bluuebunny/crossref_metadata_2025 huggingface dataset:
RCA2: a scalable supervised clustering algorithm that reduces batch effects in scRNA-seq data
Authors: Schmidt Florian , Ranjan Bobby , Lin Quy Xiao Xuan , Krishnan Vaidehi , Joanito Ignasius , Honardoost Mohammad Amin , Nawaz Zahid , Venkatesh Prasanna Nori , Tan Joanna , Rayan Nirmala Arul , Ong Sin Tiong , Prabhakar Shyam
Published: July 2021

The transcriptomic diversity of cell types in the human body can be analysed in unprecedented detail using single cell (SC) technologies. Unsupervised clustering of SC transcriptomes, which is the default technique for defining cell types, is prone to group cells by technical, rather than biological, variation. Compared to de-novo (unsupervised) clustering, we demonstrate using multiple benchmarks that supervised clustering, which uses reference transcriptomes as a guide, is robust to batch effects and data quality artifacts. Here, we present RCA2, the first algorithm to combine reference projection (batch effect robustness) with graph-based clustering (scalability). In addition, RCA2 provides a user-friendly framework incorporating multiple commonly used downstream analysis modules. RCA2 also provides new reference panels for human and mouse and supports generation of custom panels. Furthermore, RCA2 facilitates cell type-specific QC, which is essential for accurate clustering of data from heterogeneous tissues. We demonstrate the advantages of RCA2 on SC data from human bone marrow, healthy PBMCs and PBMCs from COVID-19 patients. Scalable supervised clustering methods such as RCA2 will facilitate unified analysis of cohort-scale SC datasets.
VEGFA’s distal enhancer regulates its alternative splicing in CML
Authors: Dahan Sara , Sharma Aveksha , Cohen Klil , Baker Mai , Taqatqa Nadeen , Bentata Mercedes , Engal Eden , Siam Ahmad , Kay Gillian , Drier Yotam , Elias Shlomo , Salton Maayan
Published: July 2021

Enhancer demethylation in leukemia has been shown to lead to overexpression of genes which promote cancer characteristics. The vascular endothelial growth factor A (VEGFA) enhancer, located 157 Kb downstream of its promoter, is demethylated in chronic myeloid leukemia (CML). VEGFA has several alternative splicing isoforms with different roles in cancer progression. Since transcription and splicing are coupled, we wondered whether VEGFA enhancer activity can also regulate the gene’s alternative splicing to contribute to the pathology of CML. Our results show that mutating the VEGFA +157 enhancer promotes exclusion of exons 6a and 7 and activating the enhancer by tethering a chromatin activator has the opposite effect. In line with these results, CML patients present with high expression of +157 eRNA and inclusion of VEGFA exons 6a and 7. In addition, our results show that the positive regulator of RNAPII transcription elongation, CCNT2, binds VEGFA’s promoter and enhancer, and its silencing promotes exclusion of exons 6a and 7 as it slows down RNAPII elongation rate. Thus our results suggest that VEGFA’s +157 enhancer regulates its alternative splicing by increasing RNAPII elongation rate via CCNT2. Our work demonstrates for the first time a connection between an endogenous enhancer and alternative splicing regulation of its target gene.
Characterization of a Cytosolic Acyl-Activating Enzyme Catalyzing the Formation of 4-Methylvaleryl-CoA for Pogostone Biosynthesis inPogostemon Cablin
Authors: Chen Jing , Liu Lang , Wang Ying , Li Zhengguo , Wang Guodong , Kraus George A , Pichersky Eran , Xu Haiyang
Published: July 2021

Pogostone, a compound with various pharmaceutical activities, is a major constituent of the essential oil preparation called Pogostemonis Herba, which is obtained from the plant Pogostemon cablin. The biosynthesis of pogostone has not been elucidated, but 4-methylvaleryl-CoA (4MVCoA) is a likely precursor. We analyzed the distribution of pogostone in P. cablin using gas chromatography-mass spectrometry (GC-MS) and found that pogostone accumulates at high levels in the main stems and leaves of young plants. A search for the acyl-activating enzyme (AAE) that catalyzes the formation of 4MVCoA from 4-methylvaleric acid was launched, using an RNAseq-based approach to identify 31 unigenes encoding putative AAEs including the PcAAE2, the transcript profile of which shows a strong positive correlation with the distribution pattern of pogostone. The protein encoded by PcAAE2 was biochemically characterized in vitro and shown to catalyze the formation of 4MVCoA from 4-methylvaleric acid. Phylogenetic analysis showed that PcAAE2 is closely related to other AAE proteins in P. cablin and other species that are localized to the peroxisomes. However, PcAAE2 lacks a peroxisome targeting sequence 1 (PTS1) and is localized in the cytosol.
ArabidopsisRAB8A, RAB8B and RAB8D Proteins Interact with Several RTNLB Proteins and are Involved in theAgrobacterium tumefaciensInfection Process
Authors: Huang Fan-Chen , Chi Shin-Fei , Chien Pei-Ru , Liu Yin-Tzu , Chang Hsin-Nung , Lin Choun-Sea , Hwang Hau-Hsuan
Published: July 2021

Arabidopsis thaliana small GTP-binding proteins, AtRAB8s, associate with the endomembrane system and modulate tubulovesicular trafficking between compartments of the biosynthetic and endocytic pathways. There are five members in Arabidopsis, namely AtRAB8A-8E. Yeast two-hybrid assays, bimolecular fluorescence complementation assays and glutathione-S-transferase pull-down assays showed that RAB8A, 8B and 8D interacted with several membrane-associated reticulon-like (AtRTNLB) proteins in yeast, plant cells and in vitro. Furthermore, RAB8A, 8B and 8D proteins showed interactions with the Agrobacterium tumefaciens virulence protein, VirB2, a component of a type IV secretion system (T4SS). A. tumefaciens uses a T4SS to transfer T-DNA and Virulence proteins to plants, which causes crown gall disease in plants. The Arabidopsis rab8A, rab8B and rab8D single mutants showed decreased levels of Agrobacterium-mediated root and seedling transformation, while the RAB8A, 8B and 8D overexpression transgenic Arabidopsis plants were hypersusceptible to A. tumefaciens and Pseudomonas syringae infections. RAB8A-8E transcripts accumulated differently in roots, rosette leaves, cauline leaves, inflorescence and flowers of wild-type plants. In summary, RAB8A, 8B and 8D interacted with several RTNLB proteins and participated in A. tumefaciens and P. syringae infection processes.
Estimating leaf area index using unmanned aerial vehicle data: shallow vs. deep machine learning algorithms
Authors: Liu Shuaibing , Jin Xiuliang , Nie Chenwei , Wang Siyu , Yu Xun , Cheng Minghan , Shao Mingchao , Wang Zixu , Tuohuti Nuremanguli , Bai Yi , Liu Yadong
Published: July 2021

Measuring leaf area index (LAI) is essential for evaluating crop growth and estimating yield, thereby facilitating high-throughput phenotyping of maize (Zea mays). LAI estimation models use multi-source data from unmanned aerial vehicles (UAVs), but using multimodal data to estimate maize LAI, and the effect of tassels and soil background, remain understudied. Our research aims to (1) determine how multimodal data contribute to LAI and propose a framework for estimating LAI based on remote-sensing data, (2) evaluate the robustness and adaptability of an LAI estimation model that uses multimodal data fusion and deep neural networks (DNNs) in single- and whole growth stages, and (3) explore how soil background and maize tasseling affect LAI estimation. To construct multimodal datasets, our UAV collected red–green–blue, multispectral, and thermal infrared images. We then developed partial least square regression (PLSR), support vector regression, and random forest regression models to estimate LAI. We also developed a deep learning model with three hidden layers. This multimodal data structure accurately estimated maize LAI. The DNN model provided the best estimate (coefficient of determination [R2] = 0.89, relative root mean square error [rRMSE] = 12.92%) for a single growth period, and the PLSR model provided the best estimate (R2 = 0.70, rRMSE = 12.78%) for a whole growth period. Tassels reduced the accuracy of LAI estimation, but the soil background provided additional image feature information, improving accuracy. These results indicate that multimodal data fusion using low-cost UAVs and DNNs can accurately and reliably estimate LAI for crops, which is valuable for high-throughput phenotyping and high-spatial precision farmland management.
Percutaneous Radiofrequency Rhizotomy Is Equally Effective for Trigeminal Neuralgia Patients with or Without Neurovascular Compression
Authors: Kao Chih-Hao , Lee Ming-Hsueh , Yang Jen-Tsung , Tsai Yuan-Hsiung , Lin Martin Hsiu-Chu
Published: July 2021

Background

Neurovascular compression (NVC) in patients with trigeminal neuralgia (TN) can be a factor of treatment outcome, especially in microvascular decompression and stereotactic radiosurgery. No such effect has been reported in percutaneous radiofrequency rhizotomy (RF). This study aims to investigate whether NVC affects the efficacy of RF in patients with TN.

Methods

We retrospectively reviewed patients with TN who received RF in our institution. Pretreatment magnetic resonance imaging was performed in every patient, and the presence of NVC was reviewed independently by two physicians. The patients were followed up at least for a year after the treatment. Pain severity was assessed with a numeric rating scale (NRS).

Results

Sixty-two patients were included in the study. All of the patients had single-sided lesions, and 35 patients had NVC. There were no significant differences between these two groups of patients in terms of gender distribution, age, and pretreatment pain severity. Comparable pain severity improvement was found at 1-year follow-up between these two groups (NRS 7.93 ± 0.492 without compression vs 7.57 ± 0.451 with compression, P = 0.600). No significant difference in posttreatment pain severity at 1 year was found between these two patient groups (NRS 1.37 ± 0.466 without compression vs 1.66 ± 0.458 with compression, P = 0.667).

Conclusions

For patients with TN treated by RF, the presence or absence of NVC is not likely to affect the 1-year pain control rate.
Limb girdle muscular dystrophy R12 (LGMD 2L, anoctaminopathy) mimicking idiopathic inflammatory myopathy: key points to prevent misdiagnosis
Authors: Marago Italo , Roberts Mark , Roncaroli Federico , DuPlessis Daniel , Sewry Caroline , Nagaraju Santhosh , Limbada Faheema , Marini-Bettolo Chiara , Hudson Judith , Banerjee Siwalik , Newton Laura , Bukhari Marwan , Chinoy Hector , Lilleker James B
Published: July 2021

Objectives

Diagnosing the idiopathic inflammatory myopathies (IIMs) can be challenging as several conditions, including genetic myopathies such as limb girdle muscular dystrophy type R12 (LGMD 2 l, anoctaminopathy) mimic the presentation. Here we describe learning points identified from review of four patients with LGMD 2 l who were initially incorrectly diagnosed with IIM. Our aim is to provide clinicians working in adult rheumatology services with a toolkit to help identify non-inflammatory presentations of myopathy.

Methods

We performed retrospective review of medical notes, laboratory results, muscle imaging and histological findings of four patients with LGMD 2 l who were previously misdiagnosed with IIM. We focussed on clinical presentation and progression, therapeutic agents used and events leading to revision of the diagnosis.

Results

Three male patients and one female patient with a mean age of 51 years at presentation were reviewed. In each case, treatment with immunosuppressants, in one case for >15 years, was observed without a clear therapeutic response. All patients were negative for anti-nuclear antibodies and available myositis-associated/specific autoantibodies and associated connective tissue disease features were absent. Prominent fatty infiltration and selective muscle involvement on thigh MRI was found in common.

Conclusions

Adult-onset genetic myopathies, particularly LGMD R12, can mimic IIM. Accurate diagnosis is crucial to avoid the use of potentially harmful immunosuppressive therapies, to allow appropriate genetic counselling and to facilitate involvement in research studies.
Real-time vs static scoring in musculoskeletal ultrasonography in patients with inflammatory hand osteoarthritis
Authors: van de Stadt Lotte A , Kroon Féline P B , Rosendaal Frits R , van der Heijde Desirée , Reijnierse Monique , Riyazi Naghmeh , de Slegte Ragnhild , van Zeben Jendé , Allaart Cornelia F , Kloppenburg Margreet , Kortekaas Marion C
Published: July 2021

Objectives

Agreement between real-time and static ultrasonography has not been studied in musculoskeletal diseases. We studied this agreement in inflammatory hand OA.

Methods

Ultrasonography was performed blinded to clinical information of 30 joints of 75 patients with hand OA, treated with prednisolone in a randomized placebo-controlled double-blind trial. Images were scored real-time at acquisition and stored images were scored static (paired in known chronological order) for inflammatory features and osteophytes (score 0–3). Agreement between methods was studied at joint level with quadratic weighted kappa. At patient level intra-class correlations (ICC) of sum scores and change in sum-scores (delta baseline—week 6) were calculated. Responsiveness of scoring methods was analysed with generalized estimating equations (GEE) with treatment as independent and ultrasonography findings as dependent variable.

Results

Agreement at baseline was good to excellent at joint level (kappa 0.72–0.88) and moderate to excellent at patient level (ICC 0.58–0.91). Agreement for change in sum scores was poor to fair for synovial thickening and effusion (ICC 0.18 and 0.34, respectively), while excellent for Doppler signal (ICC 0.80). Real-time ultrasonography discriminated between prednisolone and placebo with a mean between-group difference of synovial thickening of −2.5 (95% CI: −4.7, −0.3). Static ultrasonography did not show a decrease in synovial thickening.

Conclusion

While cross-sectional agreement between real-time and static ultrasonography is good, static ultrasonography measurement of synovial thickening did not show responsiveness to prednisone therapy while real-time ultrasonography did. Therefore, when ultrasonography is used in clinical trials, real-time dynamic scoring should remain the standard for now.
Poverty from Space: Using High Resolution Satellite Imagery for Estimating Economic Well-being
Authors: Engstrom Ryan , Hersh Jonathan , Newhouse David
Published: July 2021

Can features extracted from high spatial resolution satellite imagery accurately estimate poverty and economic well-being? The present study investigates this question by extracting both object and texture features from satellite images of Sri Lanka. These features are used to estimate poverty rates and average expected log consumption taken from small-area estimates derived from census data, for 1,291 administrative units. Features extracted include the number and density of buildings, the prevalence of building shadows (proxying building height), the number of cars, length of roads, type of agriculture, roof material, and several texture and spectral features. A linear regression model explains between 49 and 61 percent of the variation in average expected log consumption, and between 37 and 62 percent for poverty rates. Estimates remain accurate throughout the consumption distribution, and when extrapolating predictions into adjacent areas, although performance falls when using fewer households to calculate estimates of poverty and welfare.
Written Care Summaries Facilitate Communication Between Families and Providers of ICU Patients: A Pilot Study
Authors: Bulger Jeffrey L. , Quinn Thomas V. , Glover Crystal M. , Basapur Santosh , Shah Raj C. , Greenberg Jared A.
Published: July 2021

OBJECTIVES:

ICU providers may invite families to participate in daily rounds to inform them of the patient’s condition and to support their emotional well-being. Daily written summaries of care may provide complementary benefits.

DESIGN:

Qualitative interviews with surrogates of ICU patients who received daily written summaries of care.

SETTING:

Single, urban academic medical center.

PATIENTS/SUBJECTS:

A convenience sample of 30 surrogates of nondecisional, medical ICU patients.

INTERVENTIONS:

Daily written summaries detailed each of the patient’s main ICU problems, the presumed causes of each of the problems, and the medical team’s plan to address each of the problems for each ICU day.

MEASUREMENTS AND MAIN RESULTS:

There were four ways that written summaries affected the participant’s experience: 1) providing clarity to participants regarding the patient’s condition, 2) facilitating participant understanding of the patient’s clinical course, 3) facilitating communication between participants and medical providers, and 4) facilitating communication between participants and other family members. Overarching themes were that summaries were understandable, had appropriate level of detail, and added value to the ICU experience.

CONCLUSIONS:

In this pilot study, family members had positive impressions of receiving daily written summaries of care. Further study is needed to determine the extent to which written communication may affect family and patient outcomes.
A Full-Stack Application for Detecting Seizures and Reducing Data During Continuous Electroencephalogram Monitoring
Authors: Bernabei John M. , Owoputi Olaoluwa , Small Shyon D. , Nyema Nathaniel T. , Dumenyo Elom , Kim Joongwon , Baldassano Steven N. , Painter Christopher , Conrad Erin C. , Ganguly Taneeta M. , Balu Ramani , Davis Kathryn A. , Levine Joshua M. , Pathmanathan Jay , Litt Brian
Published: July 2021

BACKGROUND:

Continuous electroencephalogram monitoring is associated with lower mortality in critically ill patients; however, it is underused due to the resource-intensive nature of manually interpreting prolonged streams of continuous electroencephalogram data. Here, we present a novel real-time, machine learning–based alerting and monitoring system for epilepsy and seizures that dramatically reduces the amount of manual electroencephalogram review.

METHODS:

We developed a custom data reduction algorithm using a random forest and deployed it within an online cloud-based platform, which streams data and communicates interactively with caregivers via a web interface to display algorithm results. We developed real-time, machine learning–based alerting and monitoring system for epilepsy and seizures on continuous electroencephalogram recordings from 77 patients undergoing routine scalp ICU electroencephalogram monitoring and tested it on an additional 20 patients.

RESULTS

We achieved a mean seizure sensitivity of 84% in cross-validation and 85% in testing, as well as a mean specificity of 83% in cross-validation and 86% in testing, corresponding to a high level of data reduction. This study validates a platform for machine learning–assisted continuous electroencephalogram analysis and represents a meaningful step toward improving utility and decreasing cost of continuous electroencephalogram monitoring. We also make our high-quality annotated dataset of 97 ICU continuous electroencephalogram recordings public for others to validate and improve upon our methods.
Frequency of Withdrawal of Life-Sustaining Therapy for Perceived Poor Neurologic Prognosis
Authors: Steinberg Alexis , Abella Benjamin S. , Gilmore Emily J. , Hwang David Y. , Kennedy Niki , Lau Winnie , Mullen Isabelle , Ravishankar Nidhi , Tisch Charlotte F. , Waddell Adam , Wallace David J. , Zhang Qiang , Elmer Jonathan
Published: July 2021

OBJECTIVES:

To measure the frequency of withdrawal of life-sustaining therapy for perceived poor neurologic prognosis among decedents in hospitals of different sizes and teaching statuses.

DESIGN:

We performed a multicenter, retrospective cohort study.

SETTING:

Four large teaching hospitals, four affiliated small teaching hospitals, and nine affiliated nonteaching hospitals in the United States.

PATIENTS:

We included a sample of all adult inpatient decedents between August 2017 and August 2019.

MEASUREMENTS AND MAIN RESULTS:

We reviewed inpatient notes and categorized the immediately preceding circumstances as withdrawal of life-sustaining therapy for perceived poor neurologic prognosis, withdrawal of life-sustaining therapy for nonneurologic reasons, limitations or withholding of life support or resuscitation, cardiac death despite full treatment, or brain death. Of 2,100 patients, median age was 71 years (interquartile range, 60–81 yr), median hospital length of stay was 5 days (interquartile range, 2–11 d), and 1,326 (63%) were treated at four large teaching hospitals. Withdrawal of life-sustaining therapy for perceived poor neurologic prognosis occurred in 516 patients (25%) and was the sole contributing factor to death in 331 (15%). Withdrawal of life-sustaining therapy for perceived poor neurologic prognosis was common in all hospitals: 30% of deaths at large teaching hospitals, 19% of deaths in small teaching hospitals, and 15% of deaths at nonteaching hospitals. Withdrawal of life-sustaining therapy for perceived poor neurologic prognosis happened frequently across all hospital units. Withdrawal of life-sustaining therapy for perceived poor neurologic prognosis contributed to one in 12 deaths in patients without a primary neurologic diagnosis. After accounting for patient and hospital characteristics, significant between-hospital variability in the odds of withdrawal of life-sustaining therapy for perceived poor neurologic prognosis persisted.

CONCLUSIONS:

A quarter of inpatient deaths in this cohort occurred after withdrawal of life-sustaining therapy for perceived poor neurologic prognosis. The rate of withdrawal of life-sustaining therapy for perceived poor neurologic prognosis occurred commonly in all type of hospital settings. We observed significant unexplained variation in the odds of withdrawal of life-sustaining therapy for perceived poor neurologic prognosis across participating hospitals.
Improved Surgical Outcome with Double Incision and Free Nipple Graft in Gender Confirmation Mastectomy
Authors: Kamali Alexander , Sigurjónsson Hannes , Gran Isak , Farnebo Filip , Conneryd Lundgren Kalle , Granath Fredrik , Sommar Pehr
Published: July 2021

Background:

Mastectomy and chest-wall contouring is the most common gender confirmation surgery. With increasing prevalence of transgender individuals, there is a demand for better surgical outcomes and aesthetic results. Our aim was to evaluate surgical techniques used and assess modifications in gender confirmation mastectomies at Karolinska University hospital in Stockholm, Sweden.

Methods:

A retrospective cohort study was performed on 464 patients undergoing gender confirmation mastectomies in our department between 2009 and 2018. Patient demographics, psychiatric comorbidity, surgical method, and outcome were analyzed. Follow-up was at least one year.

Results:

The most frequently used surgical technique for gender confirmation mastectomies was double incision with free nipple graft (243 patients, 52.4%), followed by periareolar incision (113 patients, 24.4%) and semicircular incision (67 patients, 14.4%). The double incision technique and periareolar technique were associated with 18.9% and 28.3% complications, 3.3% and 12.4% acute reoperations, 28.4% and 65.5% secondary revisions, respectively. The double incision technique increased from being used in 17.8% of all mastectomies during 2009–2013 to 62.9% during 2014–2018, while periareolar incision decreased from 43.0% to 18.5%.

Conclusions:

The current study describes a successful transition of surgical technique from periareolar incision to double incision with free nipple graft in gender confirmation mastectomy, leading to significant improvements in the overall outcome with fewer complications, less acute reoperations and less secondary corrections. Hence, we consider the double incision with free nipple graft technique to be the favored technique in the vast majority of cases in female-to-male chest wall contouring.
The B-cell Receptor Autoantigen LRPAP1 Can Replace Variable Antibody Regions to Target Mantle Cell Lymphoma Cells
Authors: Bewarder Moritz , Kiefer Maximilian , Will Helene , Olesch Kathrin , Moelle Clara , Stilgenbauer Stephan , Christofyllakis Konstantinos , Kaddu-Mulindwa Dominic , Bittenbring Joerg Thomas , Fadle Natalie , Regitz Evi , Kaschek Lea , Hoth Markus , Neumann Frank , Preuss Klaus-Dieter , Pfreundschuh Michael , Thurner Lorenz
Published: July 2021

Mantle cell lymphoma (MCL) accounts for 5%–10% of all lymphomas. The disease’s genetic hallmark is the t(11; 14)(q13; q32) translocation. In younger patients, the first-line treatment is chemoimmunotherapy followed by autologous stem cell transplantation. Upon disease progression, novel and targeted agents such as the BTK inhibitor ibrutinib, the BCL-2 inhibitor venetoclax, or the combination of both are increasingly used, but even after allogeneic stem cell transplantation or CAR T-cell therapy, MCL remains incurable for most patients. Chronic antigenic stimulation of the B-cell receptor (BCR) is thought to be essential for the pathogenesis of many B-cell lymphomas. LRPAP1 has been identified as the autoantigenic BCR target in about 1/3 of all MCLs. Thus, LRPAP1 could be used to target MCL cells, however, there is currently no optimal therapeutic format to integrate LRPAP1. We have therefore integrated LRPAP1 into a concept termed BAR, for B-cell receptor antigens for reverse targeting. A bispecific BAR body was synthesized consisting of the lymphoma-BCR binding epitope of LRPAP1 and a single chain fragment targeting CD3 or CD16 to recruit/engage T or NK cells. In addition, a BAR body consisting of an IgG1 antibody and the lymphoma-BCR binding epitope of LRPAP1 replacing the variable regions was synthesized. Both BAR bodies mediated highly specific cytotoxic effects against MCL cells in a dose-dependent manner at 1–20 µg/mL. In conclusion, LRPAP1 can substitute variable antibody regions in different formats to function in a new therapeutic approach to treat MCL.
OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY EVALUATION OF PERIPAPILLARY MICROVASCULAR CHANGES AFTER RHEGMATOGENOUS RETINAL DETACHMENT REPAIR
Authors: Bonfiglio Vincenza , Ortisi Elina , Nebbioso Marcella , Reibaldi Michele , Lupidi Marco , Russo Andrea , Fallico Matteo , Scollo Davide , Macchi Iacopo , Pizzo Alessandra , Panebianco Roberta , Patanè Clara , Vadalà Maria , Toro Mario D. , Rejdak Robert , Nowomiejska Katarzyna , Avitabile Teresio , Longo Antonio
Published: July 2021

Purpose:

To evaluate the radial peripapillary capillary plexus (RPCP) vessel density (VD) and the retinal nerve fiber layer (RNFL) thickness in eyes successfully treated with pars plana vitrectomy for primary rhegmatogenous retinal detachment.

Methods:

In this cross-sectional multicenter clinical study, eyes with a minimum 12-month follow-up were reexamined. The RPCP VD and RNFL thickness in the rhegmatogenous retinal detachment subfields of the affected eye (study group) were compared with the corresponding areas of the healthy fellow eyes (control group).

Results:

Fifty-three eyes were included in the study. A significantly lower RPCP VD and RNFL thickness were observed in those subfields affected by rhegmatogenous retinal detachment compared with those of the control group (P < 0.001). No statistically significant differences were observed between undetached subfields in the study group and their corresponding images in the control group. In the study group, a significant correlation was found between RPCP VD and RNFL thickness in subfields with detached retina (r = 0.393, P < 0.001) and undetached retina (r = 0.321, P < 0.001).

Conclusion:

Radial peripapillary capillary plexus VD changes were found in the subfields of detached retina successfully treated with pars plana vitrectomy and they correlated with RNFL thinning. These data suggest a coexistence of neuronal and microvascular damage in patients affected by rhegmatogenous retinal detachment.
Avoiding the blood supply to the femoral head during cannulated screw fixation: A comparison of two techniques
Authors: Pettett Brett J. , Winek Nathan C. , Schimoler Patrick J. , Kharlamov Alexander , Miller Mark Carl , Westrick Edward R.
Published: July 2021

Objectives:

To compare the strength of the inverted triangle (IT) versus the L-shaped cannulated screw fixation technique for stabilizing a Pauwels 2 femoral neck fracture. To demonstrate the risk to the blood supply to the femoral head from a posterior–superior screw.

Methods:

The IT construct was compared with the L-shaped design in 10 composite femurs. A Pauwels 2 fracture was made with a 5 mm gap. Each specimen was loaded over 5000 cycles, measuring angular/shear displacement then loaded to failure. The data were analyzed using Mann–Whitney U test. Three separate fresh frozen cadavers were injected with low-viscosity epoxy. The intraosseous bloody supply was inspected in each femoral head (no fixation, IT, L-shaped).

Results:

There was no difference in angular (P = .3) or shear displacement (P = .99) between either screw design after cyclical loading. Also, there was not statistical difference in load to failure testing between either construct (P = .99). The average load to failure in the IT group was 3204.4 N. The average was 3180.2 N in the L-shaped design. We demonstrated the presence of the intraosseous portion of the lateral epiphyseal vessel in the specimen without screw fixation. This was preserved in the specimen with the L-shaped design but absent in the specimen following IT fixation.

Conclusions:

The strength of the L-shaped construct was not statistically different than the strength of the IT design. The posterior–superior screw may put the main blood supply to the femoral head at risk and should be avoided.
Systemic Fibrocyte Levels and Keloid Expression of the Chemoattractant CXCL12 Are Upregulated Compared With Patients With Normal Scar
Authors: Campbell Chris A. , Burdick Marie D. , Strieter Robert M.
Published: July 2021

Background

Fibrocytes are bone marrow mesenchymal precursors with a surface phenotype compatible with leukocytes, fibroblasts, and hematopoietic progenitors that have been shown to traffic to wound healing sites in response to described chemokine pathways. Keloids are focal fibrotic responses to cutaneous trauma characterized by disordered collagen, which may be associated with elevated systemic fibrocyte levels and/or wound bed chemokine expression.

Methods

Blood specimens from patients with longstanding keloids and those who form grossly normal scars were assayed by fluorescence activated cell sorting analysis for fibrocytes (CD45+, Col I+). The expression of the fibrocyte chemotactic cell surface marker CXCR4, intracellular markers of fibroblast differentiation (pSMAD2/3), and plasma levels of the CXCR4 cognate CXCL12 were compared. Keloid specimens and grossly normal scars were excised, and local expression of CXCL12 was assayed.

Results

Keloid-forming patients demonstrated a significantly greater number of circulating fibrocytes (17.4 × 105 cells/mL) than control patients (1.01 × 105 cells/mL, P = 0.004). The absolute number of fibrocytes expressing CXCR4 was significantly greater (P = 0.012) in keloid-forming patients. Systemic CXCL12 levels were insignificantly greater in keloid-forming patients than controls. Keloid specimens had significantly greater CXCL12 expression (529.3 pg/mL) than normal scar (undetectable).

Conclusions

Systemic fibrocyte levels and the CXCR4/CXCL12 biologic axis responsible for fibrocyte trafficking to areas of regional fibrosis were both upregulated in patients who form keloids compared with controls. Keloids persistently expressed CXLC12, which serves both as the main chemoattractant for fibrocytes and a downstream mediator for local inflammation, suggesting a role for this biologic axis in keloid formation and possibly recurrence.
High-resolution achromatic X-ray optical systems for broad-band imaging and for focusing attosecond pulses
Authors: Chapman H. N. , Bajt S.
Published: July 2021

Achromatic focusing systems for hard X-rays are examined which consist of a refractive lens paired with a diffractive lens. Compared with previous analyses, we take into account the behaviour of thick refractive lenses, such as compound refractive lenses and waveguide gradient index refractive lenses, in which both the focal length and the position of the principal planes vary with wavelength. Achromatic systems formed by the combination of such a thick refractive lens with a multilayer Laue lens are found that can operate at a focusing resolution of about 3 nm, over a relative bandwidth of about 1%. With the appropriate distance between the refractive and diffractive lenses, apochromatic systems can also be found, which operate over relative bandwidth greater than 10%. These systems can be used to focus short pulses without distorting them in time by more than several attoseconds. Such systems are suitable for high-flux scanning microscopy and for creating high intensities from attosecond X-ray pulses.
Indentation mapping of stretched adhesive membranes
Authors: Argatov Ivan I.
Published: July 2021

Unilateral adhesive contact between a rigid indenter and a uniformly stretched membrane of arbitrary shape is considered. The generalized Johnson–Kendall–Roberts (JKR)-type and Derjaguin– Muller–Toporov (DMT)-type models of non-axisymmetric adhesive contact are presented for short- and long-range adhesion, respectively, and the JKR–DMT transition is established in the framework of the generalized Maugis–Dugdale model. A refined method of matched asymptotic expansions is applied to construct the leading-order asymptotic model for indentation mapping of freestanding two-dimensional materials with an axisymmetric probe, using the approximate analytical solution obtained in explicit form for an infinite membrane in the limit of short-range adhesive contact with an indenter in the form of an elliptic paraboloid. The cases of a spherical indenter and a rectangular membrane are studied in detail.
The influence of temperature on the seasonality of historical plague outbreaks
Authors: Krauer Fabienne , Viljugrein Hildegunn , Dean Katharine R.
Published: July 2021

Modern plague outbreaks exhibit a distinct seasonal pattern. By contrast, the seasonality of historical outbreaks and its drivers has not been studied systematically. Here, we investigate the seasonal pattern, the epidemic peak timing and growth rates, and the association with latitude, temperature, and precipitation using a large, novel dataset of plague- and all-cause mortality during the Second Pandemic in Europe and the Mediterranean. We show that epidemic peak timing followed a latitudinal gradient, with mean annual temperature negatively associated with peak timing. Based on modern temperature data, the predicted epidemic growth of all outbreaks was positive between 11.7°C and 21.5°C with a maximum around 17.3°C. Hence, our study provides evidence that the growth of plague epidemics across the whole study region depended on similar absolute temperature thresholds. Here, we present a systematic analysis of the seasonality of historical plague in the Northern Hemisphere, and we show consistent evidence for a temperature-related process influencing the epidemic peak timing and growth rates of plague epidemics.
Deep classification of cut-marks on bones from Arroyo del Vizcaíno (Uruguay)
Authors: Domínguez-Rodrigo Manuel , Baquedano Enrique , Varela Luciano , Tambusso P. Sebastián , Melián María Julia , Fariña Richard A.
Published: July 2021

The earliest widely accepted presence of humans in America dates to approximately 17.5 cal kyr BP, at the end of the Last Glacial Maximum (LGM). Among other evidence, this presence is attested by stone tools and associated cut-marks and other bone surface modifications (BSM), interpreted as the result of the consumption of animals by humans. Claims of an older human presence in the continent have been made based on the proposed anthropogenic modification of faunal remains; however, these have been controversial due to the highly subjective nature of the interpretations. Here, we employ advanced deep learning algorithms to objectively increase the accuracy of BSM identification on bones. With several models that exhibit BSM classification accuracies greater than 94%, we use ensemble learning techniques to robustly classify a selected sample of BSM from the approximately 30 kyr BP site of Arroyo del Vizcaíno, Uruguay. Our results confidently show the presence of cut-marks imparted by stone tools on bones at the site. This result supports an earlier presence of humans in the American continent, expanding additional genetic and archaeological evidence of a human LGM and pre-LGM presence in the continent.
The cibarial pump of the xylem-feeding froghopperPhilaenus spumariusproduces negative pressures exceeding 1 MPa
Authors: Bergman Elisabeth A. , Green Emma L. , Matthews Philip G. D.
Published: July 2021

The xylem sap of vascular plants is an unlikely source of nutrition, being both nutrient poor and held under tensions (negative pressures) that can exceed 1 MPa. But some insects feed on xylem sap exclusively, extracting copious quantities using a muscular cibarial pump. However, neither the strength of the insect's suction, nor the direct energetic cost of xylem ingestion, have ever been quantified.Philaenus spumariusfroghoppers were used to address these gaps in our knowledge. Micro-CT scans of its cibarium and measurements of cibarial muscle sarcomere length revealed thatP. spumariuscan generate a maximum tension of 1.3 ± 0.2 MPa within its cibarium. The energetic cost of xylem extraction was quantified using respirometry to measure the metabolic rate (MR) ofP. spumariuswhile they fed on hydroponically grown legumes, while xylem sap excretion rate and cibarial pumping frequency were simultaneously recorded. Increasing the plants' xylem tensions up to 1.1 MPa by exposing their roots to polyethylene glycol did not reduce the insects’ rate of xylem excretion, but significantly increased both MR and pumping frequency. We conclude thatP. spumariuscan gain energy feeding on xylem sap containing previously reported energy densities and at xylem tensions up to their maximum suction capacity.
Fire reduces parasite load in a Mediterranean lizard
Authors: Álvarez-Ruiz Lola , Belliure Josabel , Santos Xavier , Pausas Juli G.
Published: July 2021

Wildfires are a natural disturbance in many ecosystems. However, their effect on biotic interactions has been poorly studied. Fire consumes the vegetation and the litter layer where many parasites spend part of their life cycles. We hypothesize that wildfires reduce habitat availability for parasites with consequent potential benefits for hosts. We tested this for the lizardPsammodromus algirusand its ectoparasites in a Mediterranean ecosystem. We predicted that lizards in recently burned areas would have lower parasite load (cleaning effect) than those in unburned areas and that this phenomenon implies that lizards spending their entire lives in postfire conditions experience a lower level of parasitism than those living in unburned areas. We compared the ectoparasite load of lizards between eight paired burned/unburned sites, including recent (less than 1 year postfire) and older fires (2–4 years). We found that lizards' ectoparasites prevalence was drastically reduced in recently burned areas. Likewise, lizards in older burned areas showed less evidence of past parasitic infections. Fire disrupted the host–parasite interaction, providing the opportunity for lizards to avoid the negative effects of ectoparasites. Our results suggest that wildfires probably fulfil a role in controlling vector-borne diseases and pathogens, and highlight ecological effects of wildfires that have been overlooked.
Antifungal alternation can be beneficial for durability but at the cost of generalist resistance
Authors: Ballu Agathe , Despréaux Philomène , Duplaix Clémentine , Dérédec Anne , Carpentier Florence , Walker Anne-Sophie
Published: July 2021

The evolution of resistance to pesticides is a major burden in agriculture. Resistance management involves maximizing selection pressure heterogeneity, particularly by combining active ingredients with different modes of action. We tested the hypothesis that alternation may delay the build-up of resistance not only by spreading selection pressure over longer periods, but also by decreasing the rate of evolution of resistance to alternated fungicides, by applying an experimental evolution approach to the economically important crop pathogenZymoseptoria tritici. Our results show that alternation is either neutral or slows the overall resistance evolution rate, relative to continuous fungicide use, but results in higher levels of generalism in evolved lines. We demonstrate that the nature of the fungicides, and therefore their relative intrinsic risk of resistance may underly this trade-off, more so than the number of fungicides and the rhythm of alternation. This trade-off is also dynamic over the course of resistance evolution. These findings open up new possibilities for tailoring resistance management effectively while optimizing interplay between alternation components.
Molecular Mechanisms for Frequency Specificity in aDrosophilaHearing Organ
Authors: Hu Yufei , Jia Yinjun , Deng Tuantuan , Liu Ting , Zhang Wei
Published: July 2021

Discrimination for sound frequency is essential for auditory communications in animals. Here, by combiningin vivocalcium imaging and behavioral assay, we found thatDrosophilalarvae can sense a wide range of sound frequency and the behavioral specificity is mediated with the selectivity of the lch5 chordotonal organ neurons to sounds that forms a combinatorial coding of frequency. We also disclosed that Brivido1 (Brv1) and Piezo-like (Pzl), each expresses in a subset of lch5 neurons and mediate hearing sensation to certain frequency ranges. Intriguingly, mouse Piezo2 can rescuepzl-mutant’s phenotypes, suggesting a conserved role of the Piezo family proteins in high-frequency hearing.
PPARdelta signaling activation improves metabolic and contractile maturation of human pluripotent stem cell-derived cardiomyocytes
Authors: Wickramasinghe Nadeera M. , Sachs David , Shewale Bhavana , Gonzalez David M. , Dhanan-Krishnan Priyanka , Torre Denis , LaMarca Elizabeth , Raimo Serena , Dariolli Rafael , Serasinghe Madhavika N. , Mayourian Joshua , Sebra Robert , Beaumont Kristin , Iyengar Ravi , French Deborah L. , Hansen Arne , Eschenhagen Thomas , Chipuk Jerry E. , Sobie Eric A. , Jacobs Adam , Akbarian Schahram , Ischiropoulos Harry , Ma’ayan Avi , Houten Sander M. , Costa Kevin , Dubois Nicole C.
Published: July 2021

Pluripotent stem cell-derived cardiomyocytes (PSC-CMs) provide an unprecedented opportunity to study human heart development and disease. A major caveat however is that they remain functionally and structurally immature in culture, limiting their potential for disease modeling and regenerative approaches. Here, we address the question of how different metabolic pathways can be modulated in order to induce efficient hPSC-CM maturation. We show that PPAR signaling acts in an isoform-specific manner to balance glycolysis and fatty acid oxidation (FAO). PPARD activation or inhibition results in efficient respective up- or down-regulation of the gene regulatory networks underlying FAO in hPSC-CMs. PPARD induction further increases mitochondrial and peroxisome content, enhances mitochondrial cristae formation and augments FAO flux. Lastly PPARD activation results in enhanced myofibril organization and improved contractility. Transient lactate exposure, commonly used in hPSC-CM purification protocols, induces an independent program of cardiac maturation, but when combined with PPARD activation equally results in a metabolic switch to FAO. In summary, we identify multiple axes of metabolic modifications of hPSC-CMs and a role for PPARD signaling in inducing the metabolic switch to FAO in hPSC-CMs. Our findings provide new and easily implemented opportunities to generate mature hPSC-CMs for disease modeling and regenerative therapy.
Critical Assessment of Metagenome Interpretation - the second round of challenges
Authors: Meyer F. , Fritz A. , Deng Z.-L. , Koslicki D. , Gurevich A. , Robertson G. , Alser M. , Antipov D. , Beghini F. , Bertrand D. , Brito J. J. , Brown C.T. , Buchmann J. , Buluç A. , Chen B. , Chikhi R. , Clausen P. T. , Cristian A. , Dabrowski P. W. , Darling A. E. , Egan R. , Eskin E. , Georganas E. , Goltsman E. , Gray M. A. , Hansen L. H. , Hofmeyr S. , Huang P. , Irber L. , Jia H. , Jørgensen T. S. , Kieser S. D. , Klemetsen T. , Kola A. , Kolmogorov M. , Korobeynikov A. , Kwan J. , LaPierre N. , Lemaitre C. , Li C. , Limasset A. , Malcher-Miranda F. , Mangul S. , Marcelino V. R. , Marchet C. , Marijon P. , Meleshko D. , Mende D. R. , Milanese A. , Nagarajan N. , Nissen J. , Nurk S. , Oliker L. , Paoli L. , Peterlongo P. , Piro V. C. , Porter J. S. , Rasmussen S. , Rees E. R. , Reinert K. , Renard B. , Robertsen E. M. , Rosen G. L. , Ruscheweyh H.-J. , Sarwal V. , Segata N. , Seiler E. , Shi L. , Sun F. , Sunagawa S. , Sørensen S. J. , Thomas A. , Tong C. , Trajkovski M. , Tremblay J. , Uritskiy G. , Vicedomini R. , Wang Zi. , Wang Zhe. , Wang Zho. , Warren A. , Willassen N. P. , Yelick K. , You R. , Zeller G. , Zhao Z. , Zhu S. , Zhu J. , Garrido-Oter R. , Gastmeier P. , Hacquard S. , Häußler S. , Khaledi A. , Maechler F. , Mesny F. , Radutoiu S. , Schulze-Lefert P. , Smit N. , Strowig T. , Bremges A. , Sczyrba A. , McHardy A. C.
Published: July 2021

Evaluating metagenomic software is key for optimizing metagenome interpretation and focus of the community-driven initiative for the Critical Assessment of Metagenome Interpretation (CAMI). In its second challenge, CAMI engaged the community to assess their methods on realistic and complex metagenomic datasets with long and short reads, created from ∼1,700 novel and known microbial genomes, as well as ∼600 novel plasmids and viruses. Altogether 5,002 results by 76 program versions were analyzed, representing a 22x increase in results.

Substantial improvements were seen in metagenome assembly, some due to using long-read data. The presence of related strains still was challenging for assembly and genome binning, as was assembly quality for the latter. Taxon profilers demonstrated a marked maturation, with taxon profilers and binners excelling at higher bacterial taxonomic ranks, but underperforming for viruses and archaea. Assessment of clinical pathogen detection techniques revealed a need to improve reproducibility. Analysis of program runtimes and memory usage identified highly efficient programs, including some top performers with other metrics. The CAMI II results identify current challenges, but also guide researchers in selecting methods for specific analyses.
Cooperative escape in ants and robots
Authors: Prasath S Ganga , Mandal Souvik , Giardina Fabio , Kennedy Jordan , Murthy Venkatesh N. , Mahadevan L
Published: July 2021

The solution of complex problems by the collective action of simple agents in both biologically evolved and synthetically engineered systems involves cooperative action. Understanding the resulting emergent solutions requires integrating across the organismal behaviors of many individuals. Here we investigate an ecologically relevant collective task in black carpenter ants Camponotus pennsylvanicus: escape from a soft, erodible confining corral. Individual ants show a transition from individual exploratory excavation at random locations to spatially localized collective exploitative excavation and escape from the corral. A minimal continuum theory that coarse-grains over individual actions and considers their integrated influence on the environment leads to the emergence of an effective phase space of behaviors in terms of excavation strength and cooperation intensity. To test the theory over the range of predicted behaviors, we used custom-built robots (RAnts) that respond to stimuli and show the emergence (and failure) of cooperative excavation and escape. Overall, our approach shows how the cooperative completion of tasks can arise from relatively simple rules that involve the interaction of simple agents with a dynamically changing environment that serves as an enabler and modulator of behavior.