bluuebunny/crossref_metadata_2025_split huggingface dataset:
Discovery of small molecule guanylyl cyclase B receptor positive allosteric modulators
Authors: Ma Xiao , Peddibhotla Satyamaheshwar , Zheng Ye , Pan Shuchong , Mehta Alka , Moroni Dante G , Chen Qi-Yin , Ma Xiaoyu , Burnett John C , Malany Siobhan , Sangaralingham S Jeson 
Published: June 2024

Abstract
Myocardial fibrosis is a pathological hallmark of cardiovascular disease (CVD), and excessive fibrosis can lead to new-onset heart failure and increased mortality. Currently, pharmacological therapies for myocardial fibrosis are limited, highlighting the need for novel therapeutic approaches. The particulate guanylyl cyclase B (GC-B) receptor possesses beneficial antifibrotic actions through the binding of its natural ligand C-type natriuretic peptide (CNP) and the generation of the intracellular second messenger, cyclic guanosine 3′,5′-monophosphate (cGMP). These actions include the suppression of fibroblast proliferation and reduction in collagen synthesis. With its abundant expression on fibroblasts, the GC-B receptor has emerged as a key molecular target for innovative CVD therapeutics. However, small molecules that can bind and potentiate the GC-B/cGMP pathway have yet to be discovered. From a cell-based high-throughput screening initiative of the NIH Molecular Libraries Small Molecule Repository and hit-to-lead evolution based on a series of structure–activity relationships, we report the successful discovery of MCUF-42, a GC-B-targeted small molecule that acts as a positive allosteric modulator (PAM). Studies herein support MCUF-42's ability to enhance the binding affinity between GC-B and CNP. Moreover, MCUF-42 potentiated cGMP levels induced by CNP in human cardiac fibroblasts (HCFs) and notably also enhanced the inhibitory effect of CNP on HCF proliferation. Together, our findings highlight that MCUF-42 is a small molecule that can modulate the GC-B/cGMP signaling pathway, potentially enhancing the antifibrotic actions of CNP. Thus, these data underscore the continued development of GC-B small molecule PAMs as a novel therapeutic strategy for targeting cardiac fibrosis and CVD.
Double Citizenship as a Double-Edged Sword: Young Return Migrants’ Code-Switching for Belonging in Mexico
Authors: Ramírez Adriana P 
Published: June 2024

Abstract
In the past two decades, a growing number of Mexican migrants have left the United States to return to Mexico. Few studies have focused on the (re)integration process of these return migrants, especially children and young adults. Using semi-structured interviews, my study addresses this gap by asking how young return migrants adapt in Mexico and negotiate belonging in their communities. I argue that Mexican-U.S. dual citizenship is significant in Mexico in both a legal and cultural sense and operates as a type of double-edged sword—one that, on the one hand, provides youth with opportunities for advancement, but on the other, impedes cultural belonging. Young return migrants navigate this contradiction by learning to code-switch across different life stages and thus, selectively hiding and highlighting their U.S. ties to gain belonging and better economic opportunities. This article illuminates the ways that citizenship is an acquired and learned process that significantly marks the lives of return migrants.
Patient selection for nonoperating room anesthesia
Authors: Georgiadis Paige L. , Tsai Mitchell H. , Routman Justin S. 
Published: June 2024

Purpose of reviewGiven the rapid growth of nonoperating room anesthesia (NORA) in recent years, it is essential to review its unique challenges as well as strategies for patient selection and care optimization.Recent findingsRecent investigations have uncovered an increasing prevalence of older and higher ASA physical status patients in NORA settings. Although closed claim data regarding patient injury demonstrate a lower proportion of NORA cases resulting in a claim than traditional operating room cases, NORA cases have an increased risk of claim for death. Challenges within NORA include site-specific differences, limitations in ergonomic design, and increased stress among anesthesia providers. Several authors have thus proposed strategies focusing on standardizing processes, site-specific protocols, and ergonomic improvements to mitigate risks.SummaryConsidering the unique challenges of NORA settings, meticulous patient selection, risk stratification, and preoperative optimization are crucial. Embracing data-driven strategies and leveraging technological innovations (such as artificial intelligence) is imperative to refine quality control methods in targeted areas. Collaborative efforts led by anesthesia providers will ensure personalized, well tolerated, and improved patient outcomes across all phases of NORA care.
Opioid-free general anesthesia: considerations, techniques, and limitations
Authors: Shanthanna Harsha , Joshi Girish P. 
Published: June 2024

Purpose of review
To discuss the role of opioids during general anesthesia and examine their advantages and risks in the context of clinical practice. We define opioid-free anesthesia (OFA) as the absolute avoidance of intraoperative opioids.

Recent findings
In most minimally invasive and short-duration procedures, nonopioid analgesics, analgesic adjuvants, and local/regional analgesia can significantly spare the amount of intraoperative opioid needed. OFA should be considered in the context of tailoring to a specific patient and procedure, not as a universal approach. Strategies considered for OFA involve several adjuncts with low therapeutic range, requiring continuous infusions and resources, with potential for delayed recovery or other side effects, including increased short-term and long-term pain. No evidence indicates that OFA leads to decreased long-term opioid-related harms.

Summary
Complete avoidance of intraoperative opioids remains questionable, as it does not necessarily ensure avoidance of postoperative opioids. Multimodal analgesia including local/regional anesthesia may allow OFA for selected, minimally invasive surgeries, but further research is necessary in surgeries with high postoperative opioid requirements. Until there is definitive evidence regarding procedure and patient-specific combinations as well as the dose and duration of administration of adjunct agents, it is imperative to practice opioid-sparing approach in the intraoperative period.
Strategies for Minimizing the Effects of Observer Variability on Sagittal Parameter Measurements of the Spine
Authors: dos Santos Delgado Adimilson , Souza Morais Bruna , Luiz Aparecido Defino Helton , Neto Montagnoli Arlindo 
Published: June 2024

Study Design:
Exploratory-descriptive study.

Objective:
Evaluate the influence of observer variability on the measurements of both thoracic kyphosis (TK) and lumbar lordosis (LL) obtained with anatomic and functional spinal segmentation methods.

Background:
Parametric analysis for spinal surgery planning typically relies on anatomic parameters. However, incorporating functional parameters that consider the vertebrae orientation is important to minimizing surgical calculation errors.

Methods:
The authors developed parametric analysis software that integrates traditional and functional methodologies. The proposed method included functional thoracic kyphosis and functional lumbar lordosis calculated from the lines normal to the inflection points of the spine model. Using a synthetic lateral X-ray, the observer variability was computer-simulated generating 20 landmark sets that replicate the annotations of 20 observers. The analysis also included 10 clinical X-rays, annotated twice by 3 judges with a minimum 1-week interval. The spinal curvature angles were derived using the anatomic and functional methods. Statistical analysis were performed for comparison.

Results:
For the synthetic X-ray, the proposed method presented significantly less variability: TK (<±2.5 degrees, P=0.00023) and LL (<±5 degrees, P=0.00012). For the clinical X-rays, the interobserver reliability analysis yielded higher intraclass correlation coefficients (ICC) for functional TK (ICC>0.97) and functional LL (ICC>0.87) than for TK (ICC<0.91) and LL (ICC<0.89). Statistically significant differences were observed for both TK (P=0.001) and LL (P=0.030). Under the traditional method, observer variability led to measurement differences surpassing ±19 degrees, whereas differences with the proposed method were within ±10 degrees for both parameters.

Conclusion:
The vertebral endplate is not the most suitable place to measure spinal sagittal curvatures. Small changes in landmark position significantly alter the measured Cobb angle. The proposed method offers a substantial advantage regarding the influence of observer variability, in addition to the more individualized analysis.
To establish a prognostic model of epidermal growth factor receptor mutated non-small cell lung cancer patients based on Least Absolute Shrinkage and Selection Operator regression
Authors: Li Bowen , Zhang Xiaopeng 
Published: June 2024

Background
There is currently a shortage of effective diagnostic tools that are used for identifying long-term survival among non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. This research utilized the development of a prognostic model to assist clinicians in forecasting the survival over 24 months.

Methods
In Phase III and IV those patients who were diagnosed with EGFR mutation from January 2018 to June 2022 were enrolled into the lung cancer group of Thoracic Surgery Department of Hebei Provincial People’s Hospital. Long-run survival was stated as survival for 24 months after being diagnosed. A multivariate prognostic pattern was constructed by means of internal validation and binary logistic regression by bootstrapping. One nomogram was created with a view to boosting the explanation and applicability of the pattern.

Results
A total of 603 patients with EGFR mutation were registered. Elements linked to the whole survival beyond 24 months were age (OR 6.15); female (OR 1.79); functional status (ECOG 0–1) (OR 5.26); Exon 20 insertion mutation deletion (OR 2.08); No central nervous system metastasis (OR 2.66), targeted therapy (OR 0.43); Immunotherapy (OR 0.24). The model has good internal validation.

Conclusion
Seven pretreatment clinicopathological variables predicted survival over 24 months. That pattern owns a great discriminative capability. It is hypothesized that this pattern is capable of assisting in selecting the optimal treatment sequence for NSCLC patients with EGFR mutations.
Melanocytic Nevus With Spindle Cell Lipomatous Metaplasia
Authors: Urso Carmelo 
Published: June 2024

Abstract:
Melanocytic nevi can show a great number of morphological, cytoarchitectural, and stromal variations. Some of these histopathological patterns, infrequent or unusual, can occasionally produce diagnostic doubts or problems. A 22-year-old female patient presented a poorly pigmented cutaneous polypoid lesion of the scalp. Histopathological examination showed an intradermal melanocytic nevus composed of aggregates, nests, and cords of benign melanocytes, with collagenous stroma and large lipomatous areas. In the lipidized portion of the lesion, nevus cells, arranged in clusters, nests, and cords, were intimately associated with mature-appearing adipocytes, CD34-positive spindle cells, Alcian Blue–positive fibromyxoid stroma, and eosinophilic collagen bundles, findings resembling those typically seen in spindle cell lipoma. Spindle cell lipomatous metaplasia, rarely observed in some benign nonmelanocytic skin lesions, can be considered an additional unusual, not previously described, stromal variation occurring in melanocytic nevi.
Immunoexpression Patterns of Adhesion Molecules (E-cadherin, β-catenin, CD56) and Cytokeratins (CK19, CK20, HMWCK, CAM5.2) During Hair Development in Human Fetuses Compared With Adults
Authors: Zorlu Özge , Karabağ Sevil , Erdoğan Kıvılcım E. , Aksın Merve , Üstün Batuhan 
Published: June 2024

Abstract:
Abnormalities in the expression of cytokeratins or adhesion molecules have been associated with hair disorders. The expression patterns of these molecules in the hair follicles of developing human fetuses are not obvious. We aimed to investigate the expression patterns of some cytokeratins and adhesion molecules in the hair follicle of human fetuses and compared them with adults. Forty-eight fetuses of >16 gestational weeks and 22 adult cases with total excisions of benign nevi or cysts were enrolled. The skin samples were taken from both the scalp and back of the fetuses. The histopathologically normal skin areas were evaluated in adults. CK19, CK20, CAM5.2, high-molecular-weight cytokeratin, E-cadherin, β-catenin, and CD56 immunohistochemical stainings were performed. In the fetus group, the staining scores declined in the third trimester but elevated and reached the highest level in adults, except for CD56, which did not stain any adult samples. All stainings were mostly observed in the outer root sheath, except CD56 that stained the perifollicular dermal sheath only in fetuses. E-cadherin, β-catenin, and high-molecular-weight cytokeratin strongly and diffusely stained all adult samples. CAM5.2 and CK19 scores were correlated in fetuses (scalp scores: rs = 0.405, P = 0.004; back scores: rs = 0.422, P = 0.003) and adults (back scores: rs = 0.562, P = 0.046). CD56 negativity indicated the immune-privilege feature of adult hair follicles. As CK19, CAM5.2 may be used to find the regions of stem cells or transient amplifying cells.
Cutaneous Seeding of Glioblastoma: A Case Report and Literature Review
Authors: Knittel Ronan , Rogers Sasha , Wood Benjamin A. 
Published: June 2024

Abstract:
We present the case of a 61-year-old male patient with a history of intracranial IDH-wildtype glioblastoma with an isolated cutaneous metastasis within the previous surgical site scar. The cytomorphology of the cutaneous deposits was reminiscent of metastatic melanoma, which is a differential diagnostic pitfall. The tumor molecular characteristics are described, as these have become essential diagnostic criteria for many central nervous system tumors, along with a discussion of the role of immunohistochemical markers and potential pitfalls in the differential diagnosis of melanoma and poorly differentiated carcinoma. We discuss the biology of metastatic glioblastoma and provide a focused literature review of previous glioblastomas with tumor cell seeding within prior surgical scars.
Acute Interstitial Inflammation on Skin Biopsies and Positive Tissue Cultures in Cellulitis Patients Are Associated a Worse Prognosis
Authors: Libson Karissa , Barba Johnny , Henning Ania , Fisher Kristopher , Kirven Rachel M. , Korman Abraham M. , Plaza Jose A. , Kaffenberger Benjamin H. , Chung Catherine 
Published: June 2024

Background:
Cellulitis is a significant public health burden and lacks a gold standard for diagnosis. Up to 1/3 of patients are incorrectly diagnosed. The skin biopsy has been proposed as the gold standard.

Objective:
In this study, we evaluate the histopathologic characteristics and tissue culture positivity of biopsies in patients diagnosed with cellulitis seen by our inpatient dermatology consultation service.

Methods:
This retrospective cohort study examined patients who were hospitalized with a skin and soft tissue infection at our institution between 2011 and 2020 and underwent a skin biopsy.

Results:
Those with a positive tissue culture were more likely to die within 30 days compared with those with negative tissue cultures (26% vs. 6%, P = 0.048). Patients who died within 30 days were more likely to have acute interstitial inflammation as a feature on histopathology (38%, P = 0.03).

Limitations:
Single institutional design, unintentional exclusion of patients with organism-specific diagnosis, and selection for a medically complex patient population because of the nonroutine collection of biopsies.

Conclusion:
Positive tissue cultures and histopathology showing acute interstitial space inflammation on skin and soft tissue infection (SSTI) biopsies are associated with increased mortality and thus may serve as indicators of poor prognosis.
Nutrition during noninvasive respiratory support
Authors: Singer Pierre , Robinson Eyal , Hellerman-Itzhaki Moran 
Published: June 2024

Purpose of review
The use of noninvasive techniques [noninvasive ventilation (NIV) or high flow nasal cannula (HFNC) oxygen therapy] to support oxygenation and/or ventilation in patients with respiratory failure has become widespread, even more so since the coronavirus disease 2019 pandemic. The use of these modalities may impair the patient's ability to eat. “To breath or to eat” may become a dilemma. In this review, we identify the patients at risk of malnutrition that require medical nutritional therapy and understand the mechanisms of function of the devices to better give adapted nutritional indications for noninvasive ventilation or high flow nasal cannula.

Recent findings
The Global Leadership Initiative for Malnutrition has been validated in the Intensive Care setting and can be used in patients requiring NIV. Many patients are underfed when receiving noninvasive ventilation therapies. HFNC may impair the swallowing ability and increase dysphagia while NIV may improve the swallowing reflexes. New technology preventing reflux and ensuring enteral feeding efficacy may increase the medical nutrition therapy safety and provide near-target energy and protein provision.

Summary
The patient requiring noninvasive ventilation presents one of the most challenging nutritional challenges. The main steps to improve nutrition administration are to assess nutritional status, evaluate the presence of dysphagia, choose the most adequate tool of respiratory support, and adapt nutritional therapy (oral, enteral, or parenteral) accordingly.
What Did the Ideal Beauty of the 15th Century Look Like? An Anthropometric Analysis of Botticelli Portraits
Authors: Jung Sung Gyun , Kim Hun , Hwang Kun , Hwang Young Joong 
Published: June 2024

The aim of this study was to conduct an anthropometric analysis of the 5 portraits painted by Botticelli that depict Simonetta Vespucci. Five images in the Simonetta series by Botticelli workshop were measured. The anthropometric measurements of the face included 22 parameters on the lateral view (in 4 portraits; 18 distances and 4 angles) and 17 distances on the frontal view (in one portrait), which were measured using Adobe Photoshop. The absolute distances were calculated relative to the vertical corneal diameter (10.6 mm), which was calculated by multiplying the distance from the pupil’s center to the lower margin of the iris. In the lateral faces, the nasofrontal angle (g-n-prn) was 157.6±2.4 degrees, and the nasal tip angle (n-prn-sn) was 99.7±3.4 degrees. The nasolabial angle (prn-sn-ls) was 125.7±4.9 degrees, and the labiomental angle (li-sl-pg) was 131.6±4.4 degrees. The ratio of the upper lip height to the lower lip height (sn-sto/sto-sl) was 85.4±9.0%. The ratio of the upper lip vermillion to the upper lip height (ls-sto/sn-sto) was 27.7±3.9%. The ratio of the lower lip vermillion to the lower lip height (sto-li/sto-sl) was 47.2±6.6%. Comparing the data with 21st-century Italian females, forehead II height (tr-n), physiognomical face height (tr-gn), and morphologic face height (n-gn) of the beauties of the 15th century were significantly greater than those of 21st-century Italian females. However, there were no significant differences in lower face height (sn-gn) and nose height (n-sn). Considering the ongoing cultural relevance of Renaissance art, the esthetic proportions from this study may have reflection to the present day plastic surgery.
Comprehensive single cell transcriptomics analysis of murine osteosarcoma uncoversSkp2function in metastasis, genomic instability and immune activation and reveals additional target pathways
Authors: Ferrena Alexander , Zhang Ranxin , Wang Jichuan , Zheng Xiang Yu , Göker Barlas , Borjihan Hasibagan , Chae Sung-Suk , Lo Yungtai , Zhao Hongling , Schwartz Edward , Loeb David , Yang Rui , Geller David , Zheng Deyou , Hoang Bang 
Published: June 2024

ABSTRACTOsteosarcoma (OS) is the most common primary pediatric bone malignancy. One promising new therapeutic target isSKP2, encoding a substrate recognition factor of the SCF E3 ubiquitin ligase responsible for ubiquitination and proteasome degradation of substrate p27, thus driving cellular proliferation. We have shown previously that knockout ofSkp2in an immunocompetent transgenic mouse model of OS improved survival, drove apoptosis, and induced tumor inflammation. Here, we applied single-cell RNA-sequencing (scRNA-seq) to study primary OS tumors derived from Osx-Cre driven conditional knockout ofRb1andTrp53. We showed that murine OS models recapitulate the tumor heterogeneity and microenvironment complexity observed in patient tumors. We further compared this model with OS models with functional disruption ofSkp2: one withSkp2knockout and the other with the Skp2-p27 interaction disrupted (resulting in p27 overexpression). We found reduction of T cell exhaustion and upregulation of interferon activation, along with evidence of replicative and endoplasmic reticulum-related stress in theSkp2disruption models, and showed that interferon induction was correlated with improved survival in OS patients. Additionally, our scRNA-seq analysis uncovered decreased activities of metastasis-related gene signatures in theSkp2-disrupted OS, which we validated by observation of a strong reduction in lung metastasis in theSkp2knockout mice. Finally, we report several potential mechanisms of escape from targetingSkp2in OS, including upregulation ofMyctargets, DNA copy number amplification and overexpression of alternative E3 ligase genes, and potential alternative lineage activation. These mechanistic insights into OS tumor biology andSkp2function suggest novel targets for new, synergistic therapies, while the data and our comprehensive analysis may serve as a public resource for further big data-driven OS research.
STRAIGHTMORPH: A Voice Morphing Tool for Research in Voice Communication Sciences
Authors: Belin P , Kawahara H 
Published: June 2024

AbstractThe purpose of this paper is to make easily available to the scientific community an efficient voice morphing tool called STRAIGHTMORPH and provide a short tutorial on its use with examples. STRAIGHTMORPH consists of a set of Matlab functions allowing to generate high-quality, parametrically-controlled morphs of an arbitrary number of voice samples. A first step consists in extracting an ‘mObject’ for each voice sample, with accurate tracking of the fundamental frequency contour and manual definition of Time and Frequency anchors corresponding across samples to be morphed. The second step consists in parametrically combining the mObjects to generate novel synthetic stimuli, such as gender, identity or emotion continua, or random combinations. Although STRAIGHTMORPH has been designed for human voices it can work well with other types of sounds such as non-human primate vocalizations.