bluuebunny/crossref_metadata_2025 huggingface dataset:
Feasibility of Deep Learning-Guided Attenuation and Scatter Correction of Whole-Body 68Ga-PSMA PET Studies in the Image Domain
Authors: Mostafapour Samaneh , Gholamiankhah Faeze , Dadgar Habibollah , Arabi Hossein , Zaidi Habib
Published: March 2021

Objective

This study evaluates the feasibility of direct scatter and attenuation correction of whole-body 68Ga-PSMA PET images in the image domain using deep learning.

Methods

Whole-body 68Ga-PSMA PET images of 399 subjects were used to train a residual deep learning model, taking PET non–attenuation-corrected images (PET-nonAC) as input and CT-based attenuation-corrected PET images (PET-CTAC) as target (reference). Forty-six whole-body 68Ga-PSMA PET images were used as an independent validation dataset. For validation, synthetic deep learning–based attenuation-corrected PET images were assessed considering the corresponding PET-CTAC images as reference. The evaluation metrics included the mean absolute error (MAE) of the SUV, peak signal-to-noise ratio, and structural similarity index (SSIM) in the whole body, as well as in different regions of the body, namely, head and neck, chest, and abdomen and pelvis.

Results

The deep learning–guided direct attenuation and scatter correction produced images of comparable visual quality to PET-CTAC images. It achieved an MAE, relative error (RE%), SSIM, and peak signal-to-noise ratio of 0.91 ± 0.29 (SUV), −2.46% ± 10.10%, 0.973 ± 0.034, and 48.171 ± 2.964, respectively, within whole-body images of the independent external validation dataset. The largest RE% was observed in the head and neck region (−5.62% ± 11.73%), although this region exhibited the highest value of SSIM metric (0.982 ± 0.024). The MAE (SUV) and RE% within the different regions of the body were less than 2.0% and 6%, respectively, indicating acceptable performance of the deep learning model.

Conclusions

This work demonstrated the feasibility of direct attenuation and scatter correction of whole-body 68Ga-PSMA PET images in the image domain using deep learning with clinically tolerable errors. The technique has the potential of performing attenuation correction on stand-alone PET or PET/MRI systems.
COVID-19 Vaccine–Related Local FDG Uptake
Authors: Doss Mohan , Nakhoda Shazia K. , Li Yi , Yu Jian Q.
Published: March 2021

We present a case of increased FDG uptake in the lymph nodes after COVID-19 vaccine administration. Restaging PET/CT scan of a 70-year-old woman with a history of multiple relapsed Hodgkin lymphoma showed muscle activity in the left upper arm laterally, which is in the deep musculature of the left deltoid muscle. There was also increased activity in several normal-sized left axillary nodes as well. On further review of the patient’s history, she had received her second shot of the Pfizer-BioNTech COVID-19 vaccine approximately 2 days before the restaging PET/CT scan.
COVID-19 Vaccination Manifesting as Incidental Lymph Nodal Uptake on 18F-FDG PET/CT
Authors: Ahmed Najeeb , Muzaffar Samreen , Binns Corinne , Ilyas Muhammad Waqas , Usmani Sharjeel
Published: March 2021

Benign uptake on 18F-FDG PET can be seen with inflammatory conditions. We report a case of an 86-year-old woman with successfully treated nasal melanoma who underwent routine follow-up 18F-FDG PET, day 6 after the second dose of Pfizer-BioNTech COVID-19 vaccine inoculated in the left deltoid muscle. 18F-FDG PET showed increase tracer uptake in the left deltoid muscle and in 2 normal-sized left subpectoral nodes. These findings were considered secondary to vaccination. With the current drive of global COVID-19 immunization, this case highlights the importance of documenting vaccination history at the time of scanning to avoid false-positive results.
Donor Defect Morbidity of Intrinsic Flaps in the Posttraumatized Hand
Authors: Moog Philipp , Kükrek Haydar , Palm-Bröking Katrin , Kirkegaard Simone , Germann Günter , Betzl Julia , Megerle Kai
Published: March 2021

Introduction

There are many types of intrinsic flaps to cover wound defects on the hand, which have been well described in scientific literature. However, the donor sites are often neglected in such studies. Therefore, we aimed to evaluate donor site morbidity for homodigital island flaps, cross-finger flaps, Foucher's pedicle flaps, and flaps of the dorsal metacarpal artery system (DMCA).

Materials and Methods

A total of 106 intrinsic flap procedures were performed on 106 patients (16 women, 90 men). The donor sites were retrospectively followed up after an average of 3.4 years by a questionnaire, a Disability of the Arm, Shoulder and Hand score, and clinical examination. Donor sites of different flap types were compared for aesthetic outcome, trophic level, and sensation, including 2-point discrimination, temperature, sharp/dull discrimination, the Semmes-Weinstein monofilament test, pain (visual analog scale), and functionality.

Results

In general, primarily closed donor sites showed more favorable results than did grafted donor sites. Satisfaction among patients regarding aesthetics of the donor site was highest in patients who had received homodigital island flaps. Grip strength and pain at the operated hand were very heterogeneous and rather influenced by the primary trauma than the type of flap. Homodigital island flap donor sites demonstrated the best results for 2-point discrimination and sharp/dull discrimination, and those for DMCA flaps in the Semes-Weinstein test.

Conclusions

Overall, intrinsic flaps demonstrated low donor site morbidity with reliable coverage of the defects. Of these, the DMCA (especially after primary closure) and homodigital island flaps seemed to produce the best donor site results.
Early Surgical Treatment of Both Tumor and Fracture in Patients With Enchondroma of the Hand Combined With Pathologic Fracture
Authors: Li Qingyuan , Kim Jihyeung , Kim Sang Yoon , Baek Goo Hyun
Published: March 2021

Purpose

The aims of this study were to evaluate the degree of cortical thinning and the tumor area in simple radiographs in patients with enchondroma of the hand combined with pathologic fracture and to determine the surgical outcome of simultaneous tumor curettage and internal fixation of fracture.

Methods

We enrolled 23 bone lesions of 21 patients diagnosed with enchondroma of the hand. Of them, 9 bone lesions of 8 patients had pathologic fracture. We evaluated the degree of cortical thinning and tumor area in simple radiographs and compared them between patients with and without pathologic fracture. For patients with pathologic fracture, we performed curettage of the tumor through the fracture site and fixed the fracture using K-wires. We then evaluated the clinical outcome of these patients using the visual analog scale to measure pain intensity and Takigawa's criteria 1 year after surgery.

Results

There was a significant difference in the degree of cortical thinning between the 2 groups (P < 0.001); however, there was no significant difference in the percentage of tumor area (P = 0.259). The average time from surgery to bony union was 8.5 weeks in patients with pathologic fracture. The patients reported that they could return to their previous activities of daily living within 12 weeks of surgery. The average visual analog scale score was 0.6 at 1 year after surgery, and 6 patients were graded as excellent and 2 as good according to Takigawa's criteria.

Conclusions

Cortical thinning seems to be related to pathologic fracture. Our scoring system for cortical thinning may be helpful in evaluating the risk for pathologic fracture. Early 1-stage surgical treatment for pathologic hand fracture with enchondroma is a very useful method with satisfactory outcomes that could shorten the treatment period.
Donor Site Wound Healing in Radial Forearm Flap
Authors: Di Giuli Riccardo , Dicorato Paolo , Kaciulyte Juste , Marinari Niccolò , Conversi Francesco , Mazzocchi Marco
Published: March 2021

Radial forearm flap (RFF) is one of the most used flaps in reconstructive surgery. Despite its versatility and effectiveness, the donor site is affected by aesthetic and functional issues. In the group of techniques described to improve the donor site morbidity, dermal substitutes offer a valid approach in the wound management. A bilayered bioresorbable dermal substitute (Hyalomatrix) was used to provide the primary coverage of the RFF harvest site followed after 3 weeks by a split-thickness skin graft placement. In this study, 37 patients underwent RFF donor site reconstruction and subjected to a minimum follow-up of 1 year. The dermal substitute was applied on 15 patients, and their outcomes were compared with the data achieved by 22 patients submitted to immediate reconstruction with autologous full-thickness skin graft. Results were documented by digital photographs, the visual analog scale, the Vancouver Scar Scale, and the Disabilities of the Arm, Shoulder, and Hand questionnaire. Data were analyzed and compared through statistical analysis. Total wound coverage was achieved in 4 to 6 weeks, and no tendon impairments were reported in the dermal substitute group. In our experience, the use of the dermal substitute is a valuable mean to minimize RFF donor site morbidity with excellent functional and aesthetic outcomes.
Tibialis Posterior Tendon Transfers to Correct Bilateral Postburn Ankle Equinus
Authors: Chee Shu Ying , McKenna Johnny , Shelley Odhran P.
Published: March 2021

Treatment of joint contractures after burn injury is challenging because various factors influence the treatment options including the lack of local tissue, significant fibrotic changes with associated loss of joint pliability, increased prevalence of infection in burn patients, and patient-related medical comorbidities.

We present a case of a 60-year-old woman who had severe bilateral postburn ankle equinus deformities after self-immolation in the setting of significant soft tissue injury, fibrosis, and loss of joint movement. This deformity deprived her of the ability to walk, even aided, and she was unable to progress with her rehabilitation. We used the tibialis posterior tendon transfer to completely correct her postburn ankle equinus allowing for the restoration of both her feet to a neutral position, which enabled the patient to walk unaided after the surgery. This is a simple and effective solution to a complex problem when soft tissue reconstruction is limited. Patients with this complication are wheelchair dependent, and we suggest that posterior tibialis transfer should be considered as a surgical intervention for burns with severe equinus contracture even if there is a fixed deformity to allow for their full rehabilitation after injury.
Surgical Team Trips to Vietnam
Authors: Sue Gloria R. , Deptula Peter L. , Chang James
Published: March 2021

Background

ReSurge International is a nongovernmental organization that organizes surgical team trips to low- and middle-income countries. Cleft palate repair is commonly performed on these trips. A comprehensive cleft care program was implemented to help reduce postoperative palatal fistula rates.

Methods

A retrospective review of all patients undergoing cleft palate repair surgery with ReSurge International in Vietnam from 2013 through 2019 was performed. The cleft care program was implemented in 2018. This intervention involved preoperative education of patients and close postoperative monitoring. Critically, this program also provided closer access to providers. Subsequent follow-up was performed by a ReSurge physician. Parent-reported outcomes were assessed preoperatively and postoperatively using 5-point Likert-like survey questions.

Results

Two hundred three patients underwent cleft palate repair. The patients were older and of higher Veau classification than is usually seen in the United States. The palatal fistula rate in the preintervention group was 37.5% and 14.3% in the intervention group (P = 0.014). Patients without fistulas demonstrated improvements on parent-reported outcomes compared with those with fistulas, with food less likely to go up their nose (P < 0.001), less difficulty eating (P < 0.001), and more understandable speech (P = 0.015).

Conclusions

Implementation of a comprehensive cleft palate program reduced postoperative fistula rates by more than 50%. Improvements in parent-reported outcomes were observed after surgery among patients without fistulas. The blueprint for improved outcomes in these more complex patients includes enhanced perioperative patient counseling, close follow-up, and maintenance of communication with patients.
Surgical Lymphoedema Treatment of Morbihan Disease
Authors: Hattori Yoshitsugu , Hino Haruko , Niu Atsushi
Published: March 2021

Morbihan disease is a rare condition characterized by persistent erythema and solid edema of the upper two thirds of the face, leading to visual impairment and significant esthetic disfigurement. The underlying etiology of the disease remains uncertain, but its correlation with lymphoedema has been conjectured. Definitive treatment options are also lacking, and most current topical, systemic, and surgical interventions provide transient or partial results.

In this report, we describe a case of Morbihan disease in a 32-year-old man. He suffered from erythema and swelling over the left periorbital region for 6 years, and was diagnosed with Morbihan disease. As the edema was unresponsive to drug therapy, he was referred to our department. Indocyanine green lymphography was performed, and the diagnosis of facial lymphoedema was confirmed. Manual lymphatic drainage was not effective, so we proceeded with surgical procedures. Lymphaticovenous anastomosis was performed to improve lymphatic drainage, and blepharoplasty was performed to debulk the enlarged tissue of lymphoedema. The visual field improved significantly, and the patient remains free from reexpansion of the lesion during the 1-year follow-up.

The surgical approach for lymphoedema treatment can be a viable option for severe Morbihan disease unresponsive to nonsurgical therapies.
Outcomes Associated With Norepinephrine Use Among Cardiac Intensive Care Unit Patients with Severe Shock
Authors: Burstein Barry , Vallabhajosyula Saraschandra , Ternus Bradley , Murphree Dennis , Barsness Gregory W. , Kashani Kianoush , Jentzer Jacob C.
Published: March 2021

Background:

Recent data suggests improved outcomes among cardiac intensive care unit (CICU) patients treated with norepinephrine, especially patients with severe shock. We aimed to describe the association between norepinephrine and mortality in CICU patients with severe shock, defined as those requiring high-dose vasopressors (HDV).

Materials and Results:

We retrospectively evaluated Mayo Clinic CICU patients treated with vasopressors from 2007 to 2015. HDV was defined as a peak Cumulative Vasopressor Index of four for any vasopressor. Peak norepinephrine equivalent (NEE) dose was used to compare vasopressor doses. Multivariable logistic regression was used to determine predictors of hospital mortality.

Results:

We included 2,090 patients with a median age of 69 years (IQR 59–78), including 35% females; 44% of patients received HDV. Hospital mortality was higher among patients receiving HDV (42% vs. 16%, unadjusted OR 3.87, 95% CI 3.16–4.75, P < 0.01). On multivariable analysis in HDV patients, hospital mortality increased with rising peak NEE (adjusted OR 1.02 per 0.01 mcg/kg/min, 95% CI 1.01–1.02, P 
< 0.01) and the use of NE was associated with lower hospital mortality (adjusted OR 0.46, 95% CI 0.31–0.72, P < 0.01). After adjustment for illness severity, peak NEE and norepinephrine use were not associated with mortality among patients who did not require HDV.

Conclusions:

Mortality is high among CICU patients requiring HDV, and rises with increasing vasopressor requirements. Use of NE was associated with lower mortality among patients requiring HDV, but not among those without HDV, implying that patients with more severe shock may benefit from preferential use of NE.
Escalation and Withdrawal of Treatment for Patients on Extracorporeal Membrane Oxygenation
Authors: Hadler Rachel A. , Clapp Justin T. , Chung Jamison J. , Gutsche Jacob T. , Fleisher Lee A.
Published: March 2021

Objective:

The aim of this study was to describe decisions about the escalation and withdrawal of treatment for patients on extracorporeal membrane oxygenation (ECMO).

Summary Background Data:

Interventions premised on facilitating patient autonomy have proven problematic in guiding treatment decisions in intensive care units (ICUs). Calls have thus been made to better understand how decisions are made in critical care. ECMO is an important form of cardiac and respiratory support, but care on ECMO is characterized by prognostic uncertainty, varying time course, and high resource use. It remains unclear how decisions about treatment escalation and withdrawal should be made for patients on ECMO and what role families should play in these decisions.

Methods:

We performed a focused ethnography in 2 cardiothoracic ICUs in 2 US academic hospitals. We conducted 380 hours of observation, 34 weekly interviews with families of 20 ECMO patients, and 13 interviews with unit clinicians from January to September 2018. Qualitative analysis used an iterative coding process.

Results:

Following ECMO initiation, treatment was escalated as complications mounted until the patient either could be decannulated or interventional options were exhausted. Families were well-informed about treatment and prognosis but played minimal roles in shaping the trajectory of care.

Conclusions:

Discussion between clinicians and families about prognosis and goals was frequent but did not occasion decision-making moments. This study helps explain why communication interventions intended to maintain patient autonomy through facilitating surrogate participation in decisions have had limited impact. A more comprehensive understanding of upstream factors that predispose courses of critical care is needed.
Long-term Home Video EEG for Recording Clinical Events
Authors: Jamal Omidi Shirin , Hampson Johnson P. , Lhatoo Samden D.
Published: March 2021

Around 50 years after the first EEG acquisition by Hans Berger, its use in ambulatory setting was demonstrated. Ever since, ambulatory EEG has been widely available and routinely used in the United States (and to a lesser extent in Europe) for diagnosis and management of patients with epilepsy. This technology alone cannot help with semiological characterization, and absence of video is one of its main drawbacks. Addition of video to ambulatory EEG potentially improves diagnostic yield and opens new aspects of utility for better characterization of patient's events, including differential diagnosis, classification, and quantification of seizure burden. Studies evaluating quality of ambulatory video EEG (aVEEG) suggest good quality recordings are feasible. In the utilization of aVEEG, to maximize yield, it is important to consider pretest probability. Having clear pretest questions and a strong index of suspicion for focal, generalized convulsive or non-epileptic seizures further increases the usefulness of aVEEG. In this article, which is part of the topical issue “Ambulatory EEG,” the authors compare long-term home aVEEG to inpatient video EEG monitoring, discuss aVEEG's use in diagnosis and follow-up of patients, and present the authors' own experience of the utility of aVEEG in a teaching hospital setting.
An updated assembly strategy helps parsing the cryptic mitochondrial genome evolution in plants
Authors: Feng Yanlei , Xiang Xiaoguo , Fu Zhixi , Pan Ronghui , Jin Xiaohua
Published: March 2021

Although plant mitogenomes are small in size, their variations are no less than any other complex genomes. They are under rapid structure and size changes. These characters make the assembly a great challenge. This caused two intertwined problems, a slow growth of known mitogenomes and a poor knowledge of their evolution. In many species, mitogenome becomes the last genome that undeciphered. To have a better understanding of these two questions, we developed a strategy using short sequencing reads and combining current tools and manual steps to get high quality mitogenomes. This strategy allowed us to assembled 23 complete mitogenomes from 5 families in Fagales. Our large-scale comparative genomic analyses indicated the composition of mitogenomes is very mosaic that “horizontal transfers” can be from almost all taxa in seed plants. The largest mitogenome contains more homologous DNA with other Fagales, rather than unique sequences. Besides of real HGTs, sometimes mitovirus, nuclear insertions and other third-part DNA could also produce HGT-like sequences, accounting partially for the unusual evolutionary trajectories, including the cryptic size expansion inCarpinus. Mitochondrial plasmid was also found. Its lower GC content indicates that it may be only an interphase of a foreign DNA before accepting by the main chromosome. Our methods and results provide new insights into the assembly and mechanisms of mitogenome evolution.
Comparative Population Genetics in the Human Gut Microbiome
Authors: Shoemaker William R. , Chen Daisy , Garud Nandita R.
Published: March 2021

The genetic variation in the human gut microbiome is responsible for conferring a number of crucial phenotypes like the ability to digest food and metabolize drugs. Yet, our understanding of how this variation arises and is maintained remains relatively poor. Thus, the microbiome remains a largely untapped resource, as the large number of co-existing species in this microbiome presents a unique opportunity to compare and contrast evolutionary processes across species to identify universal trends and deviations. Here we outline features of the human gut microbiome that, while not unique in isolation, as an assemblage make it a system with unparalleled potential for comparative population genomics studies. We consciously take a broad view of comparative population genetics, emphasizing how sampling a large number of species allows researchers to identify universal evolutionary dynamics in addition to new genes, which can then be leveraged to identify exceptional species that deviate from general patterns. To highlight the potential power of comparative population genetics in the microbiome, we re-analyzed patterns of purifying selection across ~40 prevalent species in the human gut microbiome to identify intriguing trends which highlight functional categories in the microbiome that may be under more or less constraint.
Ribovirus classification by a polymerase barcode sequence
Authors: Babaian Artem , Edgar Robert C.
Published: March 2021

RNA viruses encoding a polymerase gene (riboviruses) dominate the known
eukaryotic virome. Next-generation sequencing is revealing a wealth of new
riboviruses with uncharacterised phenotypes, precluding classification by
traditional taxonomic methods. These are often classified on the basis of
polymerase sequence identity, but standardised methods to support this approach
are currently lacking. To address this need, we describe the polymerase
palmprint, a well-defined segment of the palm sub-domain delineated by
well-conserved catalytic motifs. We present a novel algorithm,
Palmscan, which identifies palmprints in
nucleotide and amino acid sequences. We describe PALMdb, a reference database of
palmprints derived from public sequence databases.
Palmscan source code and PALMdb data are
deposited at https://github.com/rcedgar/palmscan and https://github.com/rcedgar/palmdb, respectively.
Metabolic independence drives gut microbial colonization and resilience in health and disease
Authors: Watson Andrea R. , Füssel Jessika , Veseli Iva , DeLongchamp Johanna Zaal , Silva Marisela , Trigodet Florian , Lolans Karen , Shaiber Alon , Fogarty Emily , Runde Joseph M. , Quince Christopher , Yu Michael K. , Söylev Arda , Morrison Hilary G. , Lee Sonny T.M. , Kao Dina , Rubin David T. , Jabri Bana , Louie Thomas , Eren A. Murat
Published: March 2021

Changes in microbial community composition as a function of human health and disease states have sparked remarkable interest in the human gut microbiome. However, establishing reproducible insights into the determinants of microbial succession in disease has been a formidable challenge. Here we use fecal microbiota transplantation (FMT) as an in natura experimental model to investigate the association between metabolic independence and resilience in stressed gut environments. Our genome-resolved metagenomics survey suggests that FMT serves as an environmental filter that favors populations with higher metabolic independence, the genomes of which encode complete metabolic modules to synthesize critical metabolites, including amino acids, nucleotides, and vitamins. Interestingly, we observe higher completion of the same biosynthetic pathways in microbes enriched in IBD patients. These observations suggest a general mechanism that underlies changes in diversity in perturbed gut environments, and reveal taxon-independent markers of ‘dysbiosis’ that may explain why widespread yet typically low abundance members of healthy gut microbiomes can dominate under inflammatory conditions without any causal association with disease.
The “two-brain” approach reveals the active role of task-deactivated default mode network in speech comprehension
Authors: Liu Lanfang , Li Hehui , Ren Zhiting , Zhou Qi , Zhang Yuxuan , Lu Chunming , Qiu Jiang , Chen Hong , Ding Guosheng
Published: March 2021

During speech comprehension, as listeners need to keep tracking the external audio streams, the default mode network (DMN) is often de-activated and anticorrelated with task-positive networks. Such a pattern has been interpreted as the suppression of the DMN to support externally-oriented cognitive processes. Taking a “two-brain” approach, the current study demonstrated that, despite exhibiting deactivation and anticorrelated with the language network and executive control network, the DMN was not suppressed but played an active role in spoken narrative comprehension. This was evidenced by significant listener-speaker neural couplings in both the posterior and anterior DMN and the positive correlation between the coupling strength and listener’s speech comprehension. Moreover, we demonstrated that the functionality of posterior DMN depended on its interaction with the executive control network, rather than its level of activation. Finally, Dynamic Causal Modeling together with the two-brain results indicates the language and executive control networks, the anterior DMN, and the posterior DMN occupied the bottom, intermediate and top layers of a hierarchical system, respectively. These results suggest that the DMN may primarily serve as an internally-oriented system that cooperates with the externally-oriented networks, which may allow the transformation of external acoustic signals into internal mental representations during language comprehension.
A Dose-Response Model and D10-Value forMycobacterium tuberculosisExposed to Dosimetrically Verified Ionizing Radiation
Authors: Watkins Jackson V , Bell Justin , Knabenbauer Phillip , Brandl Alexander , Dobos Karen M
Published: March 2021

Techniques for pathogen inactivation have been employed by laboratories to help ease the financial, physical, and health strains associated with (A)BSL-3 work. Exposure to radiation is the most common and useful of these methods to inactivate pathogens grown in large-scale culture. While robust protocols exist for radiation exposure techniques, there are variances in methods used to determine the radiation dose and dose rate required to inactivate pathogens. Furthermore, previous studies often do not include radiation dosimetry verification or address corresponding dosimetry uncertainties for dose response-assays. Accordingly, this study was conducted with the purpose of completing a dosimetry assessment of the radiation field within the sample chamber of a sealed source irradiator, to subsequently determine the radiation dose required to inactivate pathogenic cultures. Physical dosimetry techniques (Fricke dosimetry, ion chamber measurements, and measurements with thermoluminescent dosimeters) were used to measure dose rate and rate variances within the sample chamber. By comparing the variances between the dosimetry methodologies and measurements, an estimated dose rate within the sample chamber was determined. The results of the dosimetry evaluation were used to determine the radiation dose samples ofMycobacterium tuberculosisreceived, to accurately associate biological markers of inactivation to specific doses of ionizing radiation. A D10value and dose-response curve were developed to describe the inactivation ofMtbfrom increasing doses of ionizing radiation. The D10value is experimentally relevant for comparative analysis and potentially provides a biological baseline for inactivation verification. This methodology can also easily be translated to other pathogen models.

Importance

This work set out to give us a better understanding of how much radiation is required to inactivateMycobacterium tuberculosis, the bacteria that causes tuberculosis disease. Radiation dose from a source is not something that can just be inputted, it must be calculated, so we also determined the approximate dose from the source to address ambiguities that had previously existed while inactivating microbes. We were able to generate an accurate description of inactivation ofMycobacterium tuberculosisby correlating it with a value representing 90% death of the treated cells. We also unexpectedly discovered that very low levels of radiation increase certain activity within the cell. This is important because it allows us to better understand how radiation killsMycobacterium tuberculosis, and gives us a value to compare to other organisms. It also offers other researchers a method to use under their own specific conditions.
Evidence of post-domestication hybridization and adaptive introgression in Western European grapevine varieties
Authors: Freitas S. , Gazda M.A. , Rebelo M. , Muñoz-Pajares A.J. , Vila-Viçosa C. , Muñoz-Mérida A. , Gonçalves L.M. , Azevedo-Silva D. , Afonso S. , Castro I. , Castro P.H. , Sottomayor M. , Beja-Pereira A. , Tereso J. , Ferrand N. , Gonçalves E. , Martins A. , Carneiro M. , Azevedo H.
Published: March 2021

Grapevine (Vitis viniferaL.) is one of the most significant crops in the world. Today’s richness in grapevine diversity results from a complex domestication history over multiple historical periods. Here, we employed whole genome resequencing to elucidate different aspects of the recent evolutionary history of this crop. Our results support a model in which a central domestication event in grapevine was followed by post-domestication hybridization with local wild genotypes, leading to the presence of an introgression signature in modern wine varieties across Western Europe. The strongest signal was associated with a subset of Iberian grapevine varieties, which show large introgression tracts. We targeted this study group for further analysis, demonstrating how regions under selection in wild populations from the Iberian Peninsula were preferentially passed on to the cultivated varieties by geneflow. Examination of underlying genes suggests that environmental adaptation played a fundamental role in both the evolution of wild genotypes and the outcome of hybridization with cultivated varieties, supporting a case of adaptive introgression in grapevine.
Laminar-specific functional connectivity mapping with multi-slice line-scanning fMRI
Authors: Choi Sangcheon , Zeng Hang , Chen Yi , Sobczak Filip , Qian Chunqi , Yu Xin
Published: March 2021

Laminar BOLD-fMRI has been applied to better depict the neuronal input and output circuitry and functional connectivity across cortical layers by measuring local hemodynamic changes. Despite extensive studies detecting laminar fMRI signals to illustrate the canonical microcircuit, the spatiotemporal characteristics of laminar-specific information flow across different cortical regions remain to be fully investigated in both evoked and resting states. Here, we developed a multi-slice line-scanning fMRI (MS-LS) method to detect laminar fMRI signals in adjacent cortical regions with high spatial (50 µm) and temporal resolution (100 ms) in anesthetized rats. Across different scanning trials, we detected both laminar-specific positive and negative BOLD responses in the surrounding cortical region adjacent to the most activated cortex under evoked condition. Specifically, in contrast to the typical Layer (L) 4 correlation across different regions due to the thalamocortical projections for trials with positive BOLD, a strong correlation pattern specific in L2/3 was detected for the trials with negative BOLD in adjacent regions, which indicate a brain state-dependent laminar-fMRI responses based on cortiocotical interaction from different trials. Also, we acquired the laminar-specific rs-fMRI signals across different cortical regions, of which the high spatiotemporal resolution allows us to estimate lag times based on the maximal cross-correlation of laminar-specific rs-fMRI signals. In contrast to the larger variability of lag times in L1 and 6, robust lag time differences in L2/3, 4, and 5 across multiple cortices represented the low-frequency rs-fMRI signal propagation from the caudal to the rostral slice. In summary, our work provides a unique laminar fMRI mapping scheme to better characterize trial-specific intra- and inter-laminar functional connectivity with MS-LS, presenting layer-specific spatiotemporal variation of both evoked and rs-fMRI signals.
Loneliness and the social brain: how perceived social isolation impairs human interactions
Authors: Lieberz Jana , Shamay-Tsoory Simone G. , Saporta Nira , Esser Timo , Kuskova Ekaterina , Stoffel-Wagner Birgit , Hurlemann René , Scheele Dirk
Published: March 2021

Loneliness is a painful condition associated with increased risk for premature mortality. The formation of new, positive social relationships can alleviate feelings of loneliness, but requires rapid trustworthiness decisions during initial encounters and it is still unclear how loneliness hinders interpersonal trust. Here, we use a multimodal approach including behavioral, psychophysiological, hormonal, and neuroimaging measurements to probe a trust-based mechanism underlying impaired social interactions in loneliness. Pre-stratified healthy individuals with high loneliness scores (n= 42 out of a screened sample of 3678 adults) show reduced oxytocinergic and affective responsiveness to a positive conversation, report less interpersonal trust, and prefer larger social distances compared to controls (n= 40). Moreover, lonely individuals are rated as less trustworthy compared to controls and identified by the blinded confederate better than chance. During initial trust decisions, lonely individuals exhibit attenuated limbic and striatal activation and blunted functional connectivity between the anterior insula and occipitoparietal regions, which correlates with the diminished affective responsiveness to the positive social interaction. This neural response pattern is not mediated by loneliness-associated psychological symptoms. Thus, our results indicate compromised integration of trust-related information as a shared neurobiological component in loneliness, yielding a reciprocally reinforced trust bias in social dyads.
Structures of ABCG2 under turnover conditions reveal a key step in drug transport mechanism
Authors: Yu Qin , Ni Dongchun , Kowal Julia , Manolaridis Ioannis , Jackson Scott M. , Stahlberg Henning , Locher Kaspar P.
Published: March 2021

ABCG2 is a multidrug transporter expressed widely in the human body. Its physiological substrates include steroid derivatives and uric acid. In addition, it extrudes many structurally diverse cytotoxic drugs from various cells, thus affecting drug pharmacokinetics and contributing to multidrug resistance of cancer cells. Previous studies have revealed structures of ABCG2 bound to transport substrates, nucleotides, small-molecule inhibitors and inhibitory antibodies. However, the transport mechanism is not well-understood because all previous structures described trapped states, where the reaction cycle was halted by the absence of substrates or ATP, mutation of catalytic residues, or the presence of inhibitors. Here we present cryo-EM structures of nanodisc-reconstituted human ABCG2 under turnover conditions containing either the endogenous substrate estrone-3-sulfate or the exogenous substrate topotecan. We found two distinct conformational states in which both the transport substrates and ATP are bound. Whereas the state turnover-1 features more widely separated NBDs and an accessible cavity between the TMDs, turnover-2 features semi-closed NBDs and an almost fully occluded cavity between the TMDs. The transition from turnover-1 to turnover-2 includes conformational changes that link the binding of ATP by the NBDs to the closing of the cytoplasmic side of the TMDs. The size of the substrate appears to control which turnover state corresponds to the main state in the transport cycle. The transition from turnover-1 to turnover-2 is the likely bottleneck or rate-limiting step of the reaction cycle, where the discrimination of substrates and inhibitors occurs. Our results provide a structural basis of substrate specificity of ABCG2 and provide key insight to understand the transport cycle.
Contribution of epigenetic changes to escape from X-chromosome inactivation
Authors: Balaton Bradley P. , Brown Carolyn J.
Published: March 2021

Background

X-chromosome inactivation (XCI) is the epigenetic inactivation of one of two X chromosomes in XX eutherian mammals. The facultatively heterochromatic inactive X chromosome acquires many chromatin changes including DNA methylation and histone modifications. Despite these changes, some genes escape or variably escape from inactivation, and to the extent that they have been studied, epigenetic marks correlate with expression.

Results

We downloaded data from the International Human Epigenome Consortium and compared previous XCI status calls to DNA methylation, H3K4me1, H3K4me3, H3K9me3, H3K27ac, H3K27me3 and H3K36me3. At genes subject to XCI we found heterochromatic marks enriched, and euchromatic marks depleted on the inactive X when compared to the active X. Similar results were seen for genes escaping XCI although with diminished effect with H3K27me3 being most enriched. Using sample-specific XCI status calls made using allelic expression or DNA methylation we also compared differences between samples with opposite XCI statuses at variably escaping genes. We found some marks significantly differed with XCI status, but which marks were significant was not consistent between genes. We trained a model to predict XCI status from these epigenetic marks and obtained over 75% accuracy for genes escaping and over 90% for genes subject to XCI. This model allowed us to make novel XCI status calls for genes without allelic differences or CpG islands required for other XCI status calling methods. Using these calls to examine a domain of variably escaping genes, we saw XCI status vary at the level of individual genes and not at the domain level.

Conclusion

Here we show that epigenetic marks differ between genes that are escaping and those subject to XCI, and that genes escaping XCI still differ between the active and inactive Xs. We show epigenetic differences at variably escaping genes, between samples escaping and those subject to XCI. Lastly we show gene-level regulation of variably escaping genes within a domain.
Extensive structural remodeling of the axonal arbors of parvalbumin basket cells during development
Authors: Micheva Kristina D. , Kiraly Marianna , Perez Marc M. , Madison Daniel V.
Published: March 2021

Parvalbumin-containing (PV+) basket cells are specialized cortical interneurons that regulate the activity of local neuronal circuits with high temporal precision and reliability. PV+ interneuron disfunction is associated with numerous psychiatric disorders, including schizophrenia and autism spectrum disorders. To understand how the PV+ interneuron connectivity underlying their functional properties is established during development, we used array tomography to map pairs of synaptically connected PV+ interneurons and postsynaptic neurons from the neocortex of mice of both sexes. We focused on the axon-myelin unit of the PV+ interneuron and quantified the number of synapses onto the postsynaptic neuron, length of connecting axonal paths, and their myelination at different time points between 2 weeks and 7 months of age. We find that myelination of the proximal axon occurs very rapidly during the third postnatal week and precedes a massive synapse pruning which takes place in the 4th postnatal week leading to about three-fold reduction of synaptic contacts made by the PV+ interneuron on its postsynaptic partner. Autapses, the synapses that PV+ interneurons form on themselves, however, are not subjected to pruning. Axon reorganizations continue beyond postnatal month 2, with the postsynaptic targets of PV+ interneurons gradually shifting to more proximal locations, and the length of axonal paths and their myelin becoming conspicuously uniform per connection. These continued microcircuit refinements likely provide the structural substrate for the robust inhibitory effects and fine temporal precision of PV+ basket cells.

Significance statement

The axon of adult parvalbumin-containing (PV+) interneurons is highly specialized for fast and reliable neurotransmission. It is myelinated and forms synapses mostly onto the cell bodies and proximal dendrites of postsynaptic neurons for maximal impact. In this study we follow the development of the PV+ interneuron axon, its myelination and synapse formation, revealing a rapid sequence of axonal reorganization, myelination of the PV+ interneuron proximal axon, and subsequent pruning of almost two-thirds of the synapses in an individual connection. This is followed by a prolonged period of axon refinement and additional myelination leading to a remarkable precision of connections in the adult mouse cortex, consistent with the temporal precision and fidelity of PV+ interneuron action.
Interstitial leukocyte navigation through a search and run response to gradients
Authors: Georgantzoglou Antonios , Poplimont Hugo , Lämmermann Tim , Sarris Milka
Published: March 2021

Migrating cells must interpret chemical gradients to guide themselves within tissues. A general premise has been that gradients influence the direction of leading-edge protrusions. However, recent evidence indicates that actin flows correlate better with directed motion than protrusions. A unified chemotaxis model that integrates the role of protrusions and actin flows and that accounts forin vivocell motion patterns is lacking. Here, we provide direct experimental evidence of how neutrophils sense gradients in real-timein vivoand demonstrate a two-stage process: first a ‘search’ phase, that requires actin network expansion by Arp2/3, whereby cells slow down, explore the environment and execute path corrections. This is followed by a ‘run’ phase, that requires Myosin-II-driven contractility and fast actin flows, whereby cells accelerate and persist in the source direction. Thus, protrusive forces support chemotaxis by enhancing signal detection, while actin flows act as the ultimate output of gradient processing.
Recapitulate Human Cardio-pulmonary Co-development Using Simultaneous Multilineage Differentiation of Pluripotent Stem Cells
Authors: Hoe Ng Wai , Johnston Elizabeth K. , Jie Tan Jun , Bliley Jacqueline M. , Feinberg Adam W. , Stolz Donna B. , Sun Ming , Hawkins Finn , Kotton Darrell N. , Ren Xi
Published: March 2021

The extensive crosstalk between the developing heart and lung is pivotal for their proper morphogenesis and maturation. However, there remains a lack of model systems for investigating the critical cardio-pulmonary mutual interaction during human embryogenesis. Here, we reported a novel stepwise strategy for directing simultaneous induction of both mesoderm-derived cardiac and endoderm-derived lung epithelial lineages within a single differentiation of human pluripotent stem cells (hPSCs) via temporal specific tuning of WNT and TGF-β signaling in the absence of exogenous growth factors. Using 3D suspension culture, we established concentric cardio-pulmonary micro-Tissues (μTs), and observed expedited alveolar maturation in the presence of cardiac accompany. Upon withdrawal of WNT agonist, the cardiac and pulmonary components within each dual-lineage μT effectively segregated from each other with concurrent initiation of cardiac contraction. We expect our multilineage differentiation model to offer an experimentally tractable system for investigating human cardio-pulmonary interplay and tissue boundary formation during embryogenesis.
Development and validation of FootNet; a new kinematic algorithm to improve foot-strike and toe-off detection in treadmill running
Authors: Rivadulla Adrian Rodriguez , Chen Xi , Weir Gillian , Cazzola Dario , Trewartha Grant , Hamill Joseph , Preatoni Ezio
Published: March 2021

The accurate detection of foot-strike and toe-off is often critical in the assessment of running biomechanics. The gold standard method for step event detection requires force data which are not always available. Although kinematics-based algorithms can also be used, their accuracy and generalisability are limited, often requiring corrections for speed or foot-strike pattern. The purpose of this study was to develop FootNet, a novel kinematics and deep learning-based algorithm for the detection of step events in treadmill running. Five treadmill running datasets were gathered and processed to obtain segment and joint kinematics, and to identify the contact phase within each gait cycle using force data. The proposed algorithm is based on a long short-term memory recurrent neural network and takes the distal tibia anteroposterior velocity, ankle dorsiflexion/plantar flexion angle and the anteroposterior and vertical velocities of the foot centre of mass as input features to predict the contact phase within a given gait cycle. The chosen model architecture underwent 5-fold cross-validation and the final model was tested in a subset of participants from each dataset (30%). Non-parametric Bland-Altman analyses (bias and [95% limits of agreement]) and root mean squared error (RMSE) were used to compare FootNet against the force data step event detection method. The association between detection errors and running speed, foot-strike angle and incline were also investigated. FootNet outperformed previously published algorithms (foot-strike bias = 0 [-10, 7] ms, RMSE = 5 ms; toe-off bias = 0 [-10, 10] ms, RMSE = 6 ms; and contact time bias = 0 [-15, 15] ms, RMSE = 8 ms) and proved robust to different running speeds, foot-strike angles and inclines. We have made FootNet’s source code publicly available for step event detection in treadmill running when force data are not available.