bluuebunny/crossref_metadata_2025 huggingface dataset:
Light therapy for insomnia symptoms in fatigued cancer survivors: a secondary analysis of a randomized controlled trial
Authors: Garland Sheila N. , Johnson Jillian A. , Carlson Linda E. , Rash Joshua A. , Savard Josée , Campbell Tavis S.
Published: November 2020

Background:

Cancer-related fatigue (CRF) and insomnia are highly comorbid. This association implies that treatment aimed at improving one may also simultaneously target the other. This secondary analysis examined whether severity of insomnia affects sleep outcomes in response to a light therapy intervention in cancer survivors with CRF.

Methods:

This 4-week trial recruited cancer survivors who met ICD-10 criteria for CRF. Participants were randomized to receive bright white light (BWL) or dim red light (DRL). Light devices were used daily for 30 minutes over 28 days. Participants completed the Insomnia Severity Index (ISI) at baseline, weeks 2 and 4, and the Pittsburgh Sleep Quality Index, daily sleep diaries and actigraphy at baseline and week 4. ISI scores 0 to 14 represent no/mild symptoms and scores 15+ correspond to moderate-to-severe (clinically significant) insomnia symptoms.

Results:

Of the 81 participants (BWL: n = 42; DRL: n = 39), 49% had ISI scores ≥15 at baseline. There was a significant group-by-time interaction for insomnia severity (F[2, 75.55] = 4.15, P = .020) and sleep quality (F [1, 39.25] = 7.66, P = .009), favoring the BWL condition for those individuals with no or mild insomnia symptoms. In the moderate-to-severe group, there were time effects for insomnia severity and sleep quality, diary measured wake after sleep onset and sleep efficiency, and actigraphy measured wake after sleep onset and sleep efficiency; however, participants remained in the clinical range for insomnia symptoms on the ISI and poor sleep quality on the PSQI. Effect sizes were larger, regardless of intervention condition, in participants with moderate-to-severe insomnia symptoms.

Conclusions:

The severity of insomnia symptoms may impact sleep outcomes in response to a light therapy intervention in cancer survivors with clinical levels of fatigue, but light therapy alone does not appear to be adequate to produce clinically meaningful change in sleep outcomes.

Trial registration number:

Clinicaltrials.gov identifier NCT01780623.
Different Pattern of Bone Scintigraphy in Mandibular Osteosarcoma Arising From Fibrous Dysplasia in a Patient With McCune-Albright Syndrome
Authors: Lee Tse-Hao , Chu Lee-Shing , Chang Chih-Yung , Huang Wen-Sheng
Published: November 2020

McCune-Albright syndrome is a rare condition consisting of triad of fibrous dysplasia, hyperfunctioning endocrinopathy, and café au lait macules of skin. A 31-year-old man was diagnosed with fibrous dysplasia 18 years before presenting with pathologic fracture. No workup for polyostotic fibrous dysplasia was performed at that time. He now presented with left facial swelling and skeletal features of acromegaly. MRI revealed a 15-cm enhancing tumor diagnosed histopathologically as high-grade osteosarcoma. 99mTc–methylene diphosphonate bone scintigraphy revealed decreased uptake at the tumor site contrary to the usual finding of avid uptake by the neoplastic bone forming tumor.
“Skull on Fire”
Authors: Govers Stefan , van der Zant Friso M. , Wondergem Maurits , Broos Wouter A.M. , Knol Remco J.J.
Published: November 2020

An 81-year-old woman was evaluated for a stroke. CT showed no intracranial abnormalities but diffuse patchy aspect of the neurocranium. An MRI and 18F-NA PET/CT were performed to differentiate between metastases, Paget disease, hyperostosis frontalis interna, and primary malignancy. MRI yielded no additional findings. 18F-NA PET/CT showed diffusely increased uptake in the skull and 4 spots with intense uptake. No other suspicious skeletal foci were seen elsewhere. Low-dose CT showed no sign of malignancy elsewhere. Image findings together with elevated serum alkaline phosphatase levels, slightly increased calcium levels, and normal phosphorus levels were interpreted as pathognomic for monostotic Paget.
Metastatic Poorly Differentiated Thyroid Cancer With Heterogeneous Distribution of 18F-FDG, 68Ga-DOTATATE, and 68Ga-PSMA on PET/CT
Authors: Civan Caner , Isik Emine Goknur , Simsek Duygu Has
Published: November 2020

We present a case of a 55-year-old man with a history of poorly differentiated metastatic thyroid cancer, which is rare and shows aggressive behavior. The patient had radioactive iodine–negative multiple metastasis on 18F-FDG PET/CT, therefore 68Ga-DOTATATE and 68Ga-PSMA PET/CT were performed whether an opportunity exist for DOTATATE or PSMA-directed radionuclide therapy. Different patterns of tumoral uptakes were detected on 18F-FDG, 68Ga-DOTATATE, and 68Ga-PSMA PET/CT, as a demonstration of tumor heterogeneity.
Vascular Complications in Le Fort I Osteotomy: Incidence, Reasons, and Management of the Intraoperative Hemorrhage
Authors: Ulker Omer , Demirbas Ahmet Emin , Kutuk Nukhet , Kilic Erdem , Alkan Alper
Published: November 2020

Purpose:

The aim of this study was to investigate the incidence, types, and reasons for the intraoperative hemorrhage during Le Fort I osteotomy.

Methods:

The study sample was composed of the population of the patients who underwent orthognathic surgery from April 2011 to February 2017. The vascular complications of the patients who underwent Le Fort I osteotomy during the surgery were identified. Type of the bleeding, suspected vessel, amount of the intraoperative blood loss, cause, and management of the bleeding were specified and investigated. Descriptive statistics were computed for each study variable.

Results:

A total of 200 patients underwent Le Fort I osteotomy. The sample's mean age was 22.4 ± 5.8 and 55.5% of patients were female. The intraoperative vascular complication was seen in only 10 (5%) samples. The suspected source of the hemorrhage was the descending palatine artery (DPA) in 8 (4%) cases, while the pterygoid venous plexus in the other 2 (1%) cases. The cause of the bleeding was suspected down-fracture in 8 cases, while pterygomaxillary junction (PMJ) separation in the other 2 cases. DPA was ligated with ligation clips and cauterized in arterial injury cases. The hemorrhage was taken under control using a hemostatic matrix with thrombin (Surgiflo, Ethicon, USA) in the venous bleeding cases.

Conclusions:

The down-fracture of the maxilla was found to be more related to the occurrence of vascular complications. Severe bleeding was managed by the use of the hemostatic matrix with thrombin and this hemostatic agent can be used to control this type bleedings in orthognathic surgery.
A Prospective, Multicenter Registry Study to Evaluate the Clinical Feasibility of Targeted Axillary Dissection (TAD) in Node-positive Breast Cancer Patients
Authors: Kuemmel Sherko , Heil Joerg , Rueland Anna , Seiberling Christine , Harrach Hakima , Schindowski Dorothea , Lubitz Juliane , Hellerhoff Karin , Ankel Christine , Graßhoff Sven-Thomas , Deuschle Petra , Hanf Volker , Belke Kerstin , Dall Peter , Dorn Julia , Kaltenecker Gabriele , Kuehn Thorsten , Beckmann Ulrike , Potenberg Jochem , Blohmer Jens-Uwe , Kostara Athina , Breit Elisabeth , Holtschmidt Johannes , Traut Eugen , Reinisch Mattea
Published: November 2020

Objective:

This study aimed to investigate the feasibility and accuracy of non-radioactive TLN biopsy and TAD in routine clinical practice.

Background Data:

TAD involves TLN biopsy (TLNB) and sentinel lymph node biopsy and was recently introduced as a new standard for less invasive axillary staging in BC patients undergoing neoadjuvant systemic therapy (NST); however, clinical evidence is limited.

Methods:

The SenTa study is a prospective registry study conducted at 50 centers. Patients with invasive BC who nderwent clip insertion into the most suspicious axillary lymph node were eligible. Axillary surgery was performed with or without sentinel lymph node biopsy, TLNB, and/or axillary lymph node dissection (ALND). Main endpoints were the detection rate and FNR of TLNB and TAD after NST.

Results:

Between 2017 and 2018, 548 consecutive BC patients underwent clip placement into biopsy-confirmed positive lymph nodes. After NST (n = 473), the clipped TLN was intraoperatively resected in 329 of 423 patients [77.8%, 95% confidence interval (CI): 74.0–82.0]. TAD was successful in 199 of 229 patients (detection rate: 86.9%, 95% CI: 81.8–91.0), the SLN and TLN were identical in 129 patient (64.8%). FNRs were 7.2% (8 of 111, 95% CI: 3.1–13.6) for TLNB followed by ALND (n = 203) and 4.3% (2 of 46, 95% CI: 0.5–14.8) for TAD followed by ALND (n = 77).

Conclusions:

The SenTa study demonstrates the feasibility of TAD in a real-world cohort of BC patients. Our findings are of great importance for de-escalation of surgical strategies.
The Value of Source Localization for Clinical Magnetoencephalography: Beyond the Equivalent Current Dipole
Authors: Tenney Jeffrey R. , Fujiwara Hisako , Rose Douglas F.
Published: November 2020

Source localization for clinical magnetoencephalography recordings is challenging, and many methods have been developed to solve this inverse problem. The most well-studied and validated tool for localization of the epileptogenic zone is the equivalent current dipole. However, it is often difficult to summarize the richness of the magnetoencephalography data with one or a few point sources. A variety of source localization algorithms have been developed to more fully explain the complexity of clinical magnetoencephalography data used to define the epileptogenic network. In this review, various clinically available source localization methods are described and their individual strengths and limitations are discussed.
The condition of coral reefs in Timor-Leste before and after the 2016–2017 marine heatwave
Authors: Kim Catherine JS , Roelfsema Chris , Dove Sophie , Hoegh-Guldberg Ove
Published: November 2020

El Niño Southern Oscillation global coral bleaching events are increasing in frequency; however, the severity of bleaching is not geographically uniform. There were two major objectives of the present project: 1) assess the state of reefs and coral health at several sites and 2) explore water quality and climate change impacts on Timorese reefs. The impacts of climate change (principally by following coral mortality) were surveyed on coral reefs before and after the 2016–2017 underwater heatwave, using temperature loggers deployed between surveys which were compared to Coral Reef Watch (CRW) experimental virtual station sea surface temperature (SST). CRW is an important and widely used tool; however, we found the SST was significantly warmer (> 1°C) thanin situtemperature during the austral summer accruing 5.79 degree heating weeks.In situtemperature showed no accumulation. Change in coral cover between surveys was attributed to reef heterogeneity. There were significant differences in coral cover, coral diversity, and nutrient concentrations between site and depth and a low prevalence of disease recorded in both years. The comparison of temperature and SST indicate that bleaching stress in Timor-Leste is potentially mitigated by seasonal and oceanographic dynamics. This is corroborated by Timor-Leste’s location within the Indonesian ThroughFlow. Timor-Leste is a climate refugium and the immediate conservation work lies in the management of localized anthropogenic impacts on coral reefs such as sedimentation and fishing.
Novel imprints in mouse blastocysts are predominantly DNA methylation independent
Authors: Santini Laura , Halbritter Florian , Titz-Teixeira Fabian , Suzuki Toru , Asami Maki , Ramesmayer Julia , Ma Xiaoyan , Lackner Andreas , Warr Nick , Pauler Florian , Hippenmeyer Simon , Laue Ernest , Farlik Matthias , Bock Christoph , Beyer Andreas , Perry Anthony C. F. , Leeb Martin
Published: November 2020

In mammals, chromatin marks at imprinted genes are asymmetrically inherited to control parentally-biased gene expression. This control is thought predominantly to involve parent-specific differentially methylated regions (DMR) in genomic DNA. However, neither parent-of-origin-specific transcription nor DMRs have been comprehensively mapped. We here address this by integrating transcriptomic and epigenomic approaches in mouse preimplantation embryos (blastocysts). Transcriptome-analysis identified 71 genes expressed with previously unknown parent-of-origin-specific expression in blastocysts (nBiX: novel blastocyst-imprinted expression). Uniparental expression of nBiX genes disappeared soon after implantation. Micro-whole-genome bisulfite sequencing (μWGBS) of individual uniparental blastocysts detected 859 DMRs. Only 18% of nBiXs were associated with a DMR, whereas 60% were associated with parentally-biased H3K27me3. This suggests a major role for Polycomb-mediated imprinting in blastocysts. Five nBiX-clusters contained at least one known imprinted gene, and five novel clusters contained exclusively nBiX-genes. These data suggest a complex program of stage-specific imprinting involving different tiers of regulation.
MiniFAST: A sensitive and fast miniaturized microscope forin vivoneural recording
Authors: Juneau Jill , Duret Guillaume , Chu Joshua P. , Rodriguez Alexander V. , Morozov Savva , Aharoni Daniel , Robinson Jacob T. , St-Pierre François , Kemere Caleb
Published: November 2020

Observing the activity of large populations of neuronsin vivois critical for understanding brain function and dysfunction. The use of fluorescent genetically-encoded calcium indicators (GECIs) in conjunction with miniaturized microscopes is an exciting emerging toolset for recording neural activity in unrestrained animals. Despite their potential, current miniaturized microscope designs are limited by using image sensors with low frame rates, sensitivity, and resolution. Beyond GECIs, there are many neuroscience applications which would benefit from the use of other emerging neural indicators, such as fluorescent genetically-encoded voltage indicators (GEVIs) that have faster temporal resolution to match neuron spiking, yet, require imaging at high speeds to properly sample the activity-dependent signals. We integrated an advanced CMOS image sensor into a popular open-source miniaturized microscope platform. MiniFAST is a fast and sensitive miniaturized microscope capable of 1080p video, 1.5 µm resolution, frame rates up to 500 Hz and high gain ability (up to 70 dB) to image in extremely low light conditions. We report results of high speed 500 Hzin vitroimaging of a GEVI and ∼300 Hzin vivoimaging of transgenic Thy1-GCaMP6f mice. Finally, we show the potential for a reduction in photobleaching by using high gain imaging with ultra-low excitation light power (0.05 mW) at 60 Hz frame rates while still resolving Ca2+spiking activity. Our results extend miniaturized microscope capabilities in high-speed imaging, high sensitivity and increased resolution opening the door for the open-source community to use fast and dim neural indicators.
CT-based Rapid Triage of COVID-19 Patients: Risk Prediction and Progression Estimation of ICU Admission, Mechanical Ventilation, and Death of Hospitalized Patients
Authors: Xu Qinmei , Zhan Xianghao , Zhou Zhen , Li Yiheng , Xie Peiyi , Zhang Shu , Li Xiuli , Yu Yizhou , Zhou Changsheng , Zhang Longjiang , Gevaert Olivier , Lu Guangming
Published: November 2020

The wave of COVID-19 continues to overwhelm the medical resources, especially the stressed intensive care unit (ICU) capacity and the shortage of mechanical ventilation (MV). Here we performed CT-based analysis combined with electronic health records and clinical laboratory results on Cohort 1 (n = 1662 from 17 hospitals) with prognostic estimation for the rapid stratification of PCR confirmed COVID-19 patients. These models, validated on Cohort 2 (n = 700) and Cohort 3 (n = 662) constructed from 9 external hospitals, achieved satisfying performance for predicting ICU, MV and death of COVID-19 patients (AUROC 0.916, 0.919 and 0.853), even on events happened two days later after admission (AUROC 0.919, 0.943 and 0.856). Both clinical and image features showed complementary roles in events prediction and provided accurate estimates to the time of progression (p<.001). Our findings are valuable for delivering timely treatment and optimizing the use of medical resources in the pandemic of COVID-19.
Development of an automated chemiluminescence assay system for quantitative measurement of multiple anti-SARS-CoV-2 antibodies
Authors: Kubo Sousuke , Ohtake Norihisa , Miyakawa Kei , Jeremiah Sundararaj Stanleyraj , Yamaoka Yutaro , Murohashi Kota , Hagiwara Eri , Mihara Takahiro , Goto Atsushi , Yamazaki Etsuko , Ogura Takashi , Kaneko Takeshi , Yamanaka Takeharu , Ryo Akihide
Published: November 2020

Objective

Serological tests for COVID-19 have been instrumental in studying the epidemiology of the disease. However, the performance of the currently available tests is plagued by the problem of variability. We have developed a high-throughput serological test capable of simultaneously detecting total immunoglobulins (Ig) and immunoglobulin G (IgG) against two of the most immunologically relevant SARS-CoV-2 antigens, nucleocapsid protein (NP) and spike protein (SP) and report its performance in detecting COVID-19 in clinical samples.

Methods

We designed and prepared reagents for measuring NP-IgG, NP-Total Ig, SP-IgG, and SP-Total Ig (using N-terminally truncated NP (ΔN-NP) or receptor-binding domain (RBD) antigen) on the advanced chemiluminescence enzyme immunoassay system TOSOH AIA-CL. After determining the basal thresholds based on 17 sera obtained from confirmed COVID-19 patients and 600 negative sera. Subsequently, the clinical validity of the assay was evaluated using independent 202 positive samples and 1,000 negative samples from healthy donors.

Results

All of the four test parameters showed 100% specificity individually (1,000/1,000; 95%CI, 99.63-100). The sensitivity of the assay increased proportionally to the elapsed time from symptoms onset, and all the tests achieved 100% sensitivity (153/153; 95%CI, 97.63-100) after 13 days from symptoms onset. NP-Total Ig was the earliest to attain maximal sensitivity among the other antibodies tested.

Conclusion

Our newly developed serological testing exhibited 100% sensitivity and specificity after 13 days from symptoms onset. Hence, it could be used as a reliable method for accurate detection of COVID-19 patients and to evaluate seroprevalence and possibly for surrogate assessment of herd immunity.
Platelet Activating Immune Complexes Identified in COVID-19 Associated Coagulopathy
Authors: Nazy Ishac , Jevtic Stefan D , Moore Jane C , Huynh Angela , Smith James W , Kelton John G , Arnold Donald M
Published: November 2020

Thrombosis is a prominent feature of coronavirus disease 2019 (COVID-19) and often occurs in patients who are critically ill; however, the mechanism is unclear. This COVID-19 associated coagulopathy (CAC) shares features with heparin-induced thrombocytopenia (HIT), including mild thrombocytopenia and thrombosis. We thus tested 10 CAC patients for anti-PF4/heparin antibodies and functional platelet activation. HIT was excluded in all samples based on anti-PF4/heparin antibody and serotonin release assay results. Of note, 6 CAC patients demonstrated platelet activation by the serotonin release assay that was inhibited by FcγRIIA receptor blockade, confirming an IgG-specific immune complex (IC)-mediated reaction. Platelet activation was independent of heparin, but inhibitable by both therapeutic and high dose heparin. All 6 samples were positive for IgG-specific antibodies targeting the receptor binding domain (RBD) or the spike protein of the SARS-CoV-2 virus. These samples were additionally characterized by significant endothelial activation, shown by increased von Willebrand factor antigen and activity. ADAMTS13 activity was not severely reduced, and ADAMTS13 inhibitors were not present, ruling out thrombotic thrombocytopenic purpura. Our study thus identifies platelet-activating ICs as a mechanism that contributes to CAC thrombosis.

Scientific Category

Thrombosis and Hemostasis

Key Points

Patients with COVID-19 thrombosis have immune complexes that activate platelets through FcγRIIA signalling

Patients with COVID-19 thrombosis demonstrate increased VWF antigen and activity that is not related to severe ADAMTS13 reduction
Comparison of Radiomic Feature Aggregation Methods for Patients with Multiple Tumors
Authors: Chang Enoch , Joel Marina , Chang Hannah Y. , Du Justin , Khanna Omaditya , Omuro Antonio , Chiang Veronica , Aneja Sanjay
Published: November 2020

Background

Radiomic feature analysis has been shown to be effective at modeling cancer outcomes. It has not yet been established how to best combine these radiomic features in patients with multifocal disease. As the number of patients with multifocal metastatic cancer continues to rise, there is a need for improving personalized patient-level prognostication to better inform treatment.

Methods

We compared six mathematical methods of combining radiomic features of 3596 tumors in 831 patients with multiple brain metastases and evaluated the performance of these aggregation methods using three survival models: a standard Cox proportional hazards model, a Cox proportional hazards model with LASSO regression, and a random survival forest.

Results

Across all three survival models, the weighted average of the largest three metastases had the highest concordance index (95% confidence interval) of 0.627 (0.595-0.661) for the Cox proportional hazards model, 0.628 (0.591-0.666) for the Cox proportional hazards model with LASSO regression, and 0.652 (0.565-0.727) for the random survival forest model.

Conclusions

Radiomic features can be effectively combined to establish patient-level outcomes in patients with multifocal brain metastases. Future studies are needed to confirm that the volume-weighted average of the largest three tumors is an effective method for combining radiomic features across other imaging modalities and disease sites.
Mepolizumab effectiveness in patients with severe eosinophilic asthma and co-presence of bronchiectasis: a real-world retrospective pilot study
Authors: Crimi Claudia , Campisi Raffaele , Nolasco Santi , Cacopardo Giulia , Intravaia Rossella , Porto Morena , Impellizzeri Pietro , Pelaia Corrado , Crimi Nunzio
Published: November 2020

Background

The association of bronchiectasis (BE) in patients with severe eosinophilic asthma (SEA) is quite frequent. Mepolizumab is a well-recognized treatment for SEA; we aim to evaluate its effectiveness in SEA patients with and without BE in real-life.

Methods

We performed a single-center retrospective pilot study, including patients with SEA treated with mepolizumab for one year. Asthma control test (ACT), lung function, annual exacerbations rate, oral corticosteroid dosage, FeNO, chronic mucous secretions, blood and sputum eosinophils were recorded at baseline and after 6 and 12 months.

Results

we included 32 patients (mean age: 52.3±10, 59% female). 50% showed co-presence of bronchiectasis, (SEA+BE). Significant improvements were found in ACT [(13.8±4.6 to 20.7±4.1, p=0.0009) and (13±4.8 to 20.7±4.6, p=0.0003)], annual exacerbations rate [from 7 (4-12) to 0 (0.00-0.75) and from 8 (4-12) to 0 (0-1), p<0.0001], and blood eosinophils count [748 cells/μL (400-1250) vs. 84 cells/μL (52.5-100), and from 691 cells/μL (405-798) vs. 60 cells/μL (41-105), p<0.0001] in SEA and SEA+BE group respectively, already after 6 months of treatment. A reduction in daily oral corticosteroids intake at 12 months was shown [from 15 mg (0-25) to 0 mg (0-0), p=0.003 and from 8.8 mg (0-25) to 0 mg (0-0) (p=0.01)] in both SEA and SEA+BE, respectively. Similar results were found, comparing SEA+BE patients based on the severity of bronchiectasis.

Conclusions

Mepolizumab effectively improves asthma symptoms control, reducing annual exacerbations and corticosteroid intake in all patients with SEA, even in the subgroup with coexisting bronchiectasis, independently of their severity.

Highlights

Mepolizumab is effective in the treatment of severe eosinophilic asthma (SEA) in clinical trials and real-life studies.

Bronchiectasis is a frequent comorbidity in patients with severe eosinophilic asthma.

Mepolizumab proved to be effective in improving asthma symptoms control, mucus hypersecretion, lung function, and reducing sputum and blood eosinophils, corticosteroids dependency and annual exacerbations both in severe eosinophilic asthma patients with or without co-presence of bronchiectasis.

Mepolizumab showed to be effective in patients with asthma and co-presence of bronchiectasis, regardless of BE severity.

Assessing the co-presence and severity of bronchiectasis may help clinicians select the right biologic for a prompt treatment-specific effect.
A random-walk-based epidemiological model
Authors: Chu Andrew , Huber Greg , McGeever Aaron , Veytsman Boris , Yllanes David
Published: November 2020

Random walkers on a two-dimensional square lattice are used to explore the spatio-temporal growth of an epidemic. We have found that a simple random-walk system generates non-trivial dynamics compared with traditional well-mixed models. Phase diagrams characterizing the long-term behaviors of the epidemics are calculated numerically. The functional dependence of the basic reproductive number R0 on the model’s defining parameters reveals the role of spatial fluctuations and leads to a novel expression for R0. Special attention is given to simulations of inter-regional transmission of the contagion. The scaling of the epidemic with respect to space and time scales is studied in detail in the critical region, which is shown to be compatible with the directed-percolation universality class.
Scaling up biodiversity ecosystem functioning relationships: the role of environmental heterogeneity in space and time
Authors: Thompson Patrick L. , Kéfi Sonia , Zelnik Yuval R. , Dee Laura E. , Wang Shaopeng , de Mazancourt Claire , Loreau Michel , Gonzalez Andrew
Published: November 2020

The biodiversity and ecosystem functioning (BEF) relationship is expected to be scale-dependent. The autocorrelation of environmental heterogeneity is hypothesized to explain this scale dependence because it influences how quickly biodiversity accumulates over space or time. However, this link has yet to be demonstrated in a formal model. Here we use a Lotka-Volterra competition model to simulate community dynamics when environmental conditions vary across either space or time. Species differ in their optimal environmental conditions, which results in turnover in community composition. We vary biodiversity by modelling communities with different sized regional species pools and ask how the amount of biomass per unit area depends on the number of species present, and the spatial or temporal scale at which it is measured. We find that more biodiversity is required to maintain functioning at larger temporal and spatial scales. The number of species required increases quickly when environmental autocorrelation is low, and slowly when autocorrelation is high. Both spatial and temporal environmental heterogeneity led to scale dependence in BEF, but autocorrelation had larger impacts when environmental change was temporal. These findings show how the biodiversity required to maintain functioning is expected to increase over space and time.
Prevalence of sustainable and unsustainable use of wild species inferred from the IUCN Red List
Authors: Marsh Sophie M.E. , Hoffmann Michael , Burgess Neil D. , Brooks Thomas M. , Challender Daniel W.S. , Cremona Patricia J. , Hilton-Taylor Craig , de Micheaux Flore Lafaye , Lichtenstein Gabriela , Roe Dilys , Böhm Monika
Published: November 2020

Unsustainable exploitation of wild species represents a serious threat to biodiversity and to the livelihoods of local communities and indigenous peoples. However, managed, sustainable use has the potential to forestall extinctions, aid recovery, and meet human needs. Research to date has focused on unsustainable biological resource use with little consideration of sustainable use; we infer the current prevalence of both. We analyzed species-level data for 30,923 species from 13 taxonomic groups on the IUCN Red List. Our results demonstrate the broad taxonomic prevalence of use, with 40% of species (10,098 of 25,009 species from 10 data-sufficient taxonomic groups) documented as being used. The main purposes of use are pets, display animals and horticulture, and human consumption. Use often has an adverse impact on species extinction risk (we define this as biologically unsustainable): intentional use is currently contributing to elevated extinction risk for over a quarter of all threatened or Near Threatened (NT) species (2,752 – 2,848 of 9,753 species). Intentional use also threatens 16% of all species used (1,597 – 1,631 of 10,098). However, 72% of species that are used (7,291 of 10,098) are Least Concern (LC), of which nearly half (3,469) also have stable or improving population trends. The remainder of used species are not documented as threatened by biological resource use, including 172 threatened or NT species with stable or improving populations. Around a third of species that have use documented as a threat do not currently receive targeted species management actions to directly address this threat. We offer suggestions for improving use-related Red List data. Our findings on the prevalence of sustainable and unsustainable use, and variation across taxa, can inform international policymaking, including the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services, the Convention on Biological Diversity, and the Convention on International Trade in Endangered Species.
Phosphoproteome profiling uncovers a key role for CDKs in TNF signaling
Authors: Tanzer Maria C , Bludau Isabell , Stafford Che A , Hornung Veit , Mann Matthias
Published: November 2020

Tumor necrosis factor (TNF) is one of the few cytokines successfully targeted by therapies against inflammatory diseases. However, blocking this well studied and pleiotropic ligand can cause dramatic side-effects. We reasoned that a systems-level proteomic analysis of TNF signaling could dissect its diverse functions and offer a base for developing more targeted therapies. Combining phosphoproteomics time course experiments with subcellular localization and kinase inhibitor analysis identifies functional modules of phosphorylations. The majority of regulated phosphorylations could be assigned to an upstream kinase by inhibiting master kinases and spatial proteomics revealed phosphorylation-dependent translocations of hundreds of proteins upon TNF stimulation. Phosphoproteome analysis of TNF-induced apoptosis and necroptosis uncovered a key role for transcriptional cyclin-dependent kinase (CDK) activity to promote cytokine production and prevent excessive cell death downstream of the TNF signaling receptor. Our comprehensive interrogation of TNF induced pathways and sites can be explored athttp://tnfviewer.biochem.mpg.de/.

Highlights

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Distinct phosphorylation events mark early and late TNF signaling

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Inhibition of master kinases reveals TNF stimulation dependent kinase-substrate relations

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TNF induces phosphorylation-dependent spatial rearrangement of hundreds of proteins

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CDK kinase activity promotes TNF-induced cytokine expression and inhibits cell death

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CDK12/13 inhibitors have potential as anti-inflammatory agents
Ligand-induced motions in pentameric ligand-gated ion channels revealed by EPR spectroscopy
Authors: Tiwari Varun , Borchardt Jennifer , Schuh Abby , Klug Candice S. , Czajkowski Cynthia
Published: November 2020

Signaling in the brain depends on rapid opening and closing of pentameric ligand-gated ion channels (pLGICs). These proteins are the targets of various clinical drugs and, defects in their function is linked to a variety of diseases including myasthenia, epilepsy and sleep-disorders. While recent high-resolution structures of prokaryotic and eukaryotic pLGICs have shed light on the molecular architecture of these proteins, describing their conformational dynamics in physiological lipids is essential for understanding their function. Here, we used site-directed spin labeling electron paramagnetic resonance (SDSL EPR) spectroscopy and functional channels reconstituted in liposomes to reveal ligand-induced structural changes in the extracellular domain (ECD) of GLIC. Proton-activation caused an inward motion of labeled sites at the top of β-strands (β1, 2, 5, 6, 8) towards the channel lumen, consistent with an agonist-induced inward tilting motion of the ECD. Similar proton-dependent GLIC ECD motions were detected in the presence of a non-activating (gating deficient) mutation, suggesting that the inward tilting of the ECD does not accompany channel opening but is associated with an agonist-induced closed pre-activated channel state. These findings provide new insights into the protein dynamics underlying pLGIC gating transitions.
Cell wall damage impairs root hair cell patterning and tissue morphogenesis mediated by the Arabidopsis receptor kinase STRUBBELIG
Authors: Chaudhary Ajeet , Chen Xia , Leśniewska Barbara , Gao Jin , Wolf Sebastian , Schneitz Kay
Published: November 2020

Cell wall remodeling is essential for the control of growth and development as well as the regulation of stress responses. However, the underlying cell wall monitoring mechanisms remain poorly understood. Regulation of root hair fate and flower development inArabidopsis thalianarequires signaling mediated by the atypical receptor kinase STRUBBELIG (SUB). Furthermore, SUB is involved in cell wall integrity signaling and regulates the cellular response to reduced levels of cellulose, a central component of the cell wall. Here, we show that continuous exposure to sub-lethal doses of the cellulose biosynthesis inhibitor isoxaben results in altered root hair patterning and floral morphogenesis. Genetically impairing cellulose biosynthesis also results in root hair patterning defects. We further show that isoxaben exerts its developmental effects through the attenuation of SUB signaling. Our evidence indicates that down-regulation of SUB is a multi-step process and involves changes in SUB complex architecture at the plasma membrane, enhanced removal of SUB from the cell surface, and downregulation ofSUBtranscript levels. The results provide molecular insight into how the cell wall regulates cell fate and tissue morphogenesis.
Precision medicine for the rescue of specific impairments in social behavior associated with the A350VIqsec2mutation
Authors: Jabarin Renad , Levy Nina , Abergel Yasmin , Berman Joshua H. , Zag Amir , Netser Shai , Levy Andrew P. , Wagner Shlomo
Published: November 2020

In this study we tested the hypothesis that precision medicine guided therapy targeting glutamatergic neurotransmission could rescue behavioral deficits exhibited by mice carrying a specific mutation in theIqsec2gene. The IQSEC2 protein plays a key role in glutamatergic synapses and mutations in theIQSEC2gene are a frequent cause of neurodevelopmental disorders. We have recently reported on the molecular pathophysiology of one such mutation A350V and demonstrated that this mutation downregulates AMPA type glutamatergic receptors (AMPAR) in A350V mice. Here we sought to identify behavioral deficits in A350V mice and hypothesized that we could rescue these deficits by PF-4778574, a positive AMPAR modulator. We found that A350VIqsec2mice exhibit specific deficits in sex preference and emotional state preference behaviors as well as in vocalizations when encountering a female mouse. The social discrimination deficits, but not the impaired vocalization, were rescued with PF-4778574. We conclude that social behavior deficits associated with the A350VIqsec2mutation may be rescued by enhancing AMPAR mediated synaptic transmission.
Landmark-Centered Coding in Frontal Cortex Visual Responses
Authors: Schütz Adrian , Bharmauria Vishal , Yan Xiaogang , Wang Hongying , Bremmer Frank , Crawford J. Douglas
Published: November 2020

Visual landmarks influence spatial cognition [1–3], navigation [4,5] and goal-directed behavior [6–8], but their influence on visual coding in sensorimotor systems is poorly understood [6,9–11]. We hypothesized that visual responses in frontal cortex control gaze areas encode potential targets in an intermediate gaze-centered / landmark-centered reference frame that might depend on specific target-landmark configurations rather than a global mechanism. We tested this hypothesis by recording neural activity in the frontal eye fields (FEF) and supplementary eye fields (SEF) while head-unrestrained macaques engaged in a memory-delay gaze task. Visual response fields (the area of visual space where targets modulate activity) were tested for each neuron in the presence of a background landmark placed at one of four oblique configurations relative to the target stimulus. 102 of 312 FEF and 43 of 256 SEF neurons showed spatially tuned response fields in this task. We then fit these data against a mathematical continuum between a gaze-centered model and a landmark-centered model. When we pooled data across the entire dataset for each neuron, our response field fits did not deviate significantly from the gaze-centered model. However, when we fit response fields separately for each target-landmark configuration, the best fits shifted (mean 37% / 40%) toward landmark-centered coding in FEF / SEF respectively. This confirmed an intermediate gaze / landmark-centered mechanism dependent on local (configuration-dependent) interactions. Overall, these data show that external landmarks influence prefrontal visual responses, likely helping to stabilize gaze goals in the presence of variable eye and head orientations.

Highlights

Prefrontal visual responses recorded in the presence of visual landmarks

Response fields showed intermediate gaze / landmark-centered organization

This influence depended on specific target-landmark configurations
Advanced Biophysical Model to Capture Channel Variability for EQS Capacitive HBC
Authors: Datta Arunashish , Nath Mayukh , Yang David , Sen Shreyas
Published: November 2020

Human Body Communication (HBC) has come up as a promising alternative to traditional radio frequency (RF) Wireless Body Area Network (WBAN) technologies. This is essentially due to HBC providing abroadbandcommunication channel with enhanced signal security in the physical layer due to lower radiation from the human body as compared to its RF counterparts. An in-depth understanding of the mechanism for the channel loss variability and associated biophysical model needs to be developed before EQS-HBC can be used more frequently in WBAN consumer and medical applications. Biophysical models characterizing the human body as a communication channel didn’t exist in literature for a long time. Recent developments have shown models that capture the channel response for fixed transmitter and receiver positions on the human body. These biophysical models do not capture the variability in the HBC channel for varying positions of the devices with respect to the human body. In this study, we provide a detailed analysis of the change in path loss in a capacitive-HBC channel in the electroquasistatic (EQS) domain. Causes of channel loss variability namely: inter-device coupling and effects of fringe fields due to body’s shadowing effects are investigated. FEM based simulation results are used to analyze the channel response of human body for different positions and sizes of the device which are further verified using measurement results to validate the developed biophysical model. Using the bio-physical model, we develop a closed form equation for the path loss in a capacitive HBC channel which is then analyzed as a function of the geometric properties of the device and the position with respect to the human body which will help pave the path towards future EQS-HBC WBAN design.
A Polynomial-Time Algorithm for Minimizing the Deep Coalescence Cost for Level-1 Species Networks
Authors: LeMay Matthew , Libeskind-Hadas Ran , Wu Yi-Chieh
Published: November 2020

Phylogenetic analyses commonly assume that the species history can be represented as a tree. However, in the presence of hybridization, the species history is more accurately captured as a network. Despite several advances in modeling phylogenetic networks, there is no known polynomial-time algorithm for parsimoniously reconciling gene trees with species networks while accounting for incomplete lineage sorting. To address this issue, we present a polynomial-time algorithm for the case of level-1 networks, in which no hybrid species is the direct ancestor of another hybrid species. This work enables more efficient reconciliation of gene trees with species networks, which in turn, enables more efficient reconstruction of species networks.
Relaxed 3D genome conformation facilitates the pluripotent to totipotent state transition in embryonic stem cells
Authors: Yu Jiali , Zhu Yezhang , Gu Jiahui , Xue Chaoran , Zhang Long , Chen Jiekai , Shen Li
Published: November 2020

The 3D genome organization is crucial for gene regulation. Although recent studies have revealed a uniquely relaxed genome conformation in totipotent early blastmeres of both fertilized and cloned embryos, how weakened higher-order chromatin structure is functionally linked to totipotency acquisition remains elusive. Using low-input Hi-C, ATAC-seq, and ChIP-seq, we systematically examined the dynamics of 3D genome and epigenome during pluripotency-to-totipotency transition in mouse embryonic stem cells (ESCs). The totipotent 2-cell-embro-like cells (2CLCs) exhibit more relaxed chromatin architecture compared to ESCs, including global weakening of both enhancer-promoter interactions and TAD insulation. While the former leads to inactivation of ESC enhancers and down-regulation of pluripotent genes, the latter may facilitate contacts between the new enhancers arising in 2CLCs and neighboring 2C genes. Importantly, disruption of chromatin loops by depleting CTCF or cohesin promotes ESC to 2CLC transition. Our results thus establish a critical role of 3D genome organization in totipotency acquisition.

HIGHLIGHTS

Global weakening of the 3D genome conformation during ESC to 2CLC transition

Loss of enhancer-promoter loops and down-regulation of pluripotent genes in 2CLCs

Inactivation of ESC enhancers and formation of new enhancers in 2CLCs

Disruption of chromatin loops by depleting CTCF or cohesin promotes 2CLC emergence
Genomic Characterization of Tissue Invasive Klebsiella pneumoniae Complex in a Hospital System with a Focus on Species Distribution and Hypervirulence
Authors: Bohrhunter Jessica , Taffner Samantha , Wang Jun , Hardy Dwight , Pecora Nicole
Published: November 2020

Klebsiella pneumoniae is an opportunistic pathogen known for multidrug resistance. Current research indicates that K. pneumoniae is a complex of closely related organisms (K. pneumoniae sensu stricto, K. quasipneumoniae, K. variicola, K. quasivariicola, and K. africana). Additionally, some strains of K. pneumoniae sensu stricto, known as hypervirulent K. pneumoniae (hvKp), cause severe infections in healthy members of the community. There is a paucity of research into rates of hvKp in the United States, the distribution of K. pneumoniae complex members in clinical specimens, and the pathogenic potential of complex members other than K. pneumoniae sensu stricto. We assessed the rates of hvKp and K. pneumoniae complex members in our 886 bed tertiary care facility in Rochester, New York. We performed whole genome sequencing on all inpatient, sterile-source isolates identified by routine culture work-up as K. pneumoniae from October 2018 – October 2019 (n=35). We additionally sequenced all K. pneumoniae liver isolates available in our collection, spanning 2017-2019 (n=18). In the yearlong collection of K. pneumoniae complex isolates, we found that 92.4% were K. pneumoniae sensu stricto (n=32), 5.7% were K. quasipneumoniae (n=2), and 2.9% were K. variicola (n=1). Five hvKp isolates were found, representing 5.7% (n=2) of K. pneumoniae sensu stricto isolates in the yearlong collection and 27.7% (n=5) of the liver isolate collection. All hvKp isolates were from liver; 60% were not associated with prior international residence.
gene.iobio: an interactive web tool for versatile, clinically-driven variant interrogation and prioritization
Authors: Di Sera Tonya , Velinder Matt , Ward Alistair , Qiao Yi , Georges Stephanie , Miller Chase , Pitman Anders , Richards Will , Ekawade Aditya , Viskochil David , Carey John C , Pace Laura , Bale Jim , Clardy Stacey L , Andrews Ashley , Botto Lorenzo , Marth Gabor
Published: November 2020

With increasing utilization of comprehensive genomic data to guide clinical care, anticipated to become the standard of care in many clinical settings, the practice of diagnostic medicine is undergoing a notable shift. However, the move from single-gene or panel-based genetic testing to exome and genome sequencing has not been matched by the development of tools to enable diagnosticians to interpret increasingly complex genomic findings. A new paradigm has emerged, where genome-based tests are often evaluated by a large multi-disciplinary collaborative team, typically including a diagnostic pathologist, a bioinformatician, a genetic counselor, and often a subspeciality clinician. This team-based approach calls for new computational tools to allow every member of the clinical care provider team, at varying levels of genetic knowledge and diagnostic expertise, to quickly and easily analyze and interpret complex genomic data. Here, we presentgene.iobio, a real-time, intuitive and interactive web application for clinically-driven variant interrogation and prioritization. We showgene.iobiois a novel and effective approach that significantly improves upon and reimagines existing methods. In a radical departure from existing methods that present variants and genomic data in text and table formats,gene.iobioprovides an interactive, intuitive and visually-driven analysis environment. We demonstrate that adoption ofgene.iobioin clinical and research settings empowers clinical care providers to interact directly with patient genomic data both for establishing clinical diagnoses and informing patient care, using sophisticated genomic analyses that previously were only accessible via complex command line tools.