bluuebunny/crossref_metadata_2025 huggingface dataset:
Impact of Histopathologic Changes Induced by Polyethylene Glycol Hydrogel Pleural Sealants Used During Transthoracic Biopsy on Lung Cancer Resection Specimen Staging
Authors: Butnor Kelly J. , Bodolan Adina A. , Bryant Britni R.E. , Schned Alan
Published: October 2019

Patients undergoing transthoracic needle core lung biopsy (TTNB) are at risk for biopsy-related pneumothorax. Instilling pleural sealant at the pleural puncture site reduces this risk. The impact of histologic changes associated with pleural sealant on assessing the histologic type and pathologic stage in lung cancer resection specimens has not been previously evaluated. All lung cancer resection specimens from 2015 to 2018 in which polyethylene glycol hydrogel pleural sealant was instilled during TTNB were reviewed. Thirty-three cases were identified. TTNB preceded lobectomy by an average of 35 days. Amphophilic, weakly polarizable, crinkled pleural sealant material was associated with tumor in 11 cases (33%), including 8 adenocarcinomas, 2 squamous cell carcinomas, and 1 pleomorphic carcinoma that averaged 1.7 cm in greatest dimension. Surrounding the sealant material was a 0.25 to 1.0 cm in greatest dimension pseudocystic space with a thin granulomatous rim of macrophages and multinucleated giant cells that occupied on average 17% of the tumoral area. Pleural sealant could have impaired assessment of pathologic stage in 1 case by obscuring the visceral pleural elastic layer, but definitive visceral pleural invasion was present nearby. Although hydrogel pleural sealant instilled during TTNB has the potential to obscure important histologic features, in practice, it appears to have little or no adverse impact on the assessment of histologic type and pathologic stage in subsequent lung cancer resection specimens. Recognition of the histologic appearance of hydrogel pleural sealant and its associated tissue response is important for avoiding diagnostic misinterpretation.
Evaluation of Intraarterial Thrombolysis in Treatment of Cosmetic Facial Filler-Related Ophthalmic Artery Occlusion
Authors: Zhang Li-xia , Lai Lin-ying , Zhou Gui-wen , Liang Li-ming , Zhou Yun-chao , Bai Xin-yue , Dai Qiang , Yu You-tao , Tang Wei-qiang , Chen Min-liang
Published: October 2019

Background:

With an increase in recent years in the number of people receiving cosmetic facial injection treatments of hyaluronic acid, the incidence of hyaluronic acid embolism has also increased commensurately. Hyaluronic acid embolism leads to serious complications, including blindness, eye and eyelid movement disorders, skin necrosis, and cerebral embolism. However, there is a lack of robust clinical evidence regarding the benefits of treatment for hyaluronic acid embolism by intraarterial thrombolysis therapy.

Methods:

This study included 24 patients with a decrease in visual acuity and other complications induced by facial hyaluronic acid injection. Patients underwent emergency intraarterial thrombolysis therapy by injection of hyaluronidase (500 to 1500 units) alone or hyaluronidase (750 to 1500 units) combined with urokinase (100,000 to 250,000 units), followed in both cases by a general symptomatic treatment and nutritional therapy.

Results:

Ten (42 percent) of 24 patients ultimately had improvements to visual acuity, even when the clinical application of the thrombolytic treatments had passed the recommended window for optimal treatment. In all cases, patients’ facial skin necrosis was restored to nearly normal appearance. In addition, the authors found that hyaluronidase combined with urokinase was a more effective therapy than hyaluronidase alone.

Conclusions:

The authors’ results indicate that intraarterial thrombolysis therapy is beneficial to patients suffering from blindness induced by hyaluronic acid embolism. The therapy was shown to be worthy of clinical application because it alleviated the impairment to patients’ vision and was also beneficial in the recovery from other serious complications, including eye movement disorder, eye edema, headaches, and skin necrosis.

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Therapeutic, IV.
The Relationship between Animation Deformity and Patient-Reported Outcomes: Application of the BREAST-Q to a Quantitative Stratification of Animation Severity
Authors: Fracol Megan , Qiu Cecil S. , Chiu Max Wen-Kuan , Feld Lauren N. , Sood Rachita , Mioton Lauren M. , Kearney Aaron , Kim John Y. S.
Published: October 2019

Background:

Animation deformity can occur following subpectoral breast reconstruction and is an oft-touted rationale for prepectoral reconstruction. Despite increasing recognition, there is a paucity of patient-reported outcome studies in women with animation deformity.

Methods:

Women presenting after subpectoral implant-based breast reconstruction were evaluated for animation deformity. Video analysis and quantitative deformity assessment were performed in conjunction with BREAST-Q surveys. BREAST-Q data were compared to our quantitative animation grading scale to assess the relationship between animation severity and patient-reported outcomes.

Results:

One hundred forty-one subpectoral breast reconstructions met inclusion criteria. Average scores were 67.8 ± 17.9 of 100 for satisfaction with breasts and 78.3 ± 14.1 of 100 for physical well-being. Animation deformity severity did not correlate with satisfaction with breasts (p = 0.44). Physical well-being, particularly pain-related questions, increased with increasing animation (p = 0.01); specifically, patients reported significantly less pulling, nagging, and aching in the breast (p = 0.01, p = 0.001, and p = 0.004, respectively). Patients with the least and most severe animation deformity had significantly higher numbers of revision procedures (0.89 and 1.03 procedures, respectively) compared with patients with intermediate deformity (0.49 procedures; p = 0.01 and p = 0.009, respectively).

Conclusions:

Although pectoralis release creates a more mobile—and more animating—reconstruction, this same release may lead to less pain because muscle is no longer contracting against a fixed space. This may lead to two distinct origins of subpectoral revision: (1) patients in pain (but low animation) and (2) patients with visibly distorted animation (but low pain).

CLINICAL QUESTION/LEVEL OF EVIDENCE:

Risk, II.
Development of a New Large-Animal Model for Composite Face and Whole-Eye Transplantation: A Novel Application for Anatomical Mapping Using Indocyanine Green and Liquid Latex
Authors: Bravo Miguel G. , Granoff Melisa D. , Johnson Anna Rose , Lee Bernard T.
Published: October 2019

Background:

Recent advances in the field of vascularized composite allotransplantation have revolutionized reconstructive surgery and demonstrated opportunity for restoration of orbital content and perhaps vision. The development of an animal model that would facilitate study of surgical technique, nerve regeneration, vision restoration, and immunosuppression is needed. The aim of this study is to describe three different large-animal cadaveric models suitable for composite face and whole-eye transplantation. In addition, the authors introduce a novel colored liquid latex and indocyanine green mixture for vasculature identification and visualization.

Methods:

The authors studied three different flap designs using cadaveric Yorkshire swine and modified them for face and whole-eye transplant harvest. Flaps harvested included a chimeric flap, a monobloc flap, and a bipedicled free flap. The authors injected selected vasculature with colored latex to better delineate vascular anatomy supplying the orbit and face. Indocyanine green was added to the latex solution to allow for visualization of the vascular supply using near-infrared imaging.

Results:

Colored latex and indocyanine green injections were successfully visualized in all cadaveric dissections. All three modified flap designs showed a well-defined and consistent vascular network within each face and whole-eye transplantation flap using laser-assisted near-infrared imaging.

Conclusions:

The authors present the feasibility of composite face and whole-eye transplantation models using a novel mixture of liquid latex and indocyanine green in a porcine cadaver. Further study in large animals is needed to appraise the surgical feasibility of this procedure and potential for clinically relevant outcomes, including vision restoration. The authors believe this study establishes a foundation for translation into live animal models for optic nerve regeneration.
Creating a Favorable Microenvironment for Fat Grafting in a Novel Model of Radiation-Induced Mammary Fat Pad Fibrosis
Authors: Truong Jessica L. , Liu Muhan , Tolg Cornelia , Barr Meredith , Dai Cecilia , Raissi Thomas C , Wong Eugene , DeLyzer Tanya , Yazdani Arjang , Turley Eva A.
Published: October 2019

Background:

Radiofibrosis of breast tissue compromises breast reconstruction by interfering with tissue viability and healing. Autologous fat transfer may reduce radiotherapy-related tissue injury, but graft survival is compromised by the fibrotic microenvironment. Elevated expression of receptor for hyaluronan-mediated motility (RHAMM; also known as hyaluronan-mediated motility receptor, or HMMR) in wounds decreases adipogenesis and increases fibrosis. The authors therefore developed RHAMM peptide mimetics to block RHAMM profibrotic signaling following radiation. They propose that this blocking peptide will decrease radiofibrosis and establish a microenvironment favoring adipose-derived stem cell survival using a rat mammary fat pad model.

Methods:

Rat mammary fat pads underwent a one-time radiation dose of 26 Gy. Irradiated (n = 10) and nonirradiated (n = 10) fat pads received a single intramammary injection of a sham injection or peptide NPI-110. Skin changes were examined clinically. Mammary fat pad tissue was processed for fibrotic and adipogenic markers using quantitative polymerase chain reaction and immunohistochemical analysis.

Results:

Clinical assessments and molecular analysis confirmed radiation-induced acute skin changes and radiation-induced fibrosis in rat mammary fat pads. Peptide treatment reduced fibrosis, as detected by polarized microscopy of picrosirius red staining, increased collagen ratio of 3:1, reduced expression of collagen-1 crosslinking enzymes lysyl-oxidase, transglutaminase 2, and transforming growth factor β1 protein, and increased adiponectin, an antifibrotic adipokine. RHAMM was expressed in stromal cell subsets and was downregulated by the RHAMM peptide mimetic.

Conclusion:

Results from this study predict that blocking RHAMM function in stromal cell subsets can provide a postradiotherapy microenvironment more suitable for fat grafting and breast reconstruction.
The Use of Higher Proportions of Platelet-Rich Plasma to Enrich Microfat Has Negative Effects: A Preclinical Study
Authors: Abellan Lopez Maxime , Bertrand Baptiste , Kober Frank , Boucekine Mohamed , De Fromont De Bouailles Marc , Vogtensperger Marie , Bernard Monique , Casanova Dominique , Magalon Jeremy , Sabatier Florence
Published: October 2019

Background:

Platelet-rich plasma improves engraftment after fat transfer. However, the effects of platelet dose have never been investigated. The authors used magnetic resonance imaging to compare surviving graft volumes in mice after administration of four different formulations (microfat alone, and three platelet-rich plasma–enriched microfat mixes).

Methods:

The authors used a random, double-blinded, fat transfer protocol using three different platelet levels: 1 million (low-dose), 500 million (medium-dose), and 1000 million (high-dose) platelets/ml, and fat alone (control). The authors grafted 0.4 ml of the 70/30 platelet-rich plasma–enriched microfat mixtures (0.4 million, 200 million, and 400 million platelets per 0.12 ml for the low-dose, medium-dose, and high-dose mixtures, respectively) or 0.4 ml of microfat alone into 22 nude mice and monitored surviving graft volumes every month for 3 months. Then, the authors histologically analyzed all grafts to assess neoangiogenesis status and fat integrity.

Results:

Three-dimensional magnetic resonance imaging showed that the median surviving graft volumes at 3 months were 9.5 percent (interquartile range, 0 to 25 percent; p = 0.003) (high-dose), 4.1 percent (interquartile range, 0 to 18 percent; p = 0.001) (medium-dose), and 18 percent (interquartile range, 8 to 38 percent; p = 0.41) (low-dose) compared to 36 percent (interquartile range, 28 to 53 percent) for the control value. The histologic integrity of microfat-alone grafts was significantly better than those of the other grafts, although the high-dose and low-dose grafts exhibited higher levels of neoangiogenesis.

Conclusion:

Higher platelet levels in microfat grafts were associated with poor graft survival in nude mice; a clinical review would be appropriate.
Oncoplastic Lower Eyelid Reconstruction Analysis
Authors: Orgun Doruk , Hayashi Ayato , Yoshizawa Hidekazu , Shimizu Azusa , Horiguchi Masatoshi , Mochizuki Mariko , Kamimori Tomoki , Aiba-Kojima Emiko , Mizuno Hiroshi
Published: October 2019

Background:

Oncoplastic lower eyelid reconstruction is a challenging task due to the complicated structure of the eyelid and requirement of high operative accuracy. Poorly treated defects result in ectropion and ptosis which may lead to keratitis and corneal ulceration. Previous related studies do not include a detailed comparison of the common reconstructive methods of the lower eyelid in terms of results and complication rates.

Objective:

The authors aim to demonstrate whether the choice of reconstruction affects the aesthetic and functional outcome of oncoplastic lower eyelid reconstruction.

Methods & Materials:

The authors performed a 10-year retrospective review of all oncoplastic lower eyelid reconstructions carried out in our hospital. Information on patient background, diagnosis and the choice of reconstructive method were evaluated. Postoperative photographs of each patient were then subjectively evaluated for color match, cosmesis, quality of shape, symmetry, and overall appearance. The authors hypothesized that the outcome is related to the main trajectory of the flap. Patients treated with local flaps of horizontal and vertical trajectories were then compared in terms of outcome and complication rates.

Results:

Reconstructions based on a horizontal trajectory compared with a vertical trajectory resulted with lower rates of ectropion and ptosis occurrence. The results were statistically significant.
Macrosteatotic Allografts and Obese Recipients Have Nearly Equal Negative Impact on Liver Transplant Survival
Authors: Northup Patrick G. , Intagliata Nicolas M. , Davis Jessica P.E. , Argo Curtis K. , Pelletier Shawn J.
Published: October 2019

Background.

Our aim was to evaluate liver transplant outcomes involving donors with high macrosteatosis grafts in the obese modern liver transplant recipient population.

Methods.

A high-steatosis graft was defined as donor graft macrosteatosis ≥30% on biopsy. Recipient obesity was defined as body mass index (BMI) >35 adjusted for ascites. Raw and adjusted recipient liver transplant survival were evaluated and compared between 4 cohorts: (1) high-steatosis graft in high-BMI recipient; (2) low-steatosis graft in high-BMI recipient; (3) high-steatosis graft in normal-BMI recipient; and (4) low-steatosis graft in normal-BMI recipient.

Results.

After adjustment for multiple factors, recipient high-BMI remained an independent predictor of posttransplant mortality at 30 days (P < 0.0001) and persisted at 1 year (P = 0.009). A high-steatosis graft was the strongest independent predictor of mortality at 30 days (hazard ratio 2.05, 1.66–2.53; P < 0.0001) and that effect was diminished but persistent at 1 year (1.27, 1.10–1.46; P = 0.001).

Conclusions.

Recipient high-BMI and a high-steatosis graft are both significant independent and equally powerful predictors of mortality after modern liver transplant. High-steatosis grafts transplanted into obese recipients have the highest mortality. The increase in mortality associated with a high-steatosis graft into a normal-BMI recipient is similar in magnitude to a low-steatosis graft placed into a high-BMI recipient.
Progress in rare central nervous system tumors
Authors: Penas-Prado Marta , Armstrong Terri S. , Gilbert Mark R.
Published: October 2019

Purpose of review

Although all primary central nervous system (CNS) tumors are rare, certain tumor types each represent less than 2% of the total and an annual incidence of about 1000 patients or less. Most of them are disproportionally diagnosed in children and young adults, but older adults can also be affected and are rarely recruited to clinical trials. Recent new molecular techniques have led to reclassification of some of these tumors and discovery of actionable molecular alterations.

Recent findings

We review recent progress in the molecular understanding and therapeutic options of selected rare CNS tumors, with a focus on select clinical trials (temozolomide and lapatinib for recurrent ependymoma; vemurafenib for BRAFV600E-mutated tumors), as well as tumor-agnostic approvals (pembrolizumab, larotrectinib) and their implications for rare CNS tumors.

Although rare CNS tumors are a very small fraction of the total of cancers, they represent a formidable challenge. There is a need for dedicated clinical trials with strong correlative component in patients of all ages with rare CNS tumors. Critical research questions include relevance of the selected target for specific tumor types, persistence of the actionable biomarker at recurrence, blood–brain barrier penetration, and analysis of mechanisms of primary and acquired resistance.
Complications associated with immunotherapy for brain metastases
Authors: Tran Thuy T. , Jilaveanu Lucia B. , Omuro Antonio , Chiang Veronica L. , Huttner Anita , Kluger Harriet M.
Published: October 2019

Purpose of review

Median survival after the diagnosis of brain metastases has historically been on the order of months. With the recent development of immune checkpoint inhibitors, intracranial activity and durable responses have been observed in brain metastases on multiple phase 2 clinical trials, which have primarily been conducted in patients with melanoma. Immune-related adverse events related to checkpoint inhibitor therapy of brain metastasis can present unique challenges for the clinician and underscore the need for a multidisciplinary team in the care of these patients. The goal of this review is to address the current knowledge, limitations of understanding, and future directions in research regarding immune therapy trials and neurologic toxicities based on retrospective, prospective, and case studies.

Recent findings

Immune therapy has the potential to exacerbate symptomatic edema and increase the risk of radiation necrosis in previously irradiated lesions. Neurologic toxicities will likely increase in prevalence as more patients with brain metastatic disease are eligible for immune therapy.

An improved understanding and heightened awareness of the unique neurologic toxicities that impact this patient group is vital for mitigating treatment-related morbidity and mortality.
New metabolic imaging tools in neuro-oncology
Authors: Corbin Zachary A.
Published: October 2019

Purpose of review

The current treatment of gliomas dovetails results of decades-old clinical trials with modern trends in chemotherapy. Molecular characterization now plays a pivotal role, and IDH mutations are key characteristics and the subject of active debate. IDH-mutant tumors produce the ‘onco-metabolite’, 2-hydroxyglutarate. Metabolic changes have become central to the understanding of tumor biology, and tumors display a fundamental metabolic change called the Warburg Effect. The Warburg Effect represents a preference for glycolysis, as opposed to oxidative phosphorylation. The present review details the clinical context and discusses clinical and preclinical metabolic imaging tools to characterize the Warburg Effect.

Recent findings

A clinical Warburg Index is proposed, defined as the lactate concentration measured by 1H-MRSI over the SUV measured by FDG-PET, to measure the Warburg Effect. A preclinical technique called deuterium metabolic imaging has successfully imaged the Warburg Effect in vivo in glioblastoma.

Metabolic imaging provides an opportunity to measure the Warburg Effect and other metabolic changes in brain tumors. An increased understanding of metabolic shifts integral to brain cancer has the potential to address multiple contemporary debates on glioma pathophysiology and treatment. Metabolic imaging tools thus have the potential to advance research findings, clinical trial development, and clinical care.
Humans falling in holes: adaptations in lower-limb joint mechanics in response to a rapid change in substrate height during human hopping
Authors: Dick Taylor J. M. , Punith Laksh K. , Sawicki Gregory S.
Published: October 2019

In getting from here to there, we continuously negotiate complex environments and unpredictable terrain. Our ability to stay upright in the face of obstacles, such as holes in the ground, is quite remarkable. However, we understand relatively little about how humans adjust limb mechanical behaviour to recover from unexpected perturbations. In this study, we determined how the joints of the lower-limb respond to recover from a rapid, unexpected drop in substrate height during human hopping. We recorded lower-limb kinematics and kinetics while subjects performed steady-state hopping at their preferred frequency on an elevated platform (5, 10 and 20 cm). At an unknown time, we elicited an unexpected perturbation (i.e. a hole in the ground) via the rapid removal of the platform. Based on previous research in bipedal birds, we hypothesized (i) that distal joints would play an increased role in fall recovery when compared to steady-state hopping, and (ii) that patterns of joint power redistribution would be more pronounced with increases in perturbation height. Our results suggest that humans successfully recover from falling in a hole by increasing the energy absorbed predominantly in distal lower-limb joints (i.e. the ankle) across perturbation heights ranging from 5 to 10 cm. However, with increased perturbation height (20 cm) humans increase their reliance on the more proximal lower-limb joints (i.e. the knee and the hip) to absorb mechanical energy and stabilize fall recovery. Further investigations into the muscle–tendon mechanics underlying these joint-level responses will likely provide additional insights into the neuromotor control strategies used to regain the stability following unexpected perturbations and provide biological inspiration for the future design of wearable devices capable of performing within unpredictable environments.
The golden age of arthropods: ancient mechanisms of colour production in body scales
Authors: D'Alba Liliana , Wang Bo , Vanthournout Bram , Shawkey Matthew D.
Published: October 2019

Insect colour is extremely diverse and produced by a large number of pigmentary and nanostructural mechanisms. Considerable research has been dedicated to these optical mechanisms, with most of it focused on chromatic colours, such as blues and greens, and less on achromatic colours like white and gold. Moreover, studies on the evolution of these colours are less common and largely limited to inferences from extant organisms, in part because of the limited amount and types of available fossil material. Here, we directly compare nanostructure and colour of extant and amber-preserved (approx. 15 and 99 Myr old, respectively) gold-coloured representatives of micromoths (Lepidoptera: Micropterigidae) and springtails (Collembola: Tomoceridae). Using electron microscopy, microspectrophotometry and finite domain time difference optical modelling, we show that golden coloration in the extant micromoth is produced by nanometre-scale crossribs that function as zero-order diffraction gratings and in the springtail by a diffraction grating without crossribs. Surprisingly, nanostructure and thus predicted colour of the amber-preserved specimens were nearly identical to those of their extant counterparts. Removal of amber enabled direct colour measurement of the fossil micromoth and further revealed that its colour matched both that of the extant specimen and the predicted colour, providing further support for our optical models. Our data thus clearly show an early origin and striking conservation of scale nanostructures and golden coloration, suggesting strong selection pressure either on the colour itself or on the mechanisms that produce the colour. Furthermore, we show the thus-far untapped potential for the use of amber-preserved specimens in studies on the evolution of organismal coloration.
A promising material for bone repair: PMMA bone cement modified by dopamine-coated strontium-doped calcium polyphosphate particles
Authors: Liu Xing , Cheng Can , Peng Xu , Xiao Hong , Guo Chengrui , Wang Xu , Li Li , Yu Xixun
Published: October 2019

Polymethyl methacrylate (PMMA) bone cement has been widely used in clinics as bone repair materials for its excellent mechanical properties and good injection properties. However, it also has defects such as poor biological performance, high temperature, and the monomer has certain toxicity. Our study tried to modify the PMMA bone cement by doping with various particle weight fractions (5, 10 and 15%) of SCPP particles and polydopamine-coated SCPP particles (D/SCPP) to overcome its clinical application disadvantages. Our study showed that all results of physical properties of samples are in accordance with ISO 5833. The 15% D/SCPP/PMMA composite bone cement had much better biocompatibility compared with pure PMMA bone cement and SCPP/PMMA composite bone cement due to the best cell growth-promoting mineralization deposition on the surface of 15% D/SCPP/PMMA composite bone cements and Sr
2+
released from SCPP particles. Our research also revealed that the reaction temperature was found to be reduced with an increase in doped particles after incorporating the particles into composite bone cements. The novel PMMA bone cements modified by D/SCPP particles are promising materials for bone repair.
Identifying fishing grounds from vessel tracks: model-based inference for small scale fisheries
Authors: Mendo Tania , Smout Sophie , Photopoulou Theoni , James Mark
Published: October 2019

Recent technological developments facilitate the collection of location data from fishing vessels at an increasing rate. The development of low-cost electronic systems allows tracking of small-scale fishing vessels, a sector of fishing fleets typically characterized by many, relatively small vessels. The imminent production of large spatial datasets for this previously data-poor sector creates a challenge in terms of data analysis. Several methods have been used to infer the spatial distribution of fishing activities from positional data. Here, we compare five approaches using either vessel speed, or speed and turning angle, to infer fishing activity in the Scottish inshore fleet. We assess the performance of each approach using observational records of true vessel activity. Although results are similar across methods, a trip-based Gaussian mixture model provides the best overall performance and highest computational efficiency for our use-case, allowing accurate estimation of the spatial distribution of active fishing (97% of true area captured). When vessel movement data can be validated, we recommend assessing the performance of different methods. These results illustrate the feasibility of designing a monitoring system to efficiently generate information on fishing grounds, fishing intensity, or monitoring of compliance to regulations at a nationwide scale in near-real-time.
FICD activity and AMPylation remodelling modulate human neurogenesis
Authors: Kielkowski Pavel , Buchsbaum Isabel Y. , Kirsch Volker C. , Bach Nina C. , Drukker Micha , Cappello Silvia , Sieber Stephan A.
Published: October 2019

Posttranslational modification (PTM) of proteins represents an important cellular mechanism for controlling diverse functions such as signalling, localisation or protein-protein interactions1. AMPylation (also termed adenylylation) has recently been discovered as a prevalent PTM for regulating protein activity2. In human cells AMPylation has been exclusively studied with the FICD protein3–6. Here we investigate the role of AMPylation in human neurogenesis by introducing a cell-permeable propargyl adenosine pronucleotide probe to infiltrate cellular AMPylation pathways and report distinct modifications in intact cancer cell lines, human-derived stem cells, neural progenitor cells (NPCs), neurons and cerebral organoids (COs) via LC-MS/MS as well as imaging methods. A total of 162 AMP modified proteins were identified. FICD-dependent AMPylation remodelling accelerates differentiation of neural progenitor cells into mature neurons in COs, demonstrating a so far unknown trigger of human neurogenesis.
Decoding the neural dynamics of free choice in humans
Authors: Thiery Thomas , Saive Anne-Lise , Combrisson Etienne , Dehgan Arthur , Bastin Julien , Kahane Philippe , Berthoz Alain , Lachaux Jean-Philippe , Jerbi Karim
Published: October 2019

How do we choose a particular action among equally valid alternatives? Non-human primate findings have shown that decision-making implicates modulations in unit firing rates and local field potentials (LFPs) across frontal and parietal cortices. Yet the electrophysiological brain mechanisms that underlie free choice in humans remain ill defined. Here, we address this question using rare intracerebral EEG recordings in surgical epilepsy patients performing a delayed oculomotor decision task. We find that the temporal dynamics of high gamma (HG, 60-140 Hz) neural activity in distinct frontal and parietal brain areas robustly discriminate free choice from instructed saccade planning at the level of single trials. Classification analysis was applied to the LFP signals to isolate decision-related activity from sensory and motor planning processes. Compared to instructed saccades, free choice trials exhibited delayed and longer-lasting HG activity. The temporal dynamics of these sustained decision-related responses distinguished deliberation-related from working memory processes. Taken together, these findings provide the first direct electrophysiological evidence in humans for the role of sustained high-frequency neural activation in fronto-parietal cortex in mediating the intrinsically driven process of freely choosing among competing behavioral alternatives.

Highlights

First intracerebral recordings in humans performing an oculomotor decision-making task

Machine learning analytics unravel underlying spectral and temporal brain dynamics

Free choice trials exhibit sustained fronto-parietal high gamma (HG) activity during the delay

Making a decision and maintaining it in working memory are associated with distinct sustained HG dynamics
All-atom Molecular Dynamics model for mycobacterial plasma membrane
Authors: Scaini João L. R. , Werhli Adriano V. , de Lima Vânia R. , da Silva Pedro E. A. , Bordin José Rafael , Machado Karina S.
Published: October 2019

Phosphatidyl-myo-inositol mannosides (PIMs) are an essential component of the cell envelope and the most predominant at the inner membrane (IM) ofM. tuberculosis. In this work, we propose an Molecular Dynamics (MD)M. tuberculosisIM model composed of PIM2lipids. The study was divided in three parts: influence of the temperature in the PIM2membrane stability, self-assembly abilities of the PIM2lipid and the behavior when a trans membrane protein is inserted in PIM2membrane. Our results show that the model is able to reproduce the gel phase observed at 310 K and the transition to a fluid phase at 328.15 K. Also, the spontaneous self-assembly of randomly distributed lipids in a vesicular aggregate was observed. Finally, we observe that the PIM2membrane is more stable than DPPC membranes when a Tap protein is inserted. Once Tap eflux pump is related to multidrug resistance ofM. tuberculosis, this result indicated that the use of the proper lipid model is essential to the proper depiction and modeling of these systems.

Graphical TOC Entry
Ictal recruitment of anterior nucleus of thalamus in human focal epilepsy
Authors: Toth Emilia , Chaitanya Ganne , Pizarro Diana , Kumar Sachin S , Ilyas Adeel , Romeo Andrew , Riley Kristen , Vlachos Ioannis , David Olivier , Balasubramanian Karthi , Pati Sandipan
Published: October 2019

The thalamic nuclei play diverse roles in the initiation, propagation, and termination of temporal lobe seizures. The role of the anterior nucleus of the thalamus (ANT) - a node that is integral to the limbic network is unclear. The objective of this study was to characterize temporal and - spectral patterns of ANT ictal recruitment in drug-resistant temporal lobe epilepsy (TLE). We hypothesized that seizures localized to the temporolimbic network are likely to recruit ANT, and the odds of recruitment were higher in seizures that had altered consciousness. Ten patients undergoing stereo-electroencephalography (SEEG) were recruited prospectively to record field potentials from the ANT. Using epileptogenicity index and line length, we computed the number of seizures that recruited the ANT (recruitment ratio), the recruitment latencies between the ANT and the epileptogenic zone (EZ), and latency of ANT recruitment to clinical manifestation for seventy-nine seizures. We observed that seizures localized to mesial temporal subregions (hippocampus, amygdala, anterior cingulate) have a higher predilection for ANT recruitment, and the recruitment was faster (ranged 5-12 secs) and preceded clinical onset for seizures that impaired consciousness. Seizures that recruited ANT lasted significantly longer (t=1.795, p=0.005). Recruitment latency was inversely correlated to seizure duration (r=-0.78, p=0.004). Electrical stimulation of the EZ induced seizures, in which early recruitment of ANT was confirmed. Stimulation of ANT did not induce a seizure. Finally, we tested the hypothesis that spectral and entropy-based features extracted from thalamic field potentials can distinguish its state of ictal recruitment from other interictal states (including awake, sleep). For this, we employed classification machine learning that discriminated thalamic ictal state from other interictal states with high accuracy (92.8%) and precision (93.1%). Among the features, the emergence of the theta rhythm (4-8 Hz) maximally discriminated the endogenous ictal state from other interictal states of vigilance. These results prompt a mechanistic role for the ANT in the early organization and sustaining of seizures, and the possibility to serve as a target for therapeutic closed-loop stimulation in TLE.
High-throughput and all-solution phase African Swine Fever Virus (ASFV) detection using CRISPR-Cas12a and fluorescence based point-of-care system
Authors: He Qian , Yu Dongmei , Bao Mengdi , Korensky Grant , Chen Juhong , Shin Mingyeong , Kim Juwon , Park Myeongkee , Qin Peiwu , Du Ke
Published: October 2019

Here we report the development of a high throughput, all-solution phase, and isothermal detection system to detect African Swine Fever Virus (ASFV). CRISPR-Cas12a programmed with a CRISPR RNA (crRNA) is used to detect ASFV target DNA. Upon ASFV DNA binding, the Cas12a/crRNA/ASFV DNA complex becomes activated and degrades a fluorescent single stranded DNA (ssDNA) reporter present in the assay. We combine this powerful CRISPR-Cas assay with fluorescence-based point-of-care (POC) system we developed for rapid and accurate virus detection. Without nucleic acid amplification, a detection limit of 1 pM is achieved within 2 hrs. In addition, the ternary Cas12a/crRNA/ASFV DNA complex is highly stable at physiological temperature and continues to cleave the ssDNA reporter even after 24 hrs of incubation, resulting in an improvement of the detection limit to 100 fM. We show that this system is very specific and can differentiate nucleic acid targets with closely matched sequences. The high sensitivity and selectivity of our system enables the detection of ASFV in femtomolar range. Importantly, this system features a disposable cartridge and a sensitive custom designed fluorometer, enabling compact, multiplexing, and simple ASFV detection, intended for low resource settings.
Regulation of transcription termination by FUS and TDP-43
Authors: Zhao Dorothy Yanling , Ni Zuyao , Pu Shuye , Zhong Guoqing , Schmitges Frank W. , Braunschweig Ulrich , Blencowe Benjamin J. , Greenblatt Jack F.
Published: October 2019

The carboxy-terminal domain (CTD) of the RNA polymerase II (RNAPII) subunit POLR2A is a platform for modifications specifying the recruitment of factors that regulate transcription, mRNA processing, and chromatin remodelling. We previously found that symmetrical dimethylation (me2s) of a CTD Arginine residue (R1810 in human) causes recruitment of the Tudor domain of SMN, which interacts with Senataxin. SMN is mutated in spinal muscular atrophy (SMA), and Senataxin is sometimes mutated in Amyotrophic Lateral Sclerosis (ALS). R1810me2s and SMN, like Senataxin, are important for resolving R-loops (DNA:RNA hybrids) at transcription terminators. FUS and TDP-43 (TARDBP) are DNA/RNA binding proteins that are sometimes mutated in ALS and FTD (Frontotemporal dementia). Here we show that TDP-43 and, to some extent, FUS are recruited by the R1810me2s-SMN pathway. Defects in FUS and TDP-43 recruitment influence RNAPII termination and R-loop accumulation, leading to elevated DNA damage at terminators that may contribute to neurodegenerative disorders like ALS and FTD.
Genetic architecture underlying changes in carotenoid accumulation during the evolution of the Blind Mexican cavefish,Astyanax mexicanus
Authors: Riddle Misty R. , Aspiras Ariel , Damen Fleur , Hutchinson John N. , Chinnapen Daniel , Tabin Clifford J.
Published: October 2019

Carotenoids are yellow to orange pigments produced by plants, bacteria, and fungi. They are consumed by animals and metabolized to produce molecules essential for gene regulation, vision, and pigmentation. Cave animals represent an interesting opportunity to understand how carotenoid utilization evolves. Caves are devoid of light, eliminating primary production of energy through photosynthesis and therefore limiting carotenoid availability. Moreover, the selective pressures that favor carotenoid-based traits, like pigmentation and vision, are relaxed.Astyanax mexicanusis a species of fish with river-adapted (surface) and multiple cave-adapted populations (i.e. Tinaja, Pachón, Molino). Cavefish exhibit regressive features such as loss of eyes and melanin pigment, and constructive traits, like increased sensory neuromasts and starvation resistance. Here we show that unlike surface fish, Tinaja and Pachón cavefish accumulate carotenoids in the visceral adipose tissue (VAT). Carotenoid accumulation is not observed in Molino cavefish indicating that it is not an obligatory consequence of eye loss. We used quantitative trait loci mapping and RNA sequencing to investigate genetic changes associated with this trait. Our findings suggest that multiple stages of carotenoid processing may be altered in cavefish, including absorption and transport of lipids, cleavage of carotenoids into un-pigmented molecules, and differential development of intestinal cell types involved in carotenoid assimilation. Our study establishesA. mexicanusas a model to study the genetic basis of natural variation in carotenoid accumulation and how it impacts physiology.

Research Highlights

Cavefish accumulate carotenoids in the visceral adipose tissue (VAT)

Genetic mapping reveals candidate genes associated with yellow VAT

Carotenoid accumulation is linked with decreased expression of carotenoid-processing genes
Uniform Genomic Data Analysis in the NCI Genomic Data Commons
Authors: Zhang Zhenyu , Hernandez Kyle , Savage Jeremiah , Li Shenglai , Miller Dan , Agrawal Stuti , Ortuno Francisco , Staudt Lou , Heath Allison , Grossman Robert L.
Published: October 2019

The goal of the National Cancer Institute (NCI) Genomic Data Commons (GDC) is to provide the cancer research community with a data repository of uniformly processed genomic and associated clinical data that enables data sharing and collaborative analysis in the support of precision medicine. The initial GDC dataset include genomic, epigenomic, proteomic, clinical and other data from the NCI TCGA and TARGET programs. Data production for the GDC started in June, 2015 using an OpenStack-based private cloud. By June of 2016, the GDC had analyzed more than 50,000 raw sequencing data inputs, as well as multiple other data types. Using the latest human genome reference build GRCh38, the GDC generated a variety of data types from aligned reads to somatic mutations, gene expression, miRNA expression, DNA methylation status, and copy number variation. In this paper, we describe the pipelines and workflows used to process and harmonize the data in the GDC. The generated data, as well as the original input files from TCGA and TARGET, are available for download and exploratory analysis at the GDC Data Portal and Legacy Archive (https://gdc.cancer.gov/).
Cleavage-furrow formation without F-actin inChlamydomonas
Authors: Onishi Masayuki , Umen James G. , Cross Frederick R. , Pringle John R.
Published: October 2019

It is widely believed that cleavage-furrow formation during cell division is driven by the contraction of a ring containing F-actin and type-II myosin. However, even in cells that have such rings, they are not always essential for furrow formation. Moreover, many taxonomically diverse eukaryotic cells divide by furrowing but have no type-II myosin, making it unlikely that an actomyosin ring drives furrowing. To explore this issue further, we have used one such organism, the green algaChlamydomonas reinhardtii. We found that although F-actin is concentrated in the furrow region, none of the three myosins (of types VIII and XI) is localized there. Moreover, when F-actin was eliminated through a combination of a mutation and a drug, furrows still formed and the cells divided, although somewhat less efficiently than normal. Unexpectedly, division of the largeChlamydomonaschloroplast was delayed in the cells lacking F-actin; as this organelle lies directly in the path of the cleavage furrow, this delay may explain, at least in part, the delay in cell division itself. Earlier studies had shown an association of microtubules with the cleavage furrow, and we used a fluorescently tagged EB1 protein to show that at least the microtubule plus-ends are still associated with the furrows in the absence of F-actin, consistent with the possibility that the microtubules are important for furrow formation. We suggest that the actomyosin ring evolved as one way to improve the efficiency of a core process for furrow formation that was already present in ancestral eukaryotes.
Defining relative mutational difficulty to understand cancer formation and prevention
Authors: Shan Lin , Yu Jiao , He Zhengjin , Chen Shishuang , Liu Mingxian , Ding Hongyu , Xu Liang , Zhao Jie , Yang Ailing , Jiang Hai
Published: October 2019

Most mutations in human cancer are low-frequency missense mutations, whose functional status remains hard to predict. Here we show that depending on the type of nucleotide change and the surrounding sequences, the tendency to generate each type of nucleotide mutations varies greatly, even by several hundred folds. Therefore, a cancer-promoting mutation may appear only in a small number of cancer cases, if the underlying nucleotide change is too difficult to generate. We propose a method that integrates both the original mutation counts and their relative mutational difficulty. Using this method, we can accurately predict the functionality of hundreds of low-frequency missense mutations in p53, PTEN and INK4A. Many loss-of-function p53 mutations with dominant negative effects were identified, and the functional importance of several regions in p53 structure were highlighted by this analysis. Furthermore, mutational difficulty analysis also points to potential means of cancer prevention. Our study not only established relative mutational difficulties for different types of mutations in human cancer, but also showed that by incorporating such parameter, we can bring new angles to understanding cancer formation and prevention.
Robustness and universality in organelle size control
Authors: Amiri Kiandokht Panjtan , Kalish Asa , Mukherji Shankar
Published: October 2019

One of the grand challenges in quantitative cell biology is understanding the precision with which cells assemble and maintain subcellular organelles. A critical property that governs organelle function is its size. Organelle sizes must be flexible enough to allow cells to grow or shrink them as environments demand, yet be maintained within homeostatic limits. Despite identification of numerous molecular factors that regulate organelle sizes we lack insight into the quantitative principles underlying organelle size control. Here we examine organelle sizes from Saccharomyces cerevisiae and human iPS cells with mathematical theory to show that cells can robustly control average fluctuations in organelle size. By demonstrating that organelle sizes obey a universal scaling relationship we predict theoretically, our framework suggests that organelles grow in random bursts from a limited pool of building blocks. Burst-like growth provides a general biophysical mechanism by which cells can maintain on average reliable yet plastic organelle sizes.
Cortico-striatal activity driving compulsive reward seeking
Authors: Harada Masaya , Pascoli Vincent , Hiver Agnes , Flakowski Jérôme , Lüscher Christian
Published: October 2019

Addicted individuals compulsively seek drugs. Cortico-striatal projections have been implicated in persevering to seek rewards even when punished. The temporo-spatial determinants of the activity underlying the compulsive reward seeking however remains elusive. Here we trained mice in a seek-take chain, rewarded by optogenetic dopamine neuron self-stimulation (oDASS). Mice that persevered when seeking was punished, exhibited an increased AMPA/NMDA ratio selectively at orbitofrontal cortex (OFC) to dorsal striatum (DS) synapses. In addition, an activity peak of spiny projection neurons (SPNs) in the DS at the moment of signalled reward availability was detected. Chemogenetic inhibition of OFC neurons curbed the activity peak and reduced punished reward seeking, as did optogenetic hyperpolarization of SPNs time locked to the cue predicting reward availability, establishing a causal link. Taken together, we conclude that the strengthening of OFC-DS synapses drives SPNs activity when a reward predictive cue is delivered, thus encouraging reward seeking in subsequent trials.