsRNA.
Detecting Horseradish Peroxidase-Labeled Cells
Authors: Rodig Scott J.
Published: April 2019

A range of substrates is available for detection of cells labeled with horseradish peroxidase (HRP). Diaminobenzidine (DAB) is the most commonly used substrate and one of the most sensitive. It yields an intense brown product that is insoluble in both water and alcohol. DAB staining is compatible with a wide range of common histological stains. DAB can be made more sensitive by adding metal salts such as cobalt or nickel to the substrate solution. The reaction product is slate gray to black, and the products are stable in both water and alcohol. DAB/metal staining is compatible with a wide range of common histological stains. Alternatively, chloronaphthol gives a blue–black product and aminoethylcarbazole (AEC) yields a red product. These substrates are less sensitive than DAB and the products are soluble in alcohol, but they can be used if the DAB reaction gives too high a background or if alternative product colors are required.
Noise analysis of band pass filters using stochastic differential equations
Authors: Nabati Parisa , Babazadeh Hadiseh , Azadfar Hamed
Published: April 2019

Purpose

The purpose of this paper is to analyze the effects of white noise perturbations of the input voltage on the band pass filter response, both on pass band and reject band.

Design/methodology/approach

By adding white noise term in the input voltage of the filter circuit, the deterministic ordinary differential equation (ODE) is replaced by a stochastic differential equation (SDE). With the application of Ito lemma, the analytical solution of SDE has been obtained. Furthermore, based on the Euler–Maruyama approximation, the numerical simulation for SDE has been done.

Practical implications

Numerical examples are performed using MATLAB programming to show the efficiency and accuracy of the present work.

Originality/value

All previous noise analyses of filter circuits were done using ODEs or component noise formulas in the electrical domain. The stochastic perspective for these circuits is adopted for the first time in this paper.
Emotions in leaders’ enactment of professional agency
Authors: Hökkä Päivi , Vähäsantanen Katja , Paloniemi Susanna , Herranen Sanna , Eteläpelto Anneli
Published: April 2019

Purpose

Although there has been an increase in workplace studies on professional agency, few of these have examined the role of emotions in the enactment of agency at work. To date, professional agency has been mainly conceptualised as a goal-oriented, rational activity aimed at influencing a current state of affairs. Challenged by this, this study aims to elaborate the nature and quality of emotions and how they might be connected to the enactment of professional agency.

Design/methodology/approach

Data are collected in the context of a leadership coaching programme that aimed to promote the leaders’ professional agency over the course of a year. The participants (11 middle-management leaders working in university and hospital contexts) were interviewed before and after the programme, and the data were analysed using qualitative content analysis.

Findings

Findings showed that emotions played an important role in the leaders’ enactment of professional agency, as it pertained to their work and to their professional identity. The study suggests that enacting professional agency is by no means a matter of purely rational actions.

Practical implications

The study suggests that emotional agency can be learned and enhanced through group-based interventions reflecting on and processing one’s own professional roles and work.

Originality/value

As a theoretical conclusion, the study argues that professional agency should be reconceptualised in such a way as to acknowledge the importance of emotions (one’s own and those of one’s fellow workers) in practising agency within organisational contexts.
Low KISS1 expression predicts poor prognosis for patients with colorectal cancer: A meta‐analysis
Authors: Wang Xiao‐Qing , Fang Pei‐Fei , Zhang Cheng , Xu Ya‐Yun , Song Xian‐Bing , Liang Jun , Xia Qing‐Rong
Published: April 2019

KISS1 and KISS1R, a novel pair of metastasis suppressors, are likely to be associated with the prognosis of colorectal cancer (CRC). Here, a meta‐analysis was performed to study the role of KISS1 and KISS1R in CRC. Heterogeneity, stability and publication bias were all estimated. Six publications describing a total of 559 CRC patients were included in the present study. Low KISS1 expression predicted 70% higher risk of poor prognosis for general patients (HR, 1.71; 95% CI, 1.28–2.29) and 99% higher risk for East Asian patients (HR, 1.99; 95% CI, 1.46–2.72). Limited evidence indicated that decreased KISS1R expression might predict poor outcome (HR, 2.96; 95% CI, 1.51–5.82). Neither heterogeneity nor publication bias was identified. The current analyses suggest that low KISS1 expression predicts poor overall survival among East Asian patients with CRC. Evidence on other races and KISS1R are still insufficient, and additional studies are required to clarify the risk of CRC associated with KISS1R by race.
Rei1‐like protein regulates nutritional metabolism and transport required for the asexual cycle in vitro and in vivo of a fungal insect pathogen
Authors: Shao Wei , Cai Qing , Tong Sen‐Miao , Ying Sheng‐Hua , Feng Ming‐Guang
Published: April 2019

Rei1 is a cytoplasm‐specific pre‐60S subunit export factor that functions exclusively in cold‐sensitive yeast growth but remains unexplored in filamentous fungi. Here, we report that Rei1‐like BbRei1 is localized in both cytoplasm and nucleus and acts as a vital regulator in Beauveria bassiana. Deletion of BbRei1 resulted in delayed conidial germination, abnormally polarized germlings, severe growth defects on various carbon/nitrogen sources and reduced conidiation capacity as well as low temperature‐sensitive growth. In ΔBbrei1, greatly attenuated virulence correlated with reduced activities of enzymes secreted for cuticular penetration and blocked formation of hyphal bodies in vivo essential for facilitation of host mummification. Revealed by transcriptomic analysis, 560 and 840 genes were significantly up‐ and down‐regulated in ΔBbrei1 versus wild‐type respectively, representing 13.5% of the fungal genome. Many repressed genes were involved in metabolism and transport of carbohydrates and amino acids. However, electrophoretic mobility shift assays presented no interactions of purified BbRei1 with 14 promoter DNA fragments. Conclusively, BbRei1 plays a pivotal role in gene expression and metabolism of nutrients and energy essential for the asexual cycle in vitro and in vivo of B. bassiana and functions much beyond the role for the yeast Rei1 in cold‐sensitive cell growth.
Partitioning, phytocommunicability and plant pieties
Authors: SCHULTHIES BECKY
Published: April 2019

Just as Moroccans encounter plant parts separated from the ground on a daily basis, so too do they engage more than one model for relating to plants. Different plant partitions entice a varying array of interlocutors and interactants through sensory channels and communicability ideologies. In this article, the author introduces phytocommunicability, a process of mobilizing multiple interactional ideologies in interspecies communication. She suggests that phytocommunicative pluralism is key to understanding how plant piety is recognizable, yet unknowable.
Effects of oral probiotic supplements on vaginal microbiota during pregnancy: a randomised, double‐blind, placebo‐controlled trial with microbiome analysis
Authors: Husain S , Allotey J , Drymoussi Z , Wilks M , Fernandez‐Felix BM , Whiley A , Dodds J , Thangaratinam S , McCourt C , Prosdocimi EM , Wade WG , de Tejada BM , Zamora J , Khan K , Millar M
Published: April 2019

Objective

To determine the effects on the vaginal microbiota of an oral probiotic preparation administered from early pregnancy.

Design

Randomised, double blind, placebo‐controlled trial.

Setting

Four maternity units in the UK.

Population

Women aged 16 years or older recruited at 9–14 weeks' gestation.

Methods

Participants were randomly allocated to receive oral capsules of probiotic containing Lactobacillus rhamnosus GR‐1 and Lactobacillus reuteri RC‐14 each at 2.5 × 109 colony‐forming units (CFUs) or placebo once daily from recruitment until the end of pregnancy.

Main outcome measure

Rates of bacterial vaginosis (BV, defined as Nugent score ≥7) at 18–20 weeks' gestation compared by logistic regression adjusted for possible confounders.

Results

The primary analysis included 78% (238/304) of participants who initially consented (probiotic group 123, placebo group 115). Of these participants, 95% (227/238) reported an intake of 93% or more of the required number of capsules. The rates of BV did not differ between groups at 18–20 weeks' gestation (15% (19/123) in the probiotic group vs. 9% (10/115) in the placebo group, adjusted odds ratio 1.82, 95% confidence interval 0.64–5.19). There were also no differences between the groups in the proportion of women colonised with the probiotic strains, Escherichia coli, group B streptococci or other vaginal microbiota. There were no differences in the alpha diversity or composition of the bacterial communities between or within the probiotic and placebo groups at 9–14 and 18–20 weeks’ gestation.

Conclusions

Oral probiotics taken from early pregnancy did not modify the vaginal microbiota.

Tweetable abstract

The oral probiotic preparation used in this study does not prevent BV in pregnant women.