bluuebunny/crossref_metadata_2025 huggingface dataset:
Contextualizing temporal arterial magnetic resonance angiography in the diagnosis of giant cell arteritis: a retrospective cohort study
Authors: Junek Mats , Hu Angela , Garner Stephanie , Rebello Ryan , Legault Kim , Beattie Karen , Khalidi Nader
Published: December 2020

Objectives

Imaging modalities have become common in evaluating patients for a possible diagnosis of GCA. This study seeks to contextualize how temporal arterial magnetic resonance angiography (TA-MRA) can be used in facilitating the diagnosis of GCA.

Methods

A retrospective cohort study was performed on patients who had been previously referred to a rheumatologist for evaluation of possible GCA in Hamilton, Ontario, Canada. Data including clinical features, inflammatory markers, imaging, and biopsy results were extracted. Multivariable logistic regression model to predict the diagnosis of GCA. Using these models, the utility of TA-MRA in series with or in parallel to clinical evaluation was demonstrated across the cohort as well as in subgroups defined by biopsy and imaging status.

Results

In total 268 patients had complete data. Those diagnosed with biopsy- and/or imaging-positive GCA were more likely to demonstrate classic features including jaw claudication and vision loss. Clinical multivariable modelling allowed for fair discriminability [receiver operating characteristic (ROC) 0.759, 95% CI: 0.703, 0.815] for diagnosing GCA; there was excellent discriminability in facilitating the diagnosis of biopsy-positive GCA (ROC 0.949, 0.898–1.000). When used in those with a pre-test probability of 50% or higher, TA-MRA had a positive predictive value of 93.0%; in those with a pre-test probability of 25% or less TA-MRA had a negative predictive value of 89.5%.

Conclusion

In those with high disease probability, TA-MRA can effectively rule in disease (and replace temporal artery biopsy). In those with low to medium probability, TA-MRA can help rule out the disease, but this continues to be a challenging diagnostic population.
Energy
Authors: Goldemberg José
Published: December 2020

Without a doubt, the topic of energy--from coal, oil, and nuclear to geothermal, solar and wind--is one of the most pressing across the globe. It is of paramount importance to policy makers, economists, environmentalists, and industry as they consider which technologies to invest in, how to promote use of renewable energy sources, and how to plan for dwindling reserves of non-renewable energy. In Energy: What Everyone Needs to Know, José Goldemberg, a nuclear physicist who has been hailed by Time magazine as one of the world's top "leaders and visionaries on the environment," takes readers through the basics of the world energy system, its problems, and the technical as well as non-technical solutions to the most pressing energy problems. Addressing the issues in a Q-and-A format, Goldemberg answers such questions as: What are wind, wave, and geothermal energy? What are the problems of nuclear waste disposal? What is acid rain? What is the greenhouse gas effect? What is Carbon Capture and Storage? What are smart grids? What is the Kyoto Protocol? What is "cap and trade"? The book sheds light on the role of population growth in energy consumption, renewable energy resources, the amount of available energy reserves (and when they will run out), geopolitical issues, environmental problems, the frequency of environmental disasters, energy efficiency, new technologies, and solutions to changing consumption patterns. It will be the first place to look for information on the vital topic of energy.
An uncommon cause of sepsis following dog exposure
Authors: Hexter Madison A.
Published: December 2020

Capnocytophaga canimorsus is a bacteria commonly found in the normal oral cavity of dogs that can cause bacteremia in immunocompromised patients following a dog bite. This case describes sepsis and disseminated intravascular coagulation associated with C. canimorsus in a patient with a history of alcohol abuse. Clinicians must be alert to the risk factors for this infection and provide appropriate prophylaxis following dog bites.
Prompt evaluation and treatment of third-trimester bleeding
Authors: Cunningham Jill W.
Published: December 2020

Third-trimester bleeding is an obstetric emergency and is associated with significant maternal and fetal morbidity and mortality. The two most common causes for third-trimester bleeding are placental abruption and placenta previa, which account for about half of all cases. Clinicians should have a thorough understanding of the risk factors, clinical presentation, and appropriate management of these conditions. Timely management is necessary for the survival of mother and fetus and to reduce the incidence of neonatal complications.
Triple-Methyl Blockade With Recombinant Methioninase, Cycloleucine, and Azacitidine Arrests a Pancreatic Cancer Patient-Derived Orthotopic Xenograft Model
Authors: Sugisawa Norihiko , Yamamoto Jun , Han Qinghong , Tan Yuying , Tashiro Yoshihiko , Nishino Hiroto , Inubushi Sachiko , Hamada Kazuyuki , Kawaguchi Kei , Unno Michiaki , Bouvet Michael , Hoffman Robert M.
Published: December 2020

Objectives

Methionine addiction is a fundamental and general hallmark of cancer caused by enhanced methyl flux. In the present study, we effected a novel methionine-methylation blockade to target a patient-derived orthotopic xenograft model of pancreatic cancer.

Methods

The pancreatic cancer patient-derived orthotopic xenograft mouse models were randomized into 6 groups of 8 mice each and treated for 2 weeks: untreated control; azacitidine; oral recombinant methioninase (o-rMETase); o-rMETase plus cycloleucine; o-rMETase plus cycloleucine plus azacitidine (triple-methyl blockade therapy); and gemcitabine (positive control).

Results

Triple-methyl blockade therapy arrested tumor growth (mean relative tumor volume, 1.03 [standard deviation, 0.36]) and was significantly more effective compared with azacitidine (P = 0.0001); o-rMETase (P = 0.007); or o-rMETase plus cycloleucine (P = 0.04). Gemcitabine alone also inhibited but did not arrest tumor growth (mean relative tumor volume, 1.50 [standard deviation, 0.30]). The percentage of cancer cells that were negative for 5-methylcytosine staining in immunohistochemistry, indicating reduction of DNA methylation, increased with triple-methyl blockade therapy (37.5%), compared with gemcitabine (1.8%); o-rMETase (2.8%); azacitidine (9.0%); or o-rMETase plus cycloleucine (10.6%).

Conclusions

This new concept of triple-methyl blockade therapy has clinical potential for pancreatic cancer, which is currently a recalcitrant disease.
Delayed Processing of Secretin-Induced Pancreas Fluid Influences the Quality and Integrity of Proteins and Nucleic Acids
Authors: Cruz-Monserrate Zobeida , Gumpper Kristyn , Kaul Sabrina , Badi Niharika , Terhorst Samantha , Dubay Kelly , Lesinski Gregory B. , Fisher William , McElhany Amy , Lara Luis F. , Krishna Somashekar , Mace Thomas , Higuita-Castro Natalia , Ortega-Pineda Lilibeth , Freitas Michael A. , Hinton Alice , Yadav Dhiraj , Hart Phil A. , Pandol Stephen J. , Ahmed Saima , Fatou Benoit , Steen Hanno , Conwell Darwin L. ,   on behalf of the Consortium for the Study of Chronic Pancreatitis, Diabetes, and Pancreatic Cancer##
Published: December 2020

Objectives

Endoscopic pancreatic function tests are used to diagnose pancreatic diseases and are a viable source for the discovery of biomarkers to better characterize pancreatic disorders. However, pancreatic fluid (PF) contains active enzymes that degrade biomolecules. Therefore, we tested how preservation methods and time to storage influence the integrity and quality of proteins and nucleic acids.

Methods

We obtained PF from 9 subjects who underwent an endoscopic pancreatic function test. Samples were snap frozen at the time of collection; after 1, 2, and 4 hours on ice; or after storage overnight at 4°C with or without RNase or protease inhibitors (PIs). Electrophoresis and mass spectrometry analysis determined protein abundance and quality, whereas nucleic acid integrity values determined DNA and RNA degradation.

Results

Protein degradation increased after 4 hours on ice and DNA degradation after 2 hours on ice. Adding PIs delayed degradation. RNA was significantly degraded under all conditions compared with the snap frozen samples. Isolated RNA from PF-derived exosomes exhibited similar poor quality as RNA isolated from matched PF samples.

Conclusions

Adding PIs immediately after collecting PF and processing the fluid within 4 hours of collection maintains the protein and nucleic acid integrity for use in downstream molecular analyses.
Albumin–to–Alkaline Phosphatase Ratio
Authors: Acikgoz Yusuf , Bal Oznur , Dogan Mutlu
Published: December 2020

Objectives

Neuroendocrine tumors (NETs) are very heterogeneous tumors. This study aimed to evaluate prognostic value of an albumin–to–alkaline phosphatase (ALP) ratio (AAPR) in well-differentiated NETs.

Methods

A total of 110 patients were included in this study. Albumin–to–alkaline phosphatase ratio was calculated by dividing albumin concentration (g/dL) to ALP level (U/L). Cutoff value for AAPR was determined by receiver operating characteristic analysis. Survival analysis was performed by Kaplan-Meier method with the log-rank test. A P value of less than 0.05 was considered statistically significant.

Results

The optimum cutoff value for AAPR was 0.028. Patients were divided into 2 groups as patients with AAPR of 0.028 or less (n = 22, 20%) and with AAPR of greater than 0.028 (n = 88, 80%). Patients with AAPR of greater than 0.028 had statistically longer overall survival compared with patients with 0.028 or less (not reached vs 96.8 months, P = 0.001). In addition, AAPR has been shown to be an independent prognostic factor for overall survival in multivariate analysis (hazard ratio, 3.99; 95% confidence interval, 1.26–12.61, P = 0.018).

Conclusions

Patients with higher AAPR had more favorable prognosis compared with patients with lower AAPR. We demonstrated that AAPR can be of prognostic value in well-differentiated NETs.
Survival Outcomes of Adjuvant Chemotherapy Combined With Radiation Versus Chemotherapy Alone After Pancreatectomy for Distal Pancreatic Adenocarcinoma
Authors: Batukbhai Bhavina , Herman Joseph M. , Zahurak Marianna , Laheru Daniel A. , Le Dung T. , Wolfgang Christopher Lee , Zheng Lei , De Jesus-Acosta Ana
Published: December 2020

Objective

We evaluated survival outcomes in patients with distal pancreatic ductal adenocarcinoma (D-PDAC) after distal pancreatectomy (DP) and adjuvant chemotherapy or chemoradiation.

Methods

A retrospective analysis of patients who underwent DP for D-PDAC from 2000 to 2015 at the Johns Hopkins Hospital was performed. Demographics, baseline risk factors, and type of adjuvant treatment were assessed for associations with overall survival (OS) and disease-free survival (DFS). Comparisons were made with log-rank tests and Cox proportional hazards regression models.

Results

A total of 294 patients underwent DP for D-PDAC. Of these, 105 patients were followed at the Johns Hopkins Hospital. Forty-five patients received chemotherapy only and 60 patients received chemoradiation. The median OS with chemoradiation was 33.6 months and 27.9 months (P = 0.54) with chemotherapy only. The median DFS was 15.3 months with chemoradiation and 19.8 months with chemotherapy only (P = 0.89). Elevated carbohydrate antigen 19-9, stage II to III disease, splenic vein involvement, and vascular invasion were significant risk factors in multivariate analyses.

Conclusions

In this retrospective analysis, there were no significant differences in OS or DFS with chemoradiation compared with chemotherapy alone after DP in patients with D-PDAC.
Treatment Strategies for Children With Relapsed Pancreatoblastoma: A Literature Review
Authors: Reggiani Giulia , Affinita Maria C. , Dall’Igna Patrizia , Virgone Calogero , Sorbara Silvia , Bisogno Gianni
Published: December 2020

Pancreatoblastoma (PB) is a tumor typically seen in childhood. Despite its rarity, there are some internationally agreed recommendations for its first-line treatment, but very little is known about the management of relapse. We reviewed the literature on the treatment and outcome of children with progressing/recurrent PB, and the role of high-dose chemotherapy (HD-CT) or liver transplantation in difficult cases. A first analysis concerned 15 patients: liver metastases were the most frequent cause of first-line treatment failure. Eight patients underwent surgery, only 3 were irradiated. Various second-line chemotherapy regimens were adopted, with evidence of response in 8 children. The most often-used combinations included etoposide, cyclophosphamide/ifosfamide, and cisplatin/carboplatin. Overall, 7 patients are alive with a median follow-up of 24 months (range, 3 to 88 mo). In a separate analysis, considering patients in first-line or second-line treatment, we found 5 of 6 patients alive after HD-CT and 3 of 3 after liver transplantation. Our review shows that the outcome for patients with recurrent PB is not always dismal, especially when surgery is possible. Different chemotherapy combinations can be used, and HD-CT or liver transplantation may be considered in selected cases.
Long-Term TDF-Inclusive ART and Progressive Rates of HBsAg Loss in HIV-HBV Coinfection—Lessons for Functional HBV Cure?
Authors: Audsley Jennifer , Avihingsanon Anchalee , Littlejohn Margaret , Bowden Scott , Matthews Gail V. , Fairley Christopher K. , Lewin Sharon R. , Sasadeusz Joe
Published: December 2020

Background:

Tenofovir disoproxil fumarate (TDF) is effective in suppressing HIV and hepatitis B virus (HBV) replication in HIV-HBV coinfection although HBV DNA can persist in some individuals on TDF-containing antiretroviral therapy (ART). We initiated a prospective longitudinal study to determine durability of HBV virological control and clinical outcomes after prolonged TDF-based ART in HIV-HBV coinfection.

Methods:

Ninety-two HIV-HBV coinfected participants on, or about to commence, TDF-containing ART from Australia (n = 41) and Thailand (n = 52) were enrolled. Participants were followed 6-monthly for 2 years, then annually to 5 years. Laboratory and clinical assessments and a serum sample were collected at each study visit. These analyses compare follow-up at 2 and 5 years.

Results:

12.0% (95% confidence interval 6.8 to 20.2) of total study entry cohort (n = 92) or 15.3% (95% confidence interval: 8.8 to 25.3) of those with data to year 5 (n = 72) lost hepatitis B surface antigen (HBsAg). The only statistically significant association with HBsAg loss was lower study entry quantitative HBsAg. CD4 T-cell count increased by a median 245 cells/mm3 between the preTDF sample and 5 years of follow-up. By year 5, 98.5% of the cohort had undetectable HBV DNA (<15 IU/mL) and 91.4% had undetectable HIV RNA (<20 copies/mL).

Conclusions:

HBsAg loss was high and ongoing over 5 years of follow-up in HIV-HBV coinfected individuals on TDF-containing ART and undetectable HBV was almost universal. Although the pattern of HBsAg loss temporarily parallels immune reconstitution, we could not identify predictive immune markers. The high rate of HBsAg loss in HIV-HBV coinfection may offer valuable insights into the search for a functional HBV cure.
The Risk of Presarcopenia Is Increased Among Female Patients With Primary Sjögren’s Syndrome
Authors: Colak Seda , Tekgoz Emre , Hayme Serhat , Sonaeren Ilknur , Cinar Muhammet , Yilmaz Sedat
Published: December 2020

Objectives

Sarcopenia is a progressive and generalized loss of muscle mass and function. The aim of this study was to evaluate the frequency of sarcopenia among patients with primary Sjögren’s syndrome (SS) and the factors related with sarcopenia.

Methods

Forty-four female patients with primary SS and 44 female control subjects were included in this cross-sectional study between February and August 2019. Sarcopenia was evaluated by the handgrip test, Skeletal Muscle Mass Index, and gait speed test.

Results

Eleven patients (25.0%) had presarcopenia in the SS group and 2 (4.5%) in the control group (p = 0.007). Compared with control subjects, SS patients had lower results of hand grip and gait speed tests (p = 0.005 and p < 0.001, respectively). According to the Mini Nutritional Assessment Short Form, patients with presarcopenia had higher risk of malnutrition compared with patients without sarcopenia (p = 0.043). Patients with presarcopenia had higher scores in the European League Against Rheumatism Sjögren’s Syndrome Patient-Reported Index pain domain and patient visual analog scale for global disease activity compared with patients without sarcopenia (p = 0.044 and p = 0.036, respectively). In multivariate regression analysis, European League Against Rheumatism Sjögren’s Syndrome Patient-Reported Index pain was associated with hand grip strength (p = 0.016, R
2 = 0.13) and Mini Nutritional Assessment Short Form was associated with Skeletal Muscle Mass Index (p = 0.005).

Conclusions

Risk of sarcopenia is increased in patients with SS. Pain and malnutrition may contribute to presarcopenia. Evaluating pain and patient's global disease activity may help physicians to determine patients with increased risk of sarcopenia. Controlling disease activity and pain and preventing malnutrition may reduce the risk of development of sarcopenia.
Plasmonic modes in cylindrical nanoparticles and dimers
Authors: Downing Charles A. , Weick Guillaume
Published: December 2020

We present analytical expressions for the resonance frequencies of the plasmonic modes hosted in a cylindrical nanoparticle within the quasi-static approximation. Our theoretical model gives us access to both the longitudinally and transversally polarized dipolar modes for a metallic cylinder with an arbitrary aspect ratio, which allows us to capture the physics of both plasmonic nanodisks and nanowires. We also calculate quantum mechanical corrections to these resonance frequencies due to the spill-out effect, which is of relevance for cylinders with nanometric dimensions. We go on to consider the coupling of localized surface plasmons in a dimer of cylindrical nanoparticles, which leads to collective plasmonic excitations. We extend our theoretical formalism to construct an analytical model of the dimer, describing the evolution with the inter-nanoparticle separation of the resultant bright and dark collective modes. We comment on the renormalization of the coupled mode frequencies due to the spill-out effect, and discuss some methods of experimental detection.
Fibrous gels modelled as fluid-filled continua with double-well energy landscape
Authors: Sun Chuanpeng , Chernysh Irina N. , Weisel John W. , Purohit Prashant K.
Published: December 2020

Several biological materials are fibre networks infused with fluid, often referred to as fibrous gels. An important feature of these gels is that the fibres buckle under compression, causing a densification of the network that is accompanied by a reduction in volume and release of fluid. Displacement-controlled compression of fibrous gels has shown that the network can exist in a rarefied and a densified state over a range of stresses. Continuum chemo-elastic theories can be used to model the mechanical behaviour of these gels, but they suffer from the drawback that the stored energy function of the underlying network is based on neo-Hookean elasticity, which cannot account for the existence of multiple phases. Here we use a double-well stored energy function in a chemo-elastic model of gels to capture the existence of two phases of the network. We model cyclic compression/decompression experiments on fibrous gels and show that they exhibit propagating interfaces and hysteretic stress–strain curves that have been observed in experiments. We can capture features in the rate-dependent response of these fibrous gels without recourse to finite-element calculations. We also perform experiments to show that certain features in the stress–strain curves of fibrous gels predicted by our model can be found in the compression response of blood clots. Our methods may be extended to other tissues and synthetic gels that have a fibrous structure.
Baffling: a condition-dependent alternative mate attraction strategy using self-made tools in tree crickets
Authors: Deb Rittik , Modak Sambita , Balakrishnan Rohini
Published: December 2020

Intense sexual selection in the form of mate choice can facilitate the evolution of different alternative reproductive strategies, which can be condition-dependent. Tree cricket males produce long-distance acoustic signals which are used by conspecific females for mate localization and mate choice. Our study shows that baffling, an acoustic call amplification strategy employed by male tree crickets using self-made tools, is a classic example of a condition-dependent alternative strategy. We show that though most males can baffle, less preferred males, such as smaller and lower-amplitude callers, predominantly use this alternative strategy. Baffling allows these males to increase their call amplitude and advertisement range, which attracts a higher number of females. Baffling also gives these males a mating benefit because females mate for longer durations with them. Our results suggest that the advantage of baffling in terms of gain in the number of sperm cells transferred while mating is primarily limited to less preferred males, thus maintaining the polymorphism of calling strategies in the population. We summarize that baffling is a condition-dependent strategy used by less preferred tree cricket males to obtain mating benefits.
Amoebocytes facilitate efficient carbon and nitrogen assimilation in theCassiopea-Symbiodiniaceae symbiosis
Authors: Lyndby Niclas Heidelberg , Rädecker Nils , Bessette Sandrine , Søgaard Jensen Louise Helene , Escrig Stéphane , Trampe Erik , Kühl Michael , Meibom Anders
Published: December 2020

The upside-down jellyfishCassiopeaengages in symbiosis with photosynthetic microalgae that facilitate uptake and recycling of inorganic nutrients. By contrast to most other symbiotic cnidarians, algal endosymbionts inCassiopeaare not restricted to the gastroderm but are found in amoebocyte cells within the mesoglea. While symbiont-bearing amoebocytes are highly abundant, their role in nutrient uptake and cycling inCassiopearemains unknown. By combining isotopic labelling experiments with correlated scanning electron microscopy, and Nano-scale secondary ion mass spectrometry (NanoSIMS) imaging, we quantified the anabolic assimilation of inorganic carbon and nitrogen at the subcellular level in juvenileCassiopeamedusae bell tissue. Amoebocytes were clustered near the sub-umbrella epidermis and facilitated efficient assimilation of inorganic nutrients. Photosynthetically fixed carbon was efficiently translocated between endosymbionts, amoebocytes and host epidermis at rates similar to or exceeding those observed in corals. TheCassiopeaholobionts efficiently assimilated ammonium, while no nitrate assimilation was detected, possibly reflecting adaptation to highly dynamic environmental conditions of their natural habitat. The motile amoebocytes allowCassiopeamedusae to distribute their endosymbiont population to optimize access to light and nutrients, and transport nutrition between tissue areas. Amoebocytes thus play a vital role for the assimilation and translocation of nutrients inCassiopea, providing an interesting new model for studies of metabolic interactions in photosymbiotic marine organisms.
Characterization of human embryonic stem cells in animal component-free medium
Authors: Machida Masakazu , Abutani Rie , Miyajima Hiroshi , Sasaki Tetsuji , Abe Yoshiko , Akutsu Hidenori , Umezawa Akihiro
Published: December 2020

Clinical use of human embryonic stem cells (ESCs) as a raw material requires good manufacturing practice-compliant axillary materials such as culture medium. To this end, animal components should not be used and contamination of virus/bacteria/fungus and allergens are a concern. In addition, animal components such as albumin and fetal bovine serum pose difficulties such as a lot-to-lot variation. However, only a limited number of animal component-free media have been developed to date. In this study, we investigated whether SEES2 ESCs can be stably propagated for 16 passages (54 population doublings) over a period of 60 days in a newly established Stem-Partner®ACF medium. SEES2 ESC maintained their intact karyotype, i.e. 46,XX, and their undifferentiated phenotypes after long-term culture. An in vitro differentiation assay revealed that SEES2 ESCs exhibited multipotency, i.e. endodermal, mesodermal and ectodermal differentiation. Subcutaneous implantation of SEES2 ESCs generated mature teratomas without malignant transformation. These results show that SEES2 ESCs in the Stem-Partner®ACF medium can be used to establish master cell banks for future regenerative medicine as well as other ESCs in the previously reported culture medium.
Complex eco-evolutionary dynamics induced by the coevolution of predator-prey movement strategies
Authors: Netz Christoph , Hildenbrandt Hanno , Weissing Franz J.
Published: December 2020

The coevolution of predators and prey has been the subject of much empirical and theoretical research, which has produced intriguing insights into the intricacies of eco-evolutionary dynamics. Mechanistically detailed models are rare, however, because the simultaneous consideration of individual-level behaviour (on which natural selection is acting) and the resulting ecological patterns is challenging and typically prevents mathematical analysis. Here we present an individual-based simulation model for the coevolution of predators and prey on a fine-grained resource landscape. Throughout their lifetime, predators and prey make repeated movement decisions on the basis of heritable and evolvable movement strategies. We show that these strategies evolve rapidly, inducing diverse ecological patterns like spiral waves and static spots. Transitions between these patterns occur frequently, induced by coevolution rather than by external events. Regularly, evolution leads to the emergence and stable coexistence of qualitatively different movement strategies. Although the strategy space considered is continuous, we often observe discrete variation. Accordingly, our model includes features of both population genetic and quantitative genetic approaches to coevolution. The model demonstrates that the inclusion of a richer ecological structure and higher number of evolutionary degrees of freedom results in even richer eco-evolutionary dynamics than anticipated previously.
Specialized coding patterns among dorsomedial prefrontal neuronal ensembles predict conditioned reward seeking
Authors: Grant Roger I. , Doncheck Elizabeth M. , Vollmer Kelsey M. , Winston Kion T. , Romanova Elizaveta V. , Siegler Preston N. , Bowen Christopher W. , Otis James M.
Published: December 2020

Non-overlapping cell populations within dorsomedial prefrontal cortex (dmPFC), defined by gene expression or projection target, control dissociable aspects of reward seeking through unique activity patterns. However, even within these defined cell populations considerable cell-to-cell variability is found, suggesting that greater resolution is needed to understand information processing in dmPFC. Here we use two-photon calcium imaging in awake, behaving mice to monitor the activity of dmPFC excitatory neurons throughout Pavlovian sucrose conditioning. We characterize five unique neuronal ensembles that each encode specialized information related to a reward, reward-predictive cues, and behavioral responses to reward-predictive cues. The ensembles differentially emerge across learning – and stabilize after learning – in a manner that improves the predictive validity of dmPFC activity dynamics for deciphering variables related to behavioral conditioning. Our results characterize the complex dmPFC neuronal ensemble dynamics that relay learning-dependent signals for prediction of reward availability and initiation of conditioned reward seeking.
Regional and age-dependent Effects of Cortical Magnetic Stimulation on Unconstrained Reaching Behavior
Authors: Urbin M.A. , Tian Jing , McKernan Gina P. , Kortzorg Nick , Wyers Lore , van Halewijck Florian , Boisgontier Matthieu P. , Levin Oron , Swinnen Stephan P. , Jonkers Ilse , Wittenberg George F.
Published: December 2020

Background

The specific and dynamic contributions of premotor and supplementary motor areas to reaching movements in aging humans are not well understood.

Objective

To better understand the role of cortical motor regions and age on the control of unconstrained reaches against gravity by neurologically intact, younger and older adults.

Methods

Double pulse transcranial magnetic stimulation (TMS) was applied at locations targeting primary motor cortex (M1), dorsal premotor area (PMA), supplementary motor area (SMA), or dorsolateral prefrontal cortex (DLPFC). Paired stimuli were delivered before or after a visual cue was presented to initiate self-paced right-handed reaches to one of three, vertically oriented target locations.

Results

Regional stimulation effects on movement amplitude were observed both early and late in the reach. PMA stimulation increased reach distance to a greater extent than M1, SMA, and DLPFC stimulation. M1 and PMA stimulation increased deviation from the straight-line path around the time of peak velocity to an extent that was greater than SMA and DLPFC stimulation. Cortical stimulation increased the time that elapsed after, but not before, peak velocity. Despite stronger effects of stimulation on reaches in the younger group, this group had shorter times to reach the target after reaching peak velocity.

Conclusion

These results provide support for a role of PMA in visually guided movementaftermovement initiation. For older subjects, the increased time to arrive at the target after peak velocity despite weaker stimulation effects suggests an age-related reduction in sensorimotor processing flexibility for online control of unconstrained reaching.

Highlights

Dorsal premotor area stimulation at any time during the reaction-time period and early reaching affected early reach kinematics at least as much as stimulation of primary motor cortex.

Older individuals had more stimulation-related interference in the late components of reaching despite having less early effect of stimulation, suggesting a reduction in flexibility of dynamic motor control due to aging.

The antigravity component of unconstrained reaching did not have special aspects for regional cortical effects of stimulation.
The interaction of curiosity and reward on long-term memory in younger and older adults
Authors: Swirsky Liyana T. , Shulman Audrey , Spaniol Julia
Published: December 2020

Long-term memory is sensitive to both intrinsic and extrinsic motivation, but little is known about the relative influence of these two sources of motivation on memory performance across the adult lifespan. The study examined the effects of extrinsic motivation, manipulated via monetary reward, and curiosity, a form of intrinsic motivation, on long-term memory in healthy younger and older adults. During the incidental encoding phase on Day 1, 60 younger and 53 older participants viewed high- and low-curiosity trivia items as well as unrelated face stimuli. Half of the participants in each age group received financial rewards for correctly guessing trivia answers. On Day 2, participants completed a trivia recall test and an old-new recognition test for the face stimuli. Both curiosity and reward were associated with enhanced trivia recall, but the effects were interactive, such that only low-curiosity items benefitted from monetary reward. Neither curiosity nor reward affected face recognition performance in either age group. These findings indicate that individual and joint effects of intrinsic and extrinsic motivation on long-term memory are relatively preserved in healthy aging, a finding that highlights the viability of motivational strategies for memory enhancement into old age. Identifying conditions under which memory for unrelated information benefits from motivational spillover effects in younger and older adults is a priority for future research.
SARS-CoV-2 Requires Cholesterol for Viral Entry and Pathological Syncytia Formation
Authors: Sanders David W. , Jumper Chanelle C. , Ackerman Paul J. , Bracha Dan , Donlic Anita , Kim Hahn , Kenney Devin , Castello-Serrano Ivan , Suzuki Saori , Tamura Tomokazu , Tavares Alexander H. , Saeed Mohsan , Holehouse Alex S. , Ploss Alexander , Levental Ilya , Douam Florian , Padera Robert F. , Levy Bruce D. , Brangwynne Clifford P.
Published: December 2020

Many enveloped viruses induce multinucleated cells (syncytia), reflective of membrane fusion events caused by the same machinery that underlies viral entry. These syncytia are thought to facilitate replication and evasion of the host immune response. Here, we report that co-culture of human cells expressing the receptor ACE2 with cells expressing SARS-CoV-2 spike, results in synapse-like intercellular contacts that initiate cell-cell fusion, producing syncytia resembling those we identify in lungs of COVID-19 patients. To assess the mechanism of spike/ACE2-driven membrane fusion, we developed a microscopy-based, cell-cell fusion assay to screen ∼6000 drugs and >30 spike variants. Together with cell biological and biophysical approaches, the screen reveals an essential role for membrane cholesterol in spike-mediated fusion, which extends to replication-competent SARS-CoV-2 isolates. Our findings provide a molecular basis for positive outcomes reported in COVID-19 patients taking statins, and suggest new strategies for therapeutics targeting the membrane of SARS-CoV-2 and other fusogenic viruses.

Highlights

Cell-cell fusion at ACE2-spike clusters cause pathological syncytia in COVID-19

Drug screen reveals critical role for membrane lipid composition in fusion

Spike’s unusual membrane-proximal cysteines and aromatics are essential for fusion

Cholesterol tunes relative infectivity of SARS-CoV-2 viral particles
DeepCellState: an autoencoder-based framework for predicting cell type-specific transcriptional states induced by drug treatment
Authors: Umarov Ramzan , Li Yu , Arner Erik
Published: December 2020

Drug treatment induces cell type-specific transcriptional programs, and as the number of combinations of drugs and cell types grows, the cost for exhaustive screens measuring the transcriptional drug response becomes intractable. We developed DeepCellState, a deep learning autoencoder-based framework, for predicting the induced transcriptional state in a cell type after drug treatment, based on the drug response in another cell type. Training the method on a large collection of transcriptional drug perturbation profiles, prediction accuracy improves significantly over baseline and alternative deep learning approaches when applying the method to two cell types, with improved accuracy when generalizing the framework to additional cell types. Treatments with drugs or whole drug families not seen during training are predicted with similar accuracy, and the same framework can be used for predicting the results from other interventions, such as gene knock-downs. Finally, analysis of the trained model shows that the internal representation is able to learn regulatory relationships between genes in a fully data-driven manner.
Structure-guided microbial targeting of antistaphylococcal prodrugs
Authors: Miller Justin J. , Shah Ishaan T. , Hatten Jayda , Barekatain Yasaman , Mueller Elizabeth A. , Moustafa Ahmed M. , Edwards Rachel L. , Dowd Cynthia S. , Planet Paul J. , Muller Florian L. , Jez Joseph M. , Odom John Audrey R.
Published: December 2020

Carboxy ester prodrugs have been widely employed as a means to increase oral absorption and potency of phosphonate antibiotics. Prodrugging can successfully mask problematic chemical features that prevent cellular uptake and can be used to target delivery of compounds to specific tissues. However, many carboxy ester promoieties are rapidly hydrolyzed by serum esterases, curbing their potential therapeutic applications. While carboxy ester-based prodrug targeting is feasible, it has seen limited use in microbes due to a paucity of information about the selectivity of microbial esterases. Here we identify the bacterial esterases, GloB and FrmB, that are required for carboxy ester prodrug activation inStaphylococcus aureus.Additionally, we determine the substrate specificities for FrmB and GloB and demonstrate the structural basis of these preferences. Finally, we establish the carboxy ester substrate specificities of human and mouse sera, which revealed several promoieties likely to be serum esterase-resistant while still being microbially labile. These studies lay the groundwork for structure-guided design of anti-staphyloccal promoieties and expand the range of molecules to target staphyloccal pathogens.
IFT88 transports Gucy2d, a guanylyl cyclase, to maintain sensory cilia function inDrosophila
Authors: Werner Sascha , Zitouni Sihem , Okenve-Ramos Pilar , Mendonça Susana , Sporbert Anje , Spalthoff Christian , Göpfert Martin C. , Jana Swadhin Chandra , Bettencourt-Dias Mónica
Published: December 2020

Cilia are involved in a plethora of motility and sensory-related functions. Ciliary defects cause several ciliopathies, some of which with late-onset, suggesting cilia are actively maintained. While much is known about cilia assembly, little is understood about the mechanisms of their maintenance. Given that intraflagellar transport (IFT) is essential for cilium assembly, we investigated the role of one of its main players, IFT88, in ciliary maintenance. We show that DmIFT88, theDrosophila melanogaster orthologue of IFT88, continues to move along fully formed sensory cilia, and that its acute knockdown in the ciliated neurons of the adult affects sensory behaviour. We further identify DmGucy2d, theDrosophilaguanylyl cyclase 2d, as a DmIFT88 cargo, whose loss also leads to defects in sensory behaviour maintenance. DmIFT88 binds to the intracellular part of DmGucy2d, which is evolutionarily conserved and mutated in several degenerative retina diseases, taking the cyclase into the cilia. Our results offer a novel mechanism for the maintenance of sensory cilia function and its potential role in human diseases.
Cell-derived hexameric β-amyloid: a novel insight into composition, self-assembly and nucleating properties
Authors: Vadukul Devkee M. , Vrancx Céline , Burguet Pierre , Contino Sabrina , Suelves Nuria , Serpell Louise C , Quinton Loïc , Kienlen-Campard Pascal
Published: December 2020

A key hallmark of Alzheimer’s disease (AD) is the extracellular deposition of amyloid plaques composed primarily of the amyloidogenic amyloid-β (Aβ) peptide. The Aβ peptide is a product of sequential cleavage of the Amyloid Precursor Protein (APP), the first step of which gives rise to a C-terminal Fragment (C99). Cleavage of C99 by γ-secretase activity releases Aβ of several lengths and the Aβ42 isoform in particular has been identified as being neurotoxic. The misfolding of Aβ leads to subsequent amyloid fibril formation by nucleated polymerisation. This requires an initial and critical nucleus for self-assembly. Here, we identify and characterise the composition and self-assembly properties of cell-derived hexameric Aβ42 and show its nucleating properties which are dependent on the Aβ monomer availability. Identification of nucleating assemblies that contribute to self-assembly in this way may serve as therapeutic targets to prevent the formation of toxic oligomers.
Restriction enzyme selection dictates detection range sensitivity in chromatin conformation capture-based variant-to-gene mapping approaches
Authors: Su Chun , Pahl Matthew C. , Grant Struan F. A. , Wells Andrew D.
Published: December 2020

Promoter-focused chromatin conformation techniques directly detect interactions between gene promoters and distal genomic sequences, providing structural information relevant to gene regulation without the excessive non-genic architectural data generated by full scale Hi-C. 3D promoter ‘interactome’ maps are crucial for understanding how epigenomic features like histone modifications and open chromatin, or genetic variants identified in genome wide association studies (GWAS), contribute to biological function. However, variation in sensitivity between such promoter-focused methods, principally due to restriction enzyme selection, has not been systematically assessed. Here, we performed a head-to-head comparison between promoter capture C (PCC) and promoter capture Hi-C (PCHiC) with the respective 4 cutters DpnII and MboI versus 6 cutter HindIII datasets from the same five cell types. While PCHiC generally produces a higher signal to noise ratio for significant interactions in comparison to PCC, we show that DpnII/MboI detects more proximal interactions and shows little overlap with the HindIII detection range. Promoter-interacting genomic regions mapped by 4-cutters are more enriched for regulatory features and disease-associated genetic variation than 6-cutters maps, suggesting that high-resolution maps better capture gene regulatory architectures than do lower resolution approaches.
Strain depth profiles in thin films extracted from in-plane X-ray diffraction
Authors: Cancellieri Claudia , Ariosa Daniel , Druzhinin Aleksandr V. , Unutulmazsoy Yeliz , Neels Antonia , Jeurgens Lars P.H.
Published: December 2020

Thin films generally contain depth-dependent residual stress gradients, which influence their functional properties and stability in harsh environments. An understanding of these stress gradients and their influence is crucial for many applications. Standard methods for thin-film stress determination only provide average strain values, thus disregarding possible variation in strain/stress across the film thickness. This work introduces a new method to derive depth-dependent strain profiles in thin films with thicknesses in the submicrometre range by laboratory-based in-plane grazing X-ray diffraction, as applied to magnetron-sputtering-grown polycrystalline Cu thin films with different thicknesses. By performing in-plane grazing diffraction analysis at different incidence angles, the in-plane lattice constant depth profile of the thin film can be resolved through a dedicated robust data processing procedure. Owing to the underlying intrinsic difficulties related to the inverse Laplace transform of discrete experimental data sets, four complementary procedures are presented to reliably extract the strain depth profile of the films from the diffraction data. Surprisingly, the strain depth profile is not monotonic and possesses a complex shape: highly compressive close to the substrate interface, more tensile within the film and relaxed close to the film surface. The same strain profile is obtained by the four different data evaluation methods, confirming the validity of the derived depth-dependent strain profiles as a function of the film thickness. Comparison of the obtained results with the average in-plane stresses independently derived by the standard stress analysis method in the out-of-plane diffraction geometry validates the solidity of the proposed method.
Network control and balanced scorecard as inscriptions in purchaser–provider arrangements: insights from a hybrid government agency
Authors: Zawawi Nur Haiza Muhammad , Hoque Zahirul
Published: December 2020

Purpose

This article examines the power of management control mechanisms as “inscriptions” for bringing the interests of organisations within a purchaser–provider network into alignment.

Design/methodology/approach

The study contributes to accounting and accountability literature in hybrid organisations by applying actor-network theory to a case study organisation. This enables an analysis of how a government agency, operating as a social service provider to the community, developed and used management control mechanisms in its intra-organisational units to ensure its operations were aligned with the expectations of inter-organisational networks in a purchaser–provider context. Data were collected using open-ended interviews and by examining internal accounting and management reports, government archival records and newspaper articles.

Findings

Analysis of the results demonstrates that inter-organisational network control was internalised within the provider organisation because of the ability of the controls to function as inscriptions that influenced organisational actions. The authors conclude that the network control travelled across boundaries over time and was assimilated by the provider organisation to become its internal management control mechanisms.

Research limitations/implications

A single case study of a government service provider agency may limit the generalisation of the findings to other hybrid entities or networks. The significant practical essence of this study lies in the diversity within the results that offer a rich representation of the impact of purchaser–provider arrangements on internal organisational systems within a hybrid public sector setting.

Originality/value

The outcomes enhance knowledge of how a hybrid government agency developed, mobilised and institutionalised its management control mechanisms to ensure the activities of one party are consistent with the other parties' expectations within a network.
Fake it or make it: employee well-being in emotional work settings
Authors: Mehta Poonam
Published: December 2020

Purpose

The objective of the present study is to measure the well-being of employees who are engaged in frontline roles and actively engrossed in frequent regulation and management of emotions while performing interpersonal interactions. The study has conceptualised the comprehensive model to measure employee well-being with three work-related dimensions, namely work engagement, burnout and job satisfaction in emotional work settings.

Design/methodology/approach

The study has been conducted on employees of the civil aviation industry in North India working on various frontline profiles. Data have been collected from 600 employees through a pretested questionnaire, and structural equation modelling (SEM) has been performed to test the hypothesis.

Findings

The findings of the study have revealed that all three dimensions, namely work engagement, burnout and job satisfaction are statistically significant measures of employee well-being in emotional work settings. Also, the study has determined that employees are highly satisfied and engaged at work despite having a feeling of burnout.

Research limitations/implications

The study has enriched the literature by presenting and analysing a comprehensive model of employee well-being in emotional work settings of the civil aviation industry.

Practical implications

The study will aid the various service industries in the framing of the intervention and training programs, which would help in promoting the well-being of employees who are specifically engaged in emotional work.

Social implications

The study is very substantial in offering various parameters over which national well-being policies for individuals can be framed.

Originality/value

Priorly, very few studies have attempted to recognise the role of the aforementioned variables in emotional work settings in a comprehensive manner. Further, the study has emphasised the unrecognised role of job satisfaction and work engagement where burnout is prevailing due to the presence of high emotional job demands.