bluuebunny/crossref_metadata_2025 huggingface dataset:
Reference values of bioelectrical impedance analysis for detecting breast cancer-related lymphedema
Authors: Jung Minji , Jeon Jae Yong , Yun Gi Jeong , Yang Seoyon , Kwon Sara , Seo Yu Jin
Published: October 2018

Secondary lymphedema is a chronic debilitating lifelong complication and early diagnosis is crucial. The Inbody 720, which is widely used, has no universal index of diagnostic criteria for test results. We aim to determine the normal range, cutoff values, and mean + standard deviation values of extracellular fluid (ECF) and the single frequency bioimpedance (SFBIA) ratios for the diagnosis of lymphedema and suggest the usefulness of these values for detecting lymphedema.

Seventy patients with unilateral breast cancer-related lymphedema and 643 healthy subjects were enrolled. All patients with breast cancer underwent surgeries with dissection of lymph nodes. We analyzed the ECF volume, SFBIA at 1- and 5-kHz frequencies using Inbody 720.

There were significant differences between patients with BCRL and healthy controls. The optimal cutoff values for ECF ratios were 1.010 for both the dominant and non-dominant arms. At 1 kHz, the cutoff values of SFBIA were 1.050 and 1.046, and at 5 kHz, those were 1.070 and 1.030 for the dominant and non-dominant affected arms, respectively. The mean + 2SD values for ECF ratio were 1.018 and 1.020 and at 1 kHz, the mean + 2SD values of SFBIA were 1.144 and 1.0135 and at 5 kHz, the cutoff values of SFBIA were 1.141 and 1.124 for the dominant and non-dominant affected arms, respectively. The mean + 3SD values for ECF ratio were 1.026 and 1.030 and at 1 kHz, the mean + 3SD values of SFBIA were 1.206 and 1.203 and at 5 kHz, those were 1.201 and 1.187 for the arms, respectively. The cutoff, mean + 2SD, and mean + 3SD values were applied to 70 patients with unilateral BCRL. When the cutoff values were applied, a higher proportion of BCRL patients were included.

When these figures were applied to the patient group, the cutoff values included a higher proportion of patients with lymphedema. Further studies are needed to investigate whether bioimpedance analysis can accurately predict the development of lymphedema.
Compressive optic neuropathy secondary to Ewing sarcoma in the paranasal sinus
Authors: Lee Min Jee , Kang Min Ho , Yeom Jong Hun , Yeom Hoseok , Seong Mincheol , Cho Heeyoon , Shin Yong Un
Published: October 2018

Rationale:

Ewing sarcoma localized in the paranasal sinuses, compressing the optic nerve, is very rare, with no prior case reports

Patient concerns:

A 68-year-old woman presented with decreased visual acuity in her left eye and paresthesia of the left face. Brain magnetic resonance imaging showed heterogeneously enhancing mass in the left paranasal sinuses with adjacent bone destruction, extending to the extraocular muscles and optic nerve of the left orbit. A biopsy of the nasal cavity confirmed Ewing sarcoma.

Diagnosis:

Compressive optic neuropathy secondary to Ewing sarcoma in the paranasal sinuses.

Intervention:

Neoadjuvant chemotherapy and radiotherapy were performed.

Outcomes:

Resolution of the tumor and increased visual acuity and field of the left eye.

Lessons:

Primary head and neck Ewing sarcoma can lead to compressive optic neuropathy, but the tumor responded well to the chemotherapy. Early diagnosis and immediate treatment by close cooperation between the ophthalmologist and oncologist can prevent from permanent visual loss.
Chinese herbal medicine for dyslipidemia: protocol for a systematic review and meta-analysis
Authors: He Caihong , Fu Peng , Zhang Kexin , Xia Qing , Yang Yunmei , Xie Liangzhen
Published: October 2018

Background:

Dyslipidemia is commonly characterized by the abnormal quantity and quality of lipids in plasma, which is strongly associated with an increased risk of cardiovascular disease and also a major cause of morbidity and even leads to mortality. In China and East Asia, Chinese herbal medicine has been widely used to treat diverse diseases for thousands of years. As an important means of traditional Chinese medicine treatment, Chinese herbal medicine plays a more important role in the treatment of dyslipidemia. The aim of this study is to assess the efficacy and safety of Chinese herbal medicine for dyslipidemia.

Methods:

Seven electronic databases (included The Cochrane Library, MEDLINE, Embase, CNKI, VIP, CBM, and WANGFANG) will be searched regardless of publication date or language. Randomized controlled trials will be included if they recruited participants with dyslipidemia for assessing the effect of Chinese herbal medicine vs control (placebo, no treatment, and other therapeutic agents). Primary outcomes will include serum lipid and advent events. Two authors will independently scan the articles searched, extract the data from articles included, and assess the risk of bias by Cochrane tool of risk of bias. Disagreements will be resolved by discussion among authors. All analysis will be performed based on the Cochrane Handbook for Systematic Reviews of Interventions. Dichotomous variables will be reported as risk ratio or odds ratio with 95% confidence intervals (CIs) and continuous variables will be summarized as mean difference or standard mean difference with 95% CIs.

Results:

This review will be to assess the efficacy and safety of Chinese herbal medicine for dyslipidemia.

Conclusions:

Our findings will assist clinicians and health professionals make clinical decisions regarding dyslipidemia prevention, and promising way for prevention and treatment of patients with dyslipidemia.

Ethics and dissemination:

This study is a protocol for systematic review of Chinese herbal medicine as a treatment of dyslipidemia. This review will be published in a journal and disseminated in print by peer-review.

Systematic review registration:

PROSPERO (CRD42018085556).
Expression of estrogen receptor, progesterone receptor, human epidermal growth factor receptor 2, and Ki-67 in ductal carcinoma in situ (DCIS) and DCIS with microinvasion
Authors: Wan Zhi-Bin , Gao Hong-Yi , Wei Lian , Zhang An-Qin , Zhang Jiang-Yu , Wang Yi , Wang Dong-Dong , Zhang Yan
Published: October 2018

Ductal carcinoma in situ (DCIS) represents a heterogeneous disease in its histologic appearance and biological potential. Some women treated for DCIS subsequently develop invasive breast cancer. DCIS with microinvasion is considered as the interim stage in the progression from DCIS to invasive breast cancer. Analysis of the differences between DCIS and DCIS with microinvasion may aid in understanding the characteristic of DCIS with microinvasion and identifying biological factors determining progression of DCIS to invasive disease.

Retrospective analysis of 219 cases between 2012 and 2018 was performed in our institution. The pathological results and axillary lymph nodes status were collected. Analysis of the expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER-2), and Ki-67 in pure DCIS (164 cases), and DCIS with microinvasion (55 cases) using immunohistochemistry.

DCIS with microinvasion had a higher nuclear grade (P < .001) and was more likely to have sentinel lymph node biopsy (SLNB) positivity (P = .039) than DCIS. Expression of ER, PR were significantly higher in DCIS compared with DCIS with microinvasion (P < .001, P < .001). While the expression of HER-2 in DCIS with microinvasion (56.4%) was significantly higher than in DCIS (36.6%, P = .01). Furthermore, DCIS with microinvasion was significantly more likely to have aggressive subtype (Triple-negative and HER2-enriched tumors, P = .005).

Our results indicated that DCIS with microinvasion was different from pure DCIS in clinicopathologic characteristics and molecular alterations. It displayed a more aggressive biological nature than pure DCIS. It may be a distinct entity.
Neutrophil to lymphocyte ratio predicts island sign in patients with intracranial hemorrhage
Authors: Zhang Fan , Qian Juan , Tao Chuanyuan , Wang Yuelong , Lin Sen , You Chao , Yang Mu
Published: October 2018

Our previously studies indicated that inflammatory responses are involved in the hematoma expansion (HE) after intracranial hemorrhage (ICH) ictus. Here, we aim to evaluate the correlations among the ratio of neutrophil to lymphocyte ratio (NLR), HE, and island sign in patients with ICH.

Patients with spontaneous ICH were retrospectively included. Clinical characteristics, imaging features, and laboratory parameters were obtained. Multivariable analysis was performed to evaluate the association of NLR with HE or island sign. Receiver-operator analysis was also used to estimate their predictive abilities for HE and its imaging features.

A total of 279 patients were enrolled in present study, and 78 patients had early hematoma growth, while 43 of them exhibited island sign. Elevation of both leukocyte (odds ratio [OR] 1.136, 95% confidence interval [CI] 1.037–1.245, P < .01) and neutrophil absolute numbers (OR 1.169, 95% CI 1.065–1.284, P < .01), as well as reduction of lymphocyte counts (OR 0.052, 95% CI 0.016–0.167, P < .01) were strongly associated with the existence of island sign. Moreover, despite the predictive ability of NLR on the existence of island sign (OR 1.063, 95% CI 1.036–1.090, P < .01), it also showed the best predictive accuracy (sensitivity 76.74%, specificity 79.66%, positive predictive value 40.70%, negative predictive value 94.90%, area under the curve 0.817) by comparing with peripheral leukocyte counts.

The NLR could be used as an independently marker for reflecting the island sign in patients with ICH. Our findings indicated that systemic inflammatory responses might be involved in the pathologic process of active bleeding in cerebral.
Banxia Baizhu Tianma decoction for hyperlipidemia
Authors: Cai Hairong , Guo Yongning , Zhao Zicong , Chen Yanhong , Zhao Shuai , Chen Bojun
Published: October 2018

Background:

Hyperlipidemia is one of the most common metabolic diseases worldwide, as well as a leading risk factor for cardio-cerebrovascular diseases. Banxia Baizhu Tianma decoction (BBTD) is widely used for the treatment of hyperlipidemia in China, however, systematic review and meta-analysis regarding its efficacy and safety is lacking. The aim of this protocol of systematic review is to evaluate the effectiveness and safety of BBTD in the treatment of hyperlipidemia.

Methods:

We will include the randomized controlled trials estimating the effectiveness and safety of BBTD in the treatment of hyperlipidemia. Data sources will include 5 English databases (PubMed, EMBASE, Cochrane Library, Web of Science, CINAHL) and 4 Chinese databases (CMB, CNKI, VIP, Wanfang database). The literature to be collected will be from the time when databases were established to September 2018. Efficacy will be accepted as the primary outcome, while blood lipid levels and adverse reactions as the secondary outcome. Study selection, data collection, risk of bias assessment, and evaluation of the quality of the evidence will be conducted by 2 × 2 different reviewers. Statistical syntheses will be conducted by using RevMan software V.5.3.

Results:

This study will provide a high-quality evidence for BBTD on the treatment of hyperlipidemia from efficacy, serum lipid levels, and adverse reactions.

Conclusion:

The result will provide a basis for judging whether BBTD is an effective intervention for the treatment of hyperlipidemia.

PROSPERO registration number:

PROSPERO CRD 42018081359.
An evidence-based approach to assess the accuracy of diffusion kurtosis imaging in characterization of gliomas
Authors: Huang Ruiyu , Chen Yanni , Li Wenfei , Zhang Xvfeng
Published: October 2018

Objective:

Accurate and noninvasive pathologic grading of glioma patients before surgery was crucial to guiding clinicians to select appropriate treatment and improve patient prognosis. This study was performed to investigate the potential diagnostic value of diffusion kurtosis imaging (DKI) to distinguish high-grade gliomas (HGGs) from low-grade gliomas (LGGs) based on an evidence-based approach.

Methods:

Relevant articles that used DKI to distinguish HGG from LGG in Embase, PubMed, China Knowledge Resource Integrated database (CNKI), Web of Knowledge, and Cochrane Libraries databases were electronically searched to April 31, 2018 by 2 reviewers. All analysis was performed by using Meta-disc1.4 and Stata. Influence factors on the diagnostic accuracy were evaluated using meta-regression analysis.

Results:

Five eligible studies were included in this meta-analysis. The pooled sensitivity (SEN) and specificity (SPE) was 91% (confidence interval [CI]: 0.78–0.96; P = .02) and 91% (CI: 0.80–0.97; P = .01). The pooled data showed that diagnostic odds ratio (DOR) of DKI was 79.75 (CI: 31.57–201.45). The area under the curve (AUC) of summary receiver operating characteristic curve was 0.96. There is no evidence that our research has a threshold effect (Spearman correlation coefficient: 0.300, P = .624) and publication bias. Meta regression analysis identified that country, language, field strength, and parameter of magnetic resonance imaging had no significant effect on diagnostic performance.

Conclusion:

The present meta-analysis shows that the mean kurtosis values derived from DKI may be useful in characterization of gliomas with high sensitivity and specificity. Taken into consideration the small sample of this study, we need to be cautious when interpreting the results of this study.
A retrospective study of the efficacy of sofosbuvir plus NS5A inhibitors for patients with hepatitis C virus genotype-2 chronic infection
Authors: Lv Duo-Duo , Wang Meng-Lan , Chen En-Qiang , Wu Dong-Bo , Tao Ya-Chao , Zhang Dong-Mei , Tang Hong
Published: October 2018

Background

A combination of sofosbuvir (SOF)+NS5A inhibitor therapies is the main treatment for patients with hepatitis C virus (HCV) genotype-2 (GT-2) chronic infection, but the data are rarely reported in China. This study aimed to investigate the virological response and liver fibrosis improvement among GT-2 patients receiving SOF+NS5A inhibitors.

Patients and methods

In this retrospective study, patients who received SOF+NS5A inhibitors between March 2016 and July 2017 were recruited. The treatment duration was 12 weeks and the treatment strategies included SOF+daclatasvir, SOF/ledipasvir, and SOF/velpatasvir. The primary endpoint was a sustained virologic response (serum HCV RNA undetectable) at week 12 after the end of therapy and the secondary endpoint was the improvement in liver stiffness and scores of apartate aminotransferase to platelet ratio index and fibrosis-4.

Results

A total of 30 GT-2 patients were enrolled, with 13 (43.3%) patients in SOF+daclatasvir, 13 (43.3%) patients in SOF/ledipasvir, and four (13.3%) patients in SOF/velpatasvir. All patients [30/30 (100%)] achieved SVR, irrespective of treatment regimens and degree of liver fibrosis. After the treatment, liver fibrosis scores of apartate aminotransferase to platelet ratio index (2.27±2.14 vs. 0.89±0.77, P=0.003) and fibrosis-4 (1.17±1.22 vs. 0.42±0.25, P=0.013) were both significantly lower than those before treatment.

Conclusion

SOF+NS5A inhibitor therapies may induce an excellent virological response and fibrosis improvement in HCV GT-2-infected patients.
The Latin American and Spanish Survey on Nutrition in Pediatric Intensive Care (ELAN-CIP2)*
Authors: Campos-Miño Santiago , López-Herce Cid Jesús , Figueiredo Delgado Artur , Muñoz Benavides Eliana , Coss-Bu Jorge A.
Published: November 2018

Objective:

To characterize the practices of nutritional support in Latin American and Spanish PICUs.

Design:

Survey with a questionnaire sent to Latin American Society of Pediatric Intensive Care members.

Setting:

PICUs of participant hospitals.

Patients:

Critically ill children between 1 month and 18 years old.

Interventions:

None.

Measurements and Main Results:

Forty-seven surveys from 17 countries were analyzed. Sixty-seven percent of PICUs were from university-affiliated hospitals, with a median of 380 admissions/yr. Sixty-eight percent and 48.9% had a nutritional support team and nutritional support protocol, respectively. Seventy-five percent completed nutritional evaluations, with 34.2% at admission. PICUs with high-volume admissions were likely to have a nutritional support team (p < 0.005), and university-affiliated hospitals showed a trend of having a nutritional support team (p = 0.056). Measured, estimated, and ideal weights were used in 75%, 14.6%, and 10.4%, respectively. Energy requirements were calculated using Holliday & Segar and Schofield equations in 90% of the PICUs; 43% used correction factors. Only three PICUs had indirect calorimetry. At day 3 of initiation of nutritional support, 57.3% of PICUs provided at least 50% of the calculated energy requirement, and 91.5% at day 5. Protein needs were estimated according to American Society for Parenteral and Enteral Nutrition and European Society for Clinical Nutrition and Metabolism/European Society for Paediatric Gastroenterology Hepatology and Nutrition guidelines in 55.3% and 40.4%, respectively. Enteral nutrition was the preferred feeding method, initiated in 97.7% at 48 hours. The feeding route was gastric (82.9%), by bolus (42.5%) or continuous (57.4%). Monitoring methods included gastric residual measurement in 55.3%. Enteral nutrition was discontinued in 82.8% when gastric residual was 50% of the volume. Prokinetics were used in 68%. More than half of PICUs used parenteral nutrition, with 95.8% of them within 72 hours. Parenteral nutrition was administered by central vein in 93.6%. Undernourished children received parenteral nutrition sooner, whether or not enteral nutrition intolerance was present. When enteral nutrition was not tolerated beyond 72 hours, parenteral nutrition was started in 57.4%. Parenteral nutrition was initiated when enteral nutrition delivered less than 50% in 97%.

Conclusions:

Nutritional practices are heterogeneous in Latin American PICUs, but the majority use nutritional support strategies consistent with international guidelines.
Factors influencing organic carbon accumulation in mangrove ecosystems
Authors: Pérez Alexander , Libardoni Bruno G. , Sanders Christian J.
Published: October 2018

There is growing interest in the capacity of mangrove ecosystems to sequester and store ‘blue carbon’. Here, we provide a synthesis of 66 dated sediment cores with previously calculated carbon accumulation rates in mangrove ecosystems to assess the effects of environmental and anthropogenic pressures. Conserved sedimentary environments were found to be within the range of the current global average for sediment accretion (approx. 2.5 mm yr
–1
) and carbon accumulation (approx. 160 g m
−2
yr
−1
). Moreover, similar sediment accretion and carbon accumulation rates were found between mixed and monotypic mangrove forests, however higher mean and median values were noted from within the forest as compared to adjacent areas such as mudflats. The carbon accumulation within conserved environments was up to fourfold higher than in degraded or deforested environments but threefold lower than those impacted by domestic or aquaculture effluents (more than 900 g m
−2
yr
−1
) and twofold lower than those impacted by storms and flooding (more than 500 g m
−2
yr
−1
). These results suggest that depending on the type of impact, the blue carbon accumulation capacity of mangrove ecosystems may become substantially modified.
Posner qubits: spin dynamics of entangled Ca
9
(PO
4
)
6
molecules and their role in neural processing
Authors: Player Thomas C. , Hore P. J.
Published: October 2018

It has been suggested that
31
P nuclear spins in Ca
9
(PO
4
)
6
molecules could form the basis of a quantum mechanism for neural processing in the brain. A fundamental requirement of this proposal is that spins in different Ca
9
(PO
4
)
6
molecules can become entangled and remain so for periods (estimated at many hours) that hugely exceed typical
31
P spin relaxation times. Here, we consider the coherent and incoherent spin dynamics of Ca
9
(PO
4
)
6
arising from dipolar and scalar spin-spin interactions and derive an upper bound of 37 min on the entanglement lifetime under idealized physiological conditions. We argue that the spin relaxation in Ca
9
(PO
4
)
6
is likely to be much faster than this estimate.
Estimation methods for heterogeneous cell population models in systems biology
Authors: Waldherr Steffen
Published: October 2018

Heterogeneity among individual cells is a characteristic and relevant feature of living systems. A range of experimental techniques to investigate this heterogeneity is available, and multiple modelling frameworks have been developed to describe and simulate the dynamics of heterogeneous populations. Measurement data are used to adjust computational models, which results in parameter and state estimation problems. Methods to solve these estimation problems need to take the specific properties of data and models into account. The aim of this review is to give an overview on the state of the art in estimation methods for heterogeneous cell population data and models. The focus is on models based on the population balance equation, but stochastic and individual-based models are also discussed. It starts with a brief discussion of common experimental approaches and types of measurement data that can be obtained in this context. The second part describes computational modelling frameworks for heterogeneous populations and the types of estimation problems occurring for these models. The third part starts with a discussion of observability and identifiability properties, after which the computational methods to solve the various estimation problems are described.
Microtubules play a role in trafficking prevacuolar compartments to vacuoles in tobacco pollen tubes
Authors: Onelli Elisabetta , Scali Monica , Caccianiga Marco , Stroppa Nadia , Morandini Piero , Pavesi Giulio , Moscatelli Alessandra
Published: October 2018

Fine regulation of exocytosis and endocytosis plays a basic role in pollen tube growth. Excess plasma membrane secreted during pollen tube elongation is known to be retrieved by endocytosis and partially reused in secretory pathways through the Golgi apparatus. Dissection of endocytosis has enabled distinct degradation pathways to be identified in tobacco pollen tubes and has shown that microtubules influence the transport of plasma membrane internalized in the tip region to vacuoles. Here, we used different drugs affecting the polymerization state of microtubules together with SYP21, a marker of prevacuolar compartments, to characterize trafficking of prevacuolar compartments in
Nicotiana tabacum
pollen tubes. Ultrastructural and biochemical analysis showed that microtubules bind SYP21-positive microsomes. Transient transformation of pollen tubes with LAT52-YFP-SYP21 revealed that microtubules play a key role in the delivery of prevacuolar compartments to tubular vacuoles.
The past, present and future of protein-based materials
Authors: Abascal Nadia C. , Regan Lynne
Published: October 2018

Protein-based materials are finding new uses and applications after millennia of impacting the daily life of humans. Some of the earliest uses of protein-based materials are still evident in silk and wool textiles and leather goods. Today, even as silks, wools and leathers are still be used in traditional ways, these proteins are now seen as promising materials for biomaterials, vehicles of drug delivery and components of high-tech fabrics. With the advent of biosynthetic methods and streamlined means of protein purification, protein-based materials—recombinant and otherwise—are being used in a host of applications at the cutting edge of medicine, electronics, materials science and even fashion. This commentary aims to discuss a handful of these applications while taking a critical look at where protein-based materials may be used in the future.
Cancer–malaria: hidden connections
Authors: Nordor Akpéli V. , Bellet Dominique , Siwo Geoffrey H.
Published: October 2018

Cancer and malaria exemplify two maladies historically assigned to separated research spaces. Cancer, on the one hand, ranks among the top priorities in the research agenda of developed countries. Its rise is mostly explained by the ageing of these populations and linked to environment and lifestyle. Malaria, on the other hand, represents a major health burden for developing countries in the Southern Hemisphere. These two diseases also belong to separate fields of medicine: non-communicable diseases for cancer and communicable diseases for malaria.
A Human-Machine Coupled System for Efficient Sleep Spindle Detection by Iterative Revision
Authors: Bi Dasheng
Published: October 2018

Sleep spindles are characteristic events in EEG signals during non-REM sleep, and are known to be important biological markers. Manually labeling spindles by visual inspection, however, has proved to be a tedious task. Automatic detection algorithms generalize weakly for versatile spindle forms, and machine-learning methods require large datasets to train, which are unfeasible to acquire particularly for experimental animal groups. Here, a novel, integrated system based on a process of iterative “Selection-Revision” (iSR) is introduced to aid in the efficient detection of spindles. By coupling low-threshold automatic detection of spindle events based on selected parameters with manual “Revision,” the human task is effectively simplified from searching across signal traces to binary verification. Convergence was observed between resulting spindle sets through iSR, largely independent of their initial labeling, demonstrating the robustness of the method. Although possible breakdown of the revised spindle sets could be seen after multiple rounds of Revision, due to overfitting of the revised set to the initial human labeling, this could be compensated for by a Selection scheme tolerant to higher False-Negative rates of the machine labeling relative to the standard set. It was also found that iSR is generalizable to different datasets, and that initial human labeling could be substituted by low-threshold machine detection. Overall, this human-machine coupled approach allows for fast labeling to obtain consistent spindle sets, which can also be used to train machine-learning models in the future. The principle of iSR may also be applied for many different data types to assist with other pattern detection tasks.

Significance Statement

Electroencephalography (EEG) recordings are widely adopted in brain research. Abnormalities in the occurrence of particular EEG waveforms, such as sleep spindles, can be used to diagnose psychiatric diseases. Traditionally, human experts have labeled EEG traces for sleep spindles, a time consuming process; automated detection algorithms, however, often yield inaccurate results. This study introduces a new method for efficient sleep spindle detection with a human-machine coupled system that can iteratively revise labeled datasets, enabling convergence towards a robust, accurate spindle labeling. This system eases large-scale sleep spindle detection, which can yield datasets for both biological analyses and for training machine-learning models. Furthermore, the underlying method of iterative revision can be used to analyze other types of patterns efficiently.
Demography, class-structure and kin selection in continuous-time models
Authors: Rodrigues António M. M.
Published: October 2018

The Wright-Fisher infinite island model and the neighbour-modulated approach to kin selection have enabled major advances in the understanding of social evolution in a demographic context. Due to structural assumptions, however, some important evolutionary problems are difficult to solve within the Wright-Fisher discrete-time framework. Although these major constraints are relaxed in the Moran continuous-time framework, a formal treatment of the mathematics of kin selection in continuous-time class-structured populations is still lacking. Here, I employ the neighbour-modulated approach to formalise key features of the kin selection theory in continuous-time infinite-island models. Next, I derive a general form of Hamilton’s rule to enable an inclusive fitness interpretation of social behaviours. I consider class-structure at the group and individual level, and I focus on conditional and unconditional phenotypes. I illustrate how the general theory can be applied to solve a wide range of biological problems. Finally, I show how a simple extension of the framework allows for the study of problems pertaining to the transmission of parental quality. I show that while inheritance of parental quality may either promote or inhibit selection on conditional helping behaviours, unconditional behaviours are invariant with respect to the fidelity of inheritance.
Reducing RF-induced Heating near Implanted Leads through High-Dielectric Capacitive Bleeding of Current (CBLOC)
Authors: Golestanirad Laleh , Angelone Leonardo M , Kirsch John , Downs Sean , Keil Boris , Bonmassar Giorgio , Wald Lawrence L
Published: October 2018

Patients with implanted medical devices such as deep brain stimulation or spinal cord stimulation are often unable to receive magnetic resonance imaging (MRI). This is because once the device is within the radiofrequency (RF) field of the MRI scanner, electrically conductive leads act as antenna, amplifying the RF energy deposition in the tissue and causing possible excessive tissue heating. Here we propose a novel concept in lead design in which 40cm lead wires are coated with a ~1.2mm layer of high dielectric constant material (155 < εr < 250) embedded in a weakly conductive insulation (σ = 20 S/m). The technique called High-Dielectric Capacitive Bleeding of Current, or CBLOC, works by forming a distributed capacitance along the lengths of the lead, efficiently dissipating RF energy before it reaches the exposed tip. Measurements during RF exposure at 64 MHz and 123 MHz demonstrated that CBLOC leads generated 20-fold less heating at 1.5 T, and 40-fold less heating at 3 T compared to control leads. Numerical simulations of RF exposure at 297 MHz (7T) predicted a 15-fold reduction in specific absorption rate (SAR) of RF energy around the tip of CBLOC leads compared to control leads.
Multiparameter cell characterization using nanofluidic technology facilitates real-time phenotypic and genotypic elucidation of intratumor heterogeneity
Authors: Beaumont Kristin G. , Hamou Wissam , Bozinovic Nenad , Silvers Thomas R. , Shah Hardik , Dave Arpit , Allette Kimaada , Strahl Maya , Wang Ying-chih , Arib Hanane , Antoine Alesia , Ellis Ethan , Smith Melissa , Bruhn Brandon , Dottino Peter , Martignetti John A. , Schadt Eric , White Mark , Sebra Robert
Published: October 2018

Genetic and functional complexity of bulk tumor has become evident through rapid advances in sequencing technologies. As a unique integrated approach to characterizing tumor heterogeneity, we demonstrate the multifaceted capabilities of a novel nanofluidic platform to enable single-cell phenotypic and genetic profiling of ovarian cancer patient-derived tumor cells. This approach has enabled increased resolution of tumor cell phenotypic and genetic heterogeneity, providing a better understanding of underlying biological drivers of the disease. A range of CA-125 expression levels is observed within cells from individuals, demonstrating clonal diversity consistent with other phenotypic data. Further, TP53 mutation analysis demonstrates a sub-population of cells exhibiting high mutation frequency that likely drives downstream growth kinetics and protein expression. Finally, genomic data is orthogonally used to address clonal heterogeneity across ovarian tumors when compared to bulk sequencing, illustrating the potential for single-cell sequencing data integrated with cellular functional and growth data toward future therapeutic intervention.
The proteasome biogenesis regulator Rpn4 cooperates with the unfolded protein response to promote resistance to endoplasmic reticulum stress
Authors: Schmidt Rolf M. , Schuck Sebastian
Published: October 2018

Misfolded proteins in the endoplasmic reticulum (ER) activate the unfolded protein response (UPR), which enhances protein folding to restore homeostasis. Additional pathways respond to ER stress, but how they help counteract protein misfolding is incompletely understood. Here, we develop a titratable system for the induction of ER stress in yeast to enable a genetic screen for factors that augment stress resistance independently of the UPR. We identify the proteasome biogenesis regulator Rpn4 and show that it cooperates with the UPR. Rpn4 abundance increases during ER stress, first by a post-transcriptional, then by a transcriptional mechanism. Induction of RPN4 transcription is triggered by cytosolic mislocalization of secretory proteins, is mediated by multiple signaling pathways and accelerates clearance of misfolded proteins from the cytosol. Thus, Rpn4 and the UPR are complementary elements of a modular cross-compartment response to ER stress.
Reconstructing and characterizing focal amplifications in cancer using AmpliconArchitect
Authors: Deshpande Viraj , Luebeck Jens , Bakhtiari Mehrdad , Nguyen Nam-Phuong D , Turner Kristen M , Schwab Richard , Carter Hannah , Mischel Paul S , Bafna Vineet
Published: October 2018

Focal oncogene amplification and rearrangements drive tumor growth and evolution in multiple cancer types. We developed a tool, AmpliconArchitect (AA), which can robustly reconstruct the fine structure of focally amplified regions using whole genome sequencing. AA-reconstructed amplicons in pan-cancer data and in virus-driven cervical cancer samples revealed many novel insights about focal amplifications. Specifically, the findings lend support to extrachromosomally mediated mechanisms for copy number expansion, and oncoviral pathogenesis.
The molecular pH-response mechanism of the plant light-stress sensor PsbS
Authors: Krishnan-Schmieden Maithili , Konold Patrick E. , Kennis John T.M. , Pandit Anjali
Published: October 2018

Plants need to protect themselves from excess light, which causes photo-oxidative damage and lowers the efficiency of photosynthesis. Photosystem II subunit S (PsbS) is a pH sensor protein that plays a crucial role in plant photoprotection by detecting thylakoid lumen acidification in excess light conditions via two lumen-faced glutamates. However, how PsbS is activated under low-pH conditions is unknown. To reveal the molecular response of PsbS to low pH, we performed an NMR and infrared spectroscopic analysis ofPhyscomitrella patensPsbS and of the E176Q mutant in which an active glutamate has been replaced. The PsbS response mechanism at low pH involves the concerted action of repositioning of a short amphipathic helix containing E176 facing the lumen and folding of the luminal loop fragment adjacent to E71 to a 310-helix, providing clear evidence of a conformational pH switch. We propose that this concerted mechanism is a shared motif of proteins of the light-harvesting family that may control thylakoid inter-protein interactions driving photoregulatory responses.
Physiological genomics of dietary adaptation in a marine herbivorous fish
Authors: Heras Joseph , Chakraborty Mahul , Emerson J.J. , German Donovan P.
Published: October 2018

Adopting a new diet is a significant evolutionary change and can profoundly affect an animal’s physiology, biochemistry, ecology, and its genome. To study this evolutionary transition, we investigated the physiology and genomics of digestion of a derived herbivorous fish, the monkeyface prickleback (Cebidichthys violaceus). We sequenced and assembled its genome and digestive transcriptome and revealed the molecular changes related to important dietary enzymes, finding abundant evidence for adaptation at the molecular level. In this species, two gene families experienced expansion in copy number and adaptive amino acid substitutions. These families, amylase, and bile salt activated lipase, are involved digestion of carbohydrates and lipids, respectively. Both show elevated levels of gene expression and increased enzyme activity. Because carbohydrates are abundant in the prickleback’s diet and lipids are rare, these findings suggest that such dietary specialization involves both exploiting abundant resources and scavenging rare ones, especially essential nutrients, like essential fatty acids.
Reduced variation in Wolbachia density of larval stages in comparison with adults of Onchocerca volvulus: implications for clinical outcome of infection?
Authors: Armoo Samuel , Doyle Stephen R , Hedtke Shannon M , Adjami Gilles A , Boakye Daniel A , Kuesel Annette C , Osei-Atweneboana Mike Y , Grant Warwick N
Published: October 2018

Background

Wolbachia are important endosymbionts of filarial parasites. The Wolbachia of Onchocerca volvulus, the filarial pathogen responsible for the human disease onchocerciasis, is implicated in the immunopathology of the disease and may be associated with disease severity dependent on the density of Wolbachia. However, little is known in regards to the density and heterogeneity of Wolbachia in microfilariae, the life stage that is thought to be responsible for the pathology.

Results

We used a real-time qPCR relative copy number assay to estimate the number of Wolbachia genome(s) per nuclear genome of skin microfilariae (Mf), vector L1 and iL3, and nodulectomy adult male and female O. volvulus worms sampled in Ghana and the Democratic Republic of the Congo. Relatively low median Wolbachia copy numbers and variation was observed in the Mf and vector stages, in contrast to significantly higher median and more variable Wolbachia copy number from the iL3 stage to the adult worm stages.

Conclusions

This study provides the first insight into variation in Wolbachia density between the major life stages of the parasite. The relatively invariant ratios observed for Mf and vector stages is in strong contrast to the high degree of variability of Wolbachia to nuclear ratios in adults and may indicate that the mutualistic relationship between the nematode and Wolbachia in these earlier stages is regulated differently, and certainly more stringently, than the relationship in adults.
Dynamics of transposable element invasions with piRNA clusters
Authors: Kofler Robert
Published: October 2018

In mammals and in invertebrates the proliferation of a newly invading transposable element (TE) is thought to be stopped by a random insertion of one member of the invading TE family into a piRNA cluster. This view is known as the trap model. Here we explore the dynamics of TE invasions under the trap model using large-scale computer simulations. We found that piRNA clusters confer a substantial benefit, effectively preventing extinction of host populations from an uncontrollable proliferation of deleterious TEs. We show that TE invasions under the trap model consists of three distinct phases: first the TE rapidly amplifies within the population, next TE proliferation is stopped by segregating cluster insertions and finally the TE is permanently inactivated by fixation of a cluster insertion. Suppression by segregating cluster insertions is unstable and bursts of TE activity may yet occur. The transpositon rate and the population size mostly influence the length of the phases but not the amount of TEs accumulating during an invasion. Solely the size of piRNA clusters was identified as a major factor influencing TE abundance. Investigating the impact of different cluster architectures we found that a single non-recombining cluster (e.g. the somatic cluster flamenco in Drosophila) is more efficient in stopping invasions than clusters distributed over several chromosomes (e.g germline cluster in Drosophila). With the somatic architecture fewer TEs accumulate during an invasion and fewer cluster insertions are required to stop the TE. The inefficiency of the germline architecture stems from recombination among cluster sites which makes it necessary that each diploid carries, on the average, four cluster insertions, such that most individuals will end up with at least one cluster insertion. Surprisingly we found that negative selection in a model with piRNA clusters can lead to a novel equilibrium state, where TE copy numbers remain stable despite only some individuals in a population carrying a cluster insertion. Finally when applying our approach to real data fromDrosophila melanogasterwe found that the trap model reasonably well accounts for the abundance of germline TEs but not of somatic TEs. The abundance of somatic TEs, such as gypsy, is much lower than expected.
High-resolution models of actin-bound myosin from EPR of a bifunctional spin label
Authors: Binder Benjamin P. , Thompson Andrew R. , Thomas David D.
Published: October 2018

We have employed two complementary high-resolution electron paramagnetic resonance (EPR) techniques with a bifunctional spin label (BSL) to test and refine protein structural models based on crystal structures and cryo-EM. We demonstrate this approach by investigating the effects of nucleotide binding on the structure of myosin’s catalytic domain (CD), while myosin is in complex with actin. Unlike conventional spin labels attached to single Cys, BSL reacts with a pair of Cys; in this study, we thoroughly characterize BSL’s rigid, highly stereoselective attachment to protein α-helices, which permits accurate measurements of orientation and distance. Distance constraints were obtained from double electron-electron resonance (DEER) on myosin constructs labeled with BSL specifically at two sites. Constraints for orientation of individual helices were obtained previously from continuous-wave EPR (CW-EPR) of myosin labeled at specific sites with BSL in oriented muscle fibers. We have shown previously that CW-EPR of BSL quantifies helix orientation within actin-bound myosin; here we show that the addition of high-resolution distance constraints by DEER alleviates remaining spatial ambiguity, allowing for direct testing and refinement of atomic structural models. This approach is applicable to any orientable complex (e.g., membranes or filaments) in which site-specific di- Cys mutation is feasible.
Genome-wide association study of peripheral blood DNA methylation and conventional mammographic density measures
Authors: Li Shuai , Dugué Pierre-Antoine , Baglietto Laura , Severi Gianluca , Wong Ee Ming , Nguyen Tuong L. , Stone Jennifer , English Dallas R. , Southey Melissa C. , Giles Graham G. , Hopper John L. , Milne Roger L.
Published: November 2018

Age- and body mass index (BMI)-adjusted mammographie density is one the strongest breast cancer risk factors. DNA methylation is a molecular mechanism that could underlie interindividual variation in mammographic density. We aimed to investigate the association between breast cancer risk-predicting mammographic density measures and blood DNA methylation. For 436 women from the Australian Mammographic Density Twins and Sisters Study and 591 women from the Melbourne Collaborative Cohort Study, mammographic density (dense area, non-dense area and percentage dense area) defined by the conventional brightness threshold was measured using the CUMULUS software, and peripheral blood DNA methylation was measured using the HumanMethylation450 (HM450) BeadChip assay. Associations between DNA methylation at >400,000 sites and mammographic density measures adjusted for age and BMI were assessed within each cohort and pooled using fixed-effect meta-analysis. Associations with methylation at genetic loci known to be associated with mammographic density were also examined. We found no genome-wide significant(P<10−7)association for any mammographic density measure from the meta-analysis, or from the cohort-specific analyses. None of the 299 methylation sites located at genetic loci associated with mammographic density was associated with any mammographic density measure after adjusting for multiple testing (all P>0.05/299 = 1.7 × 10−4). In summary, our study did not detect associations between blood DNA methylation, as measured by the HM450 assay, and conventional mammographic density measures that predict breast cancer risk.
Stochastic bacterial population dynamics prevent the emergence of antibiotic resistance from single cells
Authors: Alexander Helen K. , MacLean R. Craig
Published: October 2018

A better understanding of how antibiotic exposure impacts the evolution of resistance is crucial for designing more sustainable treatment strategies. The conventional approach to relating antibiotic dose to resistance evolution within a bacterial population is to measure the range of concentrations over which resistant strain(s) are selectively favoured over a sensitive strain – the “mutant selection window”. Here, we instead investigate how antibiotic concentration impacts the initial establishment of resistance from single cells, mimicking the clonal expansion of a resistant lineage following mutation or horizontal gene transfer. Using twoPseudomonas aeruginosastrains carrying distinct resistance plasmids, we show that single resistant cells have <5% probability of outgrowth at antibiotic concentrations as low as 1/8thof the resistant strain’s minimum inhibitory concentration. This low probability of establishment is due to detrimental effects of antibiotics on resistant cells, coupled with the inherently stochastic nature of cell division and death on the single-cell level, which leads to loss of many nascent resistant lineages. Our findings suggest that moderate doses of antibiotics, within the traditional mutant selection window, may be more effective at preventingde novoemergence of resistance than predicted by deterministic approaches.

Significance statement

The emergence of antibiotic resistance poses a critical threat to the efficacy of antibiotic treatments. A resistant bacterial population must originally arise from a single cell that mutates or acquires a resistance gene. This single cell may, by chance, fail to successfully reproduce before it dies, leading to loss of the nascent resistant lineage. Here we show that antibiotic concentrations that selectively favour resistance are nonetheless sufficient to reduce the chance of outgrowth from a single cell to a very low probability. Our findings suggest that lower antibiotic concentrations than previously thought may be sufficient to prevent, with high probability, emergence of resistance from single cells.
A risk-reward tradeoff of high ribosome production in proliferating cells
Authors: Tye Blake W. , Commins Nicoletta , Springer Michael , Pincus David , Churchman L. Stirling
Published: October 2018

To achieve maximal growth, cells must manage a massive economy of ribosomal proteins (r-proteins) and RNAs (rRNAs), which are required to produce thousands of new ribosomes every minute. Although ribosomes are essential in all cells, disruptions to ribosome biogenesis lead to heterogeneous phenotypes. Here, we modeled these perturbations in Saccharomyces cerevisiae and show that challenges to ribosome biogenesis result immediately in acute loss of proteostasis (protein folding homeostasis). Imbalances in the synthesis of r-proteins and rRNAs lead to the rapid aggregation of newly synthesized orphan r-proteins and compromise essential cellular processes. In response, proteostasis genes are activated by an Hsf1-dependent stress response pathway that is required for recovery from r-protein assembly stress. Importantly, we show that exogenously bolstering the proteostasis network increases cellular fitness in the face of challenges to ribosome assembly, demonstrating the direct contribution of orphan r-proteins to cellular phenotypes. Our results highlight ribosome assembly as a linchpin of cellular homeostasis, representing a key proteostasis vulnerability for rapidly proliferating cells that may be compromised by diverse genetic, environmental, and xenobiotic conditions that generate orphan r-proteins.