bluuebunny/crossref_metadata_2025 huggingface dataset:
Pain in dementia
Authors: Achterberg Wilco , Lautenbacher Stefan , Husebo Bettina , Erdal Ane , Herr Keela
Published: December 2019

The ageing revolution is changing the composition of our society with more people becoming very old with higher risks for developing both pain and dementia. Pain is normally signaled by verbal communication, which becomes more and more deteriorated in people with dementia. Thus, these individuals unnecessarily suffer from manageable but unrecognized pain. Pain assessment in patients with dementia is a challenging endeavor, with scientific advancements quickly developing. Pain assessment tools and protocols (mainly observational scales) have been incorporated into national and international guidelines of pain assessment in aged individuals. To effectively assess pain, interdisciplinary collaboration (nurses, physicians, psychologists, computer scientists, and engineers) is essential. Pain management in this vulnerable population is also preferably done in an interdisciplinary setting. Nonpharmacological management programs have been predominantly tested in younger populations without dementia. However, many of them are relatively safe, have proven their efficacy, and therefore deserve a first place in pain management programs. Paracetamol is a relatively safe and effective first-choice analgesic. There are many safety issues regarding nonsteroidal anti-inflammatory drugs, opioids, and adjuvant analgesics in dementia patients. It is therefore recommended to monitor both pain and potential side effects regularly. More research is necessary to provide better guidance for pain management in dementia.
Investigation of factors associated with spontaneous preterm birth in pregnant women living with HIV
Authors: Albert Arianne Y.K. , Elwood Chelsea , Wagner Emily C. , Pakzad Zahra , Chaworth-Musters Tessa , Berg Kyra , Van Schalkwyk Julie , Maan Evelyn J. , Azampanah Arezou , McClymont Elisabeth , Alimenti Ariane , Forbes John C. , Money Deborah M.
Published: December 2019

Objective:

To investigate factors contributing to preterm birth (PTB), including cART use and clinical and social determinants of health, in women living with HIV (WLWH) from British Columbia, Canada.

Design:

Retrospective observational cohort.

Methods:

We investigated the effect of cART use and other clinical and demographic factors on spontaneous PTB (sPTB) rates (<37 weeks gestational age) among 631 singleton pregnancies between 1997 and 2018. Exposure to cART was modelled in comparison to no exposure, exposure in the first trimester, and between regimens. Differences in sPTB risk were estimated using time-dependent Cox's proportional hazards models.

Results:

Overall, the sPTB rate was 16%. Cumulative cART use was associated with lower risk of PTB (Wald test P = 0.02; hazard ratio = 0.98, 95% CI = 0.96–0.99) and specific cART regimens were not associated with increased risk of sPTB. Exposure in the first trimester was not associated with sPTB and for each week of cART exposure, the risk of sPTB decreased by 2%. In a multivariable model, HIV viral load and substance use remained associated with risk of sPTB, but not cART exposure.

Conclusion:

The sPTB rate among pregnant WLWH was more than three times higher than in the general population. However, sPTB was not related specifically to use of cART; in fact, cART appeared to reduce the risk of sPTB. Uncontrolled HIV replication and substance use were associated with increased risk of sPTB among pregnant WLWH. This emphasizes the important role of prenatal care, access to cART, and smoking cessation and harm reduction to reduce the risk of sPTB in WLWH.
Impact of the 12 January 2010 earthquake on HIV case reporting in Haiti
Authors: Delcher Chris , Bae Jungjun , Rich Shannan N. , Klann Emily M. , Puttkammer Nancy , Joseph Nadjy
Published: December 2019

Objective:

To evaluate the impact of the 12 January 2010 earthquake on HIV cases from Haiti's national HIV surveillance system and assess the characteristics of people living with HIV 1-year before and after the earthquake.

Design:

An interrupted time-series design and cross-sectional analysis.

Methods:

We used autoregressive integrated moving average structures to model abrupt changes to the monthly, incident HIV case counts from HIV care clinics as reported to the Haitian Active Longitudinal Tracking of HIV System (French acronym SALVH) by clinical networks (n = 3) and earthquake instrumental intensity zones (n = 4). Preearthquake and postearthquake differences in patient-level characteristics including clinical values were examined using the χ2 test, t tests, Wilcoxon rank-sum test.

Results:

In the month immediately following the earthquake, all three clinical networks experienced statistically significant declines in cases reported: iSanté (−31.4%), Groupe Haïtien d’Etude du Sarcome de Kaposi et des Infections Opportunistes (−29.9%) and Zamni Lasante (−32.2%). Zone 8 (the most severe) was the only area with a statistically significant decline (−45.5%). Of the three clinical networks, only iSanté returned to preearthquake reporting levels by the end of our study period. Patient-level characteristics did not change dramatically after the earthquake.

Conclusion:

Despite case reporting declines, especially in clinics near the earthquake epicenter, SALVH remained intact with less impact than expected. This national system is a critical component of Haiti's strategic health information system initiative and plays a central role to HIV monitoring and evaluation efforts.
Transmitted HIV drug resistance among individuals with newly diagnosed HIV infection: a multicenter observational study
Authors: Ye Jingrong , Hao Mingqiang , Xing Hui , Zhang Fujie , Wu Hao , Lv Wei , Jiang Tianjun , Wang Yuncong , Wang Juan , Feng Yi , Xin Ruolei , Zeng Ji , Zhao Shuai , Hao Yinxiao , Chen Jing , Ruan Yuhua , Li Xue , Shao Yiming , Lu Hongyan
Published: December 2019

Objectives:

Fifteen years after the roll-out of antiretroviral treatment (ART) in China, there is limited information available on transmitted HIV drug resistance (TDR). This study aimed to characterize the epidemiology of TDR in China.

Design:

We conducted a prospective cross-sectional observational study.

Methods:

We analyzed the demographic, clinical, and virological data of individuals with newly diagnosed HIV infection using data from the Beijing HIV laboratory network collected between 2001 and 2017. We did population-based sequencing of the pol gene on plasma specimens and identified TDR mutations using the WHO list for surveillance of TDR mutations.

Results:

Data on TDR were available for 91% of the 10 115 individuals with newly diagnosed HIV infection tested, of whom 19.2% were from rural areas. The overall prevalence of TDR was 4.1% [95% confidence interval (CI): 3.7–4.5%], with a declining trend over the period 2001–2017. In the multivariable analysis, the risk of TDR differed significantly according to sex [odds ratio (OR) for women vs. men: 0.41, 95% CI: 0.22–0.69, P = 0.002]; infection type (OR for CRF07_BC vs. CRF01_AE: 0.24, 95% CI: 0.16–0.36, P < 0.001); and sampling period (OR for 2009–2012 vs. 2001–2008: 0.57, 95% CI: 0.41–0.79; P = 0.01), and was significantly higher among individuals from Hebei province than in those from Beijing (OR: 1.43, 95% CI: 1.05–1.96; P = 0.02).

Conclusion:

In China, the prevalence of TDR among individuals with newly diagnosed HIV infection is relatively low. Trends in TDR should be assessed in other countries with a high TDR burden.
Challenges of scale-up to dolutegravir-based regimens in sub-Saharan Africa
Authors: Salou Mounerou , Butel Christelle , Comlan Adjo S. , Konou Abla A. , Tegueni Kokou , Ehlan Amivi , Lack Fiali , Dossim Sika , Ayouba Ahidjo , Delaporte Eric , Dagnra Anoumou Y. , Peeters Martine
Published: December 2019

Objective:

Evaluate the potential effectiveness of the implementation of dolutegravir (DTG)-based regimens in patients on failing current antiretroviral treatment (ART) given the high levels of nucleoside reverse transcriptase inhibitor (NRTI) resistance in Togo.

Design:

Patients on ART attending health facilities for routine follow-up visits and for whom HIV viral load test was performed were consecutively included.

Methods:

Protease, reverse transcriptase and integrase fragments were sequenced and analyzed for presence of drug resistance mutations for patients with viral load more than 1000 copies/ml.

Results:

Among 1681 patients, 320 (19.04%) had viral load more than 1000 copies/ml and 200 were tested for drug resistance mutations. Reverse transcriptase gene was successfully sequenced for 181/200 (90.5%) patients; 140/181 (77.4%) were resistant to NRTIs and non-NRTIs, 4/181 (2.2%) to NRTIs only and 18/181 (9.9%) to non-NRTIs only. Many viral strains accumulated mutations predicting resistance to NRTIs recommended in first and second-line DTG-based ART regimens. ART switch to a DTG-based regimen after viral load testing (viral load >1000 copies/ml) or blind switch without prior viral load testing to a new DTG-based first line, estimated 31% and 47.6% of patients to be potentially on functional DTG monotherapy respectively.

Conclusion:

Overall, our results predict that, at the scale of sub-Saharan Africa a significant proportion of patients could be on functional monotherapy. To achieve the third 90 of UNAIDS objectives, implementation of DTG-based regimens should be accompanied with an accelerated scaling up of access to viral load. Studies designed to quantify the implications of use of suboptimal DTG-based regimens are also needed.
Switch from tenofovir disoproxil fumarate to raltegravir is not associated with weight gain over 96 weeks
Authors: Carr Mirella , Richardson Robyn , Tong Winnie , Bloch Mark , Baker David , Hoy Jennifer F.
Published: December 2019

Integrase strand transfer inhibitor-based antiretroviral therapy can cause weight gain. It is unknown if this is a class effect, with limited data regarding raltegravir. In 37 virologically suppressed adults (36 men, mean age 49 years) who switched from tenofovir disoproxil fumarate to raltegravir 400 mg twice daily, mean weight changes from baseline at weeks 24, 48 and 96 were not significant (maximum 0.8 kg at week 24; all P ≥ 0.16). Weight gain may not occur with all integrase strand transfer inhibitors.
Elite suppressors have low frequencies of intact HIV-1 proviral DNA
Authors: Kwaa Abena KR , Garliss Caroline C. , Ritter Kristen D. , Laird Gregory M. , Blankson Joel N.
Published: December 2019

Elite controllers or suppressors control viral replication without antiretroviral therapy. We used the intact proviral DNA assay to approximate the size of the inducible latent reservoir in elite suppressors and found that, while the median frequency of both total and intact proviral DNA was markedly lower than the frequencies seen in chronic progressors on antiretroviral therapy there was no significant difference in the ratio of intact to total proviral DNA between elite suppressors and chronic progressors.
Diffuse Alveolar Hemorrhage
Authors: Quintana Jhon H. , Aragón Cristian C. , Santos Víctor-Alfonso , de las Salas Alejandra , Tafúr Raúl-Alejandro , Aguirre-Valencia David , Cañas Carlos A. , Tobón Gabriel J.
Published: December 2019

Background/Objective

Diffuse alveolar hemorrhage (DAH) is an uncommon but potentially fatal complication in patients with systemic lupus erythematosus (SLE). Its prognosis and factors associated with mortality are not completely clear, although invasive mechanical ventilation (IMV), use of cyclophosphamide, a high Acute Physiology and Chronic Health Evaluation II score, and infections are associated with high mortality rates. We investigated clinical and immunologic characteristics and factors associated with mortality in a cohort of Latin American patients with SLE who developed DAH.

Methods

A medical records review study was conducted of patients with SLE who were admitted to the intensive care unit (ICU) with DAH between 2011 and 2018. Clinical, laboratory, and treatment variables were compared between survivors and nonsurvivors.

Results

A total of 17 patients with SLE presented with DAH during the study period, of whom 11 (64.70%) were women. The median age was 28 (19–38.5) years. The Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) on admission to the ICU was 15.94 ± 10.07. All patients received pulse methylprednisolone and therapeutic plasma exchange, and 13 (76. %) also received cyclophosphamide. During the hospital stay, 5 patients (29.41%) died. A high SLEDAI on admission, low albumin, and days of IMV and inotropic/vasoactive support were statistically significant in comparing nonsurvivors with survivors. Other scales of disease severity commonly used in the ICU, however, were not significantly associated with a fatal outcome.

Conclusions

Hypoalbuminemia, longer duration of IMV or inotropic/vasoactive treatment, and a high SLEDAI are potential prognostic factors for mortality in patients with SLE and DAH admitted to the ICU.
Assessment of Endothelial Dysfunction in Acute and Convalescent Phases of Kawasaki Disease Using Automated Edge Detection Software
Authors: Routhu Santhosh Kumar , Singhal Manphool , Jindal Ankur Kumar , Kumar Vivek , Yadav Ashok Kumar , Singh Surjit
Published: December 2019

Objective

The aim of this study was to assess endothelial dysfunction in acute and convalescent phases of Kawasaki disease (KD) using automated edge detection software.

Methods

This was a case-control study to assess the flow-mediated dilatation (FMD) of brachial artery (BA) in patients with KD during acute phase and at least 3 months after diagnosis. A 10-MHz multifrequency linear array probe attached to a high-resolution ultrasound machine (PHILIPS Medical System-IU22) was used to acquire the images. Automated edge detection software was used to assess BA diameter.

Results

A total of 16 children with KD and 16 healthy children were enrolled in the study. Mean ± SD maximum BA diameter was found to be significantly low during the acute stage of KD (2.56 ± 0.36 mm) as compared with the convalescence phase (2.93 mm ± 0.31) and in healthy controls (2.95 mm ± 0.56). The mean ± SD percentage change in the FMD was found to be significantly low in the acute phase of KD (12.32 ± 6.2) as compared with the convalescence phase of KD (17.99 ± 8.13) and healthy controls (26.88 ± 12.76). The mean ± SD percentage change in the FMD was also found to be significantly low in the convalescence phase of KD as compared with healthy controls.

Conclusions

The FMD of the BA is significantly reduced in patients during the acute and convalescence phase of KD as compared with normal healthy children. The endothelial dysfunction was present even in patients who had no obvious coronary artery abnormalities during the acute stage.
A North American History of Cannabis Use in the Treatment of Epilepsy
Authors: Carter Alexandra
Published: December 2019

Cannabis has been used for millennia in religious ceremonies, for recreation and for its medicinal qualities. There are multiple accounts detailing the specific ailments cannabis has been used to treat, many of which have included epilepsy. Racial discrimination and political stigmatization led to prohibition, which limited both patients' and researchers' access to the drug through the 20th century. Recently, academic interest has been renewed in cannabis, especially regarding the modulation of cortical excitability via the human endocannabinoid system. Modern research has produced several promising studies regarding the treatment of epileptic encephalopathies. Legalization of marijuana in Canada has potentially allowed for further trials, but it is by no means an end to the controversy surrounding the treatment of epilepsy with cannabinoids.
A New Methodology for Intraoperative Monitoring of the Functional Integrity of the Phrenic Nerve During Cardiothoracic Surgery
Authors: Lucente Giuseppe , Martinez-Barenys Carlos , Ramos-Fransi Alba , Almendrote-Muñoz Miriam , López de Castro Pedro , Deletis Vedran , Coll-Canti Jaume , Martínez-Piñeiro Alicia
Published: December 2019

Introduction:

The phrenic nerve could be easily injured during cardiothoracic surgeries because of its anatomical relationships. The aim of this study is to describe a new, feasible, and reproducible methodology to achieve a continuous intraoperative neuromonitoring of the phrenic nerve.

Methods:

Consecutive patients who underwent open-chest surgery were included. The recording active electrode was placed 5 cm superior to the tip of the xiphoid process, and a hook wire inserted at the motor point of the ipsilateral hemidiaphragm was used as the reference electrode.

Results:

We studied 45 patients (92% men, mean age 67 years). Mean height and weight were 167 ± 6.9 cm and 75.6 ± 12.3 kg, respectively. A reproducible compound motor action potential was recorded in 38 (85%) subjects. The mean latency and amplitude values were 9.68 ± 2.40 ms and 1.36 ± 3.83 mV, respectively. No intraoperative events were recorded.

Conclusions:

We reported a new methodology which allows the assessment of phrenic nerve functional integrity during surgical procedures.
Can chronic oral inflammation and masticatory dysfunction contribute to cognitive impairment?
Authors: Nangle Matthew R. , Manchery Nithin
Published: December 2019

Purpose of review

This article provides an overview of current literature focused on oral health and cognitive impairment in older adulthood, focusing in particular on whether oral inflammation, tooth loss and masticatory dysfunction might increase the risk of cognitive impairment in this age group.

Recent findings

There is now general acceptance that cognitive impairment contributes to poor oral health, largely through detrimental changes in behaviours related to maintaining good oral hygiene. There is more limited evidence for the reverse causal direction, but at least some studies now suggest that inflammatory mechanisms, tooth loss and masticatory dysfunction each have the potential to contribute to cognitive decline.

Poorer oral health significantly correlates with cognitive dysfunction, and at least some studies suggest that there may be a bi-directional causal relationship. Randomized controlled trials assessing cognitive abilities in relation to oral hygiene or oral health interventions, or provision of removable or fixed (implant-supported) dentures, are encouraged.
Going around in circles: deciphering the role of circular RNAs in neurodegenerative disease
Authors: Kondo Mari A. , Mohan Adith , Mather Karen A.
Published: December 2019

Purpose of review

Circular RNAs are highly expressed in the brain, accumulate with ageing and may play important functional roles. Hence, their role in age-related neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease, is under active investigation. This review provides an overview of our current knowledge regarding the roles of circular RNAs in Alzheimer's disease and Parkinson's disease.

Recent findings

More studies have examined Alzheimer's disease than Parkinson's disease. Circular RNA 7 (ciRS-7) has been implicated in both diseases and may play a causative pathological role in at least Alzheimer's disease. The identification of circular RNA interaction networks is a primary focus. However, different analysis pipelines can generate quite disparate results, hence bioinformatically identified candidate circular RNAs require experimental and functional validation.

Although this field of research is in its infancy, rapid advances holds promise for identifying circular RNAs that are important in neurodegenerative diseases. CiRS-7 is a promising candidate for further examination. More studies are required focussing not only on Alzheimer's disease and Parkinson's disease but also on other neurodegenerative diseases. Whether circular RNAs can be used to inform diagnostic, prognostic and therapeutic strategies for age-related neurodegenerative disease remains unclear.
On the unity and diversity of cilia
Authors: Wan Kirsty Y. , Jékely Gáspár
Published: December 2019

Cilia are specialized cellular organelles that are united in structure and implicated in diverse key life processes across eukaryotes. In both unicellular and multicellular organisms, variations on the same ancestral form mediate sensing, locomotion and the production of physiological flows. As we usher in a new, more interdisciplinary era, the way we study cilia is changing. This special theme issue brings together biologists, biophysicists and mathematicians to highlight the remarkable range of systems in which motile cilia fulfil vital functions, and to inspire and define novel strategies for future research.

This article is part of the Theo Murphy meeting issue ‘Unity and diversity of cilia in locomotion and transport’.
Motile cilia hydrodynamics: entrainment versus synchronization when coupling through flow
Authors: Hamilton Evelyn , Pellicciotta Nicola , Feriani Luigi , Cicuta Pietro
Published: December 2019

Coordinated motion of cilia is a fascinating and vital aspect of very diverse forms of eukaryotic life, enabling swimming and propulsion of fluid across cellular epithelia. There are many questions still unresolved, and broadly they fall into two classes. (i) The mechanism of how cilia physically transmit forces onto each other. It is not known for many systems if the forces are mainly of hydrodynamical origin, or if elastic forces within the cytoskeleton are important. (ii) In those systems where we know that forces are purely hydrodynamical, we do not have a framework for linking our understanding of how each cilium behaves in isolation to the collective properties of two or more cilia. In this work, we take biological data of cilia dynamics from a variety of organisms as an input for an analytical and numerical study. We calculate the relative importance of
external
flows versus
internal
cilia flows on cilia coupling. This study contributes to both the open questions outlined above: firstly, we show that it is, in general, incorrect to infer cilium–cilium coupling strength on the basis of experiments with external flows, and secondly, we show a framework to recapitulate the dynamics of single cilia (the waveform) showing classes that correspond to biological systems with the same physiological activity (swimming by propulsion, versus forming collective waves).

This article is part of the Theo Murphy meeting issue ‘Unity and diversity of cilia in locomotion and transport’.
Asymmetries in the cilia ofChlamydomonas
Authors: Dutcher Susan K.
Published: December 2019

The generation of ciliary waveforms requires the spatial and temporal regulation of dyneins. This review catalogues many of the asymmetric structures and proteins in the cilia ofChlamydomonas, a unicellular alga with two cilia that are used for motility in liquid medium. These asymmetries, which have been identified through mutant analysis, cryo-EM tomography and proteomics, provide a wealth of information to use for modelling how waveforms are generated and propagated.

This article is part of the Theo Murphy meeting issue ‘Unity and diversity of cilia in locomotion and transport’.
Cilia-driven flows in the brain third ventricle
Authors: Eichele Gregor , Bodenschatz Eberhard , Ditte Zuzana , Günther Ann-Kathrin , Kapoor Shoba , Wang Yong , Westendorf Christian
Published: December 2019

The brain ventricles are interconnected, elaborate cavities that traverse the brain. They are filled with cerebrospinal fluid (CSF) that is, to a large part, produced by the choroid plexus, a secretory epithelium that reaches into the ventricles. CSF is rich in cytokines, growth factors and extracellular vesicles that glide along the walls of ventricles, powered by bundles of motile cilia that coat the ventricular wall. We review the cellular and biochemical properties of the ventral part of the third ventricle that is surrounded by the hypothalamus. In particular, we consider the recently discovered intricate network of cilia-driven flows that characterize this ventricle and discuss the potential physiological significance of this flow for the directional transport of CSF signals to cellular targets located either within the third ventricle or in the adjacent hypothalamic brain parenchyma. Cilia-driven streams of signalling molecules offer an exciting perspective on how fluid-borne signals are dynamically transmitted in the brain.

This article is part of the Theo Murphy meeting issue ‘Unity and diversity of cilia in locomotion and transport’.
Cilia oscillations
Authors: Man Yi , Ling Feng , Kanso Eva
Published: December 2019

Cilia, or eukaryotic flagella, are microscopic active filaments expressed on the surface of many eukaryotic cells, from single-celled protozoa to mammalian epithelial surfaces. Cilia are characterized by a highly conserved and intricate internal structure in which molecular motors exert forces on microtubule doublets causing cilia oscillations. The spatial and temporal regulations of this molecular machinery are not well understood. Several theories suggest that geometric feedback control from cilium deformations to molecular activity is needed. Here, we implement a recent sliding control model, where the unbinding of molecular motors is dictated by the sliding motion between microtubule doublets. We investigate the waveforms exhibited by the model cilium, as well as the associated molecular motor dynamics, for hinged and clamped boundary conditions. Hinged filaments exhibit base-to-tip oscillations while clamped filaments exhibit both base-to-tip and tip-to-base oscillations. We report the change in oscillation frequencies and amplitudes as a function of motor activity and sperm number, and we discuss the validity of these results in the context of experimental observations of cilia behaviour.

This article is part of the Theo Murphy meeting issue ‘Unity and diversity of cilia in locomotion and transport’.
Testing the role of intraflagellar transport in flagellar length control using length-altering mutants ofChlamydomonas
Authors: Wemmer Kimberly , Ludington William , Marshall Wallace F.
Published: December 2019

Cilia and flagella are ideal model organelles in which to study the general question of organelle size control. Flagellar microtubules are steady-state structures whose size is set by the balance of assembly and disassembly. Assembly requires intraflagellar transport (IFT), and measurements of IFT have shown that the rate of entry of IFT particles into the flagellum is a decreasing function of length. It has been proposed that this length dependence of IFT may be the basis for flagellar length control. Here, we test this idea by showing that three different long-flagella mutations inChlamydomonasall cause increased IFT injection, thus confirming that IFT can influence length control. However, quantitative comparisons with mathematical models suggest that the increase in injection is not sufficient to explain the full increase in length seen in these mutants; hence, some other mechanism may be at work. One alternative mechanism that has been proposed is length-regulated binding of tubulin to the IFT particles. However, we find that the apparent length dependence of tubulin loading that has previously been reported may actually reflect length-dependent organization of IFT trains.

This article is part of the Theo Murphy meeting issue ‘Unity and diversity of cilia in locomotion and transport’.
An antibody drug conjugate targeting a GSTA glycosite-signature epitope of mucin1 expressed by non-small cell lung cancer
Authors: Pan Deng , Tang Yubo , Tong Jiao , Xie Chengmei , Chen Jiaxi , Feng Chunchao , Hwu Patrick , Huang Wei , Zhou Dapeng
Published: December 2019

Background

Antibodies targeting abnormally glycosylated proteins have been ineffective in treating cancer. Antibody-drug conjugates are emerging as an efficient option, which allow specific delivery of drugs into tumors. We and others have dissected the abnormally glycosylated tandem repeat region of MUC1 glycoprotein as three site-specific glycosylated neoantigen peptide motifs (PDTR, GSTA, GVTS) for monoclonal antibody binding.

Methods

Internalization of monoclonal antibodies was studied by immunofluorescence staining and colocalization with lysosomal markers in live cells. Antibody positivity in tumor and peritumoral tissue samples were studied by immunohistochemistry. The efficacy of anti-MUC1 ADCs were evaluated with various cancer cell lines and mouse tumor xenograft model.

Results

We describe an anti-MUC1 ADC by conjugating GSTA neoantigen-specific 16A with monomethyl auristatin E (MMAE). 16A-MMAE showed potent antitumoral efficacy with IC50ranging from 0.2 to 49.4 nM toward multiple types of cancer cells.In vivo, 16A-MMAE showed dose-dependent inhibition of tumor growth in mouse xenograft of NCI-H838 NSCLC cell line, with minimum effective dose at 1 mg/kg. At the dose of 3 mg/kg, 16A-MMAE did not cause significant toxicity in a transgenic mouse expressing human MUC1.

Conclusions

The high antitumoral efficacy of 16A-MMAE suggest that aberrant glycosylated MUC1 neoantigen is a target with high positivity in multiple cancer types for ADC development. Personalized therapy may be achieved by development of glycosite-specific antibody-drug conjugates.
Combining molecular dynamics simulations with small-angle X-ray and neutron scattering data to study multi-domain proteins in solution
Authors: Larsen Andreas Haahr , Wang Yong , Bottaro Sandro , Grudinin Sergei , Arleth Lise , Lindorff-Larsen Kresten
Published: December 2019

Many proteins contain multiple folded domains separated by flexible linkers, and the ability to describe the structure and conformational heterogeneity of such flexible systems pushes the limits of structural biology. Using the three-domain protein TIA-1 as an example, we here combine coarse-grained molecular dynamics simulations with previously measured small-angle scattering data to study the conformation of TIA-1 in solution. We show that while the coarse-grained potential (Martini) in itself leads to too compact conformations, increasing the strength of protein-water interactions results in ensembles that are in very good agreement with experiments. We show how these ensembles can be refined further using a Bayesian/Maximum Entropy approach, and examine the robustness to errors in the energy function. In particular we find that as long as the initial simulation is relatively good, reweighting against experiments is very robust. We also study the relative information in X-ray and neutron scattering experiments and find that refining against the SAXS experiments leads to improvement in the SANS data. Our results suggest a general strategy for studying the conformation of multi-domain proteins in solution that combines coarse-grained simulations with small-angle X-ray scattering data that are generally most easy to obtain. These results may in turn be used to design further small-angle neutron scattering experiments that exploit contrast variation through1H/2H isotope substitutions.
Radiomics Features of 18F-fluorodeoxyglucose Positron-Emission Tomography as a Novel Prognostic Signature in Colorectal Cancer
Authors: Kang Jeonghyun , Lee Jae-Hoon , Lee Hye Sun , Cho Eun-Suk , Park Eun Jung , Baik Seung Hyuk , Lee Kang Young , Park Chihyun , Yeu Yunku , Clemenceau Jean R. , Park Sunho , Xu Hongming , Hong Changjin , Hwang Tae Hyun
Published: December 2019

Purpose

The aim of this study was to investigate the prognostic value of radiomics signatures derived from 18F-fluorodeoxyglucose (18F-FDG) positron-emission tomography (PET) in patients with colorectal cancer (CRC).

Methods

From April 2008 to Jan 2014, we identified CRC patients who underwent 18F-FDG-PET before starting any neoadjuvant treatments and surgery. Radiomics features were extracted from the primary lesions identified on 18F-FDG-PET. Patients were divided into a training and a validation set by random sampling. A least absolute shrinkage and selection operator (LASSO) Cox regression model was applied for prognostic signature building with progression-free survival (PFS) using the training set. Using the calculated radiomics score, a nomogram was developed, and the clinical utility of this nomogram was assessed in the validation set.

Results

Three-hundred-and-eight-one patients with surgically resected CRC patients (training set 228 vs. validation set 153) were included. In the training set, a radiomics signature called a rad_score was generated using two PET-derived features such as Gray Level Run Length Matrix_Long-Run Emphasis (GLRLM_LRE) and Grey-Level Zone Length Matrix_Short-Zone Low Gray-level Emphasis (GLZLM_SZLGE). Patients with a high-rad_score in the training and validation set had shorter PFS. Multivariable analysis revealed that the rad_score was an independent prognostic factor in both training and validation sets. A radiomics nomogram, developed using rad_score, nodal stage, and lymphovascular invasion, showed good performance in the calibration curve and comparable predictive power with the staging system in the validation set.

Conclusion

Textural features derived from 18F-FDG-PET images may enable more detailed stratification of prognosis in patients with CRC.
Empirical decomposition of the explained variation in the variance components form of the mixed model
Authors: Schreck Nicholas
Published: December 2019

The coefficient of determination is a standard characteristic in linear models. It is widely used to assess the proportion of variation explained, to determine the goodness-of-fit and to compare models with different covariates. However, there has not been an agreement on a similar quantity for the class of linear mixed models yet. We introduce a natural extension of the well-known adjusted coefficient of determination in linear models to the variance components form of the linear mixed model. We propose a novel coefficient of determination which is dimensionless, has an intuitive and simple definition in terms of variance explained, is additive for several random effects and reduces to the adjusted coefficient of determination in the linear model. To this end, we prove a full decomposition of the sum of squares of the independent variable into the explained and residual variance. Based on the restricted maximum likelihood equations, we introduce a novel measure for the explained variation which we allocate specifically to the contribution of the fixed and the random covariates of the model. We illustrate on two genomic datasets that the novel coefficient of determination can be applied as an improved estimator of the heritability of complex traits. Exemplarily, we allocate the explained variation to the five chromosomes of the model plantArabidopsis thalianaand determine the contribution of each chromosome as well as cross-correlations between the chromosomes to the trait heritability.
Organelle specific protein profiling with light mediated proximal labeling in living cells
Authors: Li Zefan
Published: December 2019

Organelle specific protein identification is essential for understanding how cell functions on a subcellular level. Here, we report a light mediated proximal labeling (LIMPLA) strategy for organelle specific protein profiling in living cells. In this strategy, various commercial mitochondria-localized fluorescent trackers, such as Mitoview 405 and Rhodamine 123, can activate 2-Propynylamine (PA) to label proximal proteins in mitochondria under illumination. PA tagged proteins are subsequently derivatized via click chemistry with azido fluorescent dye for imaging or with azido biotin for further enrichment and mass-spec identification. This strategy can be generalized to other organelles specific protein labeling. For example, proteins in nucleus are labeled by utilizing the commercial nucleus tracker DRAQ5. As compared with other chemical strategies for subcellular protein labeling, there are several advantages for this LIMPLA strategy. First, this approach allows minimal interference to the cell’s status by avoiding exogenous gene tansduction and some special treatment such as hydrogen peroxide or serum starvation. Second, all reagents used in this strategy are commercially available without additional synthesis work. Further, this strategy holds the potential for analyzing proximal proteins of specific macromolecules that can be tagged with fluorescent dye by metabolic labeling strategy.
Graded recruitment of pupil-linked neuromodulation by parametric stimulation of the vagus nerve
Authors: Mridha Z. , de Gee J. W. , Shi Y. , Alkashgari R. , Williams J. , Suminski A. , Ward M. P. , Zhang W. , McGinley M. J.
Published: December 2019

Abstract

Vagus nerve stimulation (VNS) is thought to affect neural activity by recruiting brain-wide release of neuromodulators. VNS is used in treatment-resistant epilepsy, and is increasingly being explored for other disorders, such as depression, and as a cognitive enhancer. However, the promise of VNS is only partially fulfilled due to a lack of mechanistic understanding of the transfer function between stimulation parameters and neuromodulatory response, together with a lack of biosensors for assaying stimulation efficacy in real time. We here develop an approach to VNS in head-fixed mice on a treadmill and show that pupil dilation is a reliable and convenient biosensor for VNS-evoked cortical neuromodulation. In an ‘optimal’ zone of stimulation parameters, current leakage and off-target effects are minimized and the extent of pupil dilation tracks VNS-evoked basal-forebrain cholinergic axon activity in neocortex. Thus, pupil dilation is a sensitive readout of the moment-by-moment, titratable effects of VNS on brain state.
Conglomeration of highly antigenic nucleoproteins to inaugurate a heterosubtypic next generation vaccine candidate against Arenaviridae family
Authors: Azim Kazi Faizul , Lasker Tahera , Akter Rahima , Hia Mantasha Mahmud , Bhuiyan Omar Faruk , Hasan Mahmudul , Hossain Md. Nazmul
Published: December 2019

Abstract

Arenaviral infections often resulting in lethal Hemorrhagic Fevers (HF) affect primarily African and South American regions. To date, there is no FDA-approved licensed vaccine against arenaviruses and treatments have been limited to supportive therapies. Hence, the study was employed to design a highly immunogenic heterosubtypic vaccine candidate against Arenaviridae family. The whole proteomes of Lassa virus (LASV), Lymphocytic Chorio Meningitis Virus (LCMV), Lujo virus and Guanarito virus were retrieved from NCBI database and assessed to determine the most antigenic viral proteins. Only the conserved sequences were used for T cell and B cell epitope prediction to ensure protective response against a wide range of viral strains. For each virus, nucleoproteins were identified as most antigenic which generated a plethora of antigenic epitopes. The proposed epitopes were highly conserved (up to 100%) and showed high cumulative population coverage. Moreover, results revealed that among the top epitopes, T cell epitope GWPYIGSRS were conserved in Argentine mammarenavirus (Junin virus) and Brazilian mammarenavirus (Sabia virus), while B cell epitope NLLYKICLSG were conserved in Bolivian mammarenavirus (Machupo virus) and Brazilian mammarenavirus (Sabia virus), indicating the possibility of final vaccine constructs to confer broad range immunity in the host. A total 3 constructs were designed by the combination of top epitopes from each protein along with suitable adjuvant and linkers. Different physicochemical properties revealed the superiority of construct V1 in terms of safety and efficacy. Docking analysis of the refined vaccine structure with different MHC molecules and human immune receptors were also biologically significant. The vaccine receptor complex (V1-TLR3) showed minimal deformability at molecular level. Moreover, construct V1 was compatible for insertion into pET28a(+) vector and heterologous cloning inE. colisrain K12. However, the results were based on different sequence analysis and various immune databases. Further wet lab based studies using model animals are highly recommended for the experimental validation of the designed vaccine candidates.
Genomic adaptations to aquatic and aerial life in mayflies and the origin of wings in insects
Authors: Almudi Isabel , Vizueta Joel , de Mendoza Alex , Wyatt Chris , Marletaz Ferdinand , Firbas Panos , Feuda Roberto , Masiero Giulio , Medina Patricia , Alcaina Ana , Cruz Fernando , Gómez-Garrido Jessica , Gut Marta , Alioto Tyler S. , Vargas-Chavez Carlos , Davie Kristofer , Misof Bernhard , González Josefa , Aerts Stein , Lister Ryan , Paps Jordi , Rozas Julio , Sánchez-Gracia Alejandro , Irimia Manuel , Maeso Ignacio , Casares Fernando
Published: December 2019

The first winged insects underwent profound morphological and functional transformations leading to the most successful animal radiations in the history of earth. Despite this, we still have a very incomplete picture of the changes in their genomes that underlay this radiation. Mayflies (Ephemeroptera) are one of the extant sister groups of all other winged insects and therefore are at a key phylogenetic position to understand this radiation. Here, we describe the genome of the cosmopolitan mayflyCloeon dipterumand study its expression along development and in specific organs. We discover an expansion of odorant-binding proteins, some expressed specifically in the breathing gills of aquatic nymphs, suggesting a novel sensory role for gills. In contrast, as flying adults, mayflies make use of an enlarged set of opsins and utilise these visual genes in a sexually dimorphic manner, with some opsins expressed only in males. Finally, to illuminate the origin of wings, we identify a core set of deeply conserved wing-specific genes at the root of the pterygote insects. Globally, this is the first comprehensive study of the structure and expression of the genome of a paleopteran insect and shows how its genome has kept a record of its functional adaptations.
Aquaculture potential of Bohai Red and its hybrid withAgropecten irradians concentricusin southern China
Authors: Yao Gaoyou , Li Jianqiang , Wu Yuyuan , Su Xiaoying , Tan Jie , Liu Zhigang
Published: December 2019

Argopecten irradians concentricus(Say), one of four geographic subspecies of the bay scallop, has become the major cultured species in southern China since its introduction in 1995. However, its population has been significantly reduced due to high mortality.Also, poor growth rate has been observed following decades of culture.Therefore, the introduction or creation of new varieties is an urgent need. This study describes the first introduction of the new strain, Bohai Red, from the north to southern China. Hybridization trials were conducted between the recently introduced new strain and the local specie,A. irradians concentricus(Say). The success of hybridization was confirmed by SSR maker.The adult and juvenile Bohai Red cannot tolerate high temperatures compared toA. irradians concentricus(Say), whether in natural waters or under laboratory conditions. Fertilization rate forA. irradians concentricus(Say) × Bohai Red exceeded 80%, and hatching rate was 70%. The hybrids exhibit heterosis in survival rate, growth rate, and high-temperature tolerance, demonstrating substantial potential to replaceA. irradians concentricus(Say) in southern China.
Epimutations driven by small RNAs arise frequently but have limited duration in a metazoan organism
Authors: Beltran Toni , Shahrezaei Vahid , Katju Vaishali , Sarkies Peter
Published: December 2019

Epigenetic regulation involves changes in gene expression independent of DNA sequence variation that are inherited through cell division (Holliday, 2006). In addition to a fundamental role in cell differentiation, some epigenetic changes can also be transmitted transgenerationally through meiosis (Heard and Martienssen, 2014). Epigenetic alterations (“epimutations”) could thus contribute to heritable variation within populations and be subject to evolutionary processes such as natural selection and drift (Burggren, 2016). However, this suggestion is controversial, partly because unlike classical mutations involving DNA sequence changes, key parameters such as the rate at which epimutations arise and their persistence are unknown. Here, we perform the first genome-wide study of epimutations in a metazoan organism. We use experimental evolution to characterise the rate, spectrum and stability of epimutations driven by small silencing RNAs in the model nematodeC. elegans. We show that epimutations arise spontaneously at a rate ∼25 times greater than DNA sequence changes and typically have short half-lives of 2-3 generations. Nevertheless, some epimutations last at least 10 generations. Epimutations thus may contribute to evolutionary processes over a short timescale but are unlikely to bring about long-term divergence without further DNA sequence changes.
Physicochemical changes in plasma membrane mirror nanoparticle-mediated cytotoxicity
Authors: Sood Vishesh , Katti Dhirendra S.
Published: December 2019

The aim of this chapter was to understand the influence of nanoparticle challenge on physicochemical characteristics of the cells and to correlate these changes with cytotoxic response of nanoparticles. A nanoparticle surface charge and a concentration-dependent cytotoxic response were observed in the breast cancer cell lines MDA MB 231 and SKBR3. The cationic gold nanoparticles were more cytotoxic to cells as compared to anionic gold nanoparticles. It was also observed that cationic nanoparticles compromised the integrity of the plasma membrane at higher concentrations. Cationic nanoparticle challenge also caused changes in physicochemical characteristics of plasma membrane. Higher concentration of cationic nanoparticles caused an irreversible change in the surface charge density of cells. However, anionic gold nanoparticles did not show any such effect. It was observed that the ROS-mediated oxidative stress was the mechanism of cationic gold nanoparticle-mediated cytotoxic effect. Mitochondrial depolarization was observed in both anionic and cationic nanoparticle challenge. Therefore, the role of mitochondrial ROS in nanoparticle-mediated cytotoxicity is questionable. Finally, a generalized model involving modulation of intracellular Ca2+can potentially provide an explanation for the observed pluralistic response of the cells towards nanoparticle challenge.
Pragmatic spatial sampling for wearable MEG arrays
Authors: Tierney Tim M , Mellor Stephanie , O’Neill George C , Holmes Niall , Boto Elena , Roberts Gillian , Hill Ryan M , Leggett James , Bowtell Richard , Brookes Matthew J , Barnes Gareth R
Published: December 2019

Several new technologies have recently emerged promising new MEG systems in which the sensors can be placed close to the scalp. One such technology, Optically Pumped Magnetometry MEG (OP-MEG) allows for a scalp mounted flexible system that provides field measurements within mm of the scalp surface. A question that arises in developing on-scalp systems, such as OP-MEG scanners, is: how many sensors are necessary to achieve adequate performance/spatial discrimination? There are many factors to consider in answering this question such as the signal to noise ratio (SNR), the locations and depths of the sources of interest, the density of spatial sampling, sensor gain errors (due to interference, subject movement, cross-talk, etc.) and, of course, the desired spatial discrimination. In this paper, we provide simulations which show the impact these factors have on designing sensor arrays for wearable MEG. While OP-MEG has the potential to provide high information content at dense spatial samplings, we find that adequate spatial discrimination of sources (<1cm) can be achieved with relatively few sensors (<100) at coarse spatial samplings (~30mm) at high SNR. Comparable discrimination for traditional cryogenic systems require far more channels by these same metrics. Finally we show that sensor gain errors have the greatest impact on discrimination between deep sources at high SNR.