bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased 68Ga-FAPI Uptake by Mediastinal Benign Teratoma on 68Ga-FAPI PET/CT
Authors: Peng Dengsai , Wu Junhao , Zhang Tao , Chen Yue , Hu Zhi
Published: January 2022

Mediastinal teratoma is a relatively rare disease that usually contains tissue from the endoderm, mesoderm, and ectoderm. We report a finding that mediastinal benign teratoma showed intense FAPI activity on 68Ga-FAPI PET/CT, which may lead to misdiagnosis of this benign lesion. It is necessary to realize that benign teratoma is also one of the reasons for the intense FAPI uptake in mediastinal masses, so as not to be misdiagnosed as a malignant tumor.
False-Positive 131I Uptake After Transareola Endoscopic Thyroidectomy in a Patient With Papillary Thyroid Carcinoma
Authors: Wang Anbo , Fu Wenhui , Deng Ying , He Limeng , Zhang Wei
Published: January 2022

False-positive 131I accumulation in patients with thyroid carcinoma could be due to various etiologies. Herein, we reported a case of papillary thyroid carcinoma in a 36-year-old woman. She underwent a 131I radiotherapy after a transareola endoscopic total thyroidectomy. 131I scintigraphy showed a high uptake in the thyroid bed. Surprisingly, increased activity was also noted in the right areola area. This activity corresponding to the entry site of endoscope revealed on the following SPECT/CT.
A Rare Case of Pituitary Carcinoma With Bone Metastases
Authors: Filizoglu Nuh , Ozguven Salih
Published: January 2022

Pituitary carcinomas are extremely rare and aggressive tumors that comprise only 0.2% of all pituitary tumors. Because of its rarity, pituitary carcinomas are difficult to diagnose. Conventional imaging methods are inadequate to detect metastatic lesions. Pituitary carcinomas are neuroendocrine tumors and express somatostatin receptors; therefore, 68Ga-DOTATATE PET/CT may be used in the staging of these rare tumors. Herein, we present an exceptional case of pituitary carcinoma with sclerotic skeletal metastases showing 68Ga-DOTATATE uptake.
Case of Adult Metastatic Medulloblastoma Demonstrated on 18F-DOPA PET/CT
Authors: Marafi Fahad , Sadeq Alyaa , Esmail Abdulredha , Usmani Sharjeel
Published: January 2022

18F-DOPA is a promising radiotracer used for both staging and restaging of primary brain tumors based on increased transport via the L-type large neutral amino acid transport system in tumor cells. Adult medulloblastoma is extremely rare. We present a case of 25-year-old man with posterior fossa medulloblastoma treated with surgery followed by chemotherapy and radiotherapy 5 years back, which later developed metastasis to left cerebral lobe treated with gamma knife followed by surgical debulking. Recent 18F-DOPA PET/CT demonstrates recurrence and disease progression on follow-up scan. 18F-DOPA PET/CT is extremely useful for characterizing brain tumors, response assessment, and prognosis.
Expect the Unexpected
Authors: Chua Wei Ming , Tang Charlene Yu Lin , Tham Wei Ying , Yang Samantha Peiling , Tay Young Soon , Loke Kelvin Siu Hoong
Published: January 2022

A 61-year-old woman with well-differentiated thyroid cancer underwent 124I-PET/CT imaging. A 124I capsule was administered orally, and the patient was imaged 90 minutes after from the skull vertex to feet. The 124I capsule was unexpectedly lodged in the esophagus. We illustrate attenuation and scatter correction artifacts from 124I capsule unexpectedly lodged in the esophagus and the usefulness of nonattenuation correction images in such circumstances. This also highlights the importance of drinking adequate amounts of water following the ingestion of iodine capsules (123I, 124I, or 131I) to reduce the resulting radiation dose to the esophagus.
Death With Function and Graft Failure After Kidney Transplantation: Risk Factors at Baseline Suggest New Approaches to Management
Authors: Merzkani Massini A. , Bentall Andrew J. , Smith Byron H. , Benavides Lopez Xiomara , D’Costa Matthew R. , Park Walter D. , Kremers Walter K. , Issa Naim , Rule Andrew D. , Chakkera Harini , Reddy Kunam , Khamash Hasan , Wadei Hani M. , Mai Martin , Alexander Mariam P. , Amer Hatem , Kukla Aleksandra , El Ters Mireille , Schinstock Carrie A. , Gandhi Manish J. , Heilman Raymond , Stegall Mark D.
Published: January 2022

Background.

Improving both patient and graft survival after kidney transplantation are major unmet needs. The goal of this study was to assess risk factors for specific causes of graft loss to determine to what extent patients who develop either death with a functioning graft (DWFG) or graft failure (GF) have similar baseline risk factors for graft loss.

Methods.

We retrospectively studied all solitary renal transplants performed between January 1, 2006, and December 31, 2018, at 3 centers and determined the specific causes of DWFG and GF. We examined outcomes in different subgroups using competing risk estimates and cause-specific Cox models.

Results.

Of the 5752 kidney transplants, graft loss occurred in 21.6% (1244) patients, including 12.0% (691) DWFG and 9.6% (553) GF. DWFG was most commonly due to malignancy (20.0%), infection (19.7%), cardiac disease (12.6%) with risk factors of older age and pretransplant dialysis, and diabetes as the cause of renal failure. For GF, alloimmunity (38.7%), glomerular diseases (18.6%), and tubular injury (13.9%) were the major causes. Competing risk incidence models identified diabetes and older recipients with higher rates of both DWFG and nonalloimmune GF.

Conclusions.

These data suggest that at baseline, 2 distinct populations can be identified who are at high risk for renal allograft loss: a younger, nondiabetic patient group who develops GF due to alloimmunity and an older, more commonly diabetic population who develops DWFG and GF due to a mixture of causes—many nonalloimmune. Individualized management is needed to improve long-term renal allograft survival in the latter group.
Building a Utility-based Liver Allocation Model in Preparation for Continuous Distribution
Authors: Kling Catherine E. , Perkins James D. , Biggins Scott W. , Wall Anji E. , Reyes Jorge D.
Published: January 2022

Background.

The current model for end-stage liver disease-based liver allocation system in the United States prioritizes sickest patients first at the expense of long-term graft survival. In a continuous distribution model, a measure of posttransplant survival will also be included. We aimed to use mathematical optimization to match donors and recipients based on quality to examine the potential impact of an allocation system designed to maximize long-term graft survival.

Methods.

Cox proportional hazard models using organ procurement and transplantation network data from 2008 to 2012 were used to place donors and waitlist candidates into 5 groups of increasing risk for graft loss (1—lowest to 5—highest). A mixed integer programming optimization model was then used to generate allocation rules that maximized graft survival at 5 and 8 y.

Results.

Allocation based on mathematical optimization improved 5-y survival by 7.5% (78.2% versus 70.7% in historic cohort) avoiding 2271 graft losses, and 8-y survival by 9% (71.8% versus 62.8%) avoiding 2725 graft losses. Long-term graft survival for recipients within a quality group is highly dependent on donor quality. All candidates in groups 1 and 2 and 43% of group 3 were transplanted, whereas none of the candidates in groups 4 and 5 were transplanted.

Conclusions.

Long-term graft survival can be improved using a model that allocates livers based on both donor and recipient quality, and the interaction between donor and recipient quality is an important predictor of graft survival. Considerations for incorporation into a continuous distribution model are discussed.
Astrogliosis mapping in individual brains using multidimensional MRI
Authors: Benjamini Dan , Priemer David S , Perl Daniel P , Brody David L , Basser Peter J
Published: January 2022

There are currently no noninvasive imaging methods available for astrogliosis mapping in the central nervous system despite its essential role in the response to injury, disease, and infection. We have developed a machine learning-based multidimensional MRI framework that provides a signature of astrogliosis, distinguishing it from normative brain at the individual level. We investigatedex vivocortical tissue specimen derived from subjects who sustained blast induced injuries, which resulted in scar-border forming astrogliosis without being accompanied by other types of neuropathology. By performing a combined postmortem radiology and histopathology correlation study we found that astrogliosis induces microstructural changes that are robustly detected using our framework, resulting in MRI neuropathology maps that are significantly and strongly correlated with co-registered histological images of increased glial fibrillary a cidic protein deposition. The demonstrated high spatial sensitivity in detecting reactive astrocytes at the individual level has great potential to significantly impact neuroimaging studies in diseases, injury, repair, and aging.
Learning in reverse: Dopamine errors drive excitatory and inhibitory components of backward conditioning in an outcome-specific manner
Authors: Seitz Benjamin M. , Hoang Ivy B. , Blaisdell Aaron P. , Sharpe Melissa J.
Published: January 2022

For over two decades, midbrain dopamine was considered synonymous with the prediction error in temporal-difference reinforcement learning. Central to this proposal is the notion that reward-predictive stimuli become endowed with the scalar value of predicted rewards. When these cues are subsequently encountered, their predictive value is compared to the value of the actual reward received allowing for the calculation of prediction errors. Phasic firing of dopamine neurons was proposed to reflect this computation, facilitating the backpropagation of value from the predicted reward to the reward-predictive stimulus, thus reducing future prediction errors. There are two critical assumptions of this proposal: 1) that dopamine errors can only facilitate learning about scalar value and not more complex features of predicted rewards, and 2) that the dopamine signal can only be involved in anticipatory learning in which cues or actions precede rewards. Recent work has challenged the first assumption, demonstrating that phasic dopamine signals across species are involved in learning about more complex features of the predicted outcomes, in a manner that transcends this value computation. Here, we tested the validity of the second assumption. Specifically, we examined whether phasic midbrain dopamine activity would be necessary for backward conditioning—when a neutral cue reliably follows a rewarding outcome. Using a specific Pavlovian-to-Instrumental Transfer (PIT) procedure, we show rats learn both excitatory and inhibitory components of a backward association, and that this association entails knowledge of the specific identity of the reward and cue. We demonstrate that brief optogenetic inhibition of VTADA neurons timed to the transition between the reward and cue, reduces both of these components of backward conditioning. These findings suggest VTADA neurons are capable of facilitating associations between contiguously occurring events, regardless of the content of those events. We conclude that these data are in line with suggestions that the VTADA error acts as a universal teaching signal. This may provide insight into why dopamine function has been implicated in a myriad of psychological disorders that are characterized by very distinct reinforcement-learning deficits.

Graphical Abstract
cdonandbocaffect trunk neural crest cell migration non-cell autonomously through a reduction of hedgehog signaling in zebrafish slow-twitch muscle
Authors: Lencer Ezra , Prekeris Rytis , Artinger Kristin
Published: January 2022

The transmembrane proteinscdonandbocare implicated in regulating hedgehog signaling during vertebrate development. Recent work showing roles for these genes in axon guidance and neural crest cell migration suggest thatcdon/bocmay play additional functions in regulating directed cell movements. We use novel and existing mutants to investigate a role forcdonandbocin zebrafish neural crest cell migration. We find that single mutant embryos exhibit normal neural crest phenotypes, but that neural crest migration is strikingly disrupted in doublecdon;bocmutant embryos. We further show that this migration phenotype is associated with defects to the differentiation of slow-twitch muscle cells, and the loss of a Col1a1a containing extracellular matrix, suggesting that neural crest defects are a secondary consequence to defects in mesoderm development. Combined, our data add to a growing literature showing thatcdonandbocact synergistically to promote hedgehog signaling during vertebrate development, and provide a foundation for using zebrafish to study the function of hedgehog receptor paralogs.
GoPeaks: Histone Modification Peak Calling for CUT&Tag
Authors: Yashar William M , Kong Garth , VanCampen Jake , Smith Brittany M , Coleman Daniel J , Carbone Lucia , Yardimci Galip Gürkan , Maxson Julia E , Braun Theodore P
Published: January 2022

Genome-wide mapping of the histone modification landscape is critical to understanding tran-scriptional regulation. Cleavage Under Targets and Tagmentation (CUT&Tag) is a new method for profiling the localization of covalent histone modifications, offering improved sensitivity and decreased cost compared with Chromatin Immunoprecipitation Sequencing (ChIP-seq). Here, we present GoPeaks, a peak calling method specifically designed for histone modification CUT&Tag data. GoPeaks implements a Binomial distribution and stringent read count cut-off to nominate candidate genomic regions. We compared the performance of GoPeaks against commonly used peak calling algorithms to detect H3K4me3, H3K4me1, and H3K27Ac peaks from CUT&Tag data. These histone modifications display a range of peak profiles and are frequently used in epigenetic studies. We found GoPeaks robustly detects genome-wide histone modifications and, notably, identifies H3K27Ac with improved sensitivity compared to other standard peak calling algorithms.
Magnetic Temporal Interference for Noninvasive Focal Brain Stimulation
Authors: Khalifa Adam , Abrishami Seyed Mahdi , Zaeimbashi Mohsen , Tang Alexander D , Coughlin Brian , Rodger Jennifer , Sun Nian X. , Cash Sydney S.
Published: January 2022

Non-invasive stimulation of deep brain regions has been a major goal for neuroscience and neuromodulation in the past three decades. Transcranial magnetic stimulation (TMS), for instance, cannot target deep regions in the brain without activating the overlying tissues and has a poor spatial resolution. In this manuscript, we propose a new concept that relies on the temporal interference of two high-frequency magnetic fields generated by two electromagnetic solenoids. To illustrate the concept, custom solenoids were fabricated and optimized to generate temporal interfering electric fields for rodent brain stimulation. C-Fos expression was used to track neuronal activation. C-Fos expression was not present in regions impacted by only one high-frequency magnetic field indicating ineffective recruitment of neural activity in non-target regions. In contrast, regions impacted by two fields that interfere to create a low-frequency envelope display a strong increase in c-Fos expression. Therefore, this magnetic temporal interference solenoid-based system provides a framework to perform further stimulation studies that would investigate the advantages it could bring over conventional TMS systems.
NOVEL PLASMA GLYCOPROTEIN BIOMARKERS PREDICT PROGRESSION-FREE SURVIVAL IN SURGICALLY RESECTED CLEAR CELL RENAL CELL CARCINOMA
Authors: Serie Daniel , Myers Amanda A , Haehn Daniela A , Parker Alexander , Bajalia Essa , Gonzalez Giovanni , Li Qiongyu , Lindpaintner Klaus , Wong Maurice Y , Moser Kaitlynn , Zhou Bo , Thiel David D
Published: January 2022

Introduction: Limited data exists on utilization of protein post-translational modifications as biomarkers for clear cell renal cell carcinoma (ccRCC). We employed high-throughput glycoproteomics to evaluate differential expression of glycoprotein-isoforms as novel markers for ccRCC progression-free survival (PFS).
Methods: Plasma samples were obtained from 77 patients treated surgically for ccRCC. Glycoproteomic analyses were carried out after liquid chromatography tandem mass spectrometry. Age-adjusted Cox proportional hazard models were constructed to evaluate PFS. Optimized Harrells c-index was employed to dichotomize the collective for the construction of Kaplan-Meier curves.
Results: The average length of follow-up was 3.4 (range: 0.04-9.83) years. Glycoproteomic analysis identified 39 glycopeptides and 14 non-glycosylated peptides that showed statistically significant (false discovery rate p ≤0.05) differential expression associated with PFS. Five of the glycosylated peptides conferred continuous hazard ratio of > 6 (range 6.3-11.6). These included prothrombin A2G2S glycan motif (HR=6.47, P=9.53E-05), immunoglobulin J chain FA2G2S2 motif (HR=10.69, P=0.001), clusterin A2G2 motif (HR=7.38, P=0.002), complement component C8A A2G2S2 motif (HR=11.59, P=0.002), and apolipoprotein M glycopeptide with non-fucosylated and non-sialylated hybrid-type glycan (HR=6.30, P=0.003). Kaplan-Meier curves based on dichotomous expression of these five glycopeptides resulted in hazard ratios of 3.9-10.7, all with p-value < 0.03. Kaplan-Meyer plot using the multivariable model comprising 3 of the markers yielded HR of 11.96 (p <0.0001).
Conclusion: Differential glyco-isoform abundance of plasma proteins may be a useful source of biomarkers for the clinical course and prognosis of ccRCC.
Maternal immune activation induces methylation changes in schizophrenia genes
Authors: Johnson Thomas , Saatci Defne , Handunnetthi Lahiru
Published: January 2022

Susceptibility to schizophrenia is mediated by genetic and environmental risk factors. Infection driven maternal immune activation (MIA) during pregnancy is a key environmental risk factor. However, little is known about how MIA during pregnancy could contribute to adult-onset schizophrenia. In this study, we investigated if maternal immune activation induces changes in methylation of genes linked to schizophrenia. We found that differentially expressed genes in schizophrenia brain were significantly enriched among MIA induced differentially methylated genes in the foetal brain in a cell-type-specific manner. Upregulated genes in layer V pyramidal neurons were enriched among hypomethylated genes at gestational day 9 (fold change = 1.57, FDR = 0.049) and gestational day 17 (fold change = 1.97, FDR = 0.0006). We also found that downregulated genes in GABAergic Rosehip interneurons were enriched among hypermethylated genes at gestational day 17 (fold change = 1.62, FDR= 0.03). Collectively, our results highlight a connection between MIA driven methylation changes during gestation and schizophrenia gene expression signatures in the adult brain. These findings carry important implications for early preventative strategies in schizophrenia.
Rapid and Accurate Identification of SARS-CoV-2 Omicron Variants Using Droplet Digital PCR (RT-ddPCR)
Authors: Mills Margaret G. , Hajian Pooneh , Bakhash Shah Mohamed , Xie Hong , Mantzke Derrek , Zhu Haiying , Perchetti Garrett A. , Huang Meei-Li , Pepper Gregory , Jerome Keith R. , Roychoudhury Pavitra , Greninger Alexander L.
Published: January 2022

Background

Mutations in the receptor binding domain of the SARS-CoV-2 Spike protein are associated with increased transmission or substantial reductions in vaccine efficacy, including in the recently described Omicron variant. The changing frequencies of these mutations combined with their differing susceptibility to available therapies have posed significant problems for clinicians and public health professionals.

Objective

To develop an assay capable of rapidly and accurately identifying variants including Omicron in clinical specimens to enable case tracking and/or selection of appropriate clinical treatment.

Study Design

Using three duplex RT-ddPCR reactions targeting four amino acids, we tested 419 positive clinical specimens from February to December 2021 during a period of rapidly shifting variant prevalences and compared genotyping results to genome sequences for each sample, determining the sensitivity and specificity of the assay for each variant.

Results

Mutation determinations for 99.7% of detected samples agree with NGS data for those samples, and are accurate despite wide variation in RNA concentration and potential confounding factors like transport medium, presence of additional respiratory viruses, and additional mutations in primer and probe sequences. The assay accurately identified the first 15 Omicron variants in our laboratory including the first Omicron in Washington State and discriminated against an S-gene dropout Delta specimen.

Conclusion

We describe an accurate, precise, and specific RT-ddPCR assay for variant detection that remains robust despite being designed prior to the emergence of Delta and Omicron variants. The assay can quickly identify mutations in current and past SARS-CoV-2 variants, and can be adapted to future mutations.
Spatial clustering in vaccination hesitancy: the role of social influence and social selection
Authors: Alvarez Zuzek Lucila Gisele , Zipfel Casey M , Bansal Shweta
Published: January 2022

The phenomenon of vaccine hesitancy behavior has gained ground over the last three decades, jeopardizing the maintenance of herd immunity. This behavior tends to cluster spatially, creating pockets of unprotected sub-populations that can be hotspots for outbreak emergence. What remains less understood are the social mechanisms that can give rise to spatial clustering in vaccination behavior, particularly at the landscape scale. We focus on the presence of spatial clustering, and aim to mechanistically understand how different social processes can give rise to this phenomenon. In particular, we propose two hypotheses to explain the presence of spatial clustering: (i) social selection, in which vaccine-hesitant individuals share socio-demographic traits, and clustering of these traits generates spatial clustering in vaccine hesitancy; and (ii) social influence, in which hesitant behavior is contagious and spreads through neighboring societies, leading to hesitant clusters. Adopting a theoretical spatial network approach, we explore the role of these two processes in generating patterns of spatial clustering in vaccination behaviors under a range of spatial structures. We find that both processes are independently capable of generating spatial clustering, and the more spatially structured the social dynamics in a society are, the higher spatial clustering in vaccine-hesitant behavior it realizes. Together, we demonstrate that these processes result in unique spatial configurations of hesitant clusters, and we validate our models on both processes with fine-grain empirical data on vaccine hesitancy, social determinants, and social connectivity in the US. Finally, we propose, and evaluate the effectiveness of, two novel intervention strategies to diminish hesitant behavior. Our generative modeling approach informed by unique empirical data provides insights on the role of complex social processes in driving spatial heterogeneity in vaccine hesitancy.
Identifying and correcting repeat-calling errors in nanopore sequencing of telomeres
Authors: Tan Kar-Tong , Slevin Michael K. , Meyerson Matthew , Li Heng
Published: January 2022

Nanopore long-read genome sequencing is emerging as a potential approach for the study of genomes including long repetitive elements like telomeres. Here, we report extensive basecalling induced errors at telomere repeats across nanopore datasets, sequencing platforms, basecallers, and basecalling models. We found that telomeres which are represented by (TTAGGG)nand (CCCTAA)nrepeats in many organisms were frequently miscalled (~40-50% of reads) as (TTAAAA)n, or as (CTTCTT)nand (CCCTGG)nrepeats respectively in a strand-specific manner during nanopore sequencing. We showed that this miscalling is likely caused by the high similarity of current profiles between telomeric repeats and these repeat artefacts, leading to mis-assignment of electrical current profiles during basecalling. We further demonstrated that tuning of nanopore basecalling models, and selective application of the tuned models to telomeric reads led to improved recovery and analysis of telomeric regions, with little detected negative impact on basecalling of other genomic regions. Our study thus highlights the importance of verifying nanopore basecalls in long, repetitive, and poorly defined regions of the genome, and showcases how such artefacts in regions like telomeres can potentially be resolved by improvements in nanopore basecalling models.
Foveal vision predictively sensitizes to defining features of eye movement targets
Authors: Kroell Lisa M. , Rolfs Martin
Published: January 2022

Despite the fovea’s singular importance for active human vision, the impact of large eye movements on foveal processing remains elusive. Building on findings from passive fixation tasks, we hypothesized that during the preparation of rapid eye movements (saccades), foveal processing anticipates soon-to-be fixated visual features. Using a dynamic large-field noise paradigm, we indeed demonstrate that sensitivity for defining features of a saccade target is enhanced in the pre-saccadic center of gaze. Enhancement manifested in higher Hit Rates for foveal probes with target-congruent orientation, and a sensitization to incidental, target-like orientation information in foveally presented noise. Enhancement was spatially confined to the center of gaze and its immediate vicinity. We suggest a crucial contribution of foveal processing to trans-saccadic visual continuity which has previously been overlooked: Foveal processing of saccade targets commences before the movement is executed and thereby enables a seamless transition once the center of gaze reaches the target.
In vivoimaging of calcium dynamics in zebrafish hepatocytes
Authors: Pozo-Morales Macarena , Garteizgogeascoa Inés , Perazzolo Camille , Singh Sumeet Pal
Published: January 2022

Hepatocytes were the first cell-type for which oscillations of cytoplasmic calcium levels in response to hormones were described. Since then, investigation of calcium dynamics in liver explants and culture has greatly increased our understanding of calcium signaling. A bottleneck, however, exists in observing calcium dynamics in a non-invasive manner due to the optical inaccessibility of the mammalian liver. Here we take advantage of the transparency of the zebrafish larvae to develop a setup that allowsin vivoimaging of calcium flux in zebrafish hepatocytes at cellular resolution. Using this, we provide quantitative assessment of intracellular calcium dynamics during multiple contexts, including growth, feeding, ethanol-induced stress and cell ablation. Specifically, we show that synchronized calcium oscillations are presentin vivo, which are lost upon starvation. Feeding recommences calcium waves in the liver, but in a spatially restricted manner. Further, ethanol treatment as well as cell ablation induces calcium flux, but with different dynamics. The former causes asynchronous calcium oscillations, while the latter leads to a single calcium spike. Overall, we demonstrate the presence of oscillations, waves and spikesin vivo. Thus, our study introduces a platform for observing diverse calcium dynamics while maintaining the native environment of the liver, which will help investigations into the dissection of molecular mechanisms supporting the intra- and intercellular calcium signaling in the liver.
Collaborative workflow between pathologists and deep learning for evaluation of tumor cellularity in lung adenocarcinoma
Authors: Sakamoto Taro , Furukawa Tomoi , Pham Hoa H.N. , Kuroda Kishio , Tabata Kazuhiro , Kashima Yukio , Okoshi Ethan N. , Morimoto Shimpei , Bychkov Andrey , Fukuoka Junya
Published: January 2022

Owing to the high demand for molecular testing, the reporting of tumor cellularity in cancer samples has become a mandatory task for pathologists. However, the pathological estimation of tumor cellularity is often inaccurate.

We developed a collaborative workflow between pathologists and artificial intelligence (AI) models to evaluate tumor cellularity in lung cancer samples and prospectively applied it to routine practice. We also developed a quantitative model that we validated and tested on retrospectively analyzed cases and ran the model prospectively in a collaborative workflow where pathologists could access the AI results and apply adjustments (Adjusted-Score). The Adjusted-Scores were validated by comparing them with the ground truth established by manual annotation of hematoxylin-eosin slides with reference to immunostains with thyroid transcription factor-1 and napsin A. For training, validation, retrospective testing, and prospective application of the model, we used 40, 10, 50, and 151 whole slide images, respectively.

The sensitivity and specificity of tumor segmentation were 97% and 87%, and the accuracy of nuclei recognition was 99%. Pathologists altered the initial scores in 87% of the cases after referring to the AI results and found that the scores became more precise after collaborating with AI. For validation of Adjusted-Score, we found the Adjusted-Score was significantly closer to the ground truth than non-AI-aided estimates (p<0.05). Thus, an AI-based model was successfully implemented into the routine practice of pathological investigations. The proposed model for tumor cell counting efficiently supported the pathologists to improve the prediction of tumor cellularity for genetic tests.
Machine Learning-Based Enzyme Engineering of PETase for Improved Efficiency in Degrading Non-Biodegradable Plastic
Authors: Gupta Arjun , Agrawal Sangeeta
Published: January 2022

Globally, nearly a million plastic bottles are produced every minute (1). These non-biodegradable plastic products are composed of Polyethylene terephthalate (PET). In 2016, researchers discovered PETase, an enzyme from the bacteriaIdeonella sakaiensiswhich breaks down PET and nonbiodegradable plastic. However, PETase has low efficiency at high temperatures. In this project, we optimized the rate of PET degradation by PETase by designing new mutant enzymes which could break down PET much faster than PETase, which is currently the gold standard. We used machine learning (ML) guided directed evolution to modify the PETase enzyme to have a higher optimal temperature (Topt), which would allow the enzyme to degrade PET more efficiently.

First, we trained three machine learning models to predict Topt with high performance, including Logistic Regression, Linear Regression and Random Forest. We then used Random Forest to perform ML-guided directed evolution. Our algorithm generated hundreds of mutants of PETase and screened them using Random Forest to select mutants with the highest Topt, and then used the top mutants as the enzyme being mutated.

After 1000 iterations, we produced a new mutant of PETase with Topt of 71.38°C. We also produced a new mutant enzyme after 29 iterations with Topt of 61.3°C. To ensure these mutant enzymes would remain stable, we predicted their melting temperatures using an external predictor and found the 29-iteration mutant had improved thermostability over PETase.Our research is significant because using our approach and algorithm, scientists can optimize additional enzymes for improved efficiency.
Consideration of genetic variation and evolutionary history in future conservation of Indian one-horned rhinoceros (Rhinoceros unicornis)
Authors: Ghosh Tista , Kumar Shrewshree , Sharma Kirtika , Kakati Parikshit , Sharma Amit , Mondol Samrat
Published: January 2022

The extant members of the Eurasian rhino species have experienced severe population and range declines through a combination of natural and anthropogenic factors since Pleistocene. The one-horned rhino is the only Asian species recovered from such strong population decline but most of their fragmented populations in India and Nepal are reaching carrying capacity. Implementation of any future reintroduction-based conservation efforts would greatly benefit from currently unavailable detailed genetic assessments and evolutionary history of these populations. We sequenced wild one-horned rhino mitogenome from all the extant populations (n=16 individuals) for the first time, identified the polymorphic sites and assessed genetic variation (2531bp mtDNA, n=111 individuals) across India. Results showed 30 unique rhino haplotypes distributed as three distinct genetic clades (Fst value 0.68-1) corresponding to the states of Assam (n=28 haplotypes), West Bengal and Uttar Pradesh (both monomorphic). Phylogenetic analyses suggest earlier coalescence of Assam (∼0.5 Mya) followed by parallel divergence of West Bengal and Uttar Pradesh/Nepal (∼0.06-0.05Mya), supported by the paleobiogeographic history of the Indian subcontinent. Combined together, we propose recognising three ‘Evolutionary Significant Units (ESUs)’ of Indian rhino. As recent assessments suggest further genetic isolations of Indian rhinos at local scales, future management efforts should focus on identifying genetically variable founder animals and consider periodic supplementation events while planning future rhino reintroduction programs in India. Such well-informed, multidisciplinary approach is the only way to ensure evolutionary, ecological and demographic stability of the species across its range.
EagleImp: Fast and Accurate Genome-wide Phasing and Imputation in a Single Tool
Authors: Wienbrandt Lars , Ellinghaus David
Published: January 2022

Background

Reference-based phasing and genotype imputation algorithms have been developed with sublinear theoretical runtime behaviour, but runtimes are still high in practice when large genome-wide reference datasets are used.

Methods

We developed EagleImp, a software with algorithmic and technical improvements and new features for accurate and accelerated phasing and imputation in a single tool.

Results

We compared accuracy and runtime of EagleImp with Eagle2, PBWT and prominent imputation servers using whole-genome sequencing data from the 1000 Genomes Project, the Haplotype Reference Consortium and simulated data with more than 1 million reference genomes. EagleImp is 2 to 10 times faster (depending on the single or multiprocessor configuration selected) than Eagle2/PBWT, with the same or better phasing and imputation quality in all tested scenarios. For common variants investigated in typical GWAS studies, EagleImp provides same or higher imputation accuracy than the Sanger Imputation Service, Michigan Imputation Server and the newly developed TOPMed Imputation Server, despite larger (not publicly available) reference panels. It has many new features, including automated chromosome splitting and memory management at runtime to avoid job aborts, fast reading and writing of large files, and various user-configurable algorithm and output options.

Conclusions

Due to the technical optimisations, EagleImp can perform fast and accurate reference-based phasing and imputation for future very large reference panels with more than 1 million genomes. EagleImp is freely available for download from https://github.com/ikmb/eagleimp.
Limb, joint and pelvic kinematic control in the quail coping with step perturbations
Authors: Andrada Emanuel , Mothes Oliver , Stark Heiko , Tresch Matthew C. , Denzler Joachim , Fischer Martin S. , Blickhan Reinhard
Published: January 2022

Small cursorial birds display remarkable walking skills and can negotiate complex and unstructured terrains with ease. The neuromechanical control strategies necessary to adapt to these challenging terrains are still not well understood. Here, we analyzed the 2D- and 3D pelvic and leg kinematic strategies employed by the common quail to negotiate visible step-up and step-down perturbations of 1 cm, 2.5 cm, and 5 cm. We used biplanar fluoroscopy to accurately describe joint positions in three dimensions and performed semi-automatic landmark localization using deep learning.

Quails negotiated vertical perturbations without major problems and rapidly regained steady-state locomotion. When coping with step-up perturbations, the quail mostly adapted the trailing limb to permit the leading leg to step on the elevated substrate in a similar way as it did during level locomotion. When the quail negotiated step-down perturbations, both legs showed significant adaptations. For small and moderate perturbations (not inducing aerial running) the quail kept the function of the distal joints (i.e., their kinematic pattern) largely unchanged during uneven locomotion, and most changes occurred in proximal joints. The hip regulated leg length, while the distal joints maintained the spring-damped limb patterns. However, to negotiate the largest visible step perturbations, more dramatic kinematic alterations were observed. For these large perturbations, all joints contributed to leg lengthening/ shortening in the trailing leg and both the trailing and leading legs stepped more vertically and less abducted. This indicates a shift from a dynamic walking program to strategies that are focused on maximizing safety.
Tissue fibroblasts are a critical source of prostacyclin and anti-thrombotic protection
Authors: Mitchell Jane A. , Vinokurova Maria , Lopes-Pires Maria Elisa , Shala Fisnik , Armstrong Paul C. , Ahmetaj-Shala Blerina , Elghazouli Youssef , Liu Bin , Zhou Yingbi , Hao Chuan-ming , Herschman Harvey R. , Kirkby Nicholas S.
Published: January 2022

Prostacyclin is one of the bodies fundamental signalling pathways. It has long been considered principally anti-thrombotic hormone derived from the vascular endothelium. The role of non-vascular sources in prostacyclin synthesis has not been systematically evaluated, however, due to a lack of tools resulting in an underappreciation of its role in other contexts. Here we used cellspecific knockout mice and human tissues to show that lung, and other tissues, are powerful producers of prostacyclin independent of their vascular components. Instead, in mice and humans, lung prostacyclin synthesis is associated with fibroblasts. The fibroblast-derived prostaglandins enter the circulation and provide systemic anti-thrombotic protection. These observations define a new paradigm in prostacyclin biology in which fibroblast/non-vascular-derived prostacyclin works in parallel with endothelium-derived prostaglandins to control cardiovascular health and potentially a broad range of other biology. These results may explain how local diseases of the lung and elsewhere result in cardiovascular risk.
Pathological relevance of post-translationally modified alpha-synuclein (pSer87, pSer129, nTyr39) in idiopathic Parkinson’s disease and Multiple System Atrophy
Authors: Sonustun Berkiye , Altay Firat M , Strand Catherine , Hondhamuni Geshanthi , Warner Thomas T , Lashuel Hilal A , Bandopadhyay Rina
Published: January 2022

Aggregated alpha-synuclein (α-synuclein) is the main component of Lewy bodies (LBs), Lewy neurites (LNs), and glial cytoplasmic inclusions (GCIs), which are pathological hallmarks of idiopathic Parkinson’s disease (IPD) and multiple system atrophy (MSA), respectively. Initiating factors that culminate in forming LBs/LNs/GCIs remain elusive. Several species of α-synuclein exist, including phosphorylated and nitrated forms. It is unclear which α-synuclein post-translational modifications (PTMs) appear within aggregates throughout disease pathology. Herein we aimed to establish the predominant α–synuclein PTMs in post-mortem IPD and MSA pathology using immunohistochemistry. We examined the patterns of three α-synuclein PTMs (pS87, pS129, nY39) simultaneously in pathology-affected regions of 15 PD, 5 MSA, 6 neurologically normal controls. All antibodies recognized LBs, LNs, and GCIs, albeit to a variable extent. pS129 α-synuclein antibody was particularly immunopositive for LNs and synaptic dot-like structures followed by nY39 α-synuclein antibody. GCIs, neuronal inclusions, and small threads were positive for nY39 α-synuclein in MSA. Quantification of the LB scores revealed that pS129 α-synuclein was the dominant and earliest α-synuclein PTM followed by nY39 α-synuclein, while lower amounts of pSer87 α-synuclein appeared later in disease progression in PD. These results may have implications for novel biomarker and therapeutic developments.
Lightweight compositional analysis of metagenomes with FracMinHash and minimum metagenome covers
Authors: Irber Luiz , Brooks Phillip T. , Reiter Taylor , Pierce-Ward N. Tessa , Hera Mahmudur Rahman , Koslicki David , Brown C. Titus
Published: January 2022

The identification of reference genomes and taxonomic labels from metagenome data underlies many microbiome studies. Here we describe two algorithms for compositional analysis of metagenome sequencing data. We first investigate the FracMinHash sketching technique, a derivative of modulo hash that supports Jaccard containment estimation between sets of different sizes. We implement FracMinHash in the sourmash software, evaluate its accuracy, and demonstrate large-scale containment searches of metagenomes using 700,000 microbial reference genomes. We next frame shotgun metagenome compositional analysis as the problem of finding a minimum collection of reference genomes that “cover” the known k-mers in a metagenome, a minimum set cover problem. We implement a greedy approximate solution using FracMinHash sketches, and evaluate its accuracy for taxonomic assignment using a CAMI community benchmark. Finally, we show that the minimum metagenome cover can be used to guide the selection of reference genomes for read mapping. sourmash is available as open source software under the BSD 3-Clause license at github.com/dib-lab/sourmash/.
Inflammatory CD4/CD8 double positive human T cells arise from reactive CD8 T cells and are sufficient to mediate GVHD pathology
Authors: Hess Nicholas J. , Turicek David P. , Riendeau Jeremiah , McIlwain Sean J. , Guzman Emmanuel Contreras , Nadiminti Kalyan , Hudson Amy , Callander Natalie S. , Skala Melissa C. , Gumperz Jenny E. , Hematti Peiman , Capitini Christian M.
Published: January 2022

An important paradigm in allogeneic hematopoietic cell transplantations (allo-HCTs) is the prevention of graft-vs-host disease (GVHD) while preserving the graft-vs-leukemia (GVL) activity of donor T cells. From an observational clinical study of adult allo-HCT recipients, we identified a CD4+/CD8+ double positive T cell (DPT) population, not present in starting grafts, whose presence was predictive of ≥ grade 2 GVHD. Using an established xenogeneic transplant model, we reveal that the DPT population develop from antigen stimulated CD8 T cells which become transcriptionally, metabolically and phenotypically distinct from single-positive CD4 and CD8 T cells. Isolated DPTs were sufficient to mediate xeno-GVHD pathology when re-transplanted into naive mice but provided no survival benefit when mice were challenged with a human B-ALL cell line. Overall, this study reveals human DPTs as a T cell population directly involved with GVHD pathology.

One Sentence Summary

Human CD4+/CD8+ double positive T cells (DPTs) mediate xenogeneic GVHD but possess limited GVL activity.
Temperature-dependent genetics of thermotolerance between yeast species
Authors: Abrams Melanie B. , Brem Rachel B.
Published: January 2022

Many traits of industrial and basic biological interest arose long ago, and manifest now as fixed differences between a focal species and its reproductively isolated relatives. In these systems, extant individuals can hold clues to the mechanisms by which phenotypes evolved in their ancestors. We harnessed yeast thermotolerance as a test case for such molecular-genetic inferences. In viability experiments, we showed that extant Saccharomyces cerevisiae survived at temperatures where cultures of its sister species S. paradoxus died out. Then, focusing on loci that contribute to this difference, we found that the genetic mechanisms of high-temperature growth changed with temperature. We also uncovered an enrichment of low-frequency variants at thermotolerance loci in S. cerevisiae population sequences, suggestive of a history of non-neutral selective forces acting at these genes. We interpret our results in light of a model of gradual acquisition of thermotolerance in the S. cerevisiae lineage by positive selection along a temperature cline. We propose that in an ancestral S. cerevisiae population, alleles conferring defects at a given temperature would have been resolved by adaptive mutations, expanding the range and setting the stage for further temperature advances. Together, our results and interpretation underscore the power of genetic approaches to explore how an ancient trait came to be.
Inferring tumor-specific cancer dependencies through integrating ex-vivo drug response assays and drug-protein profiling
Authors: Batzilla Alina , Lu Junyan , Kivioja Jarno , Putzker Kerstin , Lewis Joe , Zenz Thorsten , Huber Wolfgang
Published: January 2022

The development of cancer therapies may be improved by the discovery of tumor-specific molecular dependencies. The requisite tools include genetic and chemical perturbations, each with its strengths and limitations. Drug perturbations can be readily applied to primary cancer samples at a large scale, but mechanistic understanding of hits and further pharmaceutical development is often complicated by the fact that a small compound has a range of affinities to multiple proteins.

To computationally infer the molecular dependencies of individual cancers from their ex-vivo drug sensitivity profiles, we developed a mathematical model that deconvolutes these data using measurements of protein-drug affinity profiles.

Our method, DepInfeR, correctly identified known dependencies, including EGFR dependence in Her2+ breast cancer cell line, FLT3 dependence in AML tumors with FLT3-ITD mutations and the differential dependencies on the B-cell receptor pathway in two major subtypes of chronic lymphocytic leukemia (CLL). Furthermore, our method uncovered new subgroup-specific dependencies, including a previously unreported dependence of high-risk CLL on Checkpoint kinase 1 (CHEK1). The method also produced a more accurate map of the molecular dependencies in a heterogeneous set of 117 CLL samples.

The ability to deconvolute polypharmacological phenotypes into underlying causal molecular dependencies should increase the utility of high-throughput drug response assays for functional precision oncology.