bluuebunny/crossref_metadata_2025 huggingface dataset:
Cadmium exposure inhibits branching morphogenesis and causes alterations consistent with HIF-1α inhibition in human primary breast organoids
Authors: Rocco Sabrina A. , Koneva Lada , Middleton Lauren Y. M. , Thong Tasha , Solanki Sumeet , Karram Sarah , Nambunmee Kowit , Harris Craig , Rozek Laura S. , Sartor Maureen A. , Shah Yatrik M. , Colacino Justin A.
Published: October 2017

Background

Developmental cadmium exposure in vivo disrupts mammary gland differentiation, while exposure of breast cell lines to cadmium causes invasion consistent with the epithelial-mesenchymal transition (EMT). The effects of cadmium on normal human breast stem cell development have not been measured.

Objective

The objective of this study was to quantify the effects of cadmium exposure on normal breast stem cell proliferation and differentiation.

Methods

We tested the effects of two physiologically relevant doses of cadmium: 0.25µM and 2.5μM on reduction mammoplasty patient-derived breast cells using the mammosphere assay, organoid formation in 3D hydrogels, and tested for molecular alterations using RNA-seq. We functionally validated our RNA-seq findings with a HIF-1α transcription factor activity reporter line and pharmaceutical inhibition of HIF-1α in mammosphere and organoid formation assays.

Results

2.5μM cadmium reduced primary and secondary mammosphere formation and branching structure organoid formation rates by 33%, 40%, and 83%, respectively. Despite no changes in mammosphere formation, 0.25μM cadmium treatment inhibited branching organoid formation in hydrogels by 68%. RNA-seq revealed that cadmium treatment downregulated genes associated with extracellular matrix formation and EMT, while upregulating genes associated with metal response including metallothioneins and zinc transporters. In the RNA-seq data, cadmium treatment also downregulated HIF-1α target genes including LOXL2, ZEB1, and VIM. Cadmium treatment significantly inhibited HIF-1α activity in a luciferase assay, and the HIF-1α inhibitor acriflavine ablated mammosphere and organoid formation.

Discussion

These findings show that cadmium, at doses relevant to human exposure, inhibited human mammary gland development, potentially through disruption of HIF-1α activity. These findings do not support cadmium being a breast cancer initiator via induction of stem cell proliferation, but instead implicate cadmium as an inhibitor of mammary gland morphogenesis.
Molecular mechanism of cell-cell adhesion mediated by cadherin-23
Authors: Singaraju G. S. , Kumar A. , Samuel J. S. , Sagar A. , Hazra J. P. , Sannigrahi M. K. , Yennamalli R. M. , Ashish  , Rakshit S.
Published: October 2017

Adherin-junctions are traditionally described by the homophilic-interactions of classical cadherin-proteins at the extracellular region. However, the role of long-chain non-classical cadherins like cadherin-23(Cdh23) is not explored as yet even though it is implicated in tissue-morphogenesis, cancer, and force-sensing in neuronal tissues. Here, we identified a novel antiparallel-binding interface of Cdh23 homodimer in solution by combining biophysical and computational methods, in-vitro cell-binding, and mutational modifications. The dimer consists of two electrostatic-based interfaces extended up to two terminal domains, atypical to classical-cadherins known so far, and forms the strongest interactions in cadherin-family as measured using single-molecule force-spectroscopy. We further identified single point-mutation, E78K, that completely disrupts this binding. Interestingly, the mutation, S77L, found in skin cancers falls within the binding interface of the antiparallel-dimer. Overall, we provide the molecular architecture of Cdh23 at the cell-cell junctions which are likely to have far-reaching applications in the fields of mechanobiology and cancer.
The Transcriptional Logic of Mammalian Neuronal Diversity
Authors: Sugino Ken , Clark Erin , Schulmann Anton , Shima Yasuyuki , Wang Lihua , Hunt David L. , Hooks Bryan M. , Tränkner Dimitri , Chandrashekar Jayaram , Picard Serge , Lemire Andrew , Spruston Nelson , Hantman Adam , Nelson Sacha B.
Published: October 2017

The mammalian nervous system is constructed of many cell types, but the principles underlying this diversity are poorly understood. To assess brain-wide transcriptional diversity, we sequenced the transcriptomes of the largest collection of genetically and anatomically identified neuronal classes. Using improved expression metrics that distinguish information content from signal-to-noise-ratio, we found that homeobox transcription factors contain the highest information about cell types and have the lowest noise. Genes that contribute the most to neuronal diversity tend to be long and enriched in factors specifically involved in neuronal function. Genome accessibility measurements reveal that long genes have more candidate regulatory elements arrayed in more distinct patterns. These elements frequently overlap interspersed repeats (mobile elements) and the pattern of repeats is predictive of gene expression. New regulatory sites resulting from elongation of neuronal genes by mobile elements may be an evolutionary force enhancing nervous system complexity.
The SAM domain of mouse SAMHD1 is critical for its activation and regulation
Authors: Buzovetsky Olga , Tang Chenxiang , Knecht Kirsten , Antonucci Jenna M. , Wu Li , Ji Xiaoyun , Xiong Yong
Published: October 2017

Human SAMHD1 (hSAMHD1) is a retroviral restriction factor that blocks HIV-1 infection by depleting the cellular nucleotides required for viral reverse transcription. SAMHD1 is allosterically activated by nucleotides that induce assembly of the active tetramer. Although the catalytic core of hSAMHD1 has been studied extensively, previous structures have not captured the regulatory SAM domain. In this study, we determined the first crystal structure of full-length SAMHD1 by capturing mouse SAMHD1 (mSAMHD1) structures in three different nucleotide bound states. Although mSAMHD1 and hSAMHD1 are highly similar in sequence and function, we found that mSAMHD1 possesses a more complex nucleotide-induced activation process, highlighting the regulatory role of the SAM domain. Our results provide new insights into the regulation of SAMHD1 activity, thereby will facilitate the improvement of HIV mouse models and the development of new therapies for certain cancers and autoimmune diseases.
Distribution of Purines and Pyrimidines over miRNAs of Human, Gorilla and Chimpanzee
Authors: Das Jayanta Kumar , Pal Choudhury Pabitra , Chaudhuri Adwitiya , Hassan Sk. Sarif , Basu Pallab
Published: October 2017

Meaningful words in English need vowels to break up the sounds that consonants make. The Nature has encoded her messages in RNA molecules using only four alphabets A, U, C and G in which the nine member double-ring bases (adenine (A) and Guanine (G)) are purines, while the six member single-ring bases (cytosine (C) and uracil (U)) are pyrimidines. Four bases A, U, C and G of RNA sequences are divided into three kinds of classifications according to their chemical properties. One of the three classifications, thepurine-pyrimidineclass is important. In understanding the distribution (organization) of purines and pyrimidines over some of the non-coding regions of RNA, all miRNAs from three species of Family Hominidae (namely human, gorilla and chimpanzee) are considered. The distribution of purines and pyrimidines over miRNA shows deviation from randomness. Based on the quantitative metrics (fractal dimension, Hurst exponent, Hamming distance, distance pattern of purine-pyrimidine, purine-pyrimidine frequency distribution and Shannon entropy) five different clusters have been made. It is identified that there exists only one miRNA in humanhsa-miR-6124which is purely made of purine bases only.

AMS Subject Classification:92B05 & 92B15
Small Molecule Inhibitors of the Human Histone Lysine Methyltransferase NSD2 / WHSC1 / MMSET Identified from a Quantitative High-Throughput Screen with Nucleosome Substrate
Authors: Coussens Nathan P. , Kales Stephen C. , Henderson Mark J. , Lee Olivia W. , Horiuchi Kurumi Y. , Wang Yuren , Chen Qing , Kuznetsova Ekaterina , Wu Jianghong , Cheff Dorian M. , Chih-Chien Cheng Ken , Shinn Paul , Brimacombe Kyle R. , Shen Min , Simeonov Anton , Ma Haiching , Jadhav Ajit , Hall Matthew D.
Published: October 2017

The activity of the histone lysine methyltransferase NSD2 is thought to play a driving role in oncogenesis. Both overexpression of NSD2 and point mutations that increase its catalytic activity are associated with a variety of human cancers. While NSD2 is an attractive therapeutic target, no potent, selective and cell-active inhibitors have been reported to date, possibly due to the challenging nature of developing high-throughput assays for NSD2. To establish a platform for the discovery and development of selective NSD2 inhibitors, multiple assays were optimized and implemented. Quantitative high-throughput screening was performed with full-length wild-type NSD2 and a nucleosome substrate against a diverse collection of known bioactives comprising 16,251 compounds. Actives from the primary screen were further interrogated with orthogonal and counter assays, as well as activity assays with the clinically relevant NSD2 mutants E1099K and T1150A. Five confirmed inhibitors were selected for follow-up, which included a radiolabeled validation assay, surface plasmon resonance studies, methyltransferase profiling, and histone methylation in cells. The identification of NSD2 inhibitors that bind the catalytic SET domain and demonstrate activity in cells validates the workflow, providing a template for identifying selective NSD2 inhibitors.
Canadian citizens volunteering in disasters: From emergence to networked governance
Authors: Waldman Suzanne , Yumagulova Lilia , Mackwani Zeenat , Benson Carly , Stone Jeremy T.
Published: October 2017

How to improve coordination between formal and unaffiliated or spontaneous volunteers after emergencies is currently an international question with a high profile. Drawing on international disaster management literature and experiences and recent crisis events in Canada, our analysis examines four Canadian case studies to show that the inclusion of citizens in EM is becoming indispensable, as simultaneously as the frequency and intensity of natural disasters are seen to be growing due to climate change, and citizens are increasingly presenting their labour and resources as assets to be drawn on in emergency and postemergency situations. In this context, Canadian municipalities are starting to better manage the unpredictability of spontaneous citizen volunteering in emergencies by building anticipatory structures of networked governance for integrating diverse, pre‐existing, and in some cases, pre‐identified groups of citizens as volunteers in emergency management functions. Additionally, as the role of voluntary service organizations is becoming elevated in emergency response and recovery in Canada, these organizations can prospectively play the role of brokers to help emergency management agencies access and manage community‐based networks of voluntary resources.
Testing Area‐Scale Fractal Complexity (Asfc) and Laser Scanning Confocal Microscopy (LSCM) to Document and Discriminate Microwear on Experimental Quartzite Scrapers
Authors: Stemp W. J. , Lerner H. J. , Kristant E. H.
Published: October 2017

Few microwear studies have been conducted on tools made from quartzite. Most rely on visual observation of microwear features using optical light microscopes and scanning electron microscopes. Quantification of microwear on quartzite tools is extremely rare, even though numerous methods to mathematically document surface roughness have been applied to other silicate tools. In this paper, laser scanning confocal microscopy (LSCM) was used to document surface roughness on four experimental scrapers made from two different subtypes of Mistassini quartzite that were used on either fresh or dry deer hide. Surface roughness data were analysed using area‐scale fractal complexity (Asfc). The results of this test case indicate that Asfc can effectively discriminate between the unused and used regions on the quartzite tools based on surface roughness, and that it can also discriminate between surface roughness produced by working dry versus fresh hides. Differences in the subtypes of Mistassini quartzite did affect surface roughness, but not significantly enough to prevent discrimination of the dry and fresh hide‐working tools. Although the use of the Asfc parameter for lithic microwear analysis requires further testing, these first results suggest it could be a reliable technique to mathematically document and discriminate wear patterns on archaeological quartzite tools.
Novel 1,3,5‐triazine derivatives exert potent anti‐cervical cancer effects by modulating Bax, Bcl2 and Caspases expression
Authors: Wang Xiwen , Yi Yuexiong , Lv Qiongying , Zhang Juan , Wu Kejia , Wu Wanrong , Zhang Wei
Published: October 2017

This study aimed to develop novel 1,3,5‐triazine derivatives as potent anti‐cervical cancer agents. The compounds were synthesized in short steps with an excellent yield and characterized via various spectroscopic and analytical methods. A structure–activity relationship study suggested that electron‐withdrawing substituents showed greater anticancer activity than electron‐donating groups. Compound 7p (p‐fluoro) showed the highest activity against cervical cancer cells. In a nude mouse xenograft model inoculated with HeLa cells, 7p showed dose‐dependent inhibition of cervical tumour growth. Histopathological examination of excised tumour‐bearing tissues showed that 7p improved the microstructure in a dose‐dependent manner. Compound 7p also increased the proportions of HeLa cells in G0/G1 and S‐phase and significantly decreased that of G2/M‐phase. The effects of 7p on C‐caspase‐3, C‐caspase‐9, Bcl‐2 and Bax expression in HeLa cells were also determined.
Needs and preferences of patients with head and neck cancer in integrated care
Authors: van Overveld L.F.J. , Takes R.P. , Turan A.S. , Braspenning J.C.C. , Smeele L.E. , Merkx M.A.W. , Hermens R.P.M.G. ,   the Dutch Head and Neck Audit Group
Published: October 2017

Objectives

Incorporation of patients’ perspectives in daily practice is necessary to adapt care to users’ needs. However, information on patients’ needs and preferences for integrated care is lacking. The aim was to explore these needs and preferences, taking patients with head and neck cancer (HNC) as example, to adapt current integrated care to be more patient‐centred.

Design

Semi‐structured interviews were held with current and former patients and chairmen of patient associations. Relevant needs and preferences were identified and categorised using the eight‐dimension Picker model of patient‐centred care.

Setting

Integrated HNC in the Netherlands.

Participants

Patients with HNC and chairmen of two Dutch HNC patient associations.

Main outcome measures

Patients’ needs and preferences of integrated HNC care categorised according the Picker model.

Results

A total of 34 themes of needs and preferences were identified, by 14 patients with HNC or their delegates, using the Picker dimensions. Themes often emerged were as follows: personalisation of health care regarding patient values; clear insight into the healthcare process at organisational level; use of personalised communication, education and information that meets patients’ requirements; adequate involvement of allied health professionals for physical support; more attention to the impact of HNC and its treatment; adequate involvement of family and friends; adequate general practitioner involvement in the aftercare; and waiting time reduction.

Conclusions

Monitoring the identified themes in integrated HNC care, fitting in the Picker model, will enable us to respond better to the needs and preferences of patients, and patient‐centred care in oncological care can be enhanced.
Developing control algorithms of a voluntary cough for an artificial bioengineered larynx using surface electromyography of chest muscles: A prospective cohort study
Authors: Banus M.S. , Birchall M.A. , Graveston J.A.
Published: October 2017

Objective

This prospective cohort study investigates the prediction of a voluntary cough using surface electromyography (EMG) of intercostal and diaphragm muscles, to develop control algorithms for an EMG‐controlled artificial larynx.

Setting

The Ear Institute, London.

Main outcome measures

Electromyography onset compared to voluntary cough exhalation onset and to 100 ms (to give the artificial larynx the time to close the bioengineered vocal cords) before voluntary cough exhalation onset, in twelve healthy participants.

Results

In the 189 EMG of intercostal muscle‐detected voluntary coughs, 172 coughs (91% CI 70‐112) were detected before onset of cough exhalation and 128 coughs (67.6% CI 33.7‐101.7) 100 ms before onset of cough exhalation. In the 158 EMG of diaphragm muscle‐detected voluntary coughs, 149 coughs (94.3% CI 76.3‐112.3) were detected before onset of cough exhalation and 102 coughs (64.6% CI 26.6‐102.6) 100 ms before onset of cough exhalation. More coughs were detected before onset of cough exhalation when combining EMG activity of intercostal and diaphragm muscles and comparing this to intercostal muscle activity alone (183 coughs [96.8% CI 83.8‐109.8] vs 172 coughs, P = .0294). When comparing the mentioned combination to diaphragm muscle activity alone, the higher percentage of detected coughs before cough exhalation onset was not found to be significant (183 coughs vs 149 coughs, P = .295). In addition, more coughs were detected 100 ms before onset of cough exhalation with the mentioned combination of EMG activity and comparing this to intercostal muscles alone (149 coughs [78.8% CI 48.8‐108.8] vs 128 coughs, P = .0198) and to diaphragm muscles alone (149 coughs vs 102 coughs, P = .0038).

Conclusions

Most voluntary coughs can be predicted based on combined EMG signals of intercostal and diaphragm muscles, and therefore, these two muscle groups will be useful in controlling the bioengineered vocal cords within the artificial larynx during a voluntary cough.
Internal anal sphincter nerves – a macroanatomical and microscopic description of the extrinsic autonomic nerve supply of the internal anal sphincter
Authors: Stelzner S. , Böttner M. , Kupsch J. , Kneist W. , Quirke P. , West N. P. , Witzigmann H. , Wedel T.
Published: October 2017

Aim

The internal anal sphincter (IAS) contributes substantially to anorectal functions. While its autonomic nerve supply has been studied at the microscopic level, little information is available concerning the macroscopic topography of extrinsic nerve fibres. This study was designed to identify neural connections between the pelvic plexus and the IAS, provide a detailed topographical description, and give histological proof of autonomic nerve tissue.

Methods

Macroscopic dissection of pelvic autonomic nerves was performed under magnification in seven (five male, two female) hemipelvises obtained from body donors (67–92 years). Candidate structures were investigated by histological and immunohistochemical staining protocols to visualize nerve tissue.

Results

Nerve fibres could be traced from the anteroinferior edge of the pelvic plexus to the anorectal junction running along the neurovascular bundle anterolaterally to the rectum and posterolaterally to the prostate/vagina. Nerve fibres penetrated the longitudinal rectal muscle layer just above the fusion with the levator ani muscle (conjoint longitudinal muscle) and entered the intersphincteric space to reach the IAS. Histological and immunohistochemical findings confirmed the presence of nerve tissue.

Conclusions

Autonomic nerve fibres supplying the IAS emerge from the pelvic plexus and are distinct to nerves entering the rectum via the lateral pedicles. Thus, they should be classified as IAS nerves. The identification and precise topographical location described provides a basis for nerve‐sparing rectal resection procedures and helps to prevent postoperative functional anorectal disorders.
Histomorphometric approach to differentiate skin lesions of tuberculoid leprosy from sarcoidosis
Authors: Utino Fabiane Leonel , Damiani Gislaine Vieira , Garcia Marina , Soares Tânia Cristina Benetti , Stelini Rafael Fantelli , Velho Paulo Eduardo Neves Ferreira , de Souza Elemir Macedo , Cintra Maria Letícia
Published: October 2017

Background

More than 200 000 new cases of leprosy are detected worldwide annually. Physicians commonly have difficulty in differentiating tuberculoid form of leprosy (TL) from sarcoidosis’ cutaneous manifestation.

Methods

Skin biopsies of 33 patients with TL and 24 with sarcoidosis were reviewed on hematoxylin and eosin‐ and Gomori‐stained sections, in order to find reliable criteria for distinguishing one disease from another.

Results

Nine of the 24 features analyzed presented significant predictive value for diagnosis (P < .05). Predominance of tuberculoid granulomas in adnexal and neural distribution, and granulomas replacing the nerves localized within sweat gland glomeruli were predictive to TL diagnosis. For sarcoidosis, dermal fibrosis, back‐to‐back distribution of the granulomas, presence of atypical giant cells and plasma cells, greater number of conventional giant cells, and spared nerves beside the granuloma were predictive criteria. The median surface density of reticulin fibers was significantly higher in sarcoidosis (3.44) than in TL (2.99). Nonetheless, using logistic regression, this variable did not discriminate between the diseases (P = .096).

Conclusions

Isolated histological features are not fully predictive to differentiate the 2 diseases. However, those with statistical value can assist this distinction in diagnostic practice. Although the results of the analysis of the reticulin fibers density did not tell apart TL from sarcoidosis, they corroborate the idea of fiber fragmentation within tuberculoid leprosy granulomas, reiterating the importance of morphometry in the histological examination.
The use of pneumatic impact lithotripsy and a retrieval pouch to create a closed system for removal of cystic calculi in standing male horses
Authors: De Bernardis N. P. , Seabaugh K. A. , Ismay J. , Mudge M.
Published: October 2017

Multiple techniques exist for removal of cystic calculi in the male horse, some of which use a perineal urethrotomy (PU) to facilitate access to the urinary bladder for removal of small uroliths in the standing, sedated horse. These techniques have limited efficacy in the removal of uroliths that have a diameter larger than the PU site, typically 4–5 cm. Pneumatic lithotripsy as reported in this article provides a novel way to fragment these larger uroliths while containing the fragments and protecting the urethra and urinary bladder. Ten geldings and one stallion underwent a lithotripsy procedure to remove one (n = 10) or several (n = 1) uroliths ranging in diameter from 4 to 9 cm. A PU was performed and a laparoscopic retrieval bag was inserted into the urinary bladder through the PU site. The urolith was manipulated into the bag using blind transrectal manipulation or endoscopic guidance and the opening of the bag was exteriorised out of the PU site. A pneumatic lithotrite was used to fragment the stone. When the urolith was adequately fragmented, the fragments were removed by the use of sponge forceps and by flushing the fragments from the bag with obstetrical lube. This was continued until the bag could smoothly be withdrawn from the urinary bladder. All uroliths were successfully removed. The PU sites healed without complication and none of the horses had recurrence of presenting clinical signs. This article also discusses the difference between two types of laparoscopic retrieval bags. Pneumatic impact lithotripsy in combination with a retrieval pouch offers a safe alternative to other methods for removal of cystic calculi in the horse.
Radiological prevalence of equine odontoclastic tooth resorption and hypercementosis
Authors: Rehrl S. , Schröder W. , Müller C. , Staszyk C. , Lischer C.
Published: October 2017

Background

Equine odontoclastic tooth resorption and hypercementosis (EOTRH) is a painful and progressive dental disease that mainly affects the incisors and canine teeth of aged horses. Diagnosis is based on radiographs to detect early stages of the disease.EOTRHis probably underdiagnosed and its prevalence in Germany unknown.

Objective

This study was performed to determine the radiological prevalence ofEOTRHin a large horse population in Berlin‐Brandenburg, Germany.

Study design

Prevalence study.

Methods

The study population (142 horses) consisted of all horses 10 years and older that were presented at the Equine Hospital for a routine dental examination. The horses were either presented as clinical cases (CCpopulation) or belonged to a riding school (RSpopulation). Digital radiographs of the incisor dentition were taken and evaluated for changes related toEOTRH, leading to an overall classification for each horse.

Results

The mean age of the study population was 21 years and ranged from 10 to 37 years. Overall, 94% of all horses had at least minor and 62% had moderate to severe radiological changes of the incisor teeth associated toEOTRH. No horse older than 14 years was without radiological signs ofEOTRHand all horses over 28 years of age had at least moderate radiological changes of the incisor teeth.

Main limitations

The clinical cases group might have a bias towards horses with existing dental problems such asEOTRH, because they were presented explicitly for dental care to a clinic.

Conclusion

Focusing on radiological changes, this study shows thatEOTRHis a common condition of horses in Berlin‐Brandenburg. With older age, disease is more frequent and radiological changes become more severe. Since no horse older than 14 years was without radiological findings, it is likely that mild changes may be associated with the normal tooth ageing process.
New insights on the phylogeny of Tectaria (Tectariaceae), with special reference to Polydictyum as a distinct lineage
Authors: Dong Shi‐Yong , Chen Cheng‐Wei , Tan Shi‐Shi , Zhao Hui‐Guo , Zuo Zheng‐Yu , Chao Yi‐Shan , Chang Yi‐Han
Published: October 2017

The fern genus Tectaria (Tectariaceae) Cav. is morphologically diverse and difficult in terms of recognizing species and species groups. To infer the systematic positions of some species and identity‐unknown collections with special morphological characters, we undertook phylogenetic analyses based on sequences of five plastid regions (atpB, ndhF + ndhF‐trnL, rbcL, rps16‐matK + matK, and trnL‐F). Three analysis methods (maximum parsimony, maximum likelihood, and Bayesian inference) were used to reconstruct the phylogeny of Tectaria. The most surprising result is that T. menyanthidis (C. Presl) Copel., T. ternata (Baker) Copel., and T. variabilis Tardieu & Ching are revealed to represent a distinct lineage from Tectaria, which should be called Polydictyum C. Presl, and is supported as sister to Pteridrys C. Chr. & Ching. Other accessions of Tectaria are well resolved into four major clades, which is consistent with the results of previous studies. Of the four clades, Clade II (T. subtriphylla (Hook. & Arn.) Copel. group) is unpredictable, with morphologically very diverse species clustered there, and is supposed to be a minor evolutionary line within Tectaria in the Old World. In addition, the position of the climbing genus Arthropteris J. Sm. and the utility of molecular data in recognizing species of Tectaria are briefly discussed. As a conclusion, we formally reinstate the genus Polydictyum by providing diagnostic characters, key to species, nomenclature, and information of detailed distribution and habitat for the currently known three species.
Diagnostic utility of cortactin antibodies in myasthenia gravis
Authors: Illa Isabel , Cortés‐Vicente Elena , Martínez María Ángeles , Gallardo Eduard
Published: October 2017

Patients with myasthenia gravis (MG) without antibodies to the acetylcholine receptor (AChR) or muscle‐specific tyrosine kinase (MuSK) have been classified as having double‐seronegative myasthenia gravis (dSNMG). We used the sera from six dSNMG patients with positive immunohistochemistry assays in a protein array to screen reactivity with 9000 human proteins. We identified cortactin, an intracellular protein that interacts with agrin/MuSK favoring AChR aggregation, as a new antigen in dSNMG. We then designed an in‐house enzyme‐linked immunosorbent assay as a screening assay and confirmed these results by western blot. We found that 19.7% of dSNMG patients had anti‐cortactin antibodies. In contrast, patients with AChR+ MG or other autoimmune disorders and healthy controls were positive at significantly lower rates. Five percent of healthy controls were positive. In a recent study, we screened sera from 250 patients (AChR+ MG, MuSK+ MG, dSNMG) and 29 healthy controls. Cortactin antibodies were identified in 23.7% of dSNMG and 9.5% AChR+ MG patients (P = 0.02). None of the MuSK+ MG patients, patients with other autoimmune disorders, or healthy controls had antibodies against cortactin. Patients with dSNMG cortactin+ MG were negative for anti‐striated muscle and anti‐LRP4 antibodies. Patients with dSNMG cortactin+ MG presented ocular or mild generalized MG without bulbar symptoms. We conclude that cortactin autoantibodies are biomarkers of MG that, when present, suggest that the disease will be mild.
Experimental duration and predator satiation levels systematically affect functional response parameters
Authors: Li Yuanheng , Rall Björn C. , Kalinkat Gregor
Published: October 2017

Empirical feeding studies where density‐dependent consumption rates are fitted to functional response models are often used to parameterize the interaction strengths in models of population or food‐web dynamics. However, the relationship between functional response parameter estimates from short‐term feeding studies and real‐world, long‐term, trophic interaction strengths remains largely unexamined. In a critical first step to address this void, we tested for systematic effects of experimental duration and predator satiation on the estimate of functional response parameters, namely attack rate and handling time. Analyzing a large data set covering a wide range of predator taxa and body masses, we show that attack rates decrease with increasing experimental duration, and that handling times of starved predators are consistently shorter than those of satiated predators. Therefore, both the experimental duration and the predator satiation level have a strong and systematic impact on the predictions of population dynamics and food‐web stability. Our study highlights potential pitfalls at the intersection of empirical and theoretical applications of functional responses. We conclude our study with some practical suggestions for how these implications should be addressed in the future to improve predictive abilities and realism in models of predator–prey interactions.
Sedimentary architecture beneath lakes subjected to storms: Control by turbidity current bypass and turbidite armouring, interpreted from ground‐penetrating radar images
Authors: Arcone Steven A.
Published: October 2017

Turbidites within Holocene lacustrine sediment cores occur worldwide and are valued deposits that record a history of earthquakes or storms. Without sedimentary architecture, however, interpretation of the cause, provenance and behaviour of their parent turbidity currents are speculative. Here, these interpretations are made from two‐dimensional ground‐penetrating radar images of ‘shore to shore’ architecture beneath three, previously cored lakes within the low seismicity New England (USA) region. Shallow depths, low water and sediment conductivities, and signal sensitivity to density contrasts uniquely provided up to 30 m of sediment signal penetration. Core comparisons and signal analysis reveal that most horizons represent multidecimetre‐thick clusters of Holocene turbidites, which are denser than their organic‐rich silt matrix. Some horizons also represent erosional unconformities and sediment bypass interfaces. The key, common, architectural consequences of turbidity current activity include limited foreset progradation, conformably pinched or unconformable layers of organic‐rich sediment onlapped against slopes beneath 5 to 6 m of water, and mounded stratified sediments beneath rises. These features indicate that turbidity currents repeatedly bypassed the same slope without deposition and regardless of dip, and then simultaneously armoured and bypassed inter‐turbidite sediment along rises and basins to provide basinward, generally age‐conformable accumulation. The mounding precludes significant basinward focusing. Variable horizon amplitude suggests metre‐scale changes in armouring density. Unconformities localized near breaks in dip beneath slopes suggest erosive hydraulic jumps. One lake shows evidence of historically maintained channels associated with specific deltas. Shelf strata indicating inland current generation, similar key architecture in other, uncored lakes, countable, lake‐wide horizons, and absent slumps, slides and faults are consistent with storm‐driven turbidity currents, and with previous, core‐based conclusions that severe, Holocene storms were episodic throughout this region. The results generalize marine bypass and armouring to lacustrine settings, and so probably occur worldwide in lakes subject only to storms, including lakes where ground‐penetrating radar may locate core sites.
Serum alpha1‐proteinase inhibitor concentrations in dogs with systemic inflammatory response syndrome or sepsis
Authors: Heilmann Romy M. , Grützner Niels , Thames Brittany E. , Steiner Jörg M. , Barr James W.
Published: October 2017

Objective

To determine whether the concentration of serum canine alpha1‐proteinase inhibitor (cα1‐PI) has diagnostic or prognostic utility in dogs with sepsis or noninfectious systemic inflammatory response syndrome (SIRS).

Design

Prospective, observational study from May to December 2010.

Setting

University teaching hospital ICU.

Animals

Sixty‐nine client‐owned dogs: 19 dogs with SIRS or sepsis and 50 healthy control dogs.

Interventions

None.

Measurements and Main Results

Serum and plasma samples were collected from dogs with SIRS or sepsis on the day of hospital admission and once on the following 2 days, and on a single day in healthy controls. Patients were assessed using the 10‐parameter Acute Patient Physiologic and Laboratory Evaluation (APPLEfull) and 5‐parameter (APPLEfast) score. Serum cα1‐PI concentrations were measured, compared among groups of dogs, and evaluated for a correlation with the concentration of serum C‐reactive protein, plasma interleukin‐6, tumor necrosis factor‐α, the APPLE scores, and survival to discharge.

Serum cα1‐PI concentrations were significantly lower in dogs with SIRS/sepsis (P < 0.001) than in healthy controls. While day 1 serum cα1‐PI concentrations did not differ between dogs with SIRS and those with sepsis (P = 0.592), septic dogs had significantly lower serum cα1‐PI concentrations on days 2 (P = 0.017) and 3 (P = 0.036) than dogs with SIRS. Serum cα1‐PI concentrations did not differ between survivors and nonsurvivors (P = 1.000), but were inversely correlated with the APPLEfull score (ρ = –0.48; P = 0.040) and plasma interleukin‐6 concentrations (ρ = –0.50; P = 0.037).

Conclusions

These results suggest a role of cα1‐PI as a negative acute phase protein in dogs. The concentration of serum cα1‐PI at the time of hospital admission does not have utility to identify dogs with sepsis from those with noninfectious SIRS, but may be a useful surrogate marker for early stratification of illness severity.
Evolution-informed forecasting of seasonal influenza A (H3N2)
Authors: Du Xiangjun , King Aaron A. , Woods Robert J. , Pascual Mercedes
Published: October 2017

A transmission model including virus evolution quantified from genetic sequences produces H3N2 influenza forecasts ahead of the season.
Both Sphingomyelin and Cholesterol in the Host Cell Membrane Are Essential for Rubella Virus Entry
Authors: Otsuki Noriyuki , Sakata Masafumi , Saito Kyoko , Okamoto Kiyoko , Mori Yoshio , Hanada Kentaro , Takeda Makoto
Published: October 2017

Rubella virus (RuV) causes a systemic infection, and transplacental fetal infection causes congenital rubella syndrome. In this study, we showed that treatment of cells with sphingomyelinase inhibited RuV infection. Assays using inhibitors of serine palmitoyl transferase and ceramide transport protein demonstrated the contribution of sphingomyelin (SM) to RuV infection. Compelling evidence for direct binding of RuV to lipid membranes at neutral pH was obtained using liposome coflotation assays. The absence of either SM or cholesterol (Chol) abrogated the RuV-liposome interaction. SM and Chol (SM/Chol) were also critical for RuV binding to erythrocytes and lymphoid cells. Removal of Ca2+from the assay buffer or mutation of RuV envelope E1 protein Ca2+-binding sites abrogated RuV binding to liposomes, erythrocytes, and lymphoid cells. However, RuV bound to various nonlymphoid adherent cell lines independently of extracellular Ca2+or SM/Chol. Even in these adherent cell lines, both the E1 protein Ca2+-binding sites and cellular SM/Chol were essential for the early stage of RuV infection, possibly affecting envelope-membrane fusion in acidic compartments. Myelin oligodendrocyte glycoprotein (MOG) has recently been identified as a cellular receptor for RuV. However, RuV bound to MOG-negative cells in a Ca2+-independent manner. Collectively, our data demonstrate that RuV has two distinct binding mechanisms: one is Ca2+dependent and the other is Ca2+independent. Ca2+-dependent binding observed in lymphoid cells occurs by the direct interaction between E1 protein fusion loops and SM/Chol-enriched membranes. Clarification of the mechanism of Ca2+-independent RuV binding is an important next step in understanding the pathology of RuV infection.

IMPORTANCERubella has a significant impact on public health as infection during early pregnancy can result in babies being born with congenital rubella syndrome. Even though effective rubella vaccines are available, rubella outbreaks still occur in many countries. We studied the entry mechanism of rubella virus (RuV) and found that RuV binds directly to the host plasma membrane in the presence of Ca2+at neutral pH. This Ca2+-dependent binding is specifically directed to membranes enriched in sphingomyelin and cholesterol and is critical for RuV infection. Importantly, RuV also binds to many cell lines in a Ca2+-independent manner. An unidentified RuV receptor(s) is involved in this Ca2+-independent binding. We believe that the data presented here may aid the development of the first anti-RuV drug.
Mechanisms of CNS Viral Seeding by HIV+CD14+CD16+Monocytes: Establishment and Reseeding of Viral Reservoirs Contributing to HIV-Associated Neurocognitive Disorders
Authors: Veenstra Mike , León-Rivera Rosiris , Li Ming , Gama Lucio , Clements Janice E. , Berman Joan W.
Published: October 2017

HIV reservoirs persist despite antiretroviral therapy (ART) and are established within a few days after infection. Infected myeloid cells in the central nervous system (CNS) may contribute to the establishment of a CNS viral reservoir. The mature CD14+CD16+monocyte subset enters the CNS in response to chemokines, including CCL2. Entry of infected CD14+CD16+monocytes may lead to infection of other CNS cells, including macrophages or microglia and astrocytes, and to release of neurotoxic early viral proteins and additional cytokines. This contributes to neuroinflammation and neuronal damage leading to HIV-associated neurocognitive disorders (HAND) in ~50% of HIV-infected individuals despite ART. We examined the mechanisms of monocyte entry in the context of HIV infection and report for the first time that HIV+CD14+CD16+monocytes preferentially transmigrate across the blood-brain barrier (BBB). The junctional proteins JAM-A and ALCAM and the chemokine receptor CCR2 are essential to their preferential transmigration across the BBB to CCL2. We show here that JAM-A and ALCAM are increased on HIV+CD14+CD16+monocytes compared to their expression on HIVexpCD14+CD16+monocytes—cells that are uninfected but exposed to HIV, viral proteins, and inflammatory mediators. Antibodies against JAM-A and ALCAM and the novel CCR2/CCR5 dual inhibitor cenicriviroc prevented or significantly reduced preferential transmigration of HIV+CD14+CD16+monocytes. This indicates that JAM-A, ALCAM, and CCR2 may be potential therapeutic targets to block entry of these infected cells into the brain and prevent or reduce the establishment and replenishment of viral reservoirs within the CNS.

IMPORTANCEHIV infects different tissue compartments of the body, including the central nervous system (CNS). This leads to establishment of viral reservoirs within the CNS that mediate neuroinflammation and neuronal damage, contributing to cognitive impairment. Our goal was to examine the mechanisms of transmigration of cells that contribute to HIV infection of the CNS and to continued replenishment of CNS viral reservoirs, to establish potential therapeutic targets. We found that an HIV-infected subset of monocytes, mature HIV+CD14+CD16+monocytes, preferentially transmigrates across the blood-brain barrier. This was mediated, in part, by increased junctional proteins JAM-A and ALCAM and chemokine receptor CCR2. We show that the CCR2/CCR5 dual inhibitor cenicriviroc and blocking antibodies against the junctional proteins significantly reduce, and often completely block, the transmigration of HIV+CD14+CD16+monocytes. This suggests new opportunities to eliminate infection and seeding or reseeding of viral reservoirs within the CNS, thus reducing neuroinflammation, neuronal damage, and cognitive impairment.
Evidence of homologous and heterologous effects after unilateral leg training in youth
Authors: Ben Othman Aymen , Behm David G. , Chaouachi Anis
Published: October 2017

The positive effects of unilateral training on contralateral muscles (cross education) has been demonstrated with adults for over a century. There is limited evidence for cross education of heterologous muscles. Cross education has not been demonstrated with children. It was the objective of this study to investigate cross-education training in children examining ipsilateral and contralateral homologous and heterologous muscles. Forty-eight male children (aged 10–13 years) were assessed for unilateral, ipsilateral and contralateral lower limb strength, power and endurance (1-repetition maximum (RM) leg press, knee extensors (KE) and flexors (KF) maximum voluntary isometric contractions (MVIC), countermovement jump, muscle endurance test (leg press repetitions with 60% 1RM)), and upper body unilateral MVIC elbow flexors (EF) and handgrip strength. An 8-week training program involved 2 unilateral leg press resistance-training groups (high load/low repetitions: 4–8 sets of 5RM, and low load/high repetitions: 1–2 sets of 20RM) and control (untrained) group. All muscles exhibited improvements of 6.1% to 89.1%. The trained limb exhibited greater adaptations than the untrained limb for leg press 1RM (40.3% vs. 25.2%; p = 0.005), and 60% 1RM leg press (104.1% vs. 73.4%; p = 0.0001). The high load/low repetition training induced (p < 0.0001) greater improvements than low load/high repetition with KE, KF, EF MVIC and leg press 1RM. This is the first study to demonstrate cross-education effects with children and that the effects of unilateral training involve both contralateral homologous and heterologous muscles with the greatest strength-training responses from high-load/low-repetition training.
Reflections on Disciplines and Fields, Problems, Policies, and Life
Authors: Short James F.
Published: October 2017

Following a cursory review of early childhood influences, I discuss growing up during World War II and the subsequent experiences that led me to sociology and criminology. Early encounters with ideas, realities, and people—far too many to acknowledge properly—are noted briefly. I close with observations concerning a few issues of special significance and my experiences with them.
Correlates and Consequences of Worker Polymorphism in Ants
Authors: Wills Bill D. , Powell Scott , Rivera Michael D. , Suarez Andrew V.
Published: October 2017

Body size is a key life-history trait influencing all aspects of an organism's biology. Ants provide an interesting model for examining body-size variation because of the high degree of worker polymorphism seen in many taxa. We review worker-size variation in ants from the perspective of factors internal and external to the colony that may influence body-size distributions. We also discuss proximate and ultimate causes of size variation and how variation in worker size can promote worker efficiency and colony fitness. Our review focuses on two questions: What is our current understanding of factors influencing worker-size variation? And how does variation in body size benefit the colony? We conclude with recommendations for future work aimed at addressing current limitations and ask, How can we better understand the contribution of worker body-size variation to colony success? And, what research is needed to address gaps in our knowledge?
First evidence of nocturnin in fish: two isoforms in goldfish differentially regulated by feeding
Authors: Blanco Ayelén M. , Gómez-Boronat Miguel , Madera Diego , Valenciano Ana I. , Alonso-Gómez Angel L. , Delgado María J.
Published: October 2017

Nocturnin (NOC) is a unique deadenylase with robust rhythmic expression involved in the regulation of metabolic processes in mammals. Currently, the possible presence of NOC in fish is unknown. This report aimed to identify NOC in a fish model, the goldfish ( Carassius auratus), and to study the possible regulation of its expression by feeding. Two partial-length cDNAs of 293 and 223 bp, named nocturnin-a ( noc-a) and nocturnin-b ( noc-b), were identified and found to be highly conserved among vertebrates. Both mRNAs show a similar widespread distribution in central and peripheral tissues, with higher levels detected for noc-a compared with noc-b. The periprandial expression profile revealed that noc-a mRNAs rise sharply after a meal in hypothalamus, intestinal bulb, and liver, whereas almost no changes were observed for noc-b. Food deprivation was found to exert opposite effects on the expression of both NOCs (generally inhibitory for noc-a, and stimulatory for noc-b) in the three mentioned tissues. A single meal after a 48-h food deprivation period reversed (totally or partially) the fasting-induced decreases in noc-a transcripts in all studied tissues and the increases in noc-b expression in the intestinal bulb. Together, this study offers the first report of NOC in fish and shows a high dependence of its expression on feeding and nutritional status. The differential responses to feeding of the two NOCs raise the possibility that they might be underlying different physiological mechanisms (e.g., food intake, lipid mobilization, energy homeostasis) in fish.
Lignin and Cellulose Extraction from Vietnam’s Rice Straw Using Ultrasound-Assisted Alkaline Treatment Method
Authors: Dinh Vu Ngo , Thi Tran Hang , Bui Nhi Dinh , Duc Vu Cuong , Viet Nguyen Hung
Published: October 2017

The process of cellulose and lignin extraction from Vietnam’s rice straw without paraffin pretreatment was proposed to improve economic efficiency and reduce environmental pollution. Treatment of the rice straw with ultrasonic irradiation for 30 min increased yields of lignin separation from 72.8% to 84.7%. In addition, the extraction time was reduced from 2.5 h to 1.5 h when combined with ultrasonic irradiation for the same extraction yields. Results from modern analytical methods of FT-IR, SEM, EDX, TG-DTA, and GC-MS indicated that lignin obtained by ultrasound-assisted alkaline treatment method had a high purity and showed a higher molecular weight than that of lignin extracted from rice straw without ultrasonic irradiation. The lignin and cellulose which were extracted from rice straw showed higher thermal stability with 5% degradation at a temperature of over 230°C. The ultrasonic-assisted alkaline extraction method was recommended for lignin and cellulose extraction from Vietnam’s rice straw.