bluuebunny/crossref_metadata_2025 huggingface dataset:
A Herniorrhaphy Lamination Technique for the Reconstruction of Midline Abdominal Wall Defects
Authors: Kurabayashi Takashi , Asato Hirotaka , Suzuki Yasutoshi , Takada Goro , Ishizuka Noriyuki , Sasaki Shoichi , Moteki Michihiko
Published: April 2021

The primary goal of abdominal wall reconstruction is to prevent hernia recurrence through robust and durable repair. Synthetic mesh utilization can provide sound strength but is susceptible to extrusion, infection, and intestinal fistulization. The use of autologous fasciae latae to reinforce the primary fascial reapproximation has mostly been abandoned, presumably because synthetic patches are readily available. There is a specific demand for a sustainable, less-invasive, and ready-to-use repair method without mesh. The authors devised a herniorrhaphy lamination technique using local musculofascial flaps inspired by composite laminates. In this procedure, the primary fascial reapproximation is reinforced with 3 additional laminated musculofascial layers: (1) turnover hinge flaps of the anterior sheath of the rectus abdominis, (2) bilateral rectus abdominis, and (3) advancement flaps of newly generated edges of the fascia of the rectus sheath. Our technique’s stability is essentially due to the mechanical superiority of the centralized pipe-like structure of musculofascia. Between February 2009 and November 2019, we used the lamination technique to repair midline incisional hernias in 10 patients. The operative procedure was successful in all patients, and there has been no evidence of recurrence. The follow-up period ranged from 12 to 69 months, with a mean follow-up of 35 months. The herniorrhaphy lamination technique to reinforce the primary repair can help prevent hernia recurrence. Although our technique is suitable for a small-sized defect, it is less invasive, and can be readily applied. Because it does not include any mesh, it is suitable for the contaminated abdominal wall reconstruction.
Neourethra Creation in Gender Phalloplasty: Differences in Techniques and Staging
Authors: Berli Jens U. , Monstrey Stan , Safa Bauback , Chen Mang
Published: April 2021

The creation of a sensate, aesthetic, and functional phallus for transmasculine individuals has high reported complication rates. Neourethra reconstruction is the most challenging aspect of this surgery, with widely varying techniques and staging between providers. In an operation of this complexity, surgeons should not be expected to offer all the options, but rather the specific variation that works in their given setting. For some, it is single-stage phalloplasty with full-length urethroplasty. For others, staged phalloplasty with separation of perineal masculinization from phallus reconstruction works better. In this expert opinion article, the authors strive to give an overview of the principles behind, and a detailed explanation of, the technical details of creating the penile and bulbar urethra during phalloplasty. The authors focus on the three most common strategies: single-stage phalloplasty; two-stage phalloplasty with a metoidioplasty-first approach; and two-stage phalloplasty with a phalloplasty-first (Big Ben method) approach. It is not the authors’ intent to establish the “best” or “only” way, but rather to compile different options with their respective pros and cons.
Reconstructive Management of Gunshot Wounds to the Frontal Sinus
Authors: Soto Edgar , Ovaitt Alyssa K. , Clark Ashlynn R. , Tindal Rachel R. , Chiasson Katherine F. , Aryanpour Zain , Ananthasekar Shivani , Grant John H. , Myers René P.
Published: April 2021

Introduction

In the last decade, we have seen a steady increase in the incidence of frontal sinus trauma due to gunshot wounds and a decrease in motor vehicle trauma. Penetrating gunshot wounds to the frontal sinus present a unique challenge to the reconstructive surgeon because they require careful consideration of the management principles of plastic surgery. Despite previous reviews on frontal sinus trauma, there are no studies examining the management techniques of frontal sinus fractures due specifically to gunshot wounds. In this study, we aim to retrospectively evaluate the use of a variety of tissue flaps in intervention and associated outcomes.

Methods

A retrospective chart review was completed on all patients with gunshot wound(s) to the frontal sinus from January 2010 to January 2018 at a single institution. The patients were classified based on the fracture pattern (anterior vs posterior table vs both), degree of displacement, presence of nasofrontal outflow tract injury, and evidence of cerebrospinal fluid leak. Patients were then stratified according to the type of reconstruction performed (cranialization, obliteration and need for free flap) and evaluated for major and minor complications after reconstruction.

Results

In this study, we present outcome data from 28 cases of frontal sinus trauma due to gunshot wounds. There was a statistically significant difference (P = 0.049) in the type reconstructive strategy employed with each type of flap, with pericranial flaps primarily used in cranialization, temporal grafts were more likely to be used in obliteration, and free flaps were more likely to be used in cranialization. The overall major complication rate was 52% (P = 0.248), with the most common acute major complication was cerebrospinal fluid leak (39%) and major chronic was abscess (23.5%).

Conclusions

This report explores the management of frontal sinus trauma and presents short-term outcomes of treatment for penetrating gunshot wounds at a tertiary referral center.
The Deltopectoral/Internal Mammary Artery Perforator Flap Revisited
Authors: Angrigiani Claudio , Rancati Alberto , Varela Ignacio , Rancati Agustin , Nahabedian Maurice Y. , Neligan Peter
Published: April 2021

Current understanding of the vascular anatomy of the anterior chest wall suggests that perfusion of the deltopectoral flap may be compromised when crossing the midline at the anterior thoracic wall. The traditional deltopectoral flap is designed longitudinally over the ipsilateral side to avoid the risk of distal flap necrosis. The purpose of this article is to present our experience and results with 26 deltopectoral flaps that were designed and raised with the perforating vessels on the ipsilateral side with the majority of the flap crossing the midline extending to the contralateral side. This anatomic variation in flap design indicates that the sternal midline is not a barrier and that the internal mammary perforator flap may be raised on different longitudinal axes.
Marginal Impact of Tocilizumab Monotherapy on Anti-HLA Alloantibodies in Highly Sensitized Kidney Transplant Candidates
Authors: Daligault Mélanie , Bardy Béatrice , Noble Johan , Bourdin Anne , Masson Dominique , Naciri Bennani Hamza , Bugnazet Mathilde , Malvezzi Paolo , Rostaing Lionel , Jouve Thomas
Published: April 2021

Background.

Highly HLA–sensitized kidney transplant candidates are difficult to desensitize, which reduces their chances of receiving a transplant.

Methods.

We administered tocilizumab as a monotherapy (8 mg/kg once a mo) to 14 highly sensitized kidney transplant candidates. Highest mean fluorescence intensities of anti-HLA antibodies obtained before and after tocilizumab administration were compared from raw and diluted sera.

Results.

The administration of tocilizumab significantly reduced dominant anti-HLA antibody sensitization. However, this decrease in mean fluorescence intensities was minor compared with the initial values.

Conclusions.

Tocilizumab as a monotherapy was not sufficient to allow highly sensitized kidney–transplant candidates to undergo transplantation and, therefore, was not an effective desensitization method.
Analyses of cell death mechanisms related to amino acid substitution at position 95 in the rabies virus matrix protein
Authors: Kojima Isshu , Izumi Fumiki , Ozawa Makoto , Fujimoto Yoshikazu , Okajima Misuzu , Ito Naoto , Sugiyama Makoto , Masatani Tatsunori
Published: April 2021

We previously reported that the avirulent fixed rabies virus strain Ni-CE induces a clear cytopathic effect in mouse neuroblastoma cells, whereas its virulent progenitor, the Nishigahara strain, does not. Infection with Nishigahara and Ni-CE mutants containing a single amino acid substitution in the matrix protein (M) demonstrated that the amino acid at position 95 of M (M95) is a cytopathic determinant. The characteristics of cell death induced by Ni-CE infection resemble those of apoptosis (rounded and shrunken cells, DNA fragmentation), but the intracellular signalling pathway for this process has not been fully investigated. In this study, we aimed to elucidate the mechanism by which M95 affects cell death induced by human neuroblastoma cell infection with the Nishigahara, Ni-CE and M95-mutated strains. We demonstrated that the Ni-CE strain induced DNA fragmentation, cell membrane disruption, exposure of phosphatidylserine (PS), activation of caspase-3/7 and anti-poly (ADP-ribose) polymerase 1 (PARP-1) cleavage, an early apoptosis indicator, whereas the Nishigahara strain did not induce DNA fragmentation, caspase-3/7 activation, cell membrane disruption, or PARP-1 cleavage, but did induce PS exposure. We also demonstrated that these characteristics were associated with M95 using M95-mutated strains. However, we found that Ni-CE induced cell death despite the presence of a caspase inhibitor, Z-VAD-FMK. In conclusion, our data suggest that M95 mutation-related cell death is caused by both the caspase-dependent and -independent pathways.
Genetic liability for substance use associated with medical comorbidities in electronic health records of African- and European-ancestry individuals
Authors: Hartwell Emily E. , Merikangas Alison K. , Verma Shefali S. , Ritchie Marylyn D. ,   Regeneron Genetics Center, Kranzler Henry R. , Kember Rachel L.
Published: April 2021

Polygenic risk scores (PRS) represent an individual’s summed genetic risk for a trait and can serve as biomarkers for disease. Less is known about the utility of PRS as a means to quantify genetic risk for substance use disorders (SUDs) than for many other traits. Nonetheless, the growth of large, electronic health record-based biobanks makes it possible to evaluate the association of SUD PRS with other traits. We calculated PRS for smoking initiation, alcohol use disorder (AUD), and opioid use disorder (OUD) using summary statistics from the Million Veteran Program sample. We then tested the association of each PRS with its primary phenotype in the Penn Medicine BioBank (PMBB) using all available genotyped participants of African or European ancestry (AFR and EUR, respectively) (N=18,612). Finally, we conducted phenome-wide association analyses (PheWAS) separately by ancestry and sex to test for associations across disease categories. Tobacco use disorder was the most common SUD in the PMBB, followed by AUD and OUD, consistent with the population prevalence of these disorders. All PRS were associated with their primary phenotype in both ancestry groups. PheWAS results yielded cross-trait associations across multiple domains, including psychiatric disorders and medical conditions. SUD PRS were associated with their primary phenotypes, however they are not yet predictive enough to be useful diagnostically. The cross-trait associations of the SUD PRS are indicative of a broader genetic liability. Future work should extend findings to additional population groups and for other substances of abuse.
Real World Effectiveness of COVID-19 mRNA Vaccines against Hospitalizations and Deaths in the United States
Authors: Vahidy Farhaan S. , Pischel Lauen , Tano Mauricio E , Pan Alan P , Boom Marc L , Sostman Henry Dirk , Nasir Khurram , Omer Saad B
Published: April 2021

The authors have withdrawn this manuscript because they are continuing to review the analytical methods utilized in this iteration of the work and, as of yet, do not have adequate confidence in their reproducibility. Therefore, the authors do not wish this work to be cited as reference for the project. If you have any questions, please contact the corresponding author.
Rapid evaluation of COVID-19 vaccine effectiveness against VOC/VOIs by genetic mismatch
Authors: Cao Lirong , Lou Jingzhi , Zheng Hong , Zhao Shi , Mok Chris Ka Pun , Yi Chan Renee Wan , Chong Marc Ka Chun , Chen Zigui , Yi Wong Eliza Lai , Chan Paul Kay Sheung , Zee Benny Chung-Ying , Yeoh Eng Kiong , Wang Maggie Haitian
Published: April 2021

Timely evaluation of the protective effects of COVID-19 vaccines is challenging but urgently needed to inform the pandemic control planning. Based on vaccine efficacy/effectiveness (VE) data of 11 vaccine products and 297,055 SARS-CoV-2 sequences collected in 20 regions, we analyzed the relationship between genetic mismatch of circulating viruses against the vaccine strain and VE. Variations from technology platforms are controlled by a mixed-effects model. We found that the genetic mismatch measured on the RBD is highly predictive for vaccine protection and accounted for 72.0% (p-value < 0.01) of the VE change. The NTD and S protein also demonstrate significant but weaker per amino acid substitution association with VE (p-values < 0.01). The model is applied to predict vaccine protection of existing vaccines against new genetic variants and is validated by independent cohort studies. The estimated VE against the delta variant is 79.3% (95% prediction interval: 67.0 – 92.1) using the mRNA platform, and an independent survey reported a close match of 83.0%; against the beta variant (B.1.351) the predicted VE is 53.8% (95% prediction interval: 39.9 – 67.4) using the viral-vector vaccines, and an observational study reported a close match of 48.0%. Genetic mismatch provides an accurate prediction for vaccine protection and offers a rapid evaluation method against novel variants to facilitate vaccine deployment and public health responses.
Inverting the model of genomics data sharing with the NHGRI Genomic Data Science Analysis, Visualization, and Informatics Lab-space (AnVIL)
Authors: Schatz Michael C. , Philippakis Anthony A. , Afgan Enis , Banks Eric , Carey Vincent J. , Carroll Robert J. , Culotti Alessandro , Ellrott Kyle , Goecks Jeremy , Grossman Robert L. , Hall Ira M. , Hansen Kasper D. , Lawson Jonathan , Leek Jeffrey T. , O’Donnell Luria Anne , Mosher Stephen , Morgan Martin , Nekrutenko Anton , O’Connor Brian D. , Osborn Kevin , Paten Benedict , Patterson Candace , Tan Frederick J. , Taylor Casey Overby , Vessio Jennifer , Waldron Levi , Wang Ting , Wuichet Kristin , Team AnVIL
Published: April 2021

The traditional model of genomic data analysis - downloading data from centralized warehouses for analysis with local computing resources - is increasingly unsustainable. Not only are transfers slow and cost prohibitive, but this approach also leads to redundant and siloed compute infrastructure that makes it difficult to ensure security and compliance of protected data. The NHGRI Genomic Data Science Analysis, Visualization, and Informatics Lab-space (AnVIL;https://anvilproject.org) inverts this model, providing a unified cloud computing environment for data storage, management, and analysis. AnVIL eliminates the need for data movement, allows for active threat detection and monitoring, and provides scalable, shared computing resources that can be acquired by researchers as needed. This presents many new opportunities for collaboration and data sharing that will ultimately lead to scientific discoveries at scales not previously possible.
Evolutionary rate covariation identifies SLC30A9 (ZnT9) as a mitochondrial zinc transporter
Authors: Kowalczyk Amanda , Gbadamosi Omotola , Kolor Kathryn , Sosa Jahree , St Croix Claudette , Gibson Gregory , Chikina Maria , Aizenman Elias , Clark Nathan , Kiselyov Kirill
Published: April 2021

Recent advances in genome sequencing have led to the identification of new ion and metabolite transporters, many of which have not been characterized. Due to the variety of subcellular localizations, cargo and transport mechanisms, such characterization is a daunting task, and predictive approaches focused on the functional context of transporters are very much needed. Here we present a case for identifying a transporter localization using evolutionary rate covariation (ERC), a computational approach based on pairwise correlations of amino acid sequence evolutionary rates across the mammalian phylogeny. As a case study, we find that poorly characterized transporter SLC30A9 (ZnT9) uniquely and prominently coevolves with several components of the mitochondrial oxidative phosphorylation chain, suggesting mitochondrial localization. We confirmed this computational finding experimentally using recombinant human SLC30A9. SLC30A9 loss caused zinc mishandling in the mitochondria, suggesting that under normal conditions it acts as a zinc exporter. We therefore propose that ERC can be used to predict the functional context of novel transporters and other poorly characterized proteins.
The role of neural flexibility in cognitive aging
Authors: Varangis Eleanna , Qi Weiwei , Stern Yaakov , Lee Seonjoo
Published: April 2021

Studies assessing relationships between brain and cognitive changes in healthy aging have shown that a variety of aspects of brain structure and function explain a significant portion of the variability in cognitive outcomes throughout adulthood. Many studies assessing relationships between brain function and cognition have utilized time-averaged, or static functional connectivity methods to explore ways in which brain network organization may contribute to aspects of cognitive aging. However, recent studies in this field have suggested that time-varying, or dynamic measures of functional connectivity, which assess changes in functional connectivity throughout a scan session, may play a stronger role in explaining cognitive outcomes in healthy young adults. Further, both static and dynamic functional connectivity studies suggest that there may be differences in patterns of brain-cognition relationships as a function of whether or not the participant is performing a task during the scan. Thus, the goals of the present study were threefold: (1) assess whether dynamic connectivity (neural flexibility) during both resting as well as task-based scans is related to participant age and cognitive performance in a lifespan aging sample, (2) determine whether neural flexibility moderates relationships between age and cognitive performance, and (3) explore differences in neural flexibility between rest and task. Participants in the study were 423 healthy adults between the ages of 20-80 who provided resting state and/or task-based (Matrix Reasoning) functional magnetic resonance imaging (fMRI) scan data as part of their participation in two ongoing studies of cognitive aging. Neural flexibility measures from both resting and task-based scans reflected the number of times each node changed network assignment, and were averaged both across the whole brain (global neural flexibility) as well as within nine somatosensory/cognitive networks. Results showed that neural flexibility during the task was higher in older adults, and that neural flexibility in Default Mode and Visual networks was negatively related to performance on the Matrix Reasoning task. Resting state neural flexibility was not significantly related to either participant age or cognitive performance. Additionally, no neural flexibility measures that significantly moderated relationships between participant age and cognitive outcomes. Further, neural flexibility differed as a function of scan type, with resting state neural flexibility exhibiting significantly more variability than task-based neural flexibility. Thus, neural flexibility measures computed during a cognitive task may be more strongly related to cognitive performance across the adult lifespan, and are more sensitive to the effects of participant age on brain organization.
Identification of essential β-oxidation genes and corresponding metabolites for estrogen degradation by actinobacteria
Authors: Hsiao Tsun-Hsien , Lee Tzong-Huei , Chuang Meng-Rong , Wang Po-Hsiang , Meng Menghsiao , Horinouchi Masae , Hayashi Toshiaki , Chen Yi-Lung , Chiang Yin-Ru
Published: April 2021

Steroidal estrogens (C18) are contaminants receiving increasing attention due to their endocrine-disrupting activities at sub-nanomolar concentrations. Although estrogens can be eliminated through photodegradation, microbial function is critical for removing estrogens from ecosystems devoid of sunlight exposure including activated sludge, soils, and aquatic sediments. Actinobacteria were found to be key estrogen degraders in manure-contaminated soils and estuarine sediments. Previously, we used the actinobacteriumRhodococcussp. strain B50 as a model microorganism to identify two oxygenase genes,aedAandaedB, involved in the activation and subsequent cleavage of the estrogenic A-ring, respectively. However, genes responsible for the downstream degradation of estrogen A/B-rings remained completely unknown. In this study, we employed tiered comparative transcriptomics, gene disruption experiments, and mass spectrometry–based metabolite profile analysis to identify estrogen catabolic genes. We observed the up-regulation of thiolase-encodingaedFandaedKin the transcriptome of strain B50 grown with estrone. Consistently, two downstream estrogenic metabolites, 5-oxo-4-norestrogenic acid (C17) and 2,3,4-trinorestrogenic acid (C15), were accumulated inaedF-andaedK-disrupted strain B50 cultures. Disruption offadD3[3aα-H-4α(3’-propanoate)-7aβ-methylhexahydro-1,5-indanedione (HIP)-coenzyme A ligase gene] in strain B50 resulted in apparent HIP accumulation in estrone-fed cultures, indicating the essential role offadD3in actinobacterial estrogen degradation. In addition, we detected a uniquemeta-cleavage product, 4,5-seco-estrogenic acid (C18), during actinobacterial estrogen degradation. Differentiating the estrogenic metabolite profile and degradation genes of actinobacteria and proteobacteria enables the cost-effective and time-saving identification of potential estrogen degraders in various ecosystems through liquid chromatography–mass spectrometry analysis and polymerase chain reaction–based functional assays.
Life-history predicts global population responses to the weather in the terrestrial mammals
Authors: Jackson John , Le Coeur Christie , Jones Owen R
Published: April 2021

With the looming threat of abrupt ecological disruption due to a changing climate, predicting which species are most vulnerable to environmental change is critical. The life-history of a species is an evolved response to its environmental context, and therefore a promising candidate for explaining differences in climate-change responses. However, we urgently need broad empirical assessments from across the worlds ecosystems to explore these predictions. Here, we use long-term abundance records from 157 species of terrestrial mammal and a two-step Bayesian meta-regression framework to investigate the link between annual weather anomalies, population growth rates, and species-level life-history. Overall, we found no consistent effect of temperature or precipitation anomalies on annual population growth rates. Furthermore, population responses to weather anomalies were not predicted by phylogenetic covariance, and instead there was variability in weather responses for populations within a species. Crucially, however, long-lived mammals with smaller litter sizes had responses with a reduced absolute magnitude compared to their shorter-living counterparts with larger litters. These results highlight the role of species-level life-history in driving responses to the environment.
Protein noise and distribution in a two-stage gene-expression model extended by an mRNA inactivation loop
Authors: Çelik Candan , Bokes Pavol , Singh Abhyudai
Published: April 2021

Chemical reaction networks involving molecular species at low copy numbers lead to stochasticity in protein levels in gene expression at the single-cell level. Mathematical modelling of this stochastic phenomenon enables us to elucidate the underlying molecular mechanisms quantitatively. Here we present a two-stage stochastic gene expression model that extends the standard model by an mRNA inactivation loop. The extended model exhibits smaller protein noise than the original two-stage model. Interestingly, the fractional reduction of noise is a non-monotonous function of protein stability, and can be substantial especially if the inactivated mRNA is stable. We complement the noise study by an extensive mathematical analysis of the joint steady-state distribution of active and inactive mRNA and protein species. We determine its generating function and derive a recursive formula for the protein distribution. The results of the analytical formula are cross-validated by kinetic Monte-Carlo simulation.
Incoherent modulation of bi-stable dynamics orchestrates the Mushroom and Isola bifurcations
Authors: Giri Amitava , Kar Sandip
Published: April 2021

In biological networks, steady state dynamics of cell-fate regulatory genes often exhibit Mushroom and Isola kind of bifurcations. How these complex bifurcations emerge for these complex networks, and what are the minimal network structures that can generate these bifurcations, remain elusive. Herein, by employing Waddington’s landscape theory and bifurcation analysis, we have shown that both Mushroom and Isola bifurcations can be realized with four minimal network motifs that are constituted by combining positive feedback motifs with different types of incoherent feedback motifs. Our study demonstrates that the intrinsic bi-stable dynamics due to the presence of the positive feedback motif can be fine-tuned by altering the extent of the incoherence of these proposed minimal networks to orchestrate these complex bifurcations. These modeling insights will be useful in identifying and analyzing possible network motifs that may give rise to either Mushroom or Isola bifurcation in other biological systems.
On the Reconstruction of Magnetic Resonance Current Density Images of the Human Brain: Pitfalls and Perspectives
Authors: Eroğlu Hasan H. , Puonti Oula , Göksu Cihan , Gregersen Fróði , Siebner Hartwig R. , Hanson Lars G. , Thielscher Axel
Published: April 2021

Magnetic resonance current density imaging (MRCDI) of the human brain aims to reconstruct the current density distribution caused by transcranial electric stimulation from MR-based measurements of the current-induced magnetic fields. The reconstruction problem is challenging due to a low signal-to-noise ratio and a limited volume coverage of the MR-based measurements, the lack of data from the scalp and skull regions and because MRCDI is only sensitive to the component of the current-induced magnetic field parallel to the scanner field. Most existing reconstruction approaches have been validated using simulation studies and measurements in phantoms with simplified geometries. Only one reconstruction method, the projected current density algorithm, has been applied to human in-vivo data so far, however resulting in blurred current density estimates even when applied to noise-free simulated data.

We analyze the underlying causes for the limited performance of the projected current density algorithm when applied to human brain data. In addition, we compare it with an approach that relies on the optimization of the conductivities of a small number of tissue compartments of anatomically detailed head models reconstructed from structural MR data. Both for simulated ground truth data and human in-vivo MRCDI data, our results indicate that the estimation of current densities benefits more from using a personalized volume conductor model than from applying the projected current density algorithm. In particular, we introduce a hierarchical statistical testing approach as a principled way to test and compare the quality of reconstructed current density images that accounts for the limited signal-to-noise ratio of the human in-vivo MRCDI data and the fact that the ground truth of the current density is unknown for measured data. Our results indicate that the statistical testing approach constitutes a valuable framework for the further development of accurate volume conductor models of the head. Our findings also highlight the importance of tailoring the reconstruction approaches to the quality and specific properties of the available data.
Acoustic properties across the human skull
Authors: Riis Thomas , Webb Taylor , Kubanek Jan
Published: April 2021

Transcranial ultrasound is emerging as a noninvasive tool for targeted treatments of brain disorders. Transcranial ultrasound has been used for remotely mediated surgeries, transient opening of the blood-brain barrier, local drug delivery, and neuromodulation. However, all applications have been limited by the severe attenuation and phase distortion of ultrasound by the skull. Here, we characterized the dependence of the aberrations on specific anatomical segments of the skull. In particular, we measured ultrasound propagation properties throughout the perimeter of intact human skulls at 500 kHz. We found that the parietal bone provides substantially higher transmission (average pressure transmission 31±7%) and smaller phase distortion (242±44 degrees) than frontal (13±2%, 425±47 degrees) and occipital bone regions (16±4%, 416±35 degrees). In addition, we found that across skull regions, transmission strongly anti-correlated (R= −0.79) and phase distortion correlated (R= 0.85) with skull thickness. This information guides the design, positioning, and skull correction functionality of next-generation devices for effective, safe, and reproducible transcranial focused ultrasound therapies.
Ubiquitination of G3BP1 mediates stress granule disassembly in a stress-specific manner
Authors: Gwon Youngdae , Maxwell Brian A. , Kolaitis Regina-Maria. , Zhang Peipei , Kim Hong Joo , Taylor J. Paul
Published: April 2021

Stress granules are dynamic, reversible condensates composed of RNA and protein that assemble in response to a variety of stressors and are normally disassembled after stress is removed. Whereas the composition of stress granules and the mechanisms underlying their assembly have been extensively studied, far less is known about the mechanisms that govern disassembly. Impaired disassembly has been implicated in some diseases. Here we report that stress granule disassembly is context-dependent and, in the setting of heat shock, requires ubiquitination of G3BP1, the central protein within the stress granule RNA-protein network. Ubiquitinated G3BP1 interacts with the ER-resident protein FAF2, which engages the ubiquitin-dependent segregase p97/VCP. Targeting G3BP1 enables the stress granule-specific interaction network to fall below the percolation threshold for phase separation, which causes disassembly.

One Sentence Summary

Ubiquitination of G3BP1 mediates FAF2- and p97/VCP-dependent disassembly of heat-induced stress granules
Ubiquitination is essential for recovery of cellular activities following heat shock
Authors: Maxwell Brian A. , Gwon Youngdae , Mishra Ashutosh , Peng Junmin , Zhang Ke , Kim Hong Joo , Taylor J. Paul
Published: April 2021

Eukaryotic cells respond to stress via adaptive programs that include reversible shutdown of key cellular processes, the formation of stress granules, and a global increase in ubiquitination. The primary function of this ubiquitination is generally considered to be tagging damaged or misfolded proteins for degradation. Here we show that different types of stress generate distinct ubiquitination patterns. For heat stress, ubiquitination correlates with cellular activities that are downregulated during stress, including nucleocytoplasmic transport and translation, as well as with stress granule constituents. Ubiquitination is not required for the shutdown of these processes or for stress granule formation, but is essential for resumption of cellular activities and for stress granule disassembly. These findings indicate that stress-induced ubiquitination primes the cell for recovery following heat stress.

One Sentence Summary

Stress-induced ubiquitination is essential for recovery of cellular activities following heat stress.
Disbalance of the intestinal epithelial cell turnover and apoptosis in a rat model of sporadic Alzheimer’s disease
Authors: Homolak Jan , Perhoc Ana Babic , Knezovic Ana , Barilar Jelena Osmanovic , Koc Fatma , Stanton Catherine , Ross R. Paul , Salkovic-Petrisic Melita
Published: April 2021

Background

Dyshomeostasis of the gastrointestinal (GI) system is investigated as a potential contributor to metabolic dysfunction, systemic and neuro-inflammation recognized as important pathophysiological drivers of neurodegeneration. Gastrointestinal redox dyshomeostasis and dysfunctional brain-gut incretin axis have been reported in the rat model of insulin-resistant brain state (IRBS)-driven neurodegeneration induced by intracerebroventricular administration of streptozotocin (STZ-icv). The aim was to assess i) whether GI oxidative stress is accompanied by structural and functional changes of the epithelial barrier; ii) whether the brain glucose-dependent insulinotropic polypeptide receptor (GIP-R) is also involved in redox regulation of the gut; and iii) whether the STZ-icv brain-gut axis is resistant to pharmacological inhibition of the brain GIP-R.

Methods

Forty three-month-old male Wistar rats were treated with 3mg/kg STZ-icv or vehicle. One month later the animals were randomized to receive either saline or 85 μg/kg GIP-R inhibitor [Pro3]-GIP intracerebroventricularly and sacrificed 30 minutes later. Thiobarbituric acid reactive substances (TBARS) were measured in plasma and duodenum. Duodenal sections were subjected to morphometric analysis. Caspase-3 expression and activation were analyzed by western blot and spatial signal analysis was done by multiplex fluorescent signal amplification (MFSA). Data were analyzed by linear and linear mixed modeling, and exploration was done by principal component analysis.

Results

Inhibition of the brain GIP-R decreased plasma TBARS in the controls and the STZ-icv animals and increased duodenal TBARS only in the controls. Acute inhibition of brain GIP-R affects duodenal epithelial cell, but not villus structure, while all morphometric parameters were altered in the STZ-icv-treated animals. Morphometric changes in the STZ-icv animals were accompanied by reduced levels of activated and total regulator of apoptosis – caspase-3. Acute inhibition of brain GIP-R inactivated duodenal apoptosis at the level of caspase-3 activation.

Conclusions

Brain GIP-R is involved in the regulation of the systemic and duodenal redox homeostasis and epithelial function. Duodenal oxidative stress in the STZ-icv rats is accompanied by the resistance of the brain-gut GIP axis and morphological changes indicative of abnormal epithelial cell turnover and dysfunctional GI barrier. Dysfunction of the brain-gut incretin axis might be an important etiopathogenetic factor in neurodegeneration and a potential pharmacological target.
Extracellular vesicle molecular signatures characterize metastatic dynamicity in ovarian cancer
Authors: Gonda Amber , Zhao Nanxia , Shah Jay V. , Siebert Jake N. , Gunda Srujanesh , Inan Berk , Kwon Mijung , Libutti Steven K. , Moghe Prabhas V. , Francis Nicola L. , Ganapathy Vidya
Published: April 2021

Late-stage diagnosis of ovarian cancer drastically lowers 5-year survival rate from 90% to 30%. Early screening tools that use non-invasive sampling methods combined with high specificity and sensitivity can significantly increase survival. Emerging research employing blood-based screening tools have shown promise in non-invasive detection of cancer. Our findings in this study show the potential of a small extracellular vesicle (sEV)-derived signature as a non-invasive longitudinal screening tool in ovarian cancer. We identified a 7-gene panel in these sEVs that overlapped with an established tissue-derived metastatic ovarian carcinoma signature. We found the 7-gene panel to be differentially expressed with tumor development and metastatic spread. While there were quantifiable changes in genes from the 7-gene panel in plasma-derived sEVs from ovarian cancer patients, we were unable to establish a definitive signature due to low sample number. The most notable finding was a significant change in the ascites-derived sEV gene signature that overlapped with that of the plasma-derived sEV signature at varying stages of disease progression. Taken together our findings show that differential expression of metastatic genes derived from circulating sEVs present a minimally invasive screening tool for ovarian cancer detection and longitudinal monitoring of molecular changes associated with progression and metastatic spread.
Multiple morphogens and rapid elongation promote segmental patterning during development
Authors: Qiu Yuchi , Fung Lianna , Schilling Thomas F. , Nie Qing
Published: April 2021

The vertebrate hindbrain is segmented into rhombomeres (r) initially defined by distinct domains of gene expression. Previous studies have shown that noise-induced gene regulation and cell sorting are critical for the sharpening of rhombomere boundaries, which start out rough in the forming neural plate (NP) and sharpen over time. However, the mechanisms controlling simultaneous formation of multiple rhombomeres and accuracy in their sizes are unclear. We have developed a stochastic multiscale cell-based model that explicitly incorporates dynamic morphogenetic changes (i.e. convergent-extension of the NP), multiple morphogens, and gene regulatory networks to investigate the formation of rhombomeres and their corresponding boundaries in the zebrafish hindbrain. During pattern initiation, the short-range signal, fibroblast growth factor (FGF), works together with the longer-range morphogen, retinoic acid (RA), to specify all of these boundaries and maintain accurately-sized segments with sharp boundaries. At later stages of patterning, we show a nonlinear change in the shape of rhombomeres with rapid left-right narrowing of the NP followed by slower dynamics. Rapid initial convergence improves boundary sharpness and segment size by regulating cell sorting and cell fate both independently and coordinately. Overall, multiple morphogens and tissue dynamics synergize to regulate the sizes and boundaries of multiple segments during development.

Author Summary

In segmental pattern formation, chemical gradients control gene expression in a concentration-dependent manner to specify distinct gene expression domains. Despite the stochasticity inherent to such biological processes, precise and accurate borders form between segmental gene expression domains. Previous work has revealed synergy between gene regulation and cell sorting in sharpening borders that are initially rough. However, it is still poorly understood how size and boundary sharpness ofmultiplesegments are regulated in a tissue that changes dramatically in its morphology as the embryo develops. Here we develop a stochastic multiscale cell-base model to investigate these questions. Two novel strategies synergize to promote accurate segment formation, a combination of long- and short-range morphogens plus rapid tissue convergence, with one responsible for pattern initiation and the other enabling pattern refinement.
HSP90 inhibitors reduce cholesterol storage in Niemann-Pick type C1 mutant fibroblasts
Authors: Pipalia Nina H. , Saad Syed Z. , Subramanian Kanagaraj , Cross Abigail , al-Motawa Aisha , Garg Kunal , Blagg Brian S.J. , Neckers Len , Helquist Paul , Wiest Olaf , Ory Daniel S. , Maxfield Frederick R.
Published: April 2021

Niemann Pick type C1 (NPC1) disease is a lysosomal lipid storage disorder caused by mutations of theNPC1gene. More than 300 disease-associated mutations are reported in patients, resulting in abnormal accumulation of unesterified cholesterol, glycosphingolipids and other lipids in late endosomes and lysosomes (LE/Ly) of many cell types. Previously, we showed that treatment of many differentNPC1mutant fibroblasts with histone deacetylase inhibitors resulted in reduction of cholesterol storage, and we found that this was associated with enhanced exit of the NPC1 protein from the endoplasmic reticulum and delivery to LE/Ly. This suggested that histone deacetylase inhibitors may work through changes in protein chaperones to enhance the folding of NPC1 mutants, allowing them to be delivered to LE/Ly. In this study we evaluated the effect of several HSP90 inhibitors on NPC1I1061Tskin fibroblasts. We found that HSP90 inhibition resulted in clearance of cholesterol from LE/Ly, and this was associated with enhanced delivery of the mutant NPC1I1061Tprotein to LE/Ly. We also observed that inhibition of HSP90 increased the expression of HSP70, and overexpression of HSP70 also reduced cholesterol storage inNPC1I1061Tfibroblasts. However, we did not see correction of cholesterol storage by arimoclomol, a drug that is reported to increase HSP70 expression, at doses up to 0.5 mM. These results indicate that manipulation of molecular chaperones may lead to effective treatments for NPC1 disease, but further investigation of mechanisms will be required.
Sick and Tired: Polyparasitism, Food Stress and Sickness Behaviour in a Gregarious Mammal
Authors: Blersch Rosemary , Bonnell Tyler R. , Ganswindt Andre , Young Christopher , Barrett Louise , Peter Henzi S.
Published: April 2021

Although sickness behaviour in response to non-lethal parasites has been documented in wild animals, it remains unclear how social and environmental stress might also shape an animal’s behavioural response to parasitism, nor do we know whether simultaneous infection with more than one parasite changes the way animals respond. Here, we combine physiological, environmental, behavioural and parasite measures to investigate behavioural responses to infection in wild vervet monkeys (Chlorocebus pygerythrus) living in a semi-arid region of South Africa. We quantified both activity budget and behavioural predictability to investigate the occurrence of sickness behaviour and infection with two non-lethal gastrointestinal parasite genera. Higher parasite load was linked to an increase in the time spent resting. However, the nature of the relationship with other behaviours was contingent on both the parasite genus in question, and how parasite species interacted, highlighting the importance of considering co-infection. Overall, food availability was the dominant predictor of behavioural change suggesting that, for monkeys living in a more extreme environment, coping with ecological stress may override the ability to modulate behaviour in response to other physiological stressors. Our findings provide insight into how animals living in harsh environments find ways to cope with parasite infection, avoidance, and transmission.
Lipid droplets modulate proteostasis, SQST-1/SQSTM1 dynamics, and lifespan inC. elegans
Authors: Kumar Anita V. , Mills Joslyn , Parker Wesley M. , Leitão Joshua A. , Rodriguez Diego I. , Ng Celeste , Patel Rishi , Aguilera Joseph L. , Johnson Joseph R. , Wong Shi Quan , Lapierre Louis R.
Published: April 2021

The ability of organisms to live long depends largely on the maintenance of proteome stability via proteostatic mechanisms including translational regulation, protein chaperoning and degradation machineries. In several long-livedCaenorhabditis elegansstrains, such as insulin/IGF-1 receptordaf-2mutants, enhanced proteostatic mechanisms are accompanied by elevated intestinal lipid stores, but the role of lipid droplets in longevity has remained obscure. Here, while determining the regulatory network of the selective autophagy receptor SQST-1/SQSTM1, we unexpectedly uncovered a novel role for lipid droplets in proteostasis and longevity. Using an unbiased genome-wide RNAi screening approach, we identified several SQST-1 modulators, including proteins found on lipid droplets and those prone to aggregate with age. SQST-1 accumulated on lipid droplets when autophagy was inhibited, suggesting that lipid droplets may serve a role in facilitating selective autophagy. Expansion of intestinal lipid droplets by silencing the conserved cytosolic triacylglycerol lipase geneatgl-1/ATGLenhanced autophagy, and extended lifespan in an HSF-1/HSF1-dependent and CDC-48/VCP-dependent manner. Silencingatgl-1mitigated the age-related accumulation of SQST-1 and reduced overall ubiquitination of proteins. Reducingatgl-1also improved proteostasis in proteotoxicity models of neurodegenerative diseases. Subcellular analyses revealed that lipid droplets unexpectedly harbor more soluble ubiquitinated proteins than the cytosol. Accordingly, low lipid droplet levels exacerbated the proteostatic collapse when autophagy or proteasome function was compromised. Altogether, our study uncovers a key role for lipid droplets inC. elegansas a proteostatic mediator that reduces protein ubiquitination, facilitates autophagy, and promotes longevity.
Fauxcurrence: simulating multi-species occurrences for null models in species distribution modelling and biogeography
Authors: Osborne Owen G. , Fell Henry G. , Atkins Hannah , van Tol Jan , Phillips Daniel , Herrera-Alsina Leonel , Mynard Poppy , Bocedi Greta , Gubry-Rangin Cécile , Lancaster Lesley T. , Creer Simon , Nangoy Meis , Fahri Fahri , Lupiyaningdyah Pungki , Sudiana I Made , Juliandi Berry , Travis Justin M.J. , Papadopulos Alexander S.T. , Algar Adam C.
Published: April 2021

Defining appropriate null expectations for species distribution hypotheses is important because sampling bias and spatial autocorrelation can produce realistic, but ecologically meaningless, geographic patterns. Generating null species occurrences with similar spatial structure to observed data can help overcome these problems, but existing methods focus on single or pairs of species and do not incorporate between-species spatial structure that may occlude comparative biogeographic analyses. Here, we describe an algorithm for generating randomised species occurrence points that mimic the within- and between-species spatial structure of real datasets and implement it in a new R package -fauxcurrence. The algorithm can be implemented on any geographic domain for any number of species, limited only by computing power. To demonstrate its utility, we apply the algorithm to two common analysis-types: testing the fit of species distribution models (SDMs) and evaluating niche-overlap. The method works well on all tested datasets within reasonable timescales. We found that many SDMs, despite a good fit to the data, were not significantly better than null expectations and identified only two cases (out of a possible 32) of significantly higher niche divergence than expected by chance. The package is user-friendly, flexible and has many potential applications beyond those tested here, such as joint SDM evaluation and species co-occurrence analysis, spanning the areas of ecology, evolutionary biology and biogeography.