bluuebunny/crossref_metadata_2025 huggingface dataset:
Diastolic Dysfunction and Atrial Fibrillation: Recognition, Interplay, and Management
Authors: Hadid Somar , Hajj Mahmoud El , Hadid Bana , Siddiqui Zoya , Wang Andy , Frishman William H. , Aronow Wilbert S.
Published: May 2024

Diastolic dysfunction occurs when the left ventricle loses its ability to relax normally, impairing ventricular filling during diastole. This most commonly occurs as a pathological sequela of left ventricular hypertrophy and remodeling due to chronic hypertension and/or age-related sclerotic changes of the aortic valve. This can subsequently deteriorate to diastolic heart failure or heart failure with preserved ejection fraction. There is a substantive interplay between atrial fibrillation and diastolic dysfunction, as atrial fibrillation can cause, exacerbate, or be a direct result of diastolic dysfunction and vice versa. In this review, we first independently define diastolic heart failure and atrial fibrillation while discussing the diagnostic guidelines, which encompass various modalities such as medical history, electrocardiography, echocardiography, and laboratory tests. We subsequently examine their interplay and pathophysiological links drawing on recent evidence in the literature. Finally, we discuss management approaches, including pharmacological interventions targeting rate and rhythm control, diuretics, and addressing comorbidities.
Effect of Training Backgrounds on Plastic Surgery Leadership: A Logistic Regression Analysis
Authors: Reddy Narainsai K. , Gutowski Kristof S. , Yau Alice , Lentskevich Marina A. , Aronson Sofia , Bajaj Anitesh , Weissman Joshua P. , Crawford Scott , Gosain Arun K.
Published: May 2024

Background:

Although career choices are often shaped by training and mentors, it is not clear how training backgrounds have influenced whether plastic surgeons pursue leadership positions. Analysis of these training pathways can serve as a key component of career planning for future leaders.

Methods:

The American Board of Plastic Surgery’s annual Newsletter to Diplomates was used to collate surgeons receiving board certification between 2002 and 2013. Online public profiles were used to collect training background data about each surgeon, including fellowship training, board certification year, MBA degree, otolaryngology or maxillofacial surgery training before commencing plastic surgery training, and leadership positions in surgery. A logistic multinomial regression was used to test the effect of training backgrounds on different types of leadership positions.

Results:

In total, 2190 plastic surgeons were included in the analysis. Factors increasing the probability of holding any type of position included fellowships in microsurgery, craniofacial, and hand; an international fellowship; multiple fellowships; a fellowship not otherwise specified; and MBA degree. Training background factors affected probabilities differently for each of the studied positions including chair/chief, vice chair/vice chief, program director, plastic surgery medical director, other institutional positions, and national society positions.

Conclusions:

Training backgrounds of plastic surgeons in leadership positions are multifaceted, involving a mix of intrinsic and extrinsic factors such as additional educational pursuits, subspecialty training, duration of practice, and practice setting. This analysis can help direct current trainees who aspire to future leadership in plastic surgery.
36-year Follow-up on Scalp Reconstruction Using Free Latissimus Dorsi Muscle Flap, Skin Grafting, and Scalp Expansion
Authors: Ghorbani Nourollah B.
Published: May 2024

Background:

Immediate coverage of a large area of exposed skull is the first step in reconstructing a major scalp loss. In the 1970s, the free omental flap was used for scalp reconstruction, replacing removal of the external table and skin grafting only. Introduction of flaps and expanders has revolutionized reconstruction of major scalp losses. A free muscle flap is used to cover the exposed skull. Skin graft covers the muscle flap, and next, the expanded scalp is used to restore the scalp to its original shape. In certain cases, a hair transplant could help create a more natural hairline.

Methods:

In this case, in 1987, a free latissimus dorsi muscle flap and skin grafting were used in a 27-year-old man with major scalp loss. The left latissimus dorsi muscle was harvested with its vascular pedicle intact. Left superficial temporal vessels were used as recipients. After complete healing of the free flap, scalp and forehead skin were expanded and used to restore the scalp to its preinjury shape.

Results:

Coverage of the exposed parietal skull with free latissimus dorsi muscle flap and skin graft was successful. Then, scalp tissue surrounding the defect and forehead skin were expanded and used to restore the scalp to its original shape.

Conclusions:

This 36-year follow-up in a patient who had major scalp reconstruction using free latissimus dorsi muscle and skin grafting followed by scalp and forehead expansion shows that this method provides an excellent and reliable long-term coverage for such an injury.
Meritus Health: Driving Data-Informed Decision-Making at Every Level
Authors: Critchfield Carly N. , Joshi Maulik S.
Published: May 2024

With so much data available, health system leaders are challenged with sifting through it all to find the most useful information for decision-making. Meritus Health implemented effective approaches to understand, use, and communicate large amounts of data to alleviate some of this burden. These processes include system-wide daily huddles, dashboards, and standardized communication write-ups.
Powering Up Data in the Service of Operational Excellence
Authors: Esposito, FACHE Tina
Published: May 2024

Harnessing the power of data is a necessary competency in fueling innovation, improving financial and clinical outcomes, and achieving operational excellence. It can be analyzed, visualized, dashboarded, and embedded into workflows seamlessly with very little technical expertise. Moreover, data can galvanize organizational culture with its neutrality, transparency, and portability. Using data to highlight qualitative evaluations, patient experiences, and employee performance can help validate perceptions and identify broader organizational opportunities. Yet useful data is frequently nonexistent, invalid, or insufficient. Moving from promise to realization requires reframing data management, as described here.
Effects of intestine-specific deletion of FGF15 on the development of fatty liver disease with vertical sleeve gastrectomy
Authors: Chow Monica D. , Otersen Katherine , Wassef Andrew , Kong Bo , Yamarthy Sowmya , Rizzolo Daniel , Yang Ill , Buckley Brian , Lu Alexander , Crook Naomi , Lee Matthew , Gao Judy , Naganand Sareena , Stofan Mary F. , Armstrong Laura , Schumacher Justin , Taylor Rulaiha , Henry Zakiyah , Basaly Veronia , Yang Zhenning , Zhang Min , Huang Mingxing , Kagan Leonid , Brunetti Luigi , Sadek Ragui , Lee Yi-Horng , Guo Grace L.
Published: May 2024

Background:

Vertical sleeve gastrectomy (SGx) is a type of bariatric surgery to treat morbid obesity and metabolic dysfunction–associated steatotic liver disease (MASLD). The molecular mechanisms of SGx to improve MASLD are unclear, but increased bile acids (BAs) and FGF19 (mouse FGF15) were observed. FGF15/19 is expressed in the ileum in response to BAs and is critical in not only suppressing BA synthesis in the liver but also promoting energy expenditure. We hypothesized the reduction of obesity and resolution of MASLD by SGx may be mediated by FGF15/19.

Methods:

First, we conducted hepatic gene expression analysis in obese patients undergoing SGx, with the results showing increased expression of FGF19 in obese patients’ livers. Next, we used wild-type and intestine-specific Fgf15 knockout mice (Fgf15
ile−/−) to determine the effects of FGF15 deficiency on improving the metabolic effects.

Results:

SGx improved metabolic endpoints in both genotypes, evidenced by decreased obesity, improved glucose tolerance, and reduced MASLD progression. However, Fgf15
ile−/− mice showed better improvement compared to wild-type mice after SGx, suggesting that other mediators than FGF15 are also responsible for the beneficial effects of FGF15 deficiency. Further gene expression analysis in brown adipose tissue suggests increased thermogenesis.

Conclusions:

FGF15 deficiency, the larger BA pool and higher levels of secondary BAs may increase energy expenditure in extrahepatic tissues, which may be responsible for improved metabolic functions following SGx.
Ethanol disrupts hepatocellular lipophagy by altering Rab5-centric LD-lysosome trafficking
Authors: Schott Micah B. , Rozeveld Cody N. , Bhatt Saumya , Crossman Bridget , Krueger Eugene W. , Weller Shaun G. , Rasineni Karuna , Casey Carol A. , McNiven Mark A.
Published: May 2024

Background:

Previous reports suggest that lipid droplets (LDs) in the hepatocyte can be catabolized by a direct engulfment from nearby endolysosomes (microlipophagy). Further, it is likely that this process is compromised by chronic ethanol (EtOH) exposure leading to hepatic steatosis. This study investigates the hepatocellular machinery supporting microlipophagy and EtOH-induced alterations in this process with a focus on the small, endosome-associated, GTPase Rab5.

Methods and Results:

Here we report that this small Ras-related GTPase is a resident component of LDs, and its activity is important for hepatocellular LD-lysosome proximity and physical interactions. We find that Rab5 siRNA knockdown causes an accumulation of LDs in hepatocytes by inhibiting lysosome dependent LD catabolism. Importantly, Rab5 appears to support this process by mediating the recruitment of early endosomal and or multivesicular body compartments to the LD surface before lysosome fusion. Interestingly, while wild-type or a constituently active GTPase form (Q79L) of Rab5 supports LD-lysosome transport, this process is markedly reduced in cells expressing a GTPase dead (S34N) Rab5 protein or in hepatocytes exposed to chronic EtOH.

Conclusions:

These findings support the novel premise of an early endosomal/multivesicular body intermediate compartment on the LD surface that provides a “docking” site for lysosomal trafficking, not unlike the process that occurs during the hepatocellular degradation of endocytosed ligands that is also known to be compromised by EtOH exposure.
Evaluation of In-Brace Coronal and Sagittal Plane Measurements Between CAD/Chêneau-Style and Traditionally Fabricated Wilmington Braces in Adolescent Idiopathic Scoliosis
Authors: Asma Ali , Ulusaloglu Armagan Can , Bowen J. Richard , Yorgova Petya , Michalowski Heather , Lawall Harry J. , Mackenzie W.G. Stuart , Gabos Peter G. , Shah Suken A.
Published: May 2024

Introduction

Traditional thoracolumbosacral orthosis fabrication involves truncal casting (traditionally fabricated [TF] Wilmington brace [WB]), whereas the newer Chêneau-style brace (computer-aided design [CAD]) involves three-dimensional truncal scanning technology. We sought to evaluate how these two brace styles affect the position of the spine in the coronal and sagittal plane.

Materials and Methods

Inclusion criteria included adolescent idiopathic scoliosis treated with WB or CAD Chêneau-style brace, major curve Cobb angle 20°–45°, age 10–15 years, Risser 0–3, and radiographs (prebrace and in-brace posteroanterior and lateral). Analysis included 28 CAD Chêneau-style braces and 56 WB patients.

Results

There was no difference between groups regarding age, sex, body mass index, major curve location, major curve degree, sagittal plane curvature, and pelvic parameters. In-brace analysis demonstrated decreased sagittal plane curvatures and increased T1 pelvic angle in both groups; both had significantly reduced major curve correction. Coronal plane major curve correction ratio of the two groups was similar (P = 0.236). In the CAD Chêneau-style brace group, the thoracolumbar junction became more kyphotic (P = 0.03). In the WB group, both coronal balance and thoracic trunk shift were leftward (P = 0.001). Both groups had a significant increase in T1 pelvic angle, but this increase was higher in the CAD Chêneau-style brace group (P = 0.045).

Conclusions

Both braces exert a flattening effect on the spine and positive global sagittal balance. Coronal plane major curve correction was similar for both groups. Coronal plane trunk shift and C7 coronal balance were significantly changed leftward after WB application. Kyphotic thoracolumbar transition and forward tilt of the spine (T1 pelvic angle) were significantly greater in CAD Chêneau-style brace than WB.

Clinical Relevance

A Chêneau-style brace fabricated with CAD/computer-aided manufacturing technology can produce a brace comparable to one fabricated by traditional methods using cast molding.
Napsin A Immunoreactivity in “Hobnail” Epithelium in Benign Endometrial and Endocervical Polyps
Authors: Al-Hussaini Maysa , Talia Karen L. , McCluggage W. Glenn
Published: May 2024

Endometrial and endocervical polyps not uncommonly exhibit focal benign “hobnail” change/metaplasia within the glandular epithelium, sometimes in association with inflammation or infarction. In most cases, this is readily recognized as benign but occasionally, especially in endometrial polyps, this change prompts consideration of a premalignant or malignant lesion, including early serous or clear cell carcinoma. Herein we highlight the previously unreported phenomenon of positive staining of this hobnail epithelium with Napsin A which has the potential to exacerbate concern for clear cell carcinoma. Endometrial (n = 22) and endocervical (n = 17) polyps showing hobnail change were stained with Napsin A. Six cases were positive (4 of 22 endometrial and 2 of 17 endocervical polyps). In all cases, Napsin A positivity was confined to the hobnail epithelium. The hobnail epithelium was positive with estrogen receptor and hepatocyte nuclear factor 1- beta and exhibited wild-type immunoreactivity with p53 in all cases where these markers were performed. In addition, in 2 of 3 uterine adenosarcomas with focal hobnail change the epithelium was Napsin A positive. Pathologists should be aware that Napsin A may be expressed in benign/reactive hobnail epithelium in endometrial and endocervical polyps and should not consider positivity with this marker as a diagnostic of clear cell carcinoma.
Prepectoral Breast Reconstruction Prompts Revisiting the Anatomical Boundaries of the Breast: A Radiographic and Cadaveric Study
Authors: Dassoulas Kasandra R. , Ndem Idorenyin , Holland Michael , Chou Jesse , Schroen Anneke T. , Campbell Chris A.
Published: May 2024

Background:

This study aimed to determine the location of superficial fascial system condensations in relation to classic anatomical breast boundaries. Cadaveric studies have provided some understanding, but knowledge about the precise location of these condensations remains limited.

Methods:

Preoperative breast magnetic resonance imaging (MRI) was conducted to assess the fascial condensations defining the breast footprint relative to landmarks such as the latissimus, clavicle, sternal border, and inframammary fold. Concurrently, cadaveric mastectomies were performed to measure the breast borders in relation to these landmarks for comparison.

Results:

A total of 290 breasts underwent preoperative MRI. Eight cadaveric breast dissections were completed. Radiographically, the lateral breast fascial condensation was 3.9 cm medial to the latissimus dorsi, whereas cadaveric measurements were 4.5 cm. The medial condensation was 2.1 cm lateral to the sternal border radiographically and 4.8 cm to the midline in cadavers. The superior fascial condensation was 2.3 cm inferior to the clavicle radiographically and 5.5 cm by dissection. The inferior condensation was above the inframammary fold in 82.7% of breasts by MRI and 100% of cadaveric breasts. MRI and cadaveric investigation showed similar patterns of breast tissue fascial condensations relative to standard breast boundaries. Breast skin flap thickness was greater peripherally (MRI, 11.5 mm; cadaver, 11.1 mm) than centrally (MRI, 6.6 mm; cadaver, 5.5 mm).

Conclusions:

MRI and cadaveric analysis demonstrated a close correlation between the superficial fascial system and standard breast boundaries, although variations existed between subjects. Collaborating with breast oncologists and using preoperative imaging to identify individual fascial condensations may enhance the camouflage of prepectoral implants after mastectomy.
Dead Space - The Final Frontier in Rhinoplasty: Review and 10 Key Recommendations
Authors: Rohrich Rod J. , Payton Jesse , Rohrich Rachel , Fisher Sean M. , Borab Zachary M.
Published: May 2024

Mitigating dead space has been recognized as an essential step towards ensuring a more predictable and aesthetically pleasing outcome in rhinoplasty. The current body of literature leaves a discernible gap in offering a unified, systematic approach to dead space management in rhinoplasty. The aim of our article is to bridge this gap by presenting an integrative approach to surgical and post-surgical techniques.
pREBOA versus ER-REBOA impact on blood utilization and resuscitation requirements: A pilot analysis
Authors: Meyer Courtney H. , Beckett Andrew , Dennis Bradley M. , Duchesne Juan , Kundi Rishi , Pandya Urmil , Lawless Ryan , Moore Ernest , Spalding Chance , Vassy William M. , Nguyen Jonathan ,   The AAST AORTA Study Group
Published: May 2024

BACKGROUND

Partial occlusion of the aorta is a resuscitation technique designed to maximize proximal perfusion while allowing a graduated amount of distal flow to reduce the ischemic sequelae associated with complete aortic occlusion. The pREBOA-PRO catheter affords the ability to titrate perfusion as hemodynamics allows; however, the impact of this new technology for resuscitative endovascular balloon occlusion of the aorta (REBOA) on blood use and other resuscitative requirements is currently unknown. We hypothesize that patients undergoing REBOA with the pREBOA-PRO catheter will utilize partial occlusion, when appropriate, and decrease overall resuscitative requirements when compared to patients undergoing REBOA with the ER-REBOA catheter.

METHODS

The entire American Association for the Surgery of Trauma Aortic Occlusion for Resuscitation in Trauma and Acute Care Surgery registry was used to compare resuscitation requirements between all ER-REBOA and pREBOA. Unpaired t tests were used to compare resuscitation strategies including packed red blood cells (PRBCs), fresh frozen plasma (FFP), platelets, cryoprecipitate, crystalloids, and need for pressors.

RESULTS

When comparing ER-REBOA (n = 800) use to pREBOA (n = 155), initial patient presentations were similar except for age (44 years vs. 40 years, p = 0.026) and rates of blunt injury (78.4% vs. 78.7% p < 0.010). Zone 1 occlusion was used less often in ER-REBOA (65.8 vs. 71.7, p = 0.046). Partial occlusion was performed in 85% of pREBOA compared with 11% in ER-REBOA (p < 0.050). Vitals at the time of REBOA were worse in ER-REBOA and received significantly more units of PRBCs, FFP, platelets, and liters of crystalloids than pREBOA (p < 0.05). Rates of ARDS and septic shock were lower in pREBOA (p < 0.05).

CONCLUSION

When comparing pREBOA to ER-REBOA, there has been a rise in Zone 1 and partial occlusion. In our pilot analysis of the Aortic Occlusion for Resuscitation in Trauma and Acute Care Surgery registry, there was a reduction in administration of PRBCs, FFP, platelets, and crystalloids. Although further prospective studies are required, this is the first to demonstrate an association between pREBOA, partial occlusion, and reduced blood use and resuscitative requirements.

LEVEL OF EVIDENCE

Therapeutic/Care Management; Level IV.
Analysis of ECMO Outcomes in Patients with Known Adrenal Insufficiency: Insights from the National Inpatient Sample Database
Authors: Randhawa Aastha , Jana Kundan , Sattar Moin
Published: May 2024

Adrenal crises occur due to either a complete lack or an insufficient amount of cortisol and are usually triggered by stressors like infections, trauma, surgical interventions, and dental procedures. The physiological changes associated with major surgery are well-studied stressors linked to adrenal crisis. Extracorporeal membrane oxygenation (ECMO), a strategy employed to assist with circulatory support and gas exchange, is also a significant physiologically demanding stressor to the human body. In this study, we retrospectively assess the incidence and outcomes of patients with adrenal insufficiency who were cannulated for extracorporeal membrane oxygenation (ECMO) using the National Inpatient Sample (NIS) database. Patients who were cannulated for ECMO from 2016 to 2020 were identified and divided into two cohorts depending on the presence or absence of adrenal insufficiency. The two groups were compared for the primary outcome of inpatient mortality and secondary outcomes including rates of LVAD, heart transplant, lung transplantation, stroke, GI bleed, and renal failure.

In our study, we found that mortality rates between the two groups were similar. All-cause inpatient mortality was 45% in both groups (p>0.9). We found no differences in the rates of heart transplantation, lung transplantation, or LVAD implantation between patients with and without adrenal insufficiency. We additionally find that mortality rates in our study mirror those from dedicated ECMO registries, further lending credence to our findings. Our study discusses important findings from a relatively understudied disease process, based on a large and representative population from multiple centers across the country.
Multiomics reveals gut dysbiosis links to fatty acid dysmetabolism in early phase of acute myocardial infarction
Authors: Ying Jiajun , Fan Yong , Huangfu Ning , He Kewan , Hu Teng , Su Pengpeng , Hu Xintao , He Hequn , Liang Wei , Liu Junsong , Cheng Jinsong , Wang Shiqi , Zhao Ruochi , Mao Hengyi , He Fuwei , Su Jia , Zhou Honglin , Li Zhenwei , Fei Xiaohong , Sun Xiafei , Wang Peipei , Guan Minfang , Du Weiping , Lin Shaoyi , Wang Yong , Yang Fangkun , Fang Renyuan , Kong Ziqing , Chen Xiaomin , Cui Hanbin ,   Jiajun Ying and Yong Fan contributed equally to this work
Published: May 2024

Background

Acute myocardial infarction (AMI) remains a major cause of death, with limited understanding of its early risk stratification. While gut microbiome disturbances has been associated with late-stage AMI, the connection to early-stage AMI (eAMI) is less explored.

Methods

Using metabolomics and metagenomics, we analyzed 56 samples, comprising 30 eAMI patients (within 12 hours of onset) and 26 age- and gender-matched healthy controls, to discern the influence of gut microbes and their metabolites.

Results

We found the eAMI plasma is dominated by increased long-chain fatty acids (LCFAs), 14 of which provide differentiating power of eAMI patients from HCs. Multiomics analysis reveals up to 70% of the variance in LCFAs of eAMI patients can be explained by altered gut microbiome. Higher-resolution profiling of gut bacterial species demonstrated that bacterial structural variations are mechanistically linked to LCFAs dysregulation. Byin silicomolecular docking andin vitrothrombogenic assay in isolated human platelets, we highlighted that eAMI-associated LCFAs contribute to platelet aggregation, a driving factor for AMI initiation.

Conclusions

LCFAs hold significant potential as early biomarkers of AMI and gut microbiome contributes to altered LCFAs in eAMI. Further studies are imperative to expand upon these observations to better leverage LCFAs as a potential biomarker for eAMI and as a therapeutic target for inhibition of platelet aggregation in eAMI.
Time to Hyperkalemia and Other Outcomes Post-Implementation of the 2021 CKD-EPI Creatinine Equation: An Observational Cohort Study
Authors: Baker Charlotte , Cartwright Brianna M Goodwin , Gratzl Samuel , Do Duy , Rodriguez Patricia J , Simonov Michael , Stucky Nicholas
Published: May 2024

Background Timely diagnosis can delay progression to poor clinical outcomes and biomarker endpoints in CKD. Our objective was to analyze how the implementation of the 2021 CKD-EPI Creatinine Equation (CKD-EPI 2021) affected time to the doubling of serum creatinine, prescription or dispense of potassium-lowering drugs, hyperkalemia, and creation of arteriovenous graft fistula for dialysis within one year of CKD diagnosis. Methods We used retrospective EHR data to create two cohorts of adult patients based on date of diagnosis. We followed patients from their CKD diagnosis to the occurrence of each outcome, their last medical encounter, or 1-year post diagnosis, whichever occurred first. The first cohort was diagnosed in 2021 when the CKD-EPI 2009 Creatinine Equation (pre-update cohort) was recommended. The second cohort was diagnosed in 2022 when CKD-EPI 2021 (post-update cohort) was recommended. Multivariable models for the time relationship between cohort and each outcome were adjusted for demographics, social determinants of health, and comorbidities. As CKD-EPI 2021 was race-free, we also considered the interaction between cohort and race. Results We found 261,774 patients with a first-time CKD diagnosis. After implementation of CKD-EPI 2021, patients were less likely to have a diagnosis of hyperkalemia, potassium-lowering drug prescription, a doubling of serum creatinine, or an arteriovenous graft fistula placement within a year of CKD diagnosis. Black patients in the post-update cohort were less likely to be diagnosed with hyperkalemia compared to Black patients in the pre-update cohort (AHR 0.83; CI 0.80, 0.86), but Black patients overall were significantly more likely than non-Black patients to have hyperkalemia. Conclusions Time to poor clinical outcomes and biomarkers differs by the date of CKD diagnosis. Future work should elucidate the mechanisms driving these differences, whether there have been significant changes in treatment practices since the CKD-EPI 2021 recommendation, and long-term effects of each outcome.
Characterizing interactions of ER resident proteins in situ through the YST-PPI method
Authors: Fan Xian , He Huahua , Wang Ting , Xu Pan , Zhang Faying , Hu Shantong , Yun Yueli , Mei Meng , Zhang Guimin , Yi Li
Published: May 2024

The mutual interactions of ER resident proteins in the ER maintain its functions, prompting the protein folding, modification, and transportation. Here, a new method, named YST-PPI (YESS-based Split fast TEV protease System for Protein-protein Interaction) was developed, targeting the characterization of protein interactions in ER. YST-PPI method integrated the YESS system, split-TEV technology and endoplasmic reticulum retention signal peptide (ERS) to provide an effective strategy for studying ER in situ PPIs in a fast and quantitative manner. The interactions among 15 ER resident proteins ofS. cerevisiaewere explored using the YST-PPI system, and their interaction network map was constructed, in which more than 74 interacting resident protein pairs were identified. Our studies also showed that Lhs1p plays a critical role in regulating the interactions of most of the ER resident proteins, expect the Sil1p, indicating its potential role in controlling the ER molecular chaperones. Moreover, the mutual interaction revealed by our studies further confirmed that the ER resident proteins perform their functions in a synergetic way and multimer complex might be formed during the process.
Hemoglobin as a peroxidase and drug target for oxidative stress-related diseases
Authors: Won Woojin , Lee Elijah Hwejin , Gotina Lizaveta , Chun Heejung , Lee Jae-Hun , Park Uiyeol , Kim Daeun , Kim Tai Young , Choi Jiwon , Kim Yoowon , Park Sun Jun , Bhalla Mridula , Lim Jiwoon , Park Jong-Hyun , Oh Soo-Jin , Ryu Hoon , Pae Ae Nim , Park Ki Duk , Lee C. Justin
Published: May 2024

Summary paragraph

Hemoglobin (Hb) is well-known for transporting oxygen in red blood cells within blood vessels1. Although Hb is also present in the brain2, its role remains poorly understood. Here, we show that Hb, found in astrocytes of neurodegenerative animal models and patients, displays significant antioxidant effects through its H2O2-decomposing peroxidase activity, and a small molecule enhancer boosts this activity, reducing aberrant H2O2and mitigating H2O2-induced neurodegeneration. To counteract the harmful effects of aberrant H2O2-production in Alzheimer’s disease (AD), we developed KDS12025, a blood-brain barrier (BBB)-permeable small molecule that effectively enhances the peroxidase activity of Hb by a hundredfold, especially at a low level of Hb. KDS12025 and its analogs achieve this enhancement through its electron-donating amine group. KDS12025 reduces H2O2levels in astrocytes, exhibits neuroprotective effects, and reverses memory impairment in AD models. Gene-silencing of Hbβ abrogates KDS12025’s impact in both culture and animal models of AD. Moreover, KDS12025 prevented the death of dopaminergic neurons in a Parkinson’s disease (PD) model without altering the oxygen-transporting function of Hb. KDS12025 extended survival and improved motor function even in the severe amyotrophic lateral sclerosis (ALS) mouse model. Our findings propose Hb as a new therapeutic target for neurodegenerative diseases, with KDS12025 emerging as a first-in-class drug candidate that enhances Hb’s peroxidase activity to reduce H2O2. Boosting Hb’s peroxidase activity with KDS12025 mitigates oxidative stress and alleviates neurodegeneration in AD, PD, and ALS with broad applicability for numerous oxidative-stress-driven diseases.
Leukemia inhibitory factor (LIF) receptor amplifies pathogenic activation of fibroblasts in lung fibrosis
Authors: Nguyen Hung N. , Jeong Yunju , Kim Yunhye , Kim Yaunghyun H. , Athar Humra , Castaldi Peter J. , Hersh Craig P. , Padera Robert F. , Sholl Lynette M. , Vivero Marina , Sharma Nirmal S. , Yun Jeong , Merriam Louis T. , Yuan Ke , Kim Edy Y. , Brenner Michael B.
Published: May 2024

Fibrosis drives end-organ damage in many diseases. However, clinical trials targeting individual upstream activators of fibroblasts, such as TGFβ, have largely failed. Here, we target the leukemia inhibitory factor receptor (LIFR) as a “master amplifier” of multiple upstream activators of lung fibroblasts. In idiopathic pulmonary fibrosis (IPF), the most common fibrotic lung disease, we found that lung myofibroblasts had high LIF expression. Further, TGFβ1, one of the key drivers of fibrosis, upregulated LIF expression in IPF fibroblasts. In vitro anti-LIFR antibody blocking on human IPF lung fibroblasts reduced induction of profibrotic genes downstream of TGFβ1, IL-4 and IL-13. Further, siRNA silencing of LIFR in IPF precision cut lung slices reduced expression of fibrotic proteins. Together, we find that LIFR drives an autocrine positive feedback loop that amplifies and sustains pathogenic activation of IPF fibroblasts downstream of multiple external stimuli, implicating LIFR as a therapeutic target in fibrosis.

Significance Statement

Fibroblasts have a central role in the pathogenesis of fibrotic diseases. However, due to in part to multiple profibrotic stimuli, targeting a single activator of fibroblasts, like TGFβ, has not yielded successful clinical treatments. We hypothesized that a more effective therapeutic strategy is identifying a downstream “master amplifier” of a range of upstream profibrotic stimuli. This study identifies the leukemia inhibitory factor receptor (LIFR) on fibrotic lung fibroblasts amplifies multiple profibrotic stimuli, such as IL-13 and TGFβ. Blocking LIFR reduced fibrosis in ex vivo lung tissue from patients with idiopathic pulmonary fibrosis (IPF). LIFR, acting as a master amplifier downstream of fibroblast activation, offers an alternative therapeutic strategy for fibrotic diseases.
Inferring Single-Cell RNA Kinetics from Various Biological Priors
Authors: Chen Yanshuo , Hu Zhengmian , Ni Ke , Feng Site , Chen Wei , Huang Heng
Published: May 2024

In the context of transcriptional dynamics modeled by ordinary differential equations (ODEs), the RNA level in a single cell is controlled by specific RNA kinetics parameters, which include transcription rate, splicing rate, and degradation rate. Investigating these single-cell RNA kinetics rates is pivotal for understanding RNA metabolism and the heterogeneity of complex tissues. Although metabolic labeling is an effective method to estimate these kinetics rates experimentally, it is not suitable for current large-scale conventional single-cell RNA sequencing (scRNA-seq) data. Moreover, existing methods for scRNA-seq often either neglect certain specific kinetics parameters or use inappropriate ways to fit the parameters. To address these issues, we introduce scRNAkinetics, a parallelized method that fits the kinetics parameters of the ODE for each cell using pseudo-time derived from various biological priors (e.g. cell lineage tree and differentiation potential). This approach allows for the estimation of the relative kinetics of each cell and gene in a scRNA-seq dataset. Validated on simulated datasets, scRNAkinetics can accurately infer the kinetics rates of transcription boosting, multi-branch, and time-dependent RNA degradation systems. Nevertheless, the inferred kinetics trends are concordant with previous studies on metabolic labeling and conventional scRNA-seq datasets. Furthermore, we show that scRNAkinetics can provide valuable insights into different regulatory schemes and validate the coupling between transcription and splicing in RNA metabolism. The open-source implementation of scRNAkinetics is available athttps://github.com/poseidonchan/scRNAkinetics.
Morphological, physiological and metabolic responses of diverse barley inbreds to dry down and moderate drought stress
Authors: Shrestha Asis , König Tobias , Meikle Lena Adler , Westhoff Philipp , Erban Alexander , Stich Benjamin
Published: May 2024

Drought stress alters the metabolic activity, physiological processes, and plant growth and such responses might differ with the intensity of stress. We evaluated the genotypic diversity on plant morphology, photosynthetic responses, metabolite shift and their relationship in diverse barley inbreds under dry down (DD) and moderate drought (MD) stress using 23 genetically diverse parental inbreds of genetic mapping population of barley. MD stress caused a strong growth reduction, while DD stress triggered inhibition of photosynthetic health. We observed that the induced changes occurred in a genotype-dependent manner. Compared to control conditions, the metabolism of simple sugars and polyhydroxy acids increased in MD and DD, while the maximum accumulation of amino acid, lipids and phosphates occurred in DD stress. Accumulation of hexose and metabolites with unknown classification was the metabolic signature of drought tolerant inbreds. The inbreds tolerant to MD originated from the temperate regions while those tolerant to both MD and DD came from semi-arid regions. Low stomata density, reduced water loss and retarded growth under drought stress were the key features of inbreds with better survival capacity under severe dehydration. We identified drought tolerant barley inbreds and our study offers resources for future genetic research on various drought tolerance strategies.
Sex differences in olfactory behavior and neurophysiology in Long Evans Rats
Authors: Maheshwar Kruthika V , Stuart Abigail E. , Kay Leslie M.
Published: May 2024

In many species, olfactory abilities in females are more sensitive than those in males. Studies in humans show that women have lower olfactory thresholds and are better able to discriminate and identify odors than men. In mice, odorants elicit faster activation from a larger number of olfactory sensory neurons in females than males. Our study explores sex differences in olfaction in Long Evans rats from a behavioral and electrophysiological perspective. Local field potentials (LFPs) in the olfactory bulb (OB) represent the coordinated activity of bulbar neurons. Olfactory gamma (65-120 Hz) and beta (15-30 Hz) oscillations have been functionally linked to odor perception. Spontaneous and odor-evoked OB LFPs were recorded from awake rats at the same time for 12 days. Odors used included urine of both sexes and monomolecular odorants characterized previously for correlation of volatility with behavior and OB oscillations. Sampling duration, baseline gamma and beta power, and odor-elicited beta and gamma power were analyzed. We find that females sample odorants for a shorter duration than males (close to 1s difference). While baseline gamma and beta power do not show significant differences between the two sexes, odor-elicited gamma and beta power in females is significantly lower than in males. Neither sampling duration nor beta and gamma power in females varied systematically with day of estrus. We further verify that variance of these behavioral and physiological measures is not different across sexes, adding to growing evidence that researchers need not be concerned about often- claimed additional variance in female subjects.

New and Noteworthy

Olfaction plays a large role in evolutionary processes. However, we know little about sex differences in olfactory bulb neurophysiology, and many scientists believe that females are more variable due to estrus. We show that female rats sniff odors for shorter durations than males and have lower power in neural oscillations related to cognition. Estrus was not related to variance in any measures. Finally, males and females show equal variance on these behavioral and physiological processes.
Clearing truncated tau protein restores neuronal function and prevents microglia activation in tauopathy mice
Authors: Martín-Ávila Alejandro , Modak Swananda R. , Rajamohamedsait Hameetha B. , Dodge Andie , Shamir Dov B. , Krishnaswamy Senthilkumar , Sandusky-Beltran Leslie A. , Walker Marilyn , Lin Yan , Congdon Erin E. , Sigurdsson Einar M.
Published: May 2024

Tau protein truncated at aspartate 421 (Asp421) is a characteristic feature of Alzheimer’s disease (AD) and other tauopathies. It is likely to have a role in their pathogenesis by promoting tau aggregation. Here, using two tauopathy mouse models, we show that a monoclonal antibody against Asp421, 5G2, led to a) a 59-74% clearance of insoluble tau protein in the brains of JNPL3 tauopathy mice following a thirteen-week treatment period, b) a 46% decrease of tau levels in brain interstitial fluid immediately following a single dose of 5G2 as examined by brain microdialysis in awake JNPL3 mice, c) improved neuronal function and d) reduced microglial activation as determined by two-photon imaging in awake PS19 tauopathy mice, where we also found tau accumulation earlier than signs of microglial activation. For mechanistic insight using culture models, 5G2 prevented toxicity of AD brain-derived pathological tau protein, cleared intracellular tau, and prevented microgliosis. We also knocked down the intracellular Fc receptor and ubiquitin E3 ligase, TRIM21, and found a reduction in cellular retention of tau antibodies, which appeared to reduce the acute efficacy (24 h) of tau antibodies but not their longer-term efficacy (5 days). Overall, these findings strongly support the feasibility of targeting Asp421 truncated tau protein to treat tauopathies, indicate that tau-associated abnormalities of neuronal activity precede microglial activation and that antibody-mediated tau clearance via the TRIM21 pathway is mostly transient.
Phosphodiesterase 1A physically interacts with YTHDF2 and reinforces the progression of non-small cell lung cancer
Authors: Zhang Chong , Zhang Zuoyan , Wu Yueyi , Wu Yuchen , Cheng Jing , Luo Kaizhi , Li Zhidi , Zhang Manman , Wang Jian , Li Yangling
Published: May 2024

Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer, and the prognosis is poor due to distant metastasis. Thus, there is an urgent need to discover novel therapeutic targets and strategies to overcome metastasis. A series of in vitro and in vivo phenotype experiments were performed to investigate the role of PDE1A in NSCLC. The RIP assay, mRNA stability assay and LC-MS/MS were performed to investigate the molecular mechanisms of PDE1A in NSCLC progression. We demonstrated that phosphodiesterase 1A (PDE1A) promoted metastasis and EMT progression of NSCLC. In addition, NSCLC cells overexpressing PDE1A promoted angiogenesis by regulating exosome release. IL-6/JAK/STAT3 signaling pathway was highly enriched in PDE1A-coexpresssed genes, and PDE1A promoted NSCLC metastasis by activating the STAT3 pathway. GO enrichment analysis of PDE1A-interacting genes showed that PDE1A might interact with YTHDF2 and participate in m6A-containing RNA binding. The binding between PDE1A and YTHDF2 was verified, and PDE1A regulated the STAT3 pathway by interacting with YTHDF2. The mechanism of YTHDF2/PDE1A complex in regulating STAT3 pathway was predicted by overlapping YTHDF2-interacting-RNAs, and genes coexpressed with YTHDF2 and STAT3. The interactions between YTHDF2 and target mRNAs were predicted, and there were three predicted targets of YTHDF2 with high scores: NRF2, SOCS2, and MET. Indeed, PDE1A interacted with YTHDF2, destabilized SOCS2, and activated STAT3 pathway. This work not only uncovers a novel PDE1A/YTHDF2/STAT3 pathway in NSCLC progression but also provides therapeutic strategies for treating NSCLC patients with metastasis.
Assessing different next-generation sequencing technologies for wastewater-based epidemiology
Authors: John Anika , Dreifuss David , Kang Seju , Bratus-Neuenschwander Anna , Zajac Natalia , Topolsky Ivan , Dondi Arthur , Aquino Catharine , Julian Timothy R. , Beerenwinkel Niko
Published: May 2024

Wastewater-based epidemiology has proven to be an important public health asset during the COVID-19 pandemic. It can provide less biassed and more cost-effective population-level monitoring of the disease burden as compared to clinical testing. An essential component of SARS-CoV-2 wastewater monitoring is next-generation sequencing, providing genomic data to identify and quantify circulating viral strains rapidly. However, the specific choice of sequencing method influences the quality and timeliness of generated data and hence its usefulness for wastewater-based pathogen surveillance. Here, we systematically benchmarked Illumina Novaseq 6000, Element Aviti, ONT R9.4.1 MinION flow cell, and ONT R9.4.1 Flongle flow cell sequencing data to facilitate the selection of sequencing technology. Using a time series of wastewater samples from influent of six wastewater treatment plants throughout Switzerland, along with spike-in experiments, we show that higher sequencing error rates of ONT Nanopore sequencing reduce the accuracy of estimates of the relative abundance of viral variants, but the overall trend is in good concordance among all technologies. We find that the sequencing runtime for ONT Nanopore flow cells can be reduced to as little as five hours without significant impact on the quality of variant estimates. Our findings suggest that SARS-CoV-2 variant tracking is readily achievable with all tested technologies, albeit with different tradeoffs in terms of cost, timeliness and accuracy.
Impact of heat on respiratory hospitalizations among older adults living in 120 large US urban areas
Authors: O’Lenick Cassandra R. , Cleland Stephanie E. , Neas Lucas M. , Turner Mallory W. , Mcinroe E. Melissa , Hill K. Lloyd , Ghio Andrew J. , Rebuli Meghan E. , Jaspers Ilona , Rappold Ana G.
Published: May 2024

Objectives

A nationwide study of the impact of high temperature on respiratory disease hospitalizations among older adults (65+) living in large urban centers.

Methods

Daily rates of short-stay, inpatient respiratory hospitalizations were examined with respect to variations in ZIP-code-level daily mean temperature in the 120 largest US cities between 2000-2017. For each city, we estimated cumulative associations (lag-days 0-6) between warm-season temperatures (June-September) and cause-specific respiratory hospitalizations using time-stratified conditional quasi-Poisson regression with distributed lag non-linear models. We estimated nationwide associations using meta-regression and updated city-specific associations via best linear unbiased prediction. With stratified models, we explored effect modification by age, sex, and race (Black/white). Results were reported as percent change in hospitalizations at high temperatures (95th percentile) compared to median temperatures for each outcome, demographic-group, and metropolitan area. Excess hospitalization rates were estimated for days above median temperatures.

Results

At high temperatures, we observed increases in the percent of all-cause respiratory hospitalizations [1.2 (0.4, 2.0)], primarily driven by an increase in respiratory tract infections [1.8 (0.6, 3.0)], and chronic respiratory diseases/respiratory failure [1.2 (0.0, 2.4)]. East North Central, New England, Mid-Atlantic, and Pacific cities accounted for 98.5% of the excess burden. By demographic group, we observed disproportionate burdens of heat-related respiratory hospitalizations among the oldest beneficiaries (85+ years), and among Black beneficiaries living in South Atlantic cities.

Conclusion

This study found robust impacts of high temperature on respiratory failure and chronic inflammatory and fibrotic diseases among older adults. The geographic variation suggests that contextual factors account for disproportionate burdens.
Exploring the secretion of immunogenic gluten peptides in breast milk from celiac and non celiac mothers
Authors: Ruiz-Carnicer Ángela , Segura Verónica , de Lourdes Moreno María , Coronel-Rodríguez Cristóbal , Sousa Carolina , Comino Isabel
Published: May 2024

Background

Exposure to antigens is crucial for child immune system development, aiding disease prevention and promoting infant health. Some common food antigen proteins are found in human breast milk. However, it is unclear whether gluten antigens linked to celiac disease (CD) are transmitted through breast milk, potentially impacting the development of the infant’s immune system.

Objective

This study aimed to analyze the passage of gluten immunogenic peptides (GIP) into human breast milk. We evaluated the dynamics of GIP secretion after lactating mothers adopted a controlled gluten-rich diet.

Methods

We prospectively enrolled 96 non-CD and 23 CD lactating mothers, assessing total proteins and casein in breast milk, and GIP levels in breast milk and urine. Subsequently, a longitudinal study was conducted in a subgroup of 12 non-CD lactating mothers who adopted a controlled gluten-rich diet. GIP levels in breast milk and urine samples were assayed by multiple sample collections over 96 hours.

Results

Analysis of a single sample revealed that 24% of non-CD lactating mothers on a regular unrestricted diet tested positive for GIP in breast milk, and 90% tested positive in urine, with significantly lower concentrations in breast milk. Nevertheless, on a controlled gluten-rich diet and the collection of multiple samples, GIP were detected in 75% and 100% of non-CD participants in breast milk and urine, respectively. The transfer dynamics in breast milk samples were long-enduring and GIP secretion persisted from 0 to 72 h. In contrast, GIP secretion in urine samples was limited to the first 24 h, with inter-individual variations. In the cohort of CD mothers, 82.6% and 87% tested negative for GIP in breast milk and urine, respectively.

Conclusions

This study definitively established the presence of GIP in breast milk, with substantial inter-individual variations in secretion dynamics. Our findings provide insights into distinct GIP kinetics observed in sequentially collected breast milk and urine samples, suggesting differential gluten metabolism patterns depending on the organ or system involved. Future research is essential to understand whether GIP functions as sensitizing or tolerogenic agents in the immune system of breastfed infants.