bluuebunny/crossref_metadata_2025 huggingface dataset:
A Dedifferentiated Solitary Fibrous Tumor of Soft Tissue With Retiform and Papillary Features: Report of a Case and Review of the Literature
Authors: Roitman Pablo Daniel , Cóccaro Nicolás , Jauk Federico , Rene Nicholas , Pandolfi Julieta Belen , Castiglioni Alejandro
Published: September 2021

We report a case of a dedifferentiated solitary fibrous tumor (SFT) arising in the arm of a 74-year-old man, with the dedifferentiated component showing a unique retiform and papillary architecture. The patient presented with a tumor first noticed 12 years ago, which was diagnosed as a schwannoma. It remained clinically stable for about 10 years until he noticed growth of the mass 2 years ago. On comparative magnetic resonance imaging scans, while most of the tumor did not show major changes, a proximal lobule demonstrated increase in its size. After a new biopsy, which was interpreted as malignant, preoperative radiotherapy and surgical excision were performed. The surgical specimen had areas of typical SFT, with diffuse immunohistochemical expression of STAT6 and only focal CD34 and p16. The lobule that demonstrated growth showed a much more cellular, retiform/papillary proliferation, with plump atypical cells, necrosis, diffuse expression of STAT6 and p16, and complete lack of CD34 expression. With next-generation sequencing, the NAB2(3)-STAT6(18) fusion transcript was detected in both areas of the tumor. Only a few cases of SFT with papillary or retiform/papillary features were reported, most of them in the central nervous system, and none of them interpreted as a dedifferentiated SFT. To the best of our knowledge, these morphological features have not been reported in SFT of the soft tissue or in dedifferentiated SFT of any site. We think pathologists should be aware of this rare finding, which becomes particularly challenging in small biopsies or if classic areas of SFT are not found.
Polyostotic Fibrous Dysplasia With Extensive Cartilaginous Differentiation: A Rare Case Clinically Mimicking Ollier Disease
Authors: Hakar Melanie H. , Chapman Courtney M. , Hansford Barry G. , Davis Jessica L.
Published: September 2021

Fibrous dysplasia is a dysplastic disorder of bone caused by missense mutations of the GNAS1 gene. Fibrocartilaginous dysplasia (also known as fibrochondrodysplasia or fibrous dysplasia with extensive cartilaginous differentiation) is a rare variant of fibrous dysplasia with extensive cartilaginous differentiation that shows a predilection for the lower extremities and can affect one or multiple bones. Although benign, this entity causes progressively expansile lesions that can lead to deformity and ultimately pathologic fracture. On imaging, this entity can show features consistent with a variety of benign and malignant cartilage-forming tumors. We present the case of a 16-year-old male patient who presented with clinical history of Ollier disease and multiple presumed enchondromas. He underwent below-the-knee amputation for progressive tibial deformity, pathologic fracture, and pain. Microscopic examination of multiple lower-extremity bones revealed a fibro-osseous lesion with massive cartilaginous differentiation consistent with fibrocartilaginous dysplasia.
Doing More With Fewer: Optimizing Value With Limited Numbers of Autopsies
Authors: Williamson Alex K.
Published: September 2021

The value of autopsy is best demonstrated when the procedure is competently practiced in an appropriate clinical setting. Autopsy performance is expectedly restricted when a death raises certain forensic, religious, legal, or safety concerns. Additionally, limiting the scope of postmortem examinations to deaths that fulfill various clinical indications for the procedure will be important moving forward. This is especially true as institutions that finance autopsy services face uncertain and likely difficult financial conditions in the wake of the coronavirus disease 2019 pandemic. Autopsy pathologists should actively engage with clinicians in promoting responsible autopsy practice and delivering quality postmortem care. Using a problem-oriented autopsy record, thoughtfully evaluating postmortem histology, and purposefully reporting autopsy findings can help pathologists provide valuable data to autopsy's various stakeholders.
Four Lessons in Transcranial Lesions
Authors: Johnson Nicole K. , Richard Hope T.
Published: September 2021

Background

Lesions involving the skull are rare and often discovered incidentally by imaging studies. Skull lesions are most commonly benign but may also be malignant. Typically, lesions of the skull are evaluated by computed tomography and/or magnetic resonance imaging. Imaging features can also suggest whether an identified lesion is benign or malignant. Definitive diagnosis of transcranial lesions ultimately requires biopsy and surgical resection.

Cases

Atypical meningioma: A 57-year-old woman with a history of hypertension and arthritis presented with a left frontal scalp mass. Imaging revealed a large left frontal transcranial heterogeneous mass with intracranial and extracranial extension. Malignant ossifying fibromyxoid tumor: A 26-year-old woman with history of hypothyroidism, polycystic ovarian syndrome, and sciatica presented with a left parietal scalp mass. Imaging demonstrated a large left homogenous parietal transcranial mass with intracranial and extracranial extension. Breast carcinoma metastasis: A 64-year-old woman with history of ER/PR/Her2-neu–negative, high-grade invasive ductal carcinoma status post mastectomy, lymph node dissection, and chemotherapy with early termination due to adverse effects presented with a left parietal scalp mass. Imaging demonstrated a large left parietal transcranial mass. Glioblastoma: A 52-year-old man with a history of glioblastoma status post resection x2, chemoradiation, and craniectomy, who was found to have a second recurrence. Imaging demonstrated tumor surrounding the resection cavity in the left parietal/temporal region with extension through the craniotomy defect into the scalp soft tissue.
Danon Cardiomyopathy: Asymmetric Hypertrophy and Extensive Scarring in an Explanted Heart
Authors: Jacobs Jonathan , Burke Allen , Drachenberg Cinthia
Published: September 2021

We report the gross and histologic findings of an explant with Danon cardiomyopathy, and discuss the differential diagnosis of left ventricular hypertrophy with a genetic basis.
Diagnosis of Sinonasal Ectopic Pituitary Adenomas
Authors: Berry Debra M. , Ornan David , Lopes M. Beatriz
Published: September 2021

Ectopic pituitary adenomas (EPAs) are uncommon sinonasal neoplasms that present a diagnostic challenge in practice. We present a case of a patient presenting with progressive headache. Workup revealed an enhancing mass on magnetic resonance imaging at the anterior clivus with extension into the sphenoid sinus. Resection of the tumor was performed, and microscopic examination showed a neuroendocrine tumor composed of monomorphic cells arranged in nests. The tumor expressed synaptophysin, chromogranin, growth hormone, prolactin, thyroid-stimulating hormone, follicle-stimulating hormone, α-subunit of the glycoproteins, and transcription factors steroidogenic factor 1 and Pit-1, diagnosed as a plurihormonal pituitary adenoma. Given the radiologic and surgical impression of an intact and uninvolved pituitary gland, the lesion was identified as a pituitary adenoma arising in ectopic adenohypophyseal tissue. This case demonstrates the multitude of possible tissue types involved in tumor histogenesis in the sinonasal cavity. We highlight the radiographic, intraoperative, cytologic, and histologic features of sinonasal pituitary adenoma to emphasize the role of an expanded differential, including central nervous system lesions, for neoplasms in this anatomic region.
SMARCB1 (INI1)–Deficient Sinonasal Carcinoma With Yolk Sac Tumor Differentiation: Case Report and Review of the Literature
Authors: Gradecki Sarah E. , Kelting Sarah M. , Stelow Edward B.
Published: September 2021

SMARCB1 (INI1)–deficient sinonasal carcinoma is a recently described primary neoplasm of the sinonasal tract that occurs infrequently and displays aggressive clinical behavior. Classic histopathologic findings of INI1-deficient sinonasal carcinoma include sheets and nests of basaloid tumors cells with a monomorphic appearance. Variable amounts of rhabdoid and glandular differentiation have been reported. Diagnosis of this lesion can be challenging because of significant morphologic and immunohistochemical overlap between other primary lesions of the sinonasal tract, including basaloid and other nonkeratinizing squamous cell carcinomas, sinonasal undifferentiated carcinoma, and the newly described BRG1-deficient sinonasal carcinoma, among others. Recently, yolk sac tumor (YST)–like differentiation has been described in multiple reports of INI1-deficient sinonasal carcinoma, which expands both the histologic spectrum of this lesion and its differential diagnosis. Although there is significant immunophenotypic overlap between primary YST and INI1-deficient sinonasal carcinoma with YST differentiation, loss of INI1 expression by immunohistochemistry is not seen in YST. INI1 immunohistochemistry is a sensitive and specific marker for identifying INI1-deficient sinonasal carcinoma, and pathologists should have a low threshold for performing this test on tumors with a myriad of histologic features.
Sinonasal Lymphoma: Extranodal Natural Killer/T-Cell Lymphoma and Its Differential Diagnosis
Authors: Girton Mark R. , Aguilera Nadine S. , Bateman Henry R.
Published: September 2021

Lymphoma is the second most common malignancy in the nasal tract and paranasal sinuses after squamous cell carcinoma (Acta Oncol 1997;36:45–50). Sinonasal lymphoma is the most common hematolymphoid lesion at the site, accounting for approximately 1% of all lymphomas (Virchows Arch A Pathol Anat Histopathol 1989;414:399–405). These neoplasms are diverse, including B cell, T cell, and natural killer cell differentiation. This group of lymphomas includes chronic and aggressive entities, some with clearly defined etiologies and associations including Epstein-Barr virus, HIV, and human T-cell leukemia virus infections, with variable differentiation and distinctive growth patterns. In this report, we will review the most prevalent entities with a focus on extranodal natural killer/T-cell lymphoma. A sinonasal lymphoma differential diagnosis is provided with review of the epidemiologic, histomorphologic, and immunophenotypic characteristics and discuss diagnostic pitfalls. The discussion is accompanied by representative micrographs, with an explanation of the particular features of each diagnosis. Lastly, we will briefly discuss important clinical characteristics.
A Rare Case of NUT Carcinoma and Review of the Literature
Authors: Zelman Brandon , Chen Hannah , Pambuccian Stefan , Massarani-Wafai Razan , Mehrotra Swati , Ananthanarayanan Vijayalakshmi
Published: September 2021

Nuclear protein in testis (NUT) carcinoma is a rare, aggressive, poorly differentiated malignant neoplasm. NUT carcinoma (NC) is hallmarked by its chromosomal translocation involving the NUT/NUTM1 gene, which leads to a fusion oncoprotein that blocks epithelial differentiation and maintains proliferation in tumor cells. The translocation occurs with members of the BET (bromodomain and extraterminal domain) protein family, with 70% of the cases forming the NUTM1-BRD4 fusion. It most frequently involves the thoracic cavity followed by the head and neck, with a preference for midline areas of the body, especially the sinonasal tract and mediastinum. This led to NC formerly being known as NUT midline carcinoma. However, studies have shown that NC can occur widely throughout the body, thus leading to the updated name. NUT carcinoma is histologically defined as a tumor of primitive appearing round monomorphic cells with possible foci of abrupt keratinization. Given its rarity and its morphologic and immunohistochemical overlap with other tumors, NC has been largely underdiagnosed and misdiagnosed in the past few decades. However, with the improvement of genetic testing and the availability of an anti-NUT monoclonal antibody for diagnostic immunohistochemistry, the number of cases classified as NCs has vastly increased in the recent past.
An Observational Study of the Association Between Exposure to Vacant Building Demolitions and Elevated Blood Lead Levels in Children Under Six in St Louis City
Authors: Branz Mikayla , Harris Jenine K. , Haslam Matt
Published: September 2021

Context:

St Louis City has been demolishing vacant buildings at an increasing rate. Demolition can cause lead dust spread, and childhood lead exposure can have negative effects on cognition, growth, and development. Previous studies show an association between exposure to multiple demolitions and elevated blood lead levels (EBLLs) in children, but St Louis City does not monitor the effects of demolitions on children's blood lead levels.

Objectives:

The purpose of this study was to measure the association between exposure to demolitions and EBLLs in children younger than 6 years in St Louis City from 2017 to 2020.

Design/Setting/Participants:

We analyzed blood lead testing data for children 0 to 72 months of age (n = 22 192) and proximity to demolitions. Exposure was the presence of demolitions within 400 ft of a child's address in the 33 days before their first lead test.

Main Outcome Measure:

We used logistic regression to test the association between proximity to demolition and EBLLs (≥5 µg/dL).

Results:

The percentage of children living in proximity to 1 or more demolitions was slightly higher among those with EBLLs (n = 21; 1.3%) than among those without EBLLs (n = 250; 1.2%). However, after adjusting for age, sex, year home was built, season, neighborhood socioeconomic percentile, and neighborhood racial composition, the odds of EBLLs were not significantly different for children exposed to 1 or more demolitions (OR = 0.82; 95% CI, 0.5-1.25) compared with exposed to zero demolitions.

Conclusions:

Although this study found no association between exposure to demolitions and EBLLs, results should be interpreted with caution, given numerous limitations. Given the consequences of childhood lead exposure, it is recommended that St Louis City conduct a similar analysis on demolitions conducted after 2020 using systematically collected demolition dates. Targeted testing or soil and air monitoring could also be informative.
Dance of Dollars: State Funding Effects on Local Health Department Expenditures
Authors: Viall Abigail H. , Bekemeier Betty , Yeager Valerie , Carton Thomas
Published: September 2021

Objective:

We examined changes in total local health department (LHD) expenditures in the state of Washington following introduction of a new state funding program to support core public health services and infrastructure.

Methods:

We used a pre/posttest design regression model to evaluate changes in LHD expenditures 1, 2, and 6 years into the new state program. To address potential endogeneity in the model, we repeated all 3 analyses using 2-stage least squares regression.

Results:

In the base case, overall spending among LHDs significantly increased with receipt of the new state funds in the first years of the program (2008 and 2009). However, those increases were not sustained over the longer term (2013). In subpopulation analyses, total LHD spending increased more among larger LHDs.

Conclusions:

Between 2006 and 2013, new state investments in core public health functions increased Washington State LHD expenditures in the short term, but those increases did not persist over time. For public health financial modernization efforts to translate into public health infrastructure modernization successes, the way new investments are structured may be as important as the amount of funding added.
Addressing Health Disparities: The Health Department Nurse Lead Executive's Relationship to Improved Community Health
Authors: Kett Paula M. , Bekemeier Betty , Herting Jerald R. , Altman Molly R.
Published: September 2021

Context:

The nurse-trained local health department (LHD) lead executive has been shown to be positively associated with LHD performance; however, no other research has explored whether this association translates to improved community health.

Objective:

To investigate the relationship between the type of LHD leadership—whether or not the lead executive is a nurse—and changes in health outcomes.

Design:

This study used a multivariate panel time series design. Each model was estimated as a pooled time series and using time and unit fixed effects, with a 1-year lag used for all covariates and the main predictor.

Setting:

A national, county-level data set was compiled containing variables pertaining to the LHD, community demographics, and health outcomes for the years 2010-2018.

Participants:

The unit of analysis was the LHD. The data set was restricted to those counties with measurable mortality rates during at least 8 of the 9 time periods of the study, resulting in a total of 626 LHDs.

Main Outcome Measures:

The outcomes of interest were changes in 15- to 44-year-old all-cause mortality, infant mortality, and entry into prenatal care.

Results:

In models with combined time and unit fixed effects, a significant relationship exists between a nurse-led LHD and reduced mortality in the 15- to 44-year-old Black population (−5.2%, P < .05) and a reduction in the Black-White mortality ratio (−6%, P < .05). In addition, there is a relationship between the nurse-led LHD and a reduction in the percentage of the population with late or no entry to prenatal care.

Conclusions:

The evidence presented here helps connect the known positive association between nurse lead executives and LHD performance to improvements in community health. It suggests that nurse leaders are associated with health improvements in line with addressing health inequities.
Using a Patient Safety/Quality Improvement Model to Assess Telehealth for Psychiatry and Behavioral Health Services Among Special Populations During COVID-19 and Beyond
Authors: Li Luming , Childs Amber W.
Published: September 2021

Telehealth has been rapidly deployed in the environment of the Coronavirus 2019 (COVID-19) pandemic to help meet critical mental health needs. As systems of care use telehealth during the pandemic and evaluate the future of telehealth services beyond the crisis, a quality and safety framework may be useful in weighing important considerations for using telehealth to provide psychiatric and behavioral health services within special populations. Examining access to care, privacy, diversity, inclusivity, and sustainability of telehealth to meet behavioral and psychiatric care needs in geriatric and disadvantaged youth populations can help highlight key considerations for health care organizations in an increasingly electronic health care landscape.
Diagnostic Accuracy of Longitudinal Evaluation of Central Nervous System Sonoelastography in Preterm and Term Neonates
Authors: Ozkan Mehmet Burak , Ozkan Elif Özyazici
Published: September 2021

Objectives

The objective of this study was to evaluate the brain elasticity of the central nervous system in preterm and term neonates.

Methods

Seventy-seven healthy preterm and term neonates (mean gestational age [GA], 37.5 weeks; range, 32.6–40.5 weeks) were included in the study. Periventricular and subcortical white matter, cortical gray matter, and ventricle and subdural spaces were examined with strain elastography ratios. Each patient underwent sonography evaluation twice. The mean age at the time of sonographic evaluation was 9 days (range, 4–15 days) for the first evaluation and 37 days (range, 31–47 days) for the second evaluation. The ratios were correlated with GA, birth weight.

Results

The caudate nucleus and cortical gray matter strain ratios were significantly higher than the periventricular and subcortical white matter strain ratios (P < 0.001). There was a positive relationship between GA and periventricular white matter elastographic scores on the two measurements (P = 0.022 and 0.018, respectively). The term neonates have higher strain rations compared with the preterm neonates at the first assessment (P < 0.01). At the evaluation of the area under the curve for the sonographic examination for the receiver operating characteristic curve, the periventricular white matter was 0.742 (95% confidence interval, 0.689–0.790), and it was 0.773 (95% confidence interval, 0.722–0.818) for the subcortical white matter.

Conclusions

Neonatal brain development, maturation, and myelination can be assessed by strain elastography. These findings should be evaluated with further larger cohorts that could help to prevent neonatal brain damages.
Extended Lymphadenectomy Improves Survival After Induction Chemoradiation for Esophageal Cancer
Authors: Kamel Mohamed K. , Harrison Sebron , Lee Benjamin , Port Jeffrey L. , Stiles Brendon M. , Altorki Nasser K.
Published: September 2021

Objectives:

The aim of this study was to explore the potential value of extended nodal-dissection following neoadjuvant chemoradiation (CRT), by analyzing data from the National Cancer Database (NCDB).

Background:

A CROSS-trial post-hoc analysis showed that the number of dissected lymph nodes was associated with improved survival in patients undergoing upfront surgery but not in those treated with neoadjuvant CRT.

Methods:

The NCDB was queried (2004–2014) for patients who underwent esophagectomy following induction CRT. Predictors of overall survival (OS) were assessed. The optimal number of dissected LNs associated with highest survival benefit was determined by multiple regression analyses and receiveroperating characteristic curve analysis. The whole cohort was divided into 2 groups based on the predefined cutoff number. The two groups were propensity-matched (PMs).

Results:

Esophagectomy following induction-CRT was performed in 14,503 patients. The number of resected nodes was associated with improved OS in the multivariable analysis (hazard ratio for every 10 nodes: 0.95 (95% confidence interval: 0.93–0.98). The cutoff number of resected LNs that was associated with the highest survival benefit was 20 nodes. In the PM groups, patients in the “≥20 LNs” group had a 14% relative-increase in OS (P= 0.002), despite having more advanced pathological stages (stage II-IV: 76% vs 72%, P <0.001), and higher number of positive nodes (0–2 vs 0–1, P < 0.001).

Conclusions:

The total number of resected nodes is a significant determinant of improved survival following induction CRT in patients with either node negative or node positive disease. In the matched groups, patients with higher number of resected lymph nodes had higher OS rate, despite having more advanced pathological disease and higher number of resected positive lymph nodes.
Wastewater-Based Epidemiology and Whole-Genome Sequencing for Community-Level Surveillance of SARS-CoV-2 in Selected Urban Communities of Davao City, Philippines: A Pilot Study
Authors: Otero Maria Catherine B. , Murao Lyre Anni E. , Limen Mary Antoinette G. , Gaite Paul Lorenzo A. , Bacus Michael G. , Acaso Joan T. , Corazo Kahlil , Knot Ineke E. , Sajonia Homer , de los Reyes Francis L. , Jaraula Caroline Marie B. , Baja Emmanuel S. , Del Mundo Dann Marie N.
Published: September 2021

ABSTRACT AND KEYWORDS

Background

Over 50 countries have used Wastewater-Based Epidemiology (WBE) and Whole-Genome Sequencing (WGS) of SARS-CoV-2 for monitoring COVID-19 cases. COVID-19 surveillance in the Philippines relies on clinical monitoring and contact tracing, with both having limited use in early detection or prediction of community outbreaks. Thus, complementary public health surveillance methods that can provide community-level infection data faster and using lesser resources must be explored.

Objectives

This study piloted and assessed WBE and WGS as approaches for COVID-19 surveillance in low-resource and low-sanitation communities in Davao City, Philippines.

Methods

Weekly wastewater samples were collected from six barangay community sewer pipes or creeks from November to December 2020. Samples were concentrated using a PEG-NaCl precipitation method and analyzed by RT-PCR to detect the SARS-CoV-2 N, RdRP, and E genes. In addition, SARS-CoV-2 RNA-positive samples were subjected to WGS for genomic mutation surveillance. Public data from clinical surveillance were also reviewed to interpret WBE data.

Results

Twenty-two of the 24 samples (91.7%) obtained from the six barangays tested positive for SARS-CoV-2 RNA. The cycle threshold (Ct) values were correlated with RNA concentration and attack rate. Thirty-two SARS-CoV-2 mutations were detected in WGS, including novel non-synonymous mutations or indels in seven SARS-CoV-2 genes and ten mutations previously reported in the Philippines.

Discussion

SARS-CoV-2 RNA was detected in community wastewater from the six barangays of Davao City, even when the barangays were classified as having a low risk of COVID-19 transmission and no new cases were reported. Despite the fragmented genome sequences analyzed, our genomic surveillance in wastewater confirmed the presence of previously reported mutations while identifying mutations not yet registered in clinical surveillance. The local context of a community must be considered when planning to adopt WBE and WGS as complementary COVID-19 surveillance methodologies, especially in low-sanitation and low-resource settings.
Ensemble forecast of COVID-19 in Karnataka for vulnerability assessment and policy interventions
Authors: Ganesan Sashikumaar , Subramani Deepak , Anandh Thivin , Ghose Divij , Babu Giridhara R
Published: September 2021

We present an ensemble forecast for Wave-3 of COVID-19 in the state of Karnataka, India, using the IISc Population Balance Model for infectious disease spread. The reported data of confirmed, recovered, and deceased cases in Karnataka from 1 July 2020 to 4 July 2021 is utilized to tune the model’s parameters, and an ensemble forecast is done from 5 July 2021 to 30 June 2022. The ensemble is built with 972 members by varying seven critical parameters that quantify the uncertainty in the spread dynamics (antibody waning, viral mutation) and interventions (pharmaceutical, non-pharmaceutical). The probability of Wave-3, the peak date distribution, and the peak caseload distribution are estimated from the ensemble forecast. Our analysis shows that the most significant causal factors are compliance to Covid-appropriate behavior, daily vaccination rate, and the immune escape new variant emergence-time. These causal factors determine when and how severe the Wave-3 of COVID-19 would be in Karnataka. We observe that when compliance to Covid-Appropriate Behavior is good (i.e., lockdown-like compliance), the emergence of new immune-escape variants beyond Sep ‘21 is unlikely to induce a new wave. A new wave is inevitable when compliance to Covid-Appropriate Behavior is only partial. Increasing the daily vaccination rates reduces the peak active caseload at Wave-3. Consequently, the hospitalization, ICU, and Oxygen requirements also decrease. Compared to Wave-2, the ensemble forecast indicates that the number of daily confirmed cases of children (0-17 years) at Wave-3’s peak could be seven times more on average. Our results provide insights to plan science-informed policy interventions and public health response.
Single-cell transcriptomics elucidates in vitro reprogramming of human intestinal epithelium cultured in a physiodynamic gut-on-a-chip
Authors: Shin Woojung , Su Zhe , Yi S. Stephen , Kim Hyun Jung
Published: September 2021

The microphysiological human gut-on-a-chip has demonstrated in vivo-relevant cellular fidelity of intestinal epithelium compared to its cultures in a static condition1, 2. Microfluidic control of morphogen gradients and mechanical cues robustly induced morphological histogenesis with villi-like three-dimensional (3D) microarchitecture, lineage-associated cytodifferentiation, and physiological functions of a human intestinal Caco-2 epithelium3, 4. However, transcriptomic dynamics that orchestrates morphological and functional reprogramming of the epithelium in a microphysiological culture remains elusive. Single-cell transcriptomic analysis revealed that a gut-on-a-chip culture that offers physiological motions and flow drives three distinctive subclusters that offer distinct gene expression and unique spatial representation in 3D epithelial layers. The pseudotemporal trajectory of individual cells visualized the evolutionary transition from ancestral genotypes in static cultures into more heterogeneous phenotypes in physiodynamic cultures on cell cycles, differentiation, and intestinal functions including digestion, absorption, drug transport, and metabolism of xenobiotics. Furthermore, the inversed transcriptomic signature of oncogenes and tumor-suppressor genes of Caco-2 cells verified that a gut-on-a-chip culture drives a postmitotic reprogramming of cancer-associated phenotypes. Thus, we discovered that a physiodynamic on-chip culture is necessary and sufficient for a cancer cell line to be reprogrammed to elicit in vivo-relevant heterogeneous cell populations with restored normal physiological signatures.
Dominating Lengthscales of Zebrafish Collective Behaviour
Authors: Yang Yushi , Turci Francesco , Kague Erika , Hammond Chrissy L. , Russo John , Royall C. Patrick
Published: September 2021

Collective behaviour in living systems is observed across many scales, from bacteria to insects, to fish shoals. Zebrafish have emerged as a model system amenable to laboratory study. Here we report a three-dimensional study of the collective dynamics of fifty Zebrafish. We observed the emergence of collective behaviour changing between polarised to randomised, upon adaption to new environmental conditions. We quantify the spatial and temporal correlation functions of the fish and identify two length scales, the persistence length and the nearest neighbour distance, that capture the essence of the behavioural changes. The ratio of the two length scales correlates robustly with the polarisation of collective motion that we explain with a reductionist model of self–propelled particles with alignment interactions.
Atypical chemokine receptor 3 (ACKR3) induces the perturbation of rRNA biogenesis: a novel mechanism of colorectal tumorigenesis
Authors: Yang Juan , Li Ya-Nan , Pan Ting , Miao Rong-Rong , Zhang Yue-Ying , Wu Shu-Hua , Qu Xian-Jun , Cui Shu-Xiang
Published: September 2021

Atypical chemokine receptor 3 (ACKR3), previously known as C-X-C chemokine receptor type 7 (CXCR7), has emerged as a key player in several biologic processes. Its atypical “intercepting receptor” signaling properties have established ACKR3 as the main regulator in pathophysiological processes in many diseases. However, much less is known the underlying mechanisms of ACKR3 in promoting tumorigenesis. We found, in both human and animal model, that activation of ACKR3 promotes colorectal tumorigenesis through the NOLC1-induced perturbations of rRNA biogenesis. As compared with adjacent non-neoplastic tissue, human colonic cancer tissues demonstrated higher expression of ACKR3, and high ACKR3 expression was associated with increased severity of colonic cancer. Villin-ACKR3 transgenic mice demonstrated the characteristics of ACKR3-induced colorectal cancer, showing the nuclear β-arrestin-1-activated perturbation of rRNA biogenesis. Activation of ACKR3 induced nuclear translocation of β-arrestin-1 (β-arr1), leading to the interaction of β-arr1 with nucleolar and coiled-body phosphoprotein 1 (NOLC1). As the highly phosphorylated protein in the nucleolus, NOLC1 further interacted with Fibrillarin, a highly conserved nucleolar methyltransferase responsible for ribosomal RNA methylation, leading to the increase of methylation in Histone H2A, resulting in the promotion of rRNA transcription of ribosome biogenesis. Conclusion: ACKR3 promotes colorectal tumorigenesis through the perturbation of rRNA biogenesis by nuclear β-arr1-induced interaction of NOLC1 with Fibrillarin.

HIGH LIGHTS

ACKR3 is an atypical G protein-coupled receptor (GPCR)

ACKR3 promotes colorectal tumorigenesis

ACKR3 induces nuclear translocation of β-arr1

Nuclear β-arr1 interacts with NOLC1 to activate Fibrillarin

Interaction of NOLC1 to Fibrillarin leads to perturbation of rRNA biogenesis
Tradeoff breaking as model of evolutionary transitions in individuality and the limits of the fitness decoupling metaphor
Authors: Bourrat Pierrick , Doulcier Guilhem , Rose Caroline J. , Rainey Paul B. , Hammerschmidt Katrin
Published: September 2021

Evolutionary transitions in individuality (ETIs) involve the formation of Darwinian collectives from Darwinian particles. The transition from cells to multicellular life is a prime example. During an ETI, collectives become units of selection in their own right. However, the underlying processes are poorly understood. One observation used to identify the completion of an ETI is an increase in collective-level performance accompanied by a decrease in particle-level performance, for example measured by growth rate. This seemingly counterintuitive dynamic has been referred to as “fitness decoupling” and has been used to interpret both models and experimental data. Using a mathematical approach, we show this concept to be problematic in that the fitness of particles and collectives can never decouple—calculations of particle and collective fitness performed over appropriate and equivalent time intervals are necessarily the same. By way of solution, we draw attention to the value of mechanistic approaches that emphasise traits, and tradeoffs among traits, as opposed to fitness. This trait-based approach is sufficient to capture dynamics that underpin evolutionary transitions. In addition, drawing upon both experimental and theoretical studies, we show that while early stages of transitions might often involve tradeoffs among particle traits, later—and critical—stages are likely to involve the rupture of such tradeoffs. Thus, tradeoff-breaking stands as a useful marker for ETIs.
Fluid-structure interaction simulation of tissue degradation and its effects on intra-aneurysm hemodynamics
Authors: Wang Haifeng , Uhlmann Klemens , Vedula Vijay , Balzani Daniel , Varnik Fathollah
Published: September 2021

Tissue degradation plays a crucial role in vascular diseases such as atherosclerosis and aneurysms. Computational modeling of vascular hemodynamics incorporating both arterial wall mechanics and tissue degradation has been a challenging task. In this study, we propose a novel finite element method-based approach to model the microscopic degradation of arterial walls and its interaction with blood flow. The model is applied to study the combined effects of pulsatile flow and tissue degradation on the deformation and intra-aneurysm hemodynamics. Our computational analysis reveals that tissue degradation leads to a weakening of the aneurysmal wall, which manifests itself in a larger deformation and a smaller von Mises stress. Moreover, simulation results for different heart rates, blood pressures and aneurysm geometries indicate consistently that, upon tissue degradation, wall shear stress increases near the flow-impingement region and decreases away from it. These findings are discussed in the context of recent reports regarding the role of both high and low wall shear stress for the progression and rupture of aneurysms.
Developmental and environmental plasticity in opsin gene expression in Lake Victoria cichlid fish
Authors: Irazábal-González Lucia , Wright Daniel Shane , Maan Martine
Published: September 2021

In many organisms, sensory abilities develop and evolve according to the changing demands of navigating, foraging and communication across different environments and life stages. Teleost fish inhabit heterogeneous light environments and exhibit a large diversity in visual system properties among species. Cichlids are a classic example of this diversity, generated by different tuning mechanisms that involve both genetic factors and phenotypic plasticity. Here, we document the developmental progression of visual pigment gene expression in Lake Victoria cichlids and test if these patterns are influenced by variation in light conditions. We reared two sister species of Pundamilia to adulthood in two distinct visual conditions that resemble the two light environments that they naturally inhabit in Lake Victoria. We also included interspecific first-generation hybrids. We then quantified (using RT-qPCR) the expression of the four Pundamilia opsins (SWS2B, SWS2A, RH2A and LWS) at 14 time points. We find that opsin expression profiles progress from shorter-wavelength sensitive opsins to longer-wavelength sensitive opsins with increasing age, in both species and their hybrids. The developmental trajectories of opsin expression also responded plastically to the visual conditions. Finally, we found subtle differences between reciprocal hybrids, possibly indicating parental effects and warranting further investigation. Developmental and environmental plasticity in opsin expression may provide an important stepping stone in the evolution of cichlid visual system diversity.

Research highlights

In Lake Victoria cichlid fish, expression levels of opsin genes (encoding visual pigments) differ between developmental stages and between experimental light treatments. This plasticity may contribute to the evolution of cichlid visual system diversity.
SHOOT: phylogenetic gene search and ortholog inference
Authors: Emms D.M. , Kelly S.
Published: September 2021

Determining the evolutionary relationships between genes is fundamental to comparative biological research. Here we present the phylogenetic search, SHOOT. SHOOT searches a user query sequence against a database of phylogenetic trees and returns a tree with the query sequence correctly placed within it. We show that SHOOT performs this analysis with comparable speed to a BLAST search. We demonstrate that SHOOT phylogenetic placements are as accurate as conventional tree inference and it can identify orthologs with high accuracy. In summary, SHOOT is a fast and accurate tool for phylogenetic analyses of novel query sequences. It is available online at www.shoot.bio.
Microtubule retrograde flow retains neuronal polarization in a fluctuating state
Authors: Schelski Max , Bradke Frank
Published: September 2021

In developing vertebrate neurons, a neurite is formed by more than a hundred microtubules. While individual microtubules are dynamic, the microtubule array itself has been regarded as stationary. Using live cell imaging in combination with photoconversion techniques and pharmacological manipulations, we uncovered that the microtubule array flows retrogradely within neurites to the soma. This microtubule retrograde flow drives cycles of microtubule density, a hallmark of the fluctuating state before axon formation. Shortly after axon formation, microtubule retrograde flow slows down in the axon, which stabilizes microtubule density cycles and thereby functions as a molecular wedge to enable axon extension. We propose microtubule retrograde flow and its specific slowdown in the axon to be the long-sought mechanism to single one neurite out to drive neuronal polarization.
pSiteExplorer: Visualization of the mass spectrometric data underlying phospho-site quantification
Authors: Plank Michael J.
Published: September 2021

Mass spectrometry based phospho-proteomics is a widely used approach to assess protein phosphorylation. Intensities of phospho-peptide ions are obtained by integrating the MS signal over their chromatographic peaks. How individual peptide measurements mapping to the same phospho-site are combined for the quantification of the given site is, however, in most cases hidden from researchers conducting, reviewing, and reading these studies. I here describe pSiteExplorer, an R script that visualizes the peak intensities associated with phospho-sites in MaxQuant output tables. Barplots of MS intensities originating from phospho-peptides with distinct amino acid sequences due to missed cleavages, different numbers of phosphates and from all off-line chromatographic fractions and charge states are displayed. This tool will help gaining a deeper insight into phospho-site quantifications by contrasting individual and summed phospho-peptide intensities with the site-level values derived by MaxQuant. This will support the validation of quantification results, for example, for the selection of candidates for follow-up studies.
Engineering a thixotropic and biochemically tunable hyaluronan and collagen bioink for biofabrication of multiple tissue construct types
Authors: Aleman Julio , Sivakumar Hemamylammal , DePalma Thomas , Zhou Yu , Mazzocchi Andrea , Huntwork Richard Connor , Yoo KyungMin , Banks Surya , Clark Casey , Maycock Alexandra , Leaks Kalan , Enck Kevin , Opara Emmanuel C , Gatenholm Paul , Welker Mark , Soker Shay , Herberg Samuel , Criswell Tracy , Skardal Aleksander
Published: September 2021

The field of three-dimensional (3D) bioprinting has advanced rapidly in recent years. Significant reduction in the costs associated with obtaining functional 3D bioprinting hardware platforms is both a cause and a result of these advances. As such, there are more laboratories than ever integrating bioprinting methodologies into their research. However, there is a lack of standards in the field of biofabrication governing any requirements or characteristics to support cross-compatibility with biomaterial bioinks, hardware, and different tissue types. Here we describe a modular extracellular matrix (ECM) inspired bioink comprised of collagen and hyaluronic acid base components that: 1) employ reversible internal hydrogen bonding forces to generate thixotropic materials that dynamically reduce their elastic moduli in response to increased shear stress, thus enabling increased compatibility with printing hardware; and 2) modular addons in the form of chemically-modified fibronectin and laminin that when covalently bound within the bioink support a variety of tissue types, including liver, neural, muscle, pancreatic islet, and adipose tissue. These features aim to accelerate the deployment of such bioinks for tissue engineering of functional constructs in the hands of various end users.
Ear pinnae in a neotropical katydid (Orthoptera: Tettigoniidae) function as ultrasound guides for bat detection
Authors: Pulver Christian , Celiker Emine , Woodrow Charlie , Geipel Inga , Soulsbury Carl , Cullen Darron A. , Rogers Stephen M , Veitch Daniel , Montealegre-Z Fernando
Published: September 2021

Early predator detection is a key component of the predator-prey arms race, and has driven the evolution of multiple animal hearing systems. Katydids (Insecta) have sophisticated ears, each consisting of paired tympana on each foreleg that receive sound directly externally, and internally via a narrowing ear canal through the acoustic spiracle. These ears are pressure-time difference receivers capable of sensitive and accurate directional hearing across a wide frequency range, despite the small size of katydids. Many katydid species have cuticular pinnae which form cavities around the outer tympanal surfaces, but their function is unknown. We investigated pinnal function in the katydid Copiphora gorgonensis by combining experimental biophysics and numerical modelling using 3D ear geometries. Results show that the pinnae in C. gorgonensis do not assist in directional hearing for specific call frequencies, but instead pinnae act as ultrasound detector devices. Pinnae induced large sound pressure gains that enhanced sound detection at high ultrasonic frequencies (> 60 kHz), matching the echolocation range of co-occurring insectivorous bats. Comparing pinnal mechanics of sympatric katydid species supports these findings, and suggests that pinnae evolved in katydids primarily for enhanced predator detection. Audiograms (both behavioural and neural) and tympanal cavity resonances obtained from living specimens corroborate our findings.
Functional connectivity of fMRI using differential covariance predicts structural connectivity and behavioral reaction times
Authors: Chen Yusi , Bukhari Qasim , Lin Tiger W. , Sejnowski Terrence J.
Published: September 2021

Recordings from resting state functional magnetic resonance imaging (rs-fMRI) reflect the influence of pathways between brain areas. A wide range of methods have been proposed to measure this functional connectivity (FC), but the lack of “ground truth” has made it difficult to systematically validate them. Most measures of FC produce connectivity estimates that are symmetrical between brain areas. Differential covariance (dCov) is an algorithm for analyzing FC with directed graph edges. Applied to synthetic datasets, dCov-FC was more effective than covariance and partial correlation in reducing false positive connections and more accurately matching the underlying structural connectivity. When we applied dCov-FC to resting state fMRI recordings from the human connectome project (HCP) and anesthetized mice, dCov-FC accurately identified strong cortical connections from diffusion Magnetic Resonance Imaging (dMRI) in individual humans and viral tract tracing in mice. In addition, those HCP subjects whose rs-fMRI were more integrated, as assessed by a graph-theoretic measure, tended to have shorter reaction times in several behavioral tests. Thus, dCov-FC was able to identify anatomically verified connectivity that yielded measures of brain integration causally related to behavior.
RORγt-Expressing Pathogenic CD4+T Cells Cause Brain Inflammation During Chronic Colitis
Authors: Mickael Michel Edwar , Bhaumik Suniti , Chakraborti Ayanabha , Umfress Alan , van Groen Thomas , Macaluso Matthew , Totenhagen John , Sorace Anna G , Bibb James A , Standaert David G , Basu Rajatava
Published: September 2021

Neurobehavioral disorders and brain abnormalities have been extensively reported in both Crohn’s Disease (CD) and Ulcerative Colitis (UC) patients. However, the mechanism causing neuropathological disorders in inflammatory bowel disease (IBD) patients remains unknown. Studies have linked the Th17 subset of CD4+T cells to brain diseases associated with neuroinflammation and cognitive impairment, including multiple sclerosis (MS), ischemic brain injury and Alzheimer’s disease. To better understand how CD4+T lymphocytes, contribute to brain pathology in chronic intestinal inflammation, we investigated the development of brain inflammation in the T cell transfer model of chronic colitis. Our findings demonstrate that CD4+T cells infiltrate the brain of colitic Rag1-/- mice in proportional levels to colitis severity. Colitic mice developed hypothalamic astrogliosis that correlated with neurobehavioral disorders. Moreover, the brain-infiltrating CD4+T cells expressed Th17 cell transcription factor RORγt and displayed a pathogenic Th17 cellular phenotype similar to colonic Th17 cells. Adoptive transfer of RORγt-deficient naïve CD4+T cells failed to cause brain inflammation and neurobehavioral disorders in Rag1-/- recipients, with significantly less brain infiltration of CD4+T cells. These findings suggest that pathogenic RORγt+CD4+T cells that aggravate colitis migrate preferentially into the brain, contributing to brain inflammation and neurobehavioral disorders, thereby linking colitis severity to neuroinflammation.