bluuebunny/crossref_metadata_2025 huggingface dataset:
Genomic exploration of the targets of FOXL2 and ESR2 unveils their implication in cell migration, invasion, and adhesion
Authors: Herman Laetitia , Legois Bérangère , Todeschini Anne‐Laure , Veitia Reiner A.
Published: March 2021

FOXL2 and ESR2 are key transcriptional regulators in ovarian granulosa cells. To explore their transcriptional roles and their interplay, we have depleted Foxl2 and Esr2 in mouse primary granulosa cells to assess their ability to bind their targets and/or to modulate gene expression and cellular functions. We show that FOXL2 is involved in a large number of regulatory actions essential for the maintenance of granulosa cell fate. A parallel ChIP‐seq analysis showed that FOXL2 mainly binds to sites located in intergenic regions quite far from its targets. A bioinformatic analysis demonstrated that FOXL2‐activated genes were enriched in peaks associated with the H3K27ac mark, whereas FOXL2‐repressed genes were not, suggesting that FOXL2 can activate transcription through binding to enhancer sites. We also identified about 500 deregulated genes upon Esr2 silencing, of which one third are also targets of FOXL2. We provide evidence showing that both factors modulate, through a coherent feed‐forward loop, a number of common targets. Many of the FOXL2/ESR2 targets are involved in cell motility and, consistently, granulosa cells depleted for either Foxl2 or Esr2 exhibit decreased migration, invasion and adhesion. This effect is paralleled by the depletion of their target Phactr1, involved in actin cytoskeleton dynamics. Our analysis expands the number of direct and indirect transcriptional targets of both FOXL2 and ESR2, which deserve investigation in the context of adult‐type granulosa cell tumors whose molecular diagnostic hallmark is the presence of the C134W FOXL2 pathogenic variant.
Reduced electron transport chain complex I protein abundance and function in Mfn2‐deficient myogenic progenitors lead to oxidative stress and mitochondria swelling
Authors: Luo Nanjian , Yue Feng , Jia Zhihao , Chen Jingjuan , Deng Qing , Zhao Yongju , Kuang Shihuan
Published: March 2021

Mitochondrial remodeling through fusion and fission is crucial for progenitor cell differentiation but its role in myogenesis is poorly understood. Here, we characterized the function of mitofusin 2 (Mfn2), a mitochondrial outer membrane protein critical for mitochondrial fusion, in muscle progenitor cells (myoblasts). Mfn2 expression is upregulated during myoblast differentiation in vitro and muscle regeneration in vivo. Targeted deletion of Mfn2 gene in myoblasts (Mfn2MKO) increases oxygen‐consumption rates (OCR) associated with the maximal respiration and spare respiratory capacity, and increased levels of reactive oxygen species (ROS). Skeletal muscles of Mfn2MKO mice exhibit robust mitochondrial swelling with normal mitochondrial DNA content. Additionally, mitochondria isolated from Mfn2MKO muscles have reduced OCR at basal state and for complex I respiration, associated with decreased levels of complex I proteins NDUFB8 (NADH ubiquinone oxidoreductase subunit B8) and NDUFS3 (NADH ubiquinone oxidoreductase subunit S3). However, Mfn2MKO has no obvious effects on myoblast differentiation, muscle development and function, and muscle regeneration. These results demonstrate a novel role of Mfn2 in regulating mitochondrial complex I protein abundance and respiratory functions in myogenic progenitors and myofibers.
Effects of R‐flurbiprofen and the oxygenated metabolites of endocannabinoids in inflammatory pain mice models
Authors: Buisseret Baptiste , Guillemot‐Legris Owein , Ben Kouidar Youssef , Paquot Adrien , Muccioli Giulio G. , Alhouayek Mireille
Published: March 2021

Pain is one of the cardinal signs accompanying inflammation. The prostaglandins (PGs), synthetized from arachidonic acid by cyclooxygenase (COX)‐2, are major bioactive lipids implicated in inflammation and pain. However, COX‐2 is also able to metabolize other lipids, including the endocannabinoids 2‐arachidonoylglycerol (2‐AG) and anandamide (AEA), to give glycerol ester (PG‐G) and ethanolamide (PG‐EA) derivatives of the PGs. Consequently, COX‐2 can be considered as a hub not only controlling PG synthesis, but also PG‐G and PG‐EA synthesis. As they were more recently characterized, these endocannabinoid metabolites are less studied in nociception compared to PGs. Interestingly R‐profens, previously considered as inactive enantiomers of nonsteroidal anti‐inflammatory drugs (NSAIDs), are substrate‐selective COX inhibitors. Indeed, R‐flurbiprofen can selectively block PG‐G and PG‐EA production, without affecting PG synthesis from COX‐2. Therefore, we compared the effect of R‐flurbiprofen and S‐flurbiprofen in models of inflammatory pain triggered by local administration of lipopolysaccharides (LPS) and carrageenan in mice. Remarkably, the effects of flurbiprofen enantiomers on mechanical hyperalgesia seem to depend on (i) the inflammatory stimuli, (ii) the route of administration, and (iii) the timing of administration. We also assessed the effect of administration of the PG‐Gs, PG‐EAs, and PGs on LPS‐induced mechanical hyperalgesia. Our data support the interest of studying the nonhydrolytic endocannabinoid metabolism in the context of inflammatory pain.
The Surgical Anatomy and the Deep Plane Thread Lift of the Buccal Fat Pad
Authors: Tsai Yun-Ta , Zhang Yajie , Wu Yumeng , Yang Hung-Hsu , Chen Lili , Huang Patrick Po-Han , Wang Chao-Huei
Published: March 2021

Background:

Management of facial rejuvenation by the thread lift procedure has evolved over the past few years. The role of deep plane thread lift for buccal fat pad reposition was advocated. However, there are concerns about the risks and the feasibility of the deep plane thread lift. This study was designed to determine whether the deep plane thread lift could achieve effective aesthetic results and to investigate the possible risks of critical tissue injury through cadaveric studies.

Methods:

Twelve fresh frozen cephalic specimens of 8 male and 4 female Asian body donors (mean age, 63.3 ± 8.0 years) were investigated. The deep plane thread lifts for reposition of the buccal fat pads were performed for all the left hemifaces. Cadaveric dissections were performed to investigate the moving distance of the buccal fat pad and to examine the surrounding tissue of the passage of the deep plane thread lift.

Results:

The average moving distance of the buccal fat pads after the deep plane thread lift was 3.73 cm. The difference in moving distance of buccal fat pads between bilateral sides was statistically significant (P < 0.001). No injuries of the critical vessels or nerves were found after cadaveric dissection. The passage of the deep plane thread lift was evaluated.

Conclusion:

The deep plane thread lift for reposition of the buccal fat pad is a safe, effective, and practical method.
Bilateral Eyebrow Sclerosis: A New Clinical Entity
Authors: Ueno Kazuki , Kunimoto Kayo , Iwahashi Yoshifumi , Murata Shin-ichi , Yamamoto Yuki , Jinnin Masatoshi , Asamura Shinichi
Published: March 2021

We report a man with sparse eyebrows and recurrent bilateral subcutaneous nodules beneath the eyebrows. Their histopathologic features were sclerosis of a subcutaneous lesion. The proliferation of muscle was not obvious and inflammatory cell infiltration was inconspicuous, but some dilated capillaries were noted. Collagen was regularly interlaced, thickened, and hyalinized with dispersed fibroblasts. Various skin tumors can occur on adult faces, but this presentation, to our knowledge, was unique and could not be characterized as a known condition. Plastic surgeons, dermatologists, and pathologists may encounter similar conditions, so it should be considered as a new clinical entity called bilateral eyebrow sclerosis. This may be of comfort to patients with similar conditions. Moreover, we propose enlarged resection to include the skin surface and underlying muscles as an effective treatment for recovery of the eyebrows and prevention of recurrence.
Calibration Tool to Standardize Magnification during Smartphone-based Microsurgical Skills Training
Authors: Rahman Sadeea A. , Henderson Peter W.
Published: March 2021

Acquiring microsurgical skills outside the operating room has traditionally required not only a substantial amount of time and practice, but also a significant amount of equipment, such as an operating microscope. Difficulty in accessing such equipment hinders opportunities to acquire skills, particularly in environments with limited resources. Furthermore, the current era of restricted work hours has led to an increased demand for surgical skills training outside of the clinical setting. The near-ubiquity of the standard smartphone and its ability to magnify, illuminate, and record videos give it the potential to serve as an excellent tool to conduct training in microsurgical skills—particularly in the context of self-directed, home-based training. However, the variety of smartphones available and their inherent variability in technical and optical specifications have made it difficult to create a standardized, reproducible, and interchangeable system for smartphone-based microsurgical training. Therefore, we have developed a simple and effective calibration tool that ensures accurate magnification levels so that smartphone-based microsurgical training can be performed reliably with any device and in virtually any surroundings.
Mini-midface Lift Using Polydioxanone Cog Threads
Authors: Myung Yujin , Jung Chinkoo
Published: March 2021

Background:

Deepening of the nasolabial fold with reduced malar highlight caused by sagging of the midface is one of the most important characteristics of facial aging. This report describes the use of 18-G polydioxanone (PDO) cog threads to improve midface soft tissue sagging and achieve satisfactory results through a minimally invasive procedure.

Methods:

In total, 64 patients (all women; age, 33–60 years) underwent a midface thread lift from January 2017 to January 2018. After a stab incision was made through an 18-G needle over the lateral orbital rim, three 18-G precannulated PDO cog threads were inserted, targeting the deep medial fat pad and inner layer of the superficial muscular aponeurotic system. The threads were anchored to the periosteum of the lateral orbit, suspending the soft tissue to a more superior direction. Surgical results were evaluated subjectively (patient satisfaction ratings) and objectively (blinded physician ratings based on changes in the vertical position of the malar highlight).

Results:

No major complications (postoperative hematoma, infection, or temporary sensory/motor decreases) were observed. The mean procedural time was 15 minutes, and all patients underwent local anesthesia. Patient satisfaction was the highest at 1 month postoperatively (mean, 4.7/5.0), decreasing at 1 year postoperatively (2.8/5.0). The scores on the objective assessment followed the same trend (4.5/5.0 at 1 month; 3.1/5.0 at 1 year).

Conclusion:

Using PDO cog threads for midface lifting is simpler, quicker, and less invasive than using conventional surgical methods, and this method simultaneously achieves satisfactory results for at least 6 months.
Fibroblast Heterogeneity in and Its Implications for Plastic and Reconstructive Surgery: A Basic Science Review
Authors: desJardins-Park Heather E. , Chinta Malini S. , Foster Deshka S. , Borrelli Mimi R. , Shen Abra H. , Wan Derrick C. , Longaker Michael T.
Published: March 2021

Fibroblasts’ integral role in tissue development, maintenance, and disease represents a fast-growing field of basic science research. Although fibroblasts were long thought to be a homogeneous cell population, recent research has illuminated the unforeseen complexity of these cells, giving rise to the rapidly expanding research field of “fibroblast heterogeneity.” Fibroblasts play a critical role in states of tissue fibrosis such as skin scarring, which affects hundreds of millions of patients annually and causes severe aesthetic, developmental, and functional morbidity. Beyond scarring, major organ fibrosis is an enormous public health concern responsible for nearly half of all deaths in the United States. Because fibrosis is a conserved response to tissue damage in all organs, the study of fibroblasts throughout the body may help us to understand their role in the conditions most relevant to plastic and reconstructive surgery—for instance, skin scarring (eg, from burns, traumatic lacerations, or surgical incisions), “pathological” scarring (hypertrophic scars, keloids), and capsular contracture. Here, we present a basic science review of fibroblast heterogeneity in wound healing, cancer, organ fibrosis, and human dermal architecture. The field of fibroblast heterogeneity is young, and many of the insights discussed have yet to be translated clinically. However, plastic surgeons stand in a unique position to bridge these discoveries into clinical realities. We hope this information can spur readers to consider both what questions in plastic surgery can be studied from the lens of fibroblast heterogeneity, and how these preclinical insights can be translated to improving care of our patients.
Pleuroperitoneal (Denver) Shunt for Recurrent Nonmalignant Breast Seroma in a Metastatic Breast Cancer Patient
Authors: Pflibsen Lacey R. , Velazco Cristine S. , Rhee Daniel H. , Bryant Lyndsey A. , Chapital Alyssa B. , Rebecca Alanna M.
Published: March 2021

Pleuroperitoneal (Denver) shunts have been used primarily for palliation of refractory malignant and chylous peritoneal and pleural collections.
1–5
We used a pleuroperitoneal (Denver) shunt for a recurrent, nonmalignant breast seroma in the palliation of metastatic breast cancer as a novel use of this shunt.
Efficacy of a Coriolus versicolor–Based Vaginal Gel in Women With Human Papillomavirus–Dependent Cervical Lesions: The PALOMA Study
Authors: Serrano Luis , López Andrés Carlos , González Silvia P. , Palacios Santiago , Dexeus Damián , Centeno-Mediavilla Cristina , Coronado Pluvio , de la Fuente Jesús , López José Antonio , Vanrell Cristina , Cortés Javier
Published: March 2021

Objective

The aim of the study was to evaluate the efficacy of Papilocare, a Coriolus versicolor–based vaginal gel, in repairing human papillomavirus (HPV)-related low-grade cervical lesions.

Methods

The study is a multicenter, open-label, randomized, parallel-group, watchful waiting approach-controlled trial involving 91 HPV-positive women with low-grade Pap smear alterations and consistent colposcopy.

Results

The percentage of patients with normal Pap smear and concordant colposcopy 3 and 6 months after receiving treatment (78.0% and 84.9%) was significantly higher than without treatment (54.8% and 64.5%), especially in high-risk HPV patients (79.5% and 87.8% vs 52.0% and 56.0%). At 6-month visit, overall HPV clearance was achieved by a greater number of patients receiving treatment (59.6%) compared with those without treatment (41.9%), especially high-risk HPV ones (62.5% vs 40.0%). The cervical re-epithelization score was significantly higher with treatment (mean = 4.5) than without (mean = 4.1). Compared with baseline, perceived stress decreased in the treatment group (from 21.1 to 19.0) and increased in the control group (from 17.7 to 20.7). A total of 7 possible or probable treatment-related adverse events were reported, most of them (n = 6) being mild or moderate in severity.

Conclusions

Treatment with Papilocare has demonstrated a better clinical benefit than the conventional watchful waiting approach in clinical practice for total and high-risk HPV patients in terms of its efficacy to treat HPV-related cervical lesions and to clear all HPV strains after a single 6-month period. It has demonstrated an adequate safety and tolerability and confers additional benefits such as higher re-epithelization, stress reduction, and high treatment adherence.
Efficacy of orthopaedic-inspired osteoporosis management: a secondary fracture prevention program after a fracture of the hip in a prospective randomized study
Authors: Zinger Gershon , Sylvetsky Noa , Levy Yedin , Steinberg Kobi , Bregman Alexander , Yudkevich Genady , Peyser Amos
Published: March 2021

Aims:

Patients who present with fragility fractures are consistently under-evaluated and under-treated for underlying osteoporosis. This point-of-care represents a lost opportunity to prevent future fractures. This 2-arm study evaluated the success by an orthopaedic department in osteoporosis evaluation and initiating treatment.

Methods:

Patients over the age of 50 years with a fragility fracture of the hip were candidates for inclusion. Exclusion criteria included end-of-life care and moderate or severe dementia. Patients were prospectively randomized into 1 of 2 groups. The Letter group received a letter at the time of discharge encouraging their primary care physician to start medication for osteoporosis (Letter group). The intervention group had 4 interventions including printed information, a DEXA scan, a specific treatment recommendation, and monthly phone calls for 4 months (Intervention group). The primary outcome measure was whether the patient was on recommended treatment at 4 months from the fracture.

Results:

There were 200 patients in the study, 100 in the Letter, and 100 in the Intervention group. Sixteen patients were removed from the study since they either died (9) within 4 months of their fracture, were transferred for end-of-life care (7), and 4 dropped out. This left 180 patients for analysis. The Letter group had only 6 patients (6.2%) on recommended treatment compared with the Intervention group with 64 patients (77.1%). This was statistically significant (P < 0.0001).

Conclusion:

Osteoporosis is a worldwide epidemic. Internationally, only about 20% of patients after a hip fracture are treated for their underlying weak bone. The most effective systems use a fracture liaison service (FLS) model. We present a 4-part intervention program that uses an FLS coordinator within the orthopaedic department. We encourage orthopaedic programs to adopt this or other models with the goal of taking the first step toward responsibility for bone health.

An FLS program within an orthopaedic department can successfully initiate treatment for underlying osteoporosis.
Assessment of clinical and radiographic outcomes following retrograde versus antegrade nailing of infraisthmic femoral shaft fractures without the use of intraoperative fluoroscopy in Tanzania
Authors: von Kaeppler Ericka P. , Donnelley Claire A. , Roberts Heather J. , Eliezer Edmund N. , Haonga Billy T. , Morshed Saam , Shearer David W.
Published: March 2021

Objectives:

To compare clinical and radiographic outcomes following antegrade versus retrograde intramedullary nailing of infraisthmic femoral shaft fractures.

Design:

Secondary analysis of prospective cohort study.

Setting:

Tertiary hospital in Tanzania.

Participants:

Adult patients with infraisthmic diaphyseal femur fractures.

Intervention:

Antegrade or retrograde SIGN intramedullary nail.

Outcomes:

Health-related quality of life (HRQOL), radiographic healing, knee range of motion, pain, and alignment (defined as less than or equal to 5 degrees of angular deformity in both coronal and sagittal planes) assessed at 6, 12, 24, and 52 weeks postoperatively.

Results:

Of 160 included patients, 141 (88.1%) had 1-year follow-up and were included in analyses: 42 (29.8%) antegrade, 99 (70.2%) retrograde. Antegrade-nailed patients had more loss of coronal alignment (P = .026), but less knee pain at 6 months (P = .017) and increased knee flexion at 6 weeks (P = .021). There were no significant differences in reoperations, HRQOL, hip pain, knee extension, radiographic healing, or sagittal alignment.

Conclusions:

Antegrade nailing of infraisthmic femur fractures had higher incidence of alignment loss, but no detectable differences in HRQOL, pain, radiographic healing, or reoperation. Retrograde nailing was associated with increased knee pain and decreased knee range of motion at early time points, but this dissipated by 1 year. To our knowledge, this is the first study to prospectively compare outcomes over 1 year in patients treated with antegrade versus retrograde SIGN intramedullary nailing of infraisthmic femur fractures.

Level of Evidence: III
Improving Psychiatric Care Through Integrated Digital Technologies
Authors: FOWLER J. CHRISTOPHER , MADAN ALOK , BRUCE COURTENAY R. , FRUEH B. CHRISTOPHER , KASH BITA , JONES STEPHEN L. , SASANGOHAR FARZAN
Published: March 2021

This manuscript provides an overview of our efforts to implement an integrated electronic monitoring and feedback platform to increase patient engagement, improve care delivery and outcome of treatment, and alert care teams to deterioration in functioning. Patients First utilizes CareSense, a digital care navigation and data collection system, to integrate traditional patient-reported outcomes monitoring with novel biological monitoring between visits to provide patients and caregivers with real-time feedback on changes in symptoms such as stress, anxiety, and depression. The next stage of project development incorporates digital therapeutics (computerized therapeutic interventions) for patients, and video resources for primary care physicians and nurse practitioners who serve as the de facto front line for psychiatric care. Integration of the patient-reported outcomes monitoring with continuous biological monitoring, and digital supports is a novel application of existing technologies. Video resources pushed to care providers whose patients trigger a symptom severity alert is, to our knowledge, an industry first.
Considerations for Payment Bundling in Cleft Care
Authors: Ahsanuddin Sofia , Sayegh Farah , Lu Jocelyn , Sanati-Mehrizy Paymon , Taub Peter J.
Published: March 2021

Since the introduction of the Bundled Payments for Care Improvement initiative, progress has been made in piloting bundled payment models to improve care coordination and curtail health care expenditures. In light of improvements in patient outcomes and the concomitant reduction in health care spending for certain high-volume and high-cost procedures, such as total joint arthroplasty and breast reconstruction, the authors discuss theoretical considerations for bundling payments for the care of patients with orofacial clefts. The reasons for and against adopting such a payment model to consolidate cleft care, as well as the challenges to implementation, are discussed. The authors purport that bundled payments can centralize components of cleft care and offer financial incentives to reduce costs and improve the value of care provided, but that risk adjustment based on the longitudinal nature of care, disease severity, etiologic heterogeneity, variations in outcomes reporting, and varying definitions of the episode of care remain significant barriers to implementation.
Recommended Maximum Laryngeal Prominence Size in Adult Females: A Cross-Sectional Study Proposing a Laryngeal Prominence Size Standard for Chondrolaryngoplasty in Male-to-Female Transgender Individuals
Authors: van Rossem Anna P. , Meijer Brigitte A. , Rinkel Rico N. P. M.
Published: March 2021

Background:

Although the World Professional Association for Transgender Health has provided international, multidisciplinary, evidence-based standards of care for various aspects of transgender health care, there is a lack of evidence-based guidelines for facial feminization surgery, including chondro laryngoplasty. The aim of this study was to define the recommended maximum laryngeal prominence size in adult females to propose an evidence-based laryngeal prominence size standard for chondrolaryngoplasty in male-to-female transgender individuals.

Methods:

This cross-sectional study was conducted in a tertiary care hospital. The study sample consisted of cisgender patients aged 18 to 60 years old with no history of surgery or radiotherapy in the head and neck area who visited the Otolaryngology/Head and Neck Surgery outpatient clinic. Laryngeal prominence size data were collected using three-dimensional scanning of the head and neck area.

Results:

Seventy-nine participants, 43 males and 36 females, were included in data analysis. Laryngeal prominence size was larger in male participants (median, 0.16 mm; range, 0 to 9.40 mm) than in female participants (median, 0.00 mm; range, 0 to 1.24 mm) (p < 0.001). The proportion of participants with a laryngeal prominence size larger than 0 mm was greater in male participants (55.81 percent) than in female participants (22.22 percent) (p = 0.002).

Conclusions:

To the authors’ knowledge, this is the first study to assess laryngeal prominence size in the general population. Their results suggest that 2 mm would be the recommended maximum laryngeal prominence size in females. Therefore, a laryngeal prominence size standard of 2 mm could be considered for chondrolaryngoplasty in male-to-female transgender individuals.
Liver Transplantation for Cholangiocarcinoma: Charting a Path With Lessons Learned From Center Experience
Authors: Ziogas Ioannis A. , Rauf Muhammad A. , Matsuoka Lea K. , Izzy Manhal , Rega Scott A. , Feurer Irene D. , Alexopoulos Sophoclis P.
Published: March 2021

Background.

While liver transplantation (LT) with neoadjuvant chemoradiation is increasingly utilized for the management of unresectable cholangiocarcinoma (CCA), data on post-LT survival are limited.

Methods.

We identified 844 patients who underwent LT (2002–2019) for nonincidental (CCA listing) or incidental (CCA on explant, not at listing) CCA in the Scientific Registry of Transplant Recipients. Kaplan–Meier and multivariable proportional hazards regression methods evaluated the effects of patient characteristics, donor type, transplant era (before/after 2010), and center volume (center-level CCALTs/active year) on the risk of graft failure and patient mortality.

Results.

One center performed >12 CCALTs/y, and the rest performed ≤4. Five-year graft survival was 50.6%. Multivariable models demonstrated laboratory model of end-stage liver disease ≥40 versus <15 and center volumes of 1, >1 to ≤2, and >2 to ≤4 CCALTs/y compared to >12 were associated with increased risk of graft failure and mortality (all P ≤ 0.002). Extra vessel use was associated with center volume. Among all recipients, extra vessel use occurred in 55.4% of CCALTs performed at the highest volume center and in 14.0% of cases at centers having ≤4 CCAs/y (P < 0.05).

Conclusions.

Center volume-related differences in outcomes and extra vessel use highlight the importance of establishing a unified, effective treatment protocol and the potential utility of regionalization of LT for CCA.
Intragraft Hyaluronan Increases in Association With Acute Lung Transplant Rejection
Authors: Hostetler Haley P. , Neely Megan L. , Kelly Francine L. , Belperio John A. , Budev Marie , Reynolds John M. , Shah Pali D. , Singer Lianne G. , Snyder Laurie D. , Palmer Scott M. , Todd Jamie L.
Published: March 2021

Background.

Acute perivascular rejection (AR) is common in lung recipients and increases the risk for chronic lung allograft dysfunction (CLAD). Hyaluronan (HA), an extracellular matrix constituent, accumulates in experimental AR and can act as an innate immune agonist, breaking tolerance and potentiating alloimmunity. We previously demonstrated HA accumulates in CLAD after human-lung transplantation. We sought to determine if HA accumulates in the bronchoalveolar lavage fluid (BALF) concurrent with AR in lung recipients.

Methods.

The cohort consisted of 126 first adult lung recipients at 5 transplant centers with a total of 373 BALF samples collected within the first posttransplant year. All samples were paired with a lung biopsy from the same bronchoscopy. BALF HA (ng/mL) was quantified by ELISA and log-transformed for analysis. Linear-mixed effect models, adjusted for potential confounders, were used to estimate the association between BALF HA concentration and the presence of AR on biopsy. The association between early posttransplant BALF HA levels and the development of CLAD was explored utilizing tertiles of maximum BALF HA level observed within the first 6 months of transplant.

Results.

In analyses adjusted for potential confounders, BALF HA concentration was significantly increased in association with AR (change in means on log-scale 0.31; 95% CI, 0.01-0.60; P = 0.044). When considered on the original scale (ng/mL), BALF HA concentrations were 1.36 times (36%) higher, on average, among samples with, versus without, AR. The cumulative incidence of CLAD was numerically higher in individuals in the highest tertiles of BALF HA level within the first 6 months after transplant, as compared with those in the lowest tertile; however, this difference was not statistically significant (P = 0.32).

Conclusions.

These results demonstrate accumulation of HA in clinical AR and suggest a mechanism by which innate and adaptive immune activation might interact in the development of AR and CLAD.
Preferred sound groups of vocal iconicity reflect evolutionary mechanisms of sound stability and first language acquisition: evidence from Eurasia
Authors: Dellert Johannes , Erben Johansson Niklas , Frid Johan , Carling Gerd
Published: March 2021

In speech, the connection between sounds and word meanings is mostly arbitrary. However, among basic concepts of the vocabulary, several words can be shown to exhibit some degree of form–meaning resemblance, a feature labelled vocal iconicity. Vocal iconicity plays a role in first language acquisition and was likely prominent also in pre-historic language. However, an unsolved question is how vocal iconicity survives sound evolution, which is assumed to be inevitable and ‘blind’ to the meaning of words. We analyse the evolution of sound groups on 1016 basic vocabulary concepts in 107 Eurasian languages, building on automated homologue clustering and sound sequence alignment to infer relative stability of sound groups over time. We correlate this result with the occurrence of sound groups in iconic vocabulary, measured on a cross-linguistic dataset of 344 concepts across single-language samples from 245 families. We find that the sound stability of the Eurasian set correlates with iconic occurrence in the global set. Further, we find that sound stability and iconic occurrence of consonants are connected to acquisition order in the first language, indicating that children acquiring language play a role in maintaining vocal iconicity over time.

This article is part of the theme issue ‘Reconstructing prehistoric languages'.
Inferring recent evolutionary changes in speech sounds
Authors: Moran Steven , Lester Nicholas A. , Grossman Eitan
Published: March 2021

In this paper, we investigate evolutionarily recent changes in the distributions of speech sounds in the world's languages. In particular, we explore the impact of language contact in the past two millennia on today's distributions. Based on three extensive databases of phonological inventories, we analyse the discrepancies between the distribution of speech sounds of ancient and reconstructed languages, on the one hand, and those in present-day languages, on the other. Furthermore, we analyse the degree to which the diffusion of speech sounds via language contact played a role in these discrepancies. We find evidence for substantive differences between ancient and present-day distributions, as well as for the important role of language contact in shaping these distributions over time. Moreover, our findings suggest that the distributions of speech sounds across geographic macro-areas were homogenized to an observable extent in recent millennia. Our findings suggest that what we call the Implicit Uniformitarian Hypothesis, at least with respect to the composition of phonological inventories, cannot be held uncritically. Linguists who would like to draw inferences about human language based on present-day cross-linguistic distributions must consider their theories in light of even short-term language evolution.

This article is part of the theme issue ‘Reconstructing prehistoric languages’.
Comparative study of multidrug-resistant Enterococcus faecium obtained from different hosts
Authors: Trościańczyk Aleksandra , Nowakiewicz Aneta , Gnat Sebastian , Łagowski Dominik , Osińska Marcelina , Chudzik-Rząd Beata
Published: March 2021

Introduction. The possible transfer of antimicrobial resistance genes between

Enterococcus faecium

isolates from humans and different animal species, including those not covered by monitoring programs (e.g. pet and wildlife), poses a serious threat to public health.

Hypothesis/Gap Statement. Little is known about occurrence and mechanisms of phenomenon of multidrug resistance of

E. faecium

isolated from various host species in Poland.

Aim. The aim of the study was to characterize multidrug-resistant

E. faecium

isolated from humans and animals (livestock, pets and wildlife) in terms of the occurrence of genetic markers determining resistance.

Methodology. Bacterial isolates were tested for phenotypic resistance and the presence of genes encoding resistance to macrolides, tetracycline, aminoglycosides, aminocyclitols and phenicols as well as efflux pump (emeA), resolvase (tndX) and integrase (Int-Tn) genes. The quinolone resistance-determining regions of gyrA and parC were sequenced.

Results. Human isolates of

E. faecium

were characterized by high-level resistance to: ciprofloxacin, enrofloxacin, erythromycin (100 %), as well, as aminoglycosides resistance (kanamycin – 100%, streptomycin – 78 %, gentamicin – 78%). Regardless of the animal species, high level of resistance of

E. faecium

to tetracycline (from 88–100 %), erythromycin (from 82–94 %) and kanamycin (from 36–100 %) was observed. All

E. faecium

isolates from wildlife were resistant to fluoroquinolones. However, full susceptibility to vancomycin was observed in all isolates tested. Phenotypic antimicrobial resistance of

E. faecium

was identified in the presence of the following resistance genes: erm(B) (70%), msr(A) (50 %), tet(L) (35 %), tet(K) (34 %), tet(M) (76 %), aac(6’)-Ie-aph(2″)-Ia (25%), ant(6)-Ia (31%), aph(3)-IIIa (68 %), (tndX) (23 %), and integrase gene (Int-Tn) (34 %). A correlation between an amino acid substitution at positions 83 and 87 of gyrA and position 80 of parC and the high-level fluoroquinolone resistance in

E. faecium

has been observed as well.

Conclusion. The level and range of antimicrobial resistance and the panel of resistance determinants is comparable between

E. faecium

isolates, despite host species.
Reduced BNT162b2 mRNA vaccine response in SARS-CoV-2-naive nursing home residents
Authors: Canaday David H. , Carias Lenore , Oyebanji Oladayo A. , Keresztesy Debbie , Wilk Dennis , Payne Michael , Aung Htin , Denis Kerri St. , Lam Evan C. , Wilson Brigid , Rowley Christopher F. , Berry Sarah D. , Cameron Cheryl M. , Cameron Mark J. , Balazs Alejandro B. , Gravenstein Stefan , King Christopher L.
Published: March 2021

The SARS-CoV-2 pandemic impact on nursing home (NH) residents prompted their prioritization for early vaccination. To fill the data gap for vaccine immunogenicity in NH residents, we examined antibody levels after BNT162b2 mRNA vaccine to spike, receptor binding domain (RBD) and for virus neutralization in 149 NH residents and 111 health care worker controls. SARS-CoV-2-naive NH residents mount antibody responses with nearly 4-fold lower median neutralization titers and half the anti-spike level compared to SARS-CoV-2-naive healthcare workers. By contrast, SARS-CoV-2-recovered vaccinated NH residents had neutralization, anti-spike and anti-RBD titers similar to SARS-CoV-2-recovered vaccinated healthcare workers. NH residents’ blunted antibody responses have important implications regarding the quality and durability of protection afforded by neoantigen vaccines. We urgently need better longitudinal evidence on vaccine effectiveness specific to NH resident populations to inform best practices for NH infection control measures, outbreak prevention and potential indication for a vaccine boost.
Plasma Neurofilament Light Chain predicts cognitive progression in prodromal and clinical dementia with Lewy Bodies
Authors: Pilotto Andrea , Imarisio Alberto , Carrarini Claudia , Russo Mirella , Masciocchi Stefano , Gipponi Stefano , Cottini Elisabetta , Aarsland Dag , Zetterberg Henrik , Ashton Nicholas J. , Hye Abdul , Bonanni Laura , Padovani Alessandro
Published: March 2021

Plasma neurofilament light chain (NfL) is a marker of neuronal damage in different neurological disorders and might predict disease progression in dementia with Lewy bodies (DLB). The study enrolled 45 controls and 44 DLB patients (including 17 prodromal cases) who underwent an extensive assessment at baseline and at 2 years follow-up. At baseline, plasma NfL levels were higher in both probable DLB and prodromal cases compared to controls. Plasma NfL emerged as the best predictor of cognitive decline compared to age, sex and baseline severity variables. The study supports the role of plasma NfL as a useful prognostic biomarker from the early stages of DLB.
Emotional responses toward COVID-19: A longitudinal assessment of age differences
Authors: Malesza Marta
Published: March 2021

The current study investigates the relation between age and emotional responses and coping strategies at two moments during the spread of COVID-19 in Poland, namely the first peak (March-May 2020) and the second pick (October-December 2020). A sample of 414 individuals between the ages of 18 and 81 were asked to rate the intensity of the ‘shock’, ‘sadness’, ‘anger’, and ‘fear’ they experienced due to COVID-19 and respond to items from the Brief Cope questionnaire. The present findings demonstrate that anger was consistently less intense among older adults than younger ones. Emotion-focused coping strategies were more commonly used by younger adults than middle-aged or older ones at the first peak of the outbreak; however, this trend had reversed during the second peak of the pandemic, as the older age groups demonstrated a far greater increase in the use of this form of coping. Results indicate a greater ability to use emotional regulation among older adults than younger ones, as the former are less likely to react to a crisis through anger and more able to adapt coping mechanisms to a dynamic environment.
Meta-learning local synaptic plasticity for continual familiarity detection
Authors: Tyulmankov Danil , Yang Guangyu Robert , Abbott LF
Published: March 2021

Over the course of a lifetime, a continual stream of information is encoded and retrieved from memory. To explore the synaptic mechanisms that enable this ongoing process, we consider a continual familiarity detection task in which a subject must report whether an image has been previously encountered. We design a class of feedforward neural network models endowed with biologically plausible synaptic plasticity dynamics, the parameters of which are meta-learned to optimize familiarity detection over long delay intervals. After training, we find that anti-Hebbian plasticity leads to better performance than Hebbian and replicates experimental results from the inferotemporal cortex, including repetition suppression. Unlike previous models, this network both operates continuously without requiring any synaptic resets and generalizes to intervals it has not been trained on. We demonstrate this not only for uncorrelated random stimuli but also for images of real-world objects. Our work suggests a biologically plausible mechanism for continual learning, and demonstrates an effective application of machine learning for neuroscience discovery.
Dihydropyrimidinase-like 2 (DPYSL2) regulates breast cancer migration via a JAK/STAT3/vimentin axis
Authors: Rmaileh Areej Abu , Solaimuthu Balakrishnan , Yosef Michal Ben , Khatib Anees , Lichtenstein Michal , Tanna Mayur , Hayashi Arata , Pillar Nir , Shaul Yoav D.
Published: March 2021

The intricate neuronal wiring during development requires cytoskeletal reorganization orchestrated by signaling cues. Considering that cytoskeletal remodeling is a hallmark of cell migration, we inquired whether metastatic cancer cells exploit the axon guidance proteins to migrate. Indeed, in breast cancer patients, we found a significant correlation between the mesenchymal markers and the expression of dihydropyrimidinase-like 2 (DPYSL2), a regulator of cytoskeletal dynamics in growing axons. Strikingly, DPYSL2 knockout in mesenchymal-like cells profoundly inhibited cell migration, invasion, stemness features, tumor growth rate, and metastasis. Next, we aimed to decode the molecular mechanism underlying this phenomenon and revealed an interaction between DPYSL2 and Janus kinase 1 (JAK1). This binding is crucial for triggering signal transducer and activator of transcription 3 (STAT3) and subsequently expressing vimentin, the pro-migratory intermediate filament. Collectively, we identified DPYSL2 as a molecular link between oncogenic signaling pathways and cytoskeletal reorganization in migrating breast cancer cells.

Statement of significance

This study shows that the axon guidance adaptor protein DPYSL2 is essential for promoting breast cancer migration. Specifically, this protein interacts with JAK1 to govern STAT3 signaling and subsequently vimentin expression.
SMARCA4 regulates spatially restricted metabolic plasticity in 3D multicellular tissue
Authors: Cermakova Katerina , Smith Eric A. , Chan Yuen San , Cabrera Mario Loeza , Chambers Courtney , Jarvis Maria I. , Simon Lukas M. , Xu Yuan , Jain Abhinav , Putluri Nagireddy , Chen Rui , Ripley R. Taylor , Veiseh Omid , Hodges H. Courtney
Published: March 2021

SWI/SNF and related chromatin remodeling complexes act as tissue-specific tumor suppressors and are frequently inactivated in different cancers. Although many regulatory activities of SWI/SNF have been identified using 2D cell culture, the effects of SWI/SNF alterations in more complex 3D tissues have remained poorly understood. Here we employed 3D cell culture conditions that yield transcriptomic states mirroring primary lung adenocarcinoma (LUAD) specimens better than 2D culture. By analyzing spatial patterns of gene expression and DNA accessibility in 3D spheroids using single-cell RNA-seq and ATAC-seq, we find that the SWI/SNF ATPase SMARCA4 (BRG1) induces state-specific changes to DNA accessibility that influence spatially heterogeneous expression patterns and metabolism. In 3D conditions, SMARCA4 promotes accessibility for AP-1 transcription factors, including ATF3, a regulator of metabolism and repressor of NRF2 antioxidant signaling. These changes reduce expression of SLC7A11 in a distinct portion of cells, which sensitizes A549 spheroids to cell death via ferroptosis under oxidizing conditions. Consistent with these results, we find that SMARCA4 alterations are associated with derepression of NRF2 targets in human tumors independently of NRF2/KEAP1 status. Our work reveals new 3D-specific features and unanticipated spatial complexity associated with chromatin remodeling in multicellular tissues.
Mapping T cell activation and differentiation at single cell resolution in naive hosts infected withPlasmodium vivax
Authors: Bach Florian A. , Muñoz Sandoval Diana , Mazurczyk Michalina , Themistocleous Yrene , Rawlinson Thomas A. , Kemp Alison , Silk Sarah E. , Barrett Jordan R. , Edwards Nick J. , Ivens Alasdair , Rayner Julian C. , Minassian Angela M. , Napolitani Giorgio , Draper Simon J. , Spence Philip J.
Published: March 2021

The biology ofPlasmodium vivaxis markedly different to that ofP. falciparum; how this shapes the immune response to infection remains unclear. To address this shortfall, we inoculated human volunteers with a clonal field isolate ofP. vivaxand tracked their response through infection and convalescence. High dimensional protein and RNA-seq data show thatP. vivaxtriggers an acute phase response that shares remarkable overlap with that ofP. falciparum, suggesting a hardwired emergency myeloid response that does not discriminate parasite species. We then used cytometry by time of flight to analyse the fate and function of innate-like and adaptive T cells; these data show thatP. vivaxcan activate up to one quarter of the entire T cell compartment. Heterogeneous effector memory-like CD4+T cells dominate this extraordinary response and phenotypic analysis reveals unexpected features of terminal differentiation that are normally associated with cytotoxicity and autoinflammatory disease. In line with this observation, we found that CD4+T cell activation coincides with collateral tissue damage and liver injury. Finally, comparative analyses demonstrate thatP. falciparumdrives T cell activation far in excess ofP. vivax, which may partially explain why falciparum malaria more frequently causes severe disease.
New Records of California Serogroup Virus inAedesMosquitoes and First Detection in Simulioidae Flies from Northern Canada and Alaska
Authors: Villeneuve Carol-Anne , Buhler Kayla J. , Iranpour Mahmood , Avard Ellen , Dibernardo Antonia , Fenton Heather , Hansen Cristina M. , Gouin Géraldine-G. , Loseto Lisa L. , Jenkins Emily , Lindsay Robbin L. , Dusfour Isabelle , Lecomte Nicolas , Leighton Patrick A.
Published: March 2021

An expected consequence of climate warming is an expansion of the geographic distribution of biting insects and associated arthropod-borne diseases (arboviruses). Emerging and reemerging arboviruses that can affect human health are likely to pose significant consequences for Northern communities where access to health resources is limited. In the North American Arctic, little is known about arboviruses. Thus, in 2019, we sampled biting insects in Nunavik (Kuujjuaq), Nunavut (Igloolik, Karrak Lake and Cambridge Bay), Northwest Territories (Igloolik and Yellowknife) and Alaska (Fairbanks). The main objective was to detect the presence of California serogroup viruses (CSGv) – a widespread group of arboviruses across North America and that is known to cause a wide range of symptoms, ranging from mild febrile illness to fatal encephalitis. Biting insects were captured twice daily for a 7-day period in mid-summer, using a standardized protocol consisting of 100 figure-eight movements of a sweep net. Captured specimens were separated by genus (mosquitoes) or by superfamily (other insects), and then grouped into pools of 75 by geographical locations. In total, 5079Aedesmosquitoes and 1014 Simulioidae flies were caught. We report the detection of CSGv RNA in mosquitoes captured in Nunavut (Karrak Lake) and Nunavik (Kuujjuaq). We also report, for the first time in North America, the presence of CSGv RNA in Simulioidae flies. These results highlight the potential of biting insects for tracking any future emergence of arboviruses in the North, thereby providing key information for public health in Northern communities.
A method for intuitively extracting macromolecular dynamics from structural disorder
Authors: Pearce Nicholas M. , Gros Piet
Published: March 2021

Macromolecular dynamics manifest as disorder in structure determination, which is subsequently accounted for by displacement parameters (also called temperature factors, or B-factors) or alternate conformations. Though B-factors contain detailed information about structural dynamics, they are the total of multiple sources of disorder, making them difficult to interpret and thus little-used in structural analysis. We report here an approach for decomposing molecular disorder into a parsimonious hierarchical series of contributions, providing an intuitive basis for quantitative structural-dynamics analysis. We demonstrate the decomposition of disorder on example SARS-CoV-2 and STEAP4 structures, from both crystallographic and cryo-electron microscopy data, and reveal how understanding of the macromolecular disorder leads to deeper understanding of molecular motions and flexibility, and suggests hypotheses for molecular mechanisms.