bluuebunny/crossref_metadata_2025 huggingface dataset:
New molecular targets in the treatment of rheumatoid arthritis
Authors: Wallace Beth I. , Cooney Laura , Fox David A.
Published: January 2024

Purpose of review

This review will discuss selected emerging molecular targets and associated potential therapeutic agents for rheumatoid arthritis (RA)-directed treatment.

Recent findings

Agents in active development for RA treatment include those targeted to CD40 and CD40 ligand, programmed death protein 1 (PD-1), and granulocyte-macrophage colony-stimulating factor (GM-CSF). Several other molecules with a strong theoretical role in RA pathogenesis and/or demonstrated efficacy in other autoimmune diseases are also being evaluated as potential drug targets in preclinical or translational studies in RA. These targets include interleukin 1 receptor associated kinases 1 and 4 (IRAK1, IRAK4), tyrosine kinase 2 (Tyk2), bradykinin receptor 1 (B1R), OX40 and OX40 ligand.

Identification of molecular targets for RA treatment remains an active area of investigation, with multiple therapeutic agents in clinical and preclinical development.
Relationship of calcium and magnesium intakes with the dietary approaches to stop hypertension score and blood pressure: the International Study of Macro/micronutrients and Blood Pressure
Authors: Gibson Rachel , Aljuraiban Ghadeer S. , Oude Griep Linda M. , Vu Thanh-Huyen , Steffen Lyn M. , Appel Lawrence J. , Rodriguez Beatriz L. , Daviglus Martha L. , Elliott Paul , Van Horn Linda , Chan Queenie
Published: January 2024

Objective:

Research investigating calcium and magnesium intakes from the Dietary Approaches to Stop Hypertension (DASH) pattern and other sources in association with blood pressure is limited. We aimed to characterize sources/intake levels of calcium and magnesium in relation to overall diet quality (DASH-score) and determine modification effects with DASH score and blood pressure.

Methods:

Cross-sectional United States data (average dietary and supplement intake from four 24 h recalls and eight blood pressure measurements) from two separate visits, 2195 men and women (40–59 years) in the International Study of Macro/Micronutrients and Blood Pressure were analysed. Food-based adherence to the DASH diet was estimated. Linear models tested associations between each 1-point DASH score with blood pressure. Participants were stratified by adherence to sex-specific recommended allowance for magnesium and calcium intakes. Effect-modification was tested across DASH-score quintiles and median of urinary sodium.

Results:

DASH-score was inversely associated with SBP in fully adjusted models (−0.27; 95%CI: −0.38 to −0.15 mmHg). SBP was inversely associated with dietary calcium intake from DASH food groups: −1.54 (95% CI: −2.65 to −0.43) mmHg; calcium intake from other non-DASH food groups: −1.62 (95% CI: −2.94 to −0.29) mmHg. Dietary magnesium intake from DASH food groups (−1.59; 95% CI: −2.79, −0.40 mmHg) and from other non-DASH foods (−1.92; 95% CI: −3.31, −0.53 mmHg) was inversely associated with SBP.

Conclusion:

A higher DASH score showed a consistent association with lower BP suggesting a relationship between intakes of calcium and Mg with BP regardless of whether the source is part of the DASH diet or not, even when adjusted for supplement intakes.

The INTERMAP is registered as NCT00005271 at www.clinicaltrials.gov.
Ten-year follow-up of very-high risk hypertensive patients undergoing renal sympathetic denervation
Authors: Wang Li , Li Chao , Li Zhuqing , Li Qi , Liu Chunlei , Sun Xiaoqiang , He Qiang , Xia Da-sheng , Xia Dachuan , Lu Chengzhi
Published: January 2024

Objectives:

Renal denervation (RDN) has been proven to be effective in lowering blood pressure (BP) in patients, but previous studies have had short follow-ups and have not examined the effects of RDN on major cardiovascular outcomes. This study aimed to demonstrate the effectiveness and safety of RDN in the long-term treatment of hypertension and to determine if it has an effect on cardiovascular outcomes.

Methods:

All patients with resistant hypertension who underwent RDN between 2011 and 2015 at Tianjin First Central Hospital were included in the study. Patients were followed up at 1,5 and 10 years and the longest follow-up was 12 years. Data were collected on office BP, home BP, ambulatory BP monitoring (ABPM), renal function, antihypertensive drug regimen, major adverse events (including acute myocardial infarction, stroke, cardiovascular death and all cause death) and safety events.

Results:

A total of 60 participants with mean age 50.37 ± 15.19 years (43.33% female individuals) completed long-term follow-up investigations with a mean of 10.02 ± 1.72 years post-RDN. Baseline office SBP and DBP were 179.08 ± 22.05 and 101.17 ± 16.57 mmHg under a mean number of 4.22 ± 1.09 defined daily doses (DDD), with a reduction of −35.93/−14.76 mmHg as compared with baseline estimates (P < 0.0001). Compared with baseline, ambulatory SBP and DBP after 10-years follow-up were reduced by 14.31 ± 10.18 (P < 0.001) and 9 ± 4.35 (P < 0.001) mmHg, respectively. In comparison to baseline, participants were taking fewer antihypertensive medications (P < 0.001), and their mean heart rate had decreased (P < 0.001). Changes in renal function, as assessed by estimated glomerular filtration rate (eGFR) and creatinine, were within the expected rate of age-related decline. No major adverse events related to the RDN procedure were observed in long-term consequences. All-cause mortality and cardiovascular mortality rates were 10 and 8.34%, respectively, for the 10-year period.

Conclusion:

The BP-lowering effect of RDN was safely sustained for at least 10 years post-procedure. More importantly, to the best of my knowledge, this is the first study to explore cardiovascular and all-cause mortality at 10 years after RDN.
Relationship Between Retinal Hemorrhage on Green and Red Channels of Ultra-Widefield Fundus Images and Retinal Perfusion in Acute Branch Retinal Vein Occlusion
Authors: Sun Gongpeng , Wang Xiaoling , Yi Zuohuizi , Su Yu , He Lu , Zheng Hongmei , Chen Changzheng
Published: January 2024

Purpose:

To explore the relationship between retinal hemorrhage in the green and red channels on ultra-widefield fundus images (UWFIs) and the nonperfusion area (NPA) on ultra-widefield fundus fluorescein angiography in patients with acute branch retinal vein occlusion (BRVO).

Methods:

This was a retrospective cross-sectional study with 96 patients, including 46 with ischemic BRVO and 50 with nonischemic BRVO. Correlation analysis between green channel hemorrhage (GCH), red channel hemorrhage (RCH), and NPA was performed. Panretina was divided into posterior and peripheral areas.

Results:

Ischemic BRVO showed significantly higher GCH% and RCH% than nonischemic BRVO in the peripheral regions (bothP< 0.001), while no significant differences were observed in the panretinal and posterior area (allP> 0.05). Significant correlations were found between NPA% in the panretinal and peripheral areas and the corresponding GCH% and RCH% (all P < 0.01). However, no significant correlation was observed between posterior NPA% and posterior GCH% or RCH% (bothP> 0.05). Additionally, peripheral GCH% and RCH% were related to panretinal NPA% (r = 0.506,P< 0.001; r = 0.558,P< 0.001).

Conclusion:

Retinal hemorrhage on UWFI was significantly associated with NPA, providing insights for assessing retinal perfusion status in acute BRVO patients.
CASE SERIES OF PROGRESSIVE RETINAL DETACHMENTS IN PERSISTENT FETAL VASCULATURE
Authors: Somani Nicole , Sheng Jiwei , Rao Prethy , Chang Emmanuel
Published: January 2024

Purpose:

Persistent fetal vasculature may be associated with tractional retinal detachment due to tractional contraction of the fibrovascular stalk. Persistent fetal vasculature is often believed to be congenital and nonprogressive. A rhegmatogenous component is far less common and is typically identified as a postoperative complication and has not been spontaneously reported. The authors present five cases illustrating potential progressive changes and complications that may arise in nonoperated persistent fetal vasculature.

Methods:

This was a retrospective case series of five patients who presented with progressive retinal detachments from persistent fetal vasculature.

Results:

Five unique cases of persistent fetal vasculature with significant progression from time of initial presentation, four of which included development of rhegmatogenous components.

Conclusion:

Patients with persistent fetal vasculature and a seemingly stable tractional detachment should undergo evaluation with a retinal specialist for risk stratification and management because rhegmatogenous detachments may occur due to ocular growth and stretch breaks, and tractional detachments can continue to progress over time.
Quantum Molecular Resonance Effects on Patients With Dry Eye Disease: A Randomized Controlled Trial
Authors: Shemer Asaf , Altarescu Aya , Nusbaum Lee , Vardi Maya , Dubinsky-Pertzov Biana , Hecht Idan , Or Lior , Einan-Lifshitz Adi , Pras Eran
Published: January 2024

Purpose:

The aim of the study was to evaluate the efficacy and safety of quantum molecular resonance in the treatment of dry eye disease.

Methods:

This study was a double-blind randomized control trial in 1 academic medical center, for 2 years. Participants received treatment or a placebo with the Rexon-Eye device, once per week for 4 weeks. The primary outcome was the change in dry eye symptoms assessed by the Ocular Surface Disease Index (OSDI). Secondary outcomes were clinical findings associated with the dry eye such as meibomian gland dysfunction (MGD) score, tear break-up time (TBUT), corneal fluorescein staining, Schirmer test, and best-corrected visual acuity (BCVA).

Results:

Forty patients were recruited, 20 in each arm. The mean age was 63.5 ± 15.1 years and 27 (67.5%) were female. The mean OSDI score significantly improved in the intervention group from 19.15 ± 10.3 to 10.5 ± 7.0 (P < 0.001), whereas the control group showed no significant change (14.4 ± 8.4 to 15.5 ± 8.6, P = 0.830). MGD scores significantly improved in the intervention group (1.57 ± 1.2 to 0.8 ± 0.9, P = 0.006), whereas showing no significant change in the control group (1.60 ± 0.9 to 1.99 ± 1.0, P = 0.244). The corneal staining score also showed significant improvement in the intervention group (P = 0.045) and a nonsignificant decline in the placebo group (P = 0.50). No significant difference was seen in TBUT, visual acuity, and Schirmer scores between groups. No harm resulting from treatment was reported during the duration of the trial.

Conclusions:

High-frequency electrotherapy may have a positive effect on symptoms and signs of dry eye. This emerging technology may become part of the arsenal of therapeutic modalities for this condition.
Use of Cemiplimab, an Immune Checkpoint Inhibitor for Conjunctival Intraepithelial Neoplasia
Authors: Ceylanoglu Kubra Serbest , Eisenberg Anne , Worden Francis Paul , Elner Victor Mauris , Demirci Hakan
Published: January 2024

Purpose:

Immune checkpoint inhibitors (ICIs) have been recently introduced for the treatment of locally unresectable conjunctival squamous cell carcinoma. We present 2 cases with conjunctival intraepithelial neoplasia (CIN) who were treated with ICIs.

Methods:

A report of 2 cases with CIN who were treated with systemic cemiplimab (350 mg IV every 3 weeks).

Results:

A 70-year-old man was treated with cemiplimab for metastatic cutaneous squamous cell carcinoma. The pre-existing CIN continued to progress over the nasal bulbar conjunctiva and cornea, while the other metastatic sites, including parotid glands, and neck lymph nodes showed a complete response after 16 cycles of treatment. An 84-year-old woman had bilateral diffuse CIN involving bulbar and lower eyelid palpebral conjunctiva. Cemiplimab was started because of the extent of involvement. While the bulk of CIN was reduced, it progressed over the cornea and forniceal conjunctiva on OU after 10 cycles of treatment. Excisional biopsies of conjunctival lesions after cemiplimab confirmed CIN in both patients.

Conclusions:

Although conjunctival squamous cell carcinoma tumors are reported to be highly responsive to ICIs, a similar effect has not been observed in 2 patients with CIN. Further studies are needed to evaluate ICIs in the management of CIN.
Regional Strain of Right Ventricle From Computed Tomography Improves Risk Stratification of Right Ventricle Failure
Authors: Scott Anderson , Chen Zhennong , Kligerman Seth , Kim Paul , Tran Hao , Adler Eric , Narezkina Anna , Contijoch Francisco
Published: January 2024

Patients who undergo implantation of a left ventricular assist device (LVAD) are at a high risk for right ventricular failure (RVF), presumably due to poor right ventricular (RV) function before surgery. Cine computerized tomography (cineCT) can be used to evaluate RV size, function, and endocardial strain. However, CT-based strain measures in patients undergoing workup for LVAD implantation have not been evaluated. We quantified RV strain in the free wall (FW) and septal wall (SW) in patients with end-stage heart failure using cineCT. Compared to controls, both FW and SW strains were significantly impaired in heart failure patients. The difference between FW and SW strains predicted RV failure after LVAD implantation (area-under-the curve [AUC] = 0.82). Cine CT strain can be combined with RV volumetry to risk-stratify patients. In our study, patients with preserved RV volumes and poor strain had a higher rate of RV failure (57%), than those with preserved volume and preserved strain (0%). This suggests that CT could improve risk stratification of patients receiving LVADs and that strain metrics were particularly useful in risk-stratifying patients with preserved RV volumes.
First 24-Hour-Long Intensive Care Unit Testing of a Clinical-Scale Microfluidic Oxygenator in Swine: A Safety and Feasibility Study
Authors: Roberts Teryn R. , Persello Antoine , Harea George T. , Vedula Else M. , Isenberg Brett C. , Zang Yanyi , Santos Jose , Borenstein Jeffrey T. , Batchinsky Andriy I.
Published: January 2024

Microfluidic membrane oxygenators are designed to mimic branching vasculature of the native lung during extracorporeal lung support. To date, scaling of such devices to achieve clinically relevant blood flow and lung support has been a limitation. We evaluated a novel multilayer microfluidic blood oxygenator (BLOx) capable of supporting 750–800 ml/min blood flow versus a standard hollow fiber membrane oxygenator (HFMO) in vivo during veno-venous extracorporeal life support for 24 hours in anesthetized, mechanically ventilated uninjured swine (n = 3/group). The objective was to assess feasibility, safety, and biocompatibility. Circuits remained patent and operated with stable pressures throughout 24 hours. No group differences in vital signs or evidence of end-organ damage occurred. No change in plasma free hemoglobin and von Willebrand factor multimer size distribution were observed. Platelet count decreased in BLOx at 6 hours (37% dec, P = 0.03), but not in HFMO; however, thrombin generation potential was elevated in HFMO (596 ± 81 nM·min) versus BLOx (323 ± 39 nM·min) at 24 hours (P = 0.04). Other coagulation and inflammatory mediator results were unremarkable. BLOx required higher mechanical ventilator settings and showed lower gas transfer efficiency versus HFMO, but the stable device performance indicates that this technology is ready for further performance scaling and testing in lung injury models and during longer use conditions.
The association of timing of coronary artery bypass grafting for non-ST-elevation myocardial infarction and clinical outcomes in the contemporary United States
Authors: Park Dae Yong , Singireddy Shreyas , Mangalesh Sridhar , Fishman Emily , Ambrosini Alexander , Jamil Yasser , Vij Aviral , Sikand Nikhil V. , Ahmad Yousif , Frampton Jennifer , Nanna Michael G.
Published: January 2024

Background

In contrast to the timing of coronary angiography and percutaneous coronary intervention, the optimal timing of coronary artery bypass grafting (CABG) in non-ST-elevation myocardial infarction (NSTEMI) has not been determined. Therefore, we compared in-hospital outcomes according to different time intervals to CABG surgery in a contemporary NSTEMI population in the USA.

Methods

We identified all NSTEMI hospitalizations from 2016 to 2020 where revascularization was performed with CABG. We excluded NSTEMI with high-risk features using prespecified criteria. CABG was stratified into ≤24 h, 24–72 h, 72–120 h, and >120 h from admission. Outcomes of interest included in-hospital mortality, perioperative complications, length of stay (LOS), and hospital cost.

Results

A total of 147 170 NSTEMI hospitalizations where CABG was performed were assessed. A greater percentage of females, Blacks, and Hispanics experienced delays to CABG surgery. No difference in in-hospital mortality was observed, but CABG at 72–120 h and at >120 h was associated with higher odds of non-home discharge and acute kidney injury compared with CABG at ≤24 h from admission. In addition to these differences, CABG at >120 h was associated with higher odds of gastrointestinal hemorrhage and need for blood transfusion. All 3 groups with CABG delayed >24 h had longer LOS and hospital-associated costs compared with hospitalizations where CABG was performed at ≤24 h.

Conclusion

CABG delays in patients with NSTEMI are more frequently experienced by women and minority populations and are associated with an increased burden of complications and healthcare cost.
Interleukin-15 in kidney disease and therapeutics
Authors: Hall Gentzon
Published: January 2024

Purpose of review

Interleukin 15 (IL-15) is a member of the IL-2 family of common gamma chain receptor cytokines with well described anti-inflammatory, pro-survival and pro-proliferative signaling properties. The cytoprotective role of IL-15 in the kidney is now coming into focus with recent reports of its beneficial actions in various forms of kidney disease. This review will summarize what is currently known about IL-15 signaling in the kidney and highlight recent evidence of its beneficial effects on kidney physiology.

Recent findings

IL-15 and its heterotrimeric receptor are expressed throughout the kidney. Like all IL-2 family cytokines, IL-15 can activate signaling through the Janus Kinase (JAK)/Signal transducer of activated T-cells (STAT), phosphoinositol-3 kinase (PI-3K)/AKT and mitogen activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathways and recent evidence suggests that STAT5B is an essential transcriptional mediator of prosurvival signaling in glomerular visceral epithelial cells (i.e. podocytes). IL-15 has also been shown to suppress pro-apoptotic signaling in models of acute kidney injury and pro-fibrotic signaling in models of chronic kidney disease.

The cytoprotective properties of IL-15 suggest that it may have potential as a nonimmunosuppresive therapeutic for kidney disease. A novel class of IL-15 immunotherapies has emerged for the treatment cancer and some have demonstrated efficacy in clinical trials. These well tolerated IL-15 agonists could possibly be repurposed for the treatment of kidney disease and warrant further exploration.
Facial Feminization: Perioperative Care and Surgical Approaches
Authors: Ellis Marco , Choe Joshua , Barnett Sarah L. , Chen Kevin , Bradley James P.
Published: January 2024

Learning Objectives:

After studying this article, the participant should be able to: 1. Understand the regional anatomy involved in facial feminization surgery, the key differences between the male and female face, and surgical approaches for modification. 2. Appreciate the integration of preoperative virtual planning and nonoperative approaches for facial feminization care. 3. Understand the perioperative process and potential complications and sequela. 4. Understand the importance of transgender care acceptance as it pertains to clinical outcomes.

Facial feminization surgery (FFS) is composed of a broad spectrum of gender-affirming surgical procedures with the goal of modifying specific facial features to create a more feminine appearance. As FFS continues to evolve as a subspecialty of transgender care, it is important to consider the psychosocial evaluation, evolving aesthetic tastes, nonoperative facial feminization care, preoperative virtual planning, specialized instrumentation, and potential complications/sequelae when performing these procedures. Computed tomographic imaging and virtual preoperative planning may be used to assist the surgeon with morphologic typing of the brow, supraorbital rim, chin, and lateral mandible regions and aid in performing safer, more efficient procedures. The increasing number of FFS procedures performed on transwomen annually has been supported by objective outcome studies that demonstrate progress in minimizing both misgendering in social environments and reducing dysphoric feelings.
Clinical Impact of Calcified Nodules in Patients with Severely Calcified Lesions Treated by Rotational Atherectomy: A Serial Optical Coherence Tomography Study
Authors: Narui Shuro , Yamamoto Myong Hwa , Mori Hiroyoshi , Amemiya Kisaki , Okabe Toshitaka , Koyanagi Yui , Ito Yuki , Gibo Yuma , Okura Takeshi , Fujioka Tatsuki , Ishigaki Shigehiro , Usumoto Soichiro , Kimura Taro , Shimazu Suguru , Saito Jumpei , Oyama Yuji , Igawa Wataru , Ono Morio , Isomura Naoei , Ochiai Masahiko
Published: January 2024

Background

Percutaneous coronary intervention (PCI) for lesions with calcified nodules (CNs) is associated with worse outcomes than PCI for other calcified lesions. We aimed to clarify the relationship between CNs at index PCI, optical coherence tomography (OCT) findings at 8-month follow-up, and clinical outcomes using serial OCT.

Methods

This retrospective observational study utilized data from a prospective, single-center registry. We conducted consecutive PCI for calcified lesions requiring rotational atherectomy (RA) with OCT guidance. We categorized 51 patients (54 lesions) into those with (16 patients [16 lesions]) and without CNs (35 patients [38 lesions]).

Results

Post-PCI, stent expansion was comparable between the two groups, and CN-like protrusion was observed in 75% of patients in the CN group. Follow-up OCT at 8 months revealed in-stent CNs in 54% of treated CN lesions with CN-like protrusion, whereas non-CN lesions lacked in-stent CNs. The CN group exhibited greater maximum neointimal tissue (NIT) thickness than the non-CN group (p<0.001).

Multivariate linear regression analysis demonstrated that CN was associated with maximum NIT (p=0.02). Consequently, the CN group exhibited a higher clinically-driven target lesion revascularization (TLR) rate than the non-CN group at 1 (p=0.009) and 5 years (p=0.02). TLR primarily occurred in lesions with maximum CN angles >180°.

Conclusions

Following RA treatment with acceptable stent expansion, the presence of CNs before PCI correlated with greater neointimal tissue formation with in-stent CNs, resulting in a higher TLR rate, especially in lesions with maximum CN angles exceeding 180°.

What is Known

Calcified lesions with calcified nodules (CNs) are associated with a higher target lesion revascularization (TLR) rate in percutaneous coronary intervention (PCI) than other types of calcified lesions.

In-stent CNs may appear after PCI for CNs and is a major cause of increased TLR rates after PCI for CNs.

The relationship between calcified plaque morphology at the index PCI, neointimal tissue characteristics concerning in-stent CN location and frequency during follow-up, and subsequent clinical outcomes has not been explored with serial optical coherence tomography.

What the Study Adds

Follow-up OCT at 8 months revealed in-stent CNs in 54% of treated CN lesions with CN-like protrusion, whereas non-CN lesions lacked in-stent CNs.

PCI for CNs exhibited a higher clinically-driven target lesion revascularization rate than PCI for lesions without CNs, primarily in lesions with maximum CN angles >180°.
Phylogenomics analyses of all species of Swordtails (GenusXiphophorus) highlights hybridization precedes speciation
Authors: Du Kang , Lu Yuan , Garcia-Olazabal Mateo , Walter Ronald B. , Warren Wesley C. , Dodge Tristram , Schumer Molly , Park Hyun , Meyer Axel , Schartl Manfred
Published: January 2024

Hybridization has been recognized as an important driving force for evolution, however studies of the genetic consequence and its cause are still lagging behind in vertebrates due to the lack of appropriate experimental systems. Fish of the central American genusXiphophoruswere proposed to have evolved with multiple ancient and ongoing hybridization events, and served as a valuable research model in evolutionary biology and in biomedical research on human disease for more than a century. Here, we provide the complete genome resource and its annotation of all 26Xiphophorusspecies. On this dataset we resolved the so far conflicting phylogeny. Through comparative genomic analyses we investigated the molecular evolution of genes related to melanoma, for a main sexually selected trait and for the genetic control of puberty timing, which are predicted to be involved in pre-and postzygotic isolation and thus to influence the probability of interspecific hybridization inXiphophorus. We demonstrate dramatic size-variation of some gene families across species, despite the reticulate evolution and short divergence time. Finally, we clarify the hybridization history in the genusXiphophorusgenus, settle the long dispute on the hybridization origin of two Southern swordtails, highlight hybridizations precedes speciation, and reveal the distribution of hybridization ancestry remaining in the fused genome.
Constitutive Endolysosomal Perforation in Neurons allows Induction of α-Synuclein Aggregation by Internalized Pre-Formed Fibrils
Authors: Sanyal Anwesha , Scanavachi Gustavo , Somerville Elliott , Saminathan Anand , Nair Athul , Oikonomou Athanasios , Hatzakis Nikos S. , Kirchhausen Tom
Published: January 2024

The endocytic pathway is both an essential route of molecular uptake in cells and a potential entry point for pathology-inducing cargo. The cell-to-cell spread of cytotoxic aggregates, such as those of α-synuclein (α-syn) in Parkinson’s Disease (PD), exemplifies this duality. Here we used a human iPSC-derived induced neuronal model (iNs) prone to death mediated by aggregation in late endosomes and lysosomes of endogenous α-syn, seeded by internalized pre-formed fibrils of α-syn (PFFs). This PFF-mediated death was not observed with parental iPSCs or other non-neuronal cells. Using live-cell optical microscopy to visualize the read out of biosensors reporting endo-lysosome wounding, we discovered that up to about 10% of late endosomes and lysosomes in iNs exhibited spontaneous constitutive perforations, regardless of the presence of internalized PFFs. This wounding, absent in parental iPSCs and non-neuronal cells, corresponded to partial damage by nanopores in the limiting membranes of a subset of endolysosomes directly observed by volumetric focused ion beam scanning electron microscopy (FIB-SEM) in iNs and in CA1 pyramidal neurons from mouse brain, and not found in iPSCs or in other non-neuronal cells in culture or in mouse liver and skin.

We suggest that the compromised limiting membranes in iNs and neurons in general are the primary conduit for cytosolic α-syn to access PFFs entrapped within endo-lysosomal lumens, initiating PFF-mediated α-syn aggregation. Significantly, eradicating the intrinsic endolysosomal perforations in iNs by inhibiting the endosomal Phosphatidylinositol-3-Phosphate/Phosphatidylinositol 5-Kinase (PIKfyve kinase) using Apilimod or Vacuolin-1 markedly reduced PFF-induced α-syn aggregation, despite PFFs continuing to enter the endolysosomal compartment. Crucially, this intervention also diminished iN death associated with PFF incubation.

Our results reveal the surprising presence of intrinsically perforated endo-lysosomes in neurons, underscoring their crucial early involvement in the genesis of toxic α-syn aggregates induced by internalized PFFs. This discovery offers a basis for employing PIKfyve kinase inhibition as a potential therapeutic strategy to counteract synucleinopathies.
Maternal gutBifidobacterium brevemodifies fetal brain metabolism in germ-free mice
Authors: Lopez-Tello Jorge , Kiu Raymond , Schofield Zoe , van Sinderen Douwe , Le Gall Gwénaëlle , Hall Lindsay J , Sferruzzi-Perri Amanda N
Published: January 2024

In recent years, our understanding of the gut microbiome’s impact on host physiology and metabolism has grown exponentially. Yet, the specific role of certain microorganisms in regulating gestational health and fetal development remains largely unexplored. During pregnancy,Bifidobacteriumrepresents a key beneficial microbiota genus that provides multiple benefits, including changes in placental development and fetal glycaemia. In this study, using germ-free mice colonized with or withoutBifidobacterium breveUCC2003 during pregnancy, we demonstrated that this bacterium is important for controlling fetal brain metabolism. In particular, presence of maternalBifidobacteriumled to reduced levels of ten metabolites (including citrate, 3-hydroxyisobutyrate, and carnitine) in the fetal brain, with concurrent elevated abundance of transporters involved in glucose and branched-chain amino acid uptake.B. brevesupplementation was also associated with increased expression of critical metabolic and cellular pathways, including the PI3K-AKT, AMPK, STAT5 and Wnt-β-catenin (including its receptor Frizzled-7) in the fetal brain. Furthermore, maternal-associatedBifidobacteriumresulted in HIF-2 protein stabilization and altered a number ofhttps://pubmed.ncbi.nlm.nih.gov/38269505/genes and proteins involved in cellular growth, axogenesis, and mitochondrial function. These findings highlight thatBifidobacterium brevecolonisation of the maternal gut is important for the metabolism and growth of the fetal brain.
Specifying cellular context of transcription factor regulons for exploring context-specific gene regulation programs
Authors: Minaeva Mariia , Domingo Júlia , Rentzsch Philipp , Lappalainen Tuuli
Published: January 2024

Understanding the role of transcription and transcription factors in cellular identity and disease, such as cancer and autoimmunity, is essential. However, comprehensive data resources for cell line-specific transcription factor-to-target gene annotations are currently limited. To address this, we developed a straightforward method to define regulons that capture the cell-specific aspects of TF binding and transcript expression levels. By integrating cellular transcriptome and transcription factor binding data, we generated regulons for four common cell lines comprising both proximal and distal cell line-specific regulatory events. Through systematic benchmarking involving transcription factor knockout experiments, we demonstrated performance on par with state-of-the-art methods, with our method being easily applicable to other cell types of interest. We present case studies using three cancer single-cell datasets to showcase the utility of these cell-type-specific regulons in exploring transcriptional dysregulation. In summary, this study provides a valuable tool and a resource for systematically exploring cell line-specific transcriptional regulations, emphasizing the utility of network analysis in deciphering disease mechanisms.
Transient BRD4 degradation improves cardiac reprogramming by inhibiting macrophage/Oncostatin M induced JAK/STAT pathway
Authors: Liu Liu , Guo Yijing , Tian Shuo , Lei Ienglam , Gao Wenbin , Li Zhaokai , Wang Shaomeng , Chen Y. Eugene , Wang Zhong
Published: January 2024

Reprogramming fibroblasts into induced cardiomyocytes (iCMs) holds great potential for cardiac regeneration. However, low conversion rate both in vitro and in vivo remains a significant challenge. To address this challenge, we focused on potential epigenetic barriers and screened 33 small-molecule inhibitors/degraders targeting histone acetyl post-translational modifications and related epigenetic factors. BET degraders were found to enhance cardiac reprogramming efficiency by degrading BRD4 and repressing genes involved in immune response, particularly those in the JAK/STAT pathway. We further identified that macrophage/oncostatin M activated the JAK/STAT pathway to repress cardiac reprogramming. BRD4 degrader treatment improved iCMs formation by inhibiting macrophage/oncostatin M-induced activation of the JAK/STAT pathway. Moreover, BRD4 degrader treatment enhanced MGT-mediated cardiac regeneration in vivo and improved myocardial performance post-myocardial infarction. These findings provide new insights into BRD4, macrophage/oncostatin M and JAK/STAT pathway in fibroblast to cardiomyocyte-like cell conversion and offer promising targets and small molecules to improve iCM reprogramming for clinical applications.

Highlights

Screen of histone acetylation modifiers identified BRD4, a histone acetylation reader, as an important regulator in cardiac reprogramming.

BRD4 degradation promoted cardiac reprogramming by repressing inflammation and the JAK-STAT pathway.

BRD4 degradation inhibited macrophage/oncostatin M-induced activation of the JAK/STAT pathway.

BRD4 degradation enhanced MGT-mediated cardiac regeneration in vivo and improved myocardial performance post-myocardial infarction.
Novel gramicidin-derivedβ-helical antimicrobial peptides
Authors: Lambden Edward , Wallace Mark I. , Ulmschneider Martin B.
Published: January 2024

Combating the threat of multidrug resistance bacteria requires many different approaches. Using structural motifs and sequences from existing antibacterial compounds affords a fresh attack against such bacteria, while circumventing inherited resistance against the existing compound. Gramicidin is a 16 amino acid peptide with an alternatingl- andd-motif with highly bacteriocidal effects in gram-positive membranes. In the membrane it assumes aβ-helix form with two peptides aligned by their N-terminal interactions, and only conducts in such a form. Using gramicidin as a basis, this study employs molecular dynamics simulations as an initial design step and evaluates gramicidin-derived candidates based on their backbone hydrogen-bond interactions, capacity for conductance, profile of their RMSD over the course of the simulation, and how the peptide interacts with the phospholipid headgroups. There are twelve candidate systems with results comparable to gramicidin and the factors at play in their efficacy are examined.
Chern, dipole, and quadrupole topological phases of a simple magneto-optical photonic crystal with a square lattice and an unconventional unit cell
Authors: Lan Zhihao , Chen Yafeng , An Liang , Su Zhongqing
Published: January 2024

For the study of topological phases in photonics, while quantum-Hall-type first-order chiral edge states are routinely realized in magneto-optical photonic crystals, higher-order topological states are mostly explored in all-dielectric photonic crystals. In this work, we study both first- and second-order topological photonic states in magneto-optical photonic crystals. In specific, we revisit a simple magneto-optical photonic crystal in a square lattice with one gyromagnetic cylinder in each unit cell. However, rather than investigating the conventional unit cell where the cylinder is at the center of the square unit cell as previous works have done, we consider a configuration where the cylinders are located at the four corners of the square unit cell and show that this configuration hosts rich topological phases, such as dual-band Chern, dipole, and quadrupole topological phases. Our detailed characterizations of these topological states are based on the Wannier bands and their polarizations via the Wilson loop and nested Wilson loop methods. We study in detail both the edge and corner states of the different topological phases and show that they exhibit a special feature of “spectrum robustness.” For example, though the edge and corner states of the dipole phases living in a band gap could be pushed into the bulk bands by tuning the boundary conditions, they can pass through the bulk bands and reappear within a different band gap. For dual-band quadrupole phases, we can find a regime where both band gaps host a set of corner states simultaneously and, intriguingly, the filling anomaly of one set of corner states can leave their signatures in the filling anomaly of the other set of corner states though they are separated by an extensive number of bulk states. The rich topological physics revealed in a simple magneto-optical photonic crystal not only provides new insights on higher-order topological phases in time-reversal symmetry-broken photonic systems, the results may also find promising applications by harnessing the potentials of both edge and corner states.

Published by the American Physical Society
2024
Counting linearly polarized gluons with lattice QCD
Authors: Zhao Shuai
Published: January 2024

We outline an approach to calculate the transverse-momentum-dependent distribution of linearly polarized gluons inside an unpolarized hadron on the lattice with the help of large momentum effective theory. To achieve this purpose, we propose calculating a Euclidean version of the degree of polarization for a fast-moving hadron on the lattice, which is ultraviolet finite, and no soft function subtraction is needed. It indicates a practical way to explore the distribution of the linearly polarized gluons in a proton and the linearly polarized gluon effects in hadron collisions on the lattice.

Published by the American Physical Society
2024
Electroweak phase transition with radiative symmetry breaking in a type-II seesaw model with an inert doublet
Authors: Jangid Shilpa , Okada Hiroshi
Published: January 2024

We consider the type-II seesaw model extended with another Higgs doublet, which is odd under the Z2 symmetry. We look for the possibility of triggering the electroweak symmetry breaking via radiative effects. The Higgs mass parameter changes sign from being positive at higher-energy scales to negative at lower-energy scales in the presence of the TeV scalar triplet. The Planck scale perturbativity is demanded and the electroweak phase transition is studied using two-loop β-functions. The maximum allowed values for the interaction quartic coupling of the second doublet field and the triplet field with the Higgs field are λ3=0.15 and λΦ1Δ=0.50, respectively. Considering these EW values, the first-order phase transition, i.e., ϕ+(Tc)/Tc∼0.6 is satisfied only for vanishing doublet and triplet bare mass parameters, mΦ2=0.0  GeV and mΔ=0.0  GeV. The small nonzero induced vacuum expectation value for the scalar triplet also generates the neutrino mass, and the lightest stable neutral particle from the inert doublet satisfies the dark matter constraints for the chosen parameter space. The impact of the thermal corrections on the stability of the electroweak vacuum is also studied, and the current experimental values of the Higgs mass and the top mass lie in the stable region both at the zero temperature and the finite temperature.

Published by the American Physical Society
2024
Minimal model of fermion FIMP dark matter
Authors: Yaguna Carlos E. , Zapata Óscar
Published: January 2024

We investigate a simple extension of the standard model in which the dark matter consists of a feebly interacting fermion, charged under a new Z4 symmetry, that is produced in the early Universe by the freeze-in mechanism. The only other new particle included in the model is a singlet scalar, also charged under the Z4, which couples to the fermion via Yukawa interactions and to the standard model Higgs. The model is truly minimal, as it admits just five free parameters: two masses and three dimensionless couplings. Depending on their values, the freeze-in mechanism can be realized in different ways, each characterized by its own production processes. For all of them, we numerically study the relic density as a function of the free parameters of the model and determine the regions consistent with the dark matter constraint. Our results show that this scenario is viable over a wide range of couplings and dark matter masses. This model, therefore, not only offers a novel solution to the dark matter problem, but it also provides a minimal realization of freeze-in for fermion dark matter.

Published by the American Physical Society
2024
Getting the most on supernova axions
Authors: Lella Alessandro , Carenza Pierluca , Co’ Giampaolo , Lucente Giuseppe , Giannotti Maurizio , Mirizzi Alessandro , Rauscher Thomas
Published: January 2024

Axionlike particles (ALPs) coupled to nucleons might be copiously emitted from a supernova (SN) core. We extend existing bounds on free-streaming ALPs to the case in which these are so strongly interacting with the nuclear matter to be trapped in the SN core. For strongly interacting ALPs, we also extend the bound from the absence of an ALP-induced signal in Kamiokande-II neutrino detector at the time of SN 1987A. We find that combining the different arguments, SNe exclude values of ALP-nucleon coupling gaN≳10−9 for ALP masses ma≲1  MeV. Remarkably, in the case of canonical QCD axion models, the SN bounds exclude all values of ma≳10−2  eV. This result prevents the possibility for current and future cosmological surveys to detect any signatures due to hot dark matter QCD axion mass.

Published by the American Physical Society
2024
Real-time dynamics of false vacuum decay
Authors: Batini Laura , Chatrchyan Aleksandr , Berges Jürgen
Published: January 2024

We investigate false vacuum decay of a relativistic scalar field initialized in the metastable minimum of an asymmetric double-well potential. The transition to the true ground state is a well-defined initial-value problem in real time, which can be formulated in nonequilibrium quantum field theory on a closed time path. We employ the nonperturbative framework of the two-particle irreducible (2PI) quantum effective action at next-to-leading order in a large-N expansion. We also compare to classical-statistical field theory simulations on a lattice in the high-temperature regime. By this, we demonstrate that the real-time decay rates are comparable to those obtained from the conventional Euclidean (bounce) approach. In general, we find that the decay rates are time dependent. For a more comprehensive description of the dynamics, we extract a time-dependent effective potential, which becomes convex during the nonequilibrium transition process. By solving the quantum evolution equations for the one- and two-point correlation functions for vacuum initial conditions, we demonstrate that quantum corrections can lead to transitions that are not captured by classical-statistical approximations.

Published by the American Physical Society
2024
Universal spectral correlations in interacting chaotic few-body quantum systems
Authors: Fritzsch Felix , Kieler Maximilian F. I.
Published: January 2024

The emergence of random matrix spectral correlations in interacting quantum systems is a defining feature of quantum chaos. We study such correlations in terms of the spectral form factor and its moments in interacting chaotic few- and many-body systems, modeled by suitable random-matrix ensembles. We obtain the spectral form factor exactly for large Hilbert space dimension. Extrapolating those results to finite Hilbert space dimension we find a universal transition from the noninteracting to the strongly interacting case, which can be described as a simple combination of these two limits. This transition is governed by a single scaling parameter. In the bipartite case we derive similar results also for all moments of the spectral form factor. We confirm our results by extensive numerical studies and demonstrate that they apply to more realistic systems given by a pair of quantized kicked rotors as well. Ultimately we complement our analysis by a perturbative approach covering the small-coupling regime.

Published by the American Physical Society
2024
No person is an island: how employees attribute and react to coworkers' approach crafting
Authors: Lin Xinyue , Tims Maria , Meng Liang
Published: January 2024

Purpose

Taking attribution theory as an overarching framework, the study aims to examine how employees attribute and respond to a colleague's approach crafting.

Design/methodology/approach

Two complementary studies, including a scenario experiment (Study 1; N = 114) and an online survey (Study 2; N = 220), were conducted to test the hypothesized model.

Findings

Study 1 found support for the attribution of a prosocial motive to approach crafting, which in turn led to more social support and less social undermining among observers. This mediation was stronger when the job crafter was perceived as less other-oriented. Study 2 replicated the findings of Study 1 and further showed that when observers attributed both high impression management and prosocial motives to approach crafting, the positive relationship between their prosocial motive attribution and social support for the job crafter got weakened, while the negative relationship between their prosocial motive attribution and social undermining of the job crafter was strengthened.

Originality/value

The findings demonstrate that approach crafting gives rise to specific attributions and reactions toward the job crafter, which enrich the understanding of the social consequences of job crafting in the workplace.
Nonmarket strategy and innovation performance in pharmaceutical industry: the moderating effect of internal capability and external IT environment
Authors: Li Yanyan , Gao Shanxing , Kwok Ron Chi-Wai
Published: January 2024

Purpose

The purpose of this study is to explore the relationship between nonmarket strategy and innovation performance, as well as the boundary factors that influence this relationship in the context of the pharmaceutical industry in emerging markets.

Design/methodology/approach

This study analyzed matched data of 227 Chinese pharmaceutical firms and two secondary databases with SPSS to examine the hypotheses.

Findings

Nonmarket strategy promotes the innovation performance. High level of firm internal knowledge utilization ability and strategic flexibility strengthens the effect of nonmarket strategy in promoting innovation performance, while information technology (IT) environment weakens the effect of nonmarket strategy in promoting innovation performance.

Originality/value

The research studies the positive impact of nonmarket strategy on innovation performance in the specific context of Chinese pharmaceutical industry, and it introduces the internal capabilities and external IT environment of the firm as moderators of the relationship between nonmarket strategy and innovation performance. More importantly, this research echoes the call for research on moderator of nonmarket strategy and identifies important boundary conditions. To the best of the authors’ knowledge, it also explores the impact of the IT environment on the implementation of nonmarket strategy for the first time, which deepens the research on nonmarket strategy’s effect on innovation.