bluuebunny/crossref_metadata_2025 huggingface dataset:
APACHE II-ECG scoring system: A novel and strong predictor of in-hospital mortality for patients treated in intensive care unit
Authors: Aslan Sefer , İşsever Kubilay , Olt Serdar , Yilmaz Emre , Kuloğlu Ersin , Tutak Ayşe Şahin
Published: December 2024

Some novel electrocardiographic (ECG) parameters, such as T-wave peak to T-wave end duration (Tp-Te) and Tp-Te/Q-T interval (QT) ratios, have recently been found to be associated with cardiac ischemia and effective in predicting ventricular arrhythmias and mortality. This study examined the association between ECG repolarization parameters and mortality in intensive care unit (ICU) patients. A total of 232 ICU patients were retrospectively categorized as survivors or nonsurvivors retrospectively. Laboratory, demographic, and ECG parameters were compared between the groups. A novel ECG score was measured using the QT interval, Tp-Te, and Tp-Te/QT ratio upon admission to the ICU. We compared the ECG score, Acute Physiologic and Chronic Health Evaluation II (APACHE II)-score, and APACHE II-ECG scores (the combination of APACHE II and ECG score) regarding mortality using a biostatistical program. The mean age of the 232 patients was 69.96 ± 18.01 years, and 49.1% were male. The nonsurvivor group was significantly older and had higher ECG, APACHE II, and APACHE II-ECG scores. Multivariate Cox regression analysis revealed that higher levels of all 3 scores were independent risk factors for mortality ([hazard ratio, HR (95% CI): 1.847 (1.305–2.615), P = .001], [HR (95%CI): 1.146 (1.071–1.225), P < .001], and [HR (95% CI): 1.181 (1.117–1.249), P < .001], respectively). Receiver operating curve analysis of these scoring systems for predicting mortality in the ICU revealed a stronger predictive value for the APACHE II-ECG score (AUC [95% CI]: 0.872 [0.824–0.919], P < .001, sensitivity: 88.7%, specificity: 73.3%). Kaplan–Meier survival analysis revealed the superiority of the APACHE II-ECG score in predicting the survival of ICU patients (log rank chi-square: 80.366, P < .001). Our study suggests combining ECG repolarization parameters with APACHE II score offers a new, more robust system for stronger mortality prediction in ICU patients.
A case report of varicella-zoster virus-related cerebral infarction in an AIDS patient
Authors: Cai Rentian , Yu Fengxue , Cheng Cong , Wei Hongxia
Published: December 2024

Rationale:

Acquired immune deficiency syndrome (AIDS) patients with varicella-zoster virus (VZV) encephalitis rarely progress to cerebral infarction. This case highlights the potential for such complications in immunocompromised individuals.

Patient concerns:

A 33-year-old male with AIDS experienced recurrent hospitalizations due to neurological complications associated with VZV.

Diagnoses:

During the course of 3 hospitalizations, the patient’s primary diagnoses included non-herpetic herpetic neuralgia, VZV meningoencephalitis, and cerebral infarction.

Interventions:

The patient initially presented with herpetic neuralgia due to VZV infection. Treatment with anti-VZV acyclovir, analgesics, and anti-human immunodeficiency virus therapy improved the patient’s condition, leading to discharge. However, 8 days later, the patient developed fever, slurred speech, nausea, and vomiting. Testing confirmed VZV-related meningoencephalitis with high VZV deoxyribonucleic acid levels in the cerebrospinal fluid. Treatment included ganciclovir, foscarnet, and dexamethasone. Later, the patient suffered an acute cerebral infarction, resulting in limb paralysis and aphasia. Treatment adjustments included additional medications for VZV, human immunodeficiency virus, inflammation, antiplatelet function, and plaque stabilization, leading to improvement.

Outcomes:

During rehabilitation, the patient has shown improvement in right limb paralysis and aphasia, achieving grade 4 muscle strength in the affected limb and enhanced basic communication abilities. However, complete recovery has not yet occurred.

Lessons:

This case emphasizes the rare but significant risk of cerebral infarction in AIDS patients with VZV infection. It underscores the importance of early diagnosis, aggressive management, and continuous monitoring of neurological symptoms to mitigate long-term disability and reduce mortality in this vulnerable population.
Dangerousness: T-wave pseudonormalization in a patient with Wellens’ syndrome: A case report
Authors: Lei Meixian , Yuan Mingqing , Gao Ling
Published: December 2024

Rationale:

Wellens’ syndrome electrocardiogram (ECG) pattern consists of symmetrically inverted (or biphasic) T waves in the precordial leads, frequently in V2–V3, which is associated with critical stenosis of the left anterior descending (LAD) coronary artery and impending myocardial infarction. Timely diagnosis and early treatment of Wernicke’s syndrome are of utmost importance. Here, we present the clinical characteristics and treatment outcomes of patients with Wellnes’ syndrome.

Patient concerns:

A 62-year-old male presented with intermittent chest pain for 6 days while resting, accompanied by chest tightness and sweating. On admission, the patient had no chest pain, vital signs were stable, and physical examination revealed no positive findings. ECG after admission revealed a normal sinus rhythm with poor progression of R waves in the precordial leads. Blood count, biochemical tests, and cardiac biomarkers were all within normal ranges. The patient’s ECG before admission revealed biphasic T waves in leads V2–V6.

Diagnoses and Interventions:

Dual antiplatelet, nitrate, and statin drugs were administered and the patient underwent urgent coronary angiography. The results revealed that the proximal LAD coronary artery was nearly completely occluded. Intravascular ultrasonography confirmed plaque rupture with thrombosis in the proximal LAD artery, with a minimum lumen area of 2.4 mm2. The patient was diagnosed with Wellens’ Syndrome. A drug-eluting stent was successfully implanted following balloon dilatation.

Outcomes:

The left ventricular ejection fraction and reexamination levels of troponin T and B-type natriuretic peptides were normal after the operation. The patient was discharged 6 days later.

Lessons:

Enhancing physicians’ awareness of the electrocardiographic patterns associated with Wellens’ syndrome facilitates the early identification of this condition, enabling the timely initiation of pharmacological and revascularization treatments for acute coronary syndrome. This proactive approach effectively mitigates the risk of acute myocardial infarction in patients and significantly improves their prognoses.
Facility-Level Differences in Antipsychotic Drug Use
Authors: Chen Amanda C. , Grabowski David C.
Published: December 2024

Objective:

To quantify quality of care following an admission to a nursing home with low or high antipsychotic drug use.

Background:

Misuse of antipsychotics in U.S. nursing homes is a huge concern for policymakers.

Methods:

We utilized an instrumental variable approach to estimate the effect of facility-level antipsychotic use on patient outcomes. The instrument was the differential distance to the nearest low-use antipsychotic nursing home relative to the nearest high-use antipsychotic nursing home. Post-acute care short-stay and long-stay residents in U.S. nursing homes were identified using Medicare administrative claims and the Minimum Dataset 3.0 (2014–2019). Outcomes included hospitalizations, falls, pressure ulcers, physical restraint use, medication use, and diagnosis of schizophrenia, bipolar disease, anxiety, or depression.

Results:

Among long-stay residents, receiving care from a low-use facility reduced the diagnosis of schizophrenia, use of restraints, and hospitalizations. There was also a reduction in the hospitalization rate [−0.9 percentage point (pp)], likelihood of long-stay status (−1.8 pp), and diagnosis of schizophrenia (−0.2 pp) at 90 days among short-stay residents. We also observed larger reductions among residents with dementia and serious mental illness.

Conclusions:

Admission to a nursing home with a low use of antipsychotics led to decreased hospitalizations, restraint use, and diagnosis of schizophrenia. Curbing the high use of antipsychotics remains a priority of policymakers as the centers for medicare and medicaid services conducts off-site audits to assess whether nursing homes accurately code residents with schizophrenia. It will be important to monitor if centers for medicare and medicaid services downgrades any quality star ratings due to inappropriate coding and assess the implications on quality of care.
Predicting Discharge Destination from Inpatient Rehabilitation Using Machine Learning
Authors: Anderson Hans E. , Polovneff Alexandra O. , Durand Matthew J.
Published: December 2024

Predicting discharge destination for patients at inpatient rehabilitation facilities is important as it facilitates transitions of care and can improve healthcare resource utilization. This study aims to build on previous studies investigating discharges from inpatient rehabilitation by employing machine learning models to predict discharge disposition to home versus non-home and explore related factors. Fifteen machine learning models were tested. A total of 4922 patient encounters from 4401 patients undergoing inpatient rehabilitation at a Midwestern academic center’s inpatient rehabilitation facilities were included. Input variables included demographic and hospital encounter-specific data. The total dataset contained 3687 discharges to home, and 1235 discharges to non-home destinations. A bagging classifier utilizing a decision tree base classifier utilizing random undersampling and without feature selection performed the best in terms of area under the receiver operating characteristic curve with a score of 0.722. Shapley value analysis suggested that length of stay, intravenous medication administration, urinary dysfunction, age, abnormalities white blood cell count or plasma sodium, and fatigue were the factors with the greatest impact on model output. Machine learning can help predict inpatient rehabilitation discharge disposition and identify factors associated with home or non-home discharges.
Autologous Fascia Nerve Wrap in a Rodent Primary Epineurial Repair Model and Preliminary Case Series
Authors: Rowley Emma K. , Zamore Zachary H. , Padovano William , Aslami Zohra V. , Qiu Chenhu , Mantilla-Rivas Esperanza , Weitzner Aidan S. , Suresh Rachana , Lee Erica B. , Tuffaha Sami H.
Published: December 2024

BACKGROUND:

Nerve wraps composed of various autologous and bioengineered materials have been used to bolster nerve repair sites. In this study, we describe the novel use of autologous fascia nerve wraps (AFNW) as an adjunct to epineurial repair and evaluate their effect on inflammatory cytokine expression, intraneural collagen deposition and end-organ reinnervation in rats and use of AFNW in a patient case series.

METHODS:

Lewis rats received sciatic transection with repair either with or without AFNW, sciatic-to-common peroneal nerve transfer with or without AFNW, or sham surgery (n=14/group). AFNW (1 cm2) were obtained from gluteal muscle fascia. Cytokine expression was assessed at both the coaptation site and L3-L5 dorsal root ganglia (DRG) at 4 weeks following repair using ELISA. Intraneural scarring and end-organ reinnervation were evaluated at 12 weeks. We also demonstrate the clinical application of AFNW for various potential indications in 28 patients.

RESULTS:

AFNW-treated animals demonstrated a significant (p<0.001) decrease in pro-inflammatory cytokines (TNF-α and IL-1β) and increase in anti-inflammatory cytokines (TGF-β and IL-10) within the L3-L5 DRGs and at the coaptation site. AFNW also resulted in reduced intraneural collagen content and an increased mean number of retrograde labeled sensory neurons (p<0.01). Patients receiving AFNW demonstrated favorable motor and sensory functional outcomes and no significant reports of neuropathic pain or other complications.

CONCLUSION:

AFNW serve as a valuable adjunct to epineurial coaptation that reduces intraneural inflammation and collagen deposition in both size-matched and size-mismatched nerve coaptations in a rodent model. Initial clinical experience with AFNW demonstrates feasibility for various indications.

CLINICAL RELEVANCE:

Our early clinical experience with AFNW demonstrates safety, practicality, technical feasibility, and cost-effectiveness and serves to identify a set of potential indications for nerve wrapping that warrant further consideration.
Multimodal Digital Phenotyping of Behavior in a Neurology Clinic: Development of the Neurobooth Platform and the First Two Years of Data Collection
Authors: Nunes Adonay S. , Patel Siddharth , Oubre Brandon , Jas Mainak , Kulkarni Divya D. , Luddy Anna C. , Eklund Nicole M. , Yang Faye X. , Manohar Rohin , Soja Nancy N. , Burke Katherine M. , Wong Bonnie , Isaev Dmitry , Espinosa Steven , Schmahmann Jeremy D. , Stephen Christopher D. , Wills Anne-Marie , Hung Albert , Dickerson Bradford C. , Berry James D. , Arnold Steven E. , Khurana Vikram , White Lawrence , Sapiro Guillermo , Gajos Krzysztof Z. , Khan Sheraz , Gupta Anoopum S.
Published: December 2024

Quantitative analysis of human behavior is critical for objective characterization of neurological phenotypes, early detection of neurodegenerative diseases, and development of more sensitive measures of disease progression to support clinical trials and translation of new therapies into clinical practice. Sophisticated computational modeling can support these objectives, but requires large, information-rich data sets. This work introduces Neurobooth, a customizable platform for time-synchronized multimodal capture of human behavior. Over a two year period, a Neurobooth implementation integrated into a clinical setting facilitated data collection across multiple behavioral domains from a cohort of 470 individuals (82 controls and 388 with neurologic diseases) who participated in a collective 782 sessions. Visualization of the multimodal time series data demonstrates the presence of rich phenotypic signs across a range of diseases. These data and the open-source platform offer potential for advancing our understanding of neurological diseases and facilitating therapy development, and may be a valuable resource for related fields that study human behavior.
Clear Cell Renal Cell Carcinoma: Unveiling Age-Linked Genetic Signatures, Relative Disease Aggressiveness, and Predictive Impact on Systemic Therapy
Authors: Pace-Loscos Tanguy , Dufies Maeva , Schiappa Renaud , Teisseire Manon , Chamorey Emmanuel , Kinget Lisa , Beuselinck Benoit , Borchiellini Delphine , Pagès Gilles
Published: December 2024

Background and objectives

Age influences the development and progression of clear cell renal cell carcinoma (ccRCC). Management of non-metastatic (M0) ccRCC involves surgery, adjuvant immune checkpoint inhibition (e.g., pembrolizumab) and surveillance. For metastatic (M1) ccRCC, treatment combines immune checkpoint inhibitors with anti-angiogenic therapies, achieving long-term remission in approximately 30% of patients. Despite these advancements, a definitive cure remains elusive for most individuals. Furthermore, predictive criteria for relapse that incorporate age-specific variations are lacking, highlighting the critical need for prognostic models to optimize outcomes across diverse age groups. This study aimed to validate tumor aggressiveness markers in ccRCC, focusing on age as a determinant factor.

Methods

Data from The Cancer Genome Atlas (TCGA) were analyzed to identify age-related gene expression differences, which were then validated using an independent cohort and ccRCC cell lines. Random Survival Forest models were employed to predict overall survival (OS) and disease-free survival (DFS) post nephrectomy and progression-free survival upon tyrosine kinase inhibitors and immunotherapies.

Key findings and limitations

Of 110 age-differentiated genes identified, 31 were significantly correlated with OS and DFS. Poor prognostic markers included CIAO1, EIF2B1, NARF, UBE2G2, and SART3, while TMEM167B emerged as a good prognostic marker, and a potential predictive biomarker for immunotherapy efficacy. Limitations include the need for larger independent cohort validation and deeper exploration of gene mechanisms.

Conclusions and clinical implications

The study presents age-informed prognostic models that integrate gene expression profiles, offering a foundation for personalized treatment strategies. TMEM167B stands out as a novel candidate for improving age-specific ccRCC management.

Advancing Practice

What does the study add?This study explores age-dependent differentially expressed genes in clear cell renal cell carcinoma (ccRCC) and proposes a potential age-specific prognostic gene signature that could be applicable to both non-metastatic and metastatic patients. This signature may assist in identifying individuals at higher risk of relapse. Among the identified genes,TMEM167Bis highlighted as a candidate associated with favorable prognosis and shows promise as a potential predictive biomarker for immunotherapy efficacy.

Patient Summary

Aggressiveness in ccRCC varies with age and gene expression. Tailored treatments based on these factors may enhance outcomes and minimize side effects, particularly for patients over 75 years of age.
Short and Late Term Mortality and Quality of Life in Patients Requiring Continuous Veno-Venous Hemofiltration after Cardiac Surgery
Authors: Duong Minh-Thu , Shariff Masood A , Haddad Fady G , Catella Paul , Salmane Chadi , Demissie Seleshi , El-Charabaty Elie , El-Sayegh Suzanne , McGinn Joseph T , Nabagiez John P
Published: December 2024

Purpose

Acute kidney injury (AKI) is a significant cause of morbidity and mortality post cardiac surgery sometimes requiring intermittent hemodialysis (IHD) or continuous veno-venous hemofiltration (CVVH). Previous studies included only procedures utilizing cardiopulmonary bypass (CPB). We reviewed CPB and non-CPB patients who developed AKI and required CVVH versus no CVVH.

Materials and Methods

141 patients undergoing adult cardiac surgery developed AKI. 70 required CVVH (group1) and 71 did not (group2). We compared 30 day mortality, renal recovery, respiratory status and late mortality between both groups.

Results

73% of patients in group1 required CVVH compared to 51% in group2 (p=0.007). Mortality was 38% versus 25% respectively at 1year (p=0.23) and 54% versus 17% respectively at 30 days (p<0.0001). Renal recovery was found in 47% versus 85%, freedom from ventilator support in 59% versus 83%, and discharge to long term nursing facility (LTNF) in 69% versus 44% respectively.

Conclusion

Mortality was significantly higher in CVVH group at 30 days but not at 1 year suggesting a long term benefit in those who survive the acute episode. The CVVH group demonstrated a higher rate of discharge to LTNF and lower rates of full renal recovery and freedom from ventilator support at discharge.
Autoantibodies to Arginine-rich Sequences Mimicking Epstein-Barr Virus in Post-COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
Authors: Hoheisel Friederike , Fleischer Kathrin Maria , Rubarth Kerstin , Sepúlveda Nuno , Bauer Sandra , Konietschke Frank , Kedor Claudia , Stein Annika Elisa , Wittke Kirsten , Seifert Martina , Bellmann-Strobl Judith , Mautner Josef , Behrends Uta , Scheibenbogen Carmen , Sotzny Franziska
Published: December 2024

Background

Epstein-Barr virus (EBV) infection is a known trigger and risk factor for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and post-COVID syndrome (PCS). In previous studies, we found enhanced IgG reactivity to EBV EBNA4 and EBNA6 arginine-rich sequences in postinfectious ME/CFS (piME/CFS).

Objective

This study aims to investigate IgG responses to arginine-rich (poly-R) EBNA4 and EBNA6 sequences and homologous human sequences in PCS and ME/CFS.

Methods

The IgG responses against poly-R EBNA4 and EBNA6 and corresponding homologous human 15-mer peptides and respective full-length proteins were analyzed using a cytometric bead array (CBA) and a multiplex dot-blot assay. Sera of 45 PCS patients diagnosed according to WHO criteria, with 26 patients fulfilling the Canadian Consensus criteria for ME/CFS (pcME/CFS), 36 patients with non-COVID post-infectious ME/CFS (piME/CFS), and 34 healthy controls (HC) were investigated.

Results

Autoantibodies to poly-R peptide sequences of the neuronal antigen SRRM3, the ion channel SLC24A3, TGF-β signaling regulator TSPLY2, angiogenic regulator TSPYL5, as well as to full-length α-adrenergic receptor (ADRA) proteins were more frequent in patients. Several autoantibodies were positively associated with key symptoms of autonomic dysfunction, fatigue, cognition, and pain.

Conclusion

Collectively, we identified autoantibodies with new antigen specificities with a potential role in PCS and ME/CFS.

Clinical Implication

These finding should prompt further studies on the function of these autoantibodies, their exploitation for diagnostic use, and of drugs targeting autoantibodies.

Capsule summary

Our study reveals elevated autoantibodies to EBV-related poly-R sequences and their human homologues in PCS and ME/CFS patients associated with symptom severity, suggesting a potential role in disease pathogenesis.
Cold Atmospheric Plasma Selectively Disrupts Breast Cancer Growth in a Bioprinted 3D Tumor Microenvironment Model
Authors: Bouret Laura M. , Billeau Jean-Baptiste , Weber Michael H. , Rosenzweig Derek H. , Reuter Stephan
Published: December 2024

Spine metastases are the most common bone site for breast cancer, with evolving surgery and multidisciplinary care improving outcomes. Current treatments, including chemotherapy and invasive surgery, may damage healthy tissue and may leave residual tumors that lead to recurrence. Cold atmospheric plasma (CAP) offers a non-invasive alternative by delivering reactive oxygen and nitrogen species (RONS) locally to tumor sites, selectively targeting cancer cells while sparing healthy tissue. To assess the impact and selectivity toward tumor cells adjacent to bone-like tissue, we develop a 3D bioprinted tumor-stroma model using a 1% alginate and 7% gelatin cell-laden hydrogel to mimic a bone-like microenvironment. The model co-cultures triple-negative MDA-MB-231 human breast cancer cells with primary human bone marrow mesenchymal stromal cells to simulate tumor-stroma interactions. The effects of CAP treatments are assessed through metabolic activity and viability assays over three days. Results show significant selectivity for cancer cells in both 2D and 3D cultures. CAP minimizes damage to healthy cells, offering the potential for localized treatment over systemic chemotherapies such as doxorubicin. Our novel bioprinted model, combined with a plasma source controlling RONS composition, enables detailed studies of redox-based cancer cell inactivation and highlights CAP as a personalized, non-invasive treatment for bone metastases.
Rapid clonal selection within early hematopoietic cell compartments presages outcome to ivosidenib combination therapy
Authors: Turkalj Sven , Stoilova Bilyana , Groom Angus J. , Radtke Felix A. , Mecklenbrauck Rabea , Jakobsen Niels Asger , Lachowiez Curtis A. , Metzner Marlen , Usukhbayar Batchimeg , Salazar Mirian Angulo , Zeng Zhihong , Loghavi Sanam , Marvin-Peek Jennifer , Koerber Verena , Ravandi Farhad , Issa Ghayas , Kadia Tapan , Symeonido Vasiliki , de Groot Anne P. , Kantarjian Hagop , Takahashi Koichi , Konopleva Marina , DiNardo Courtney D. , Vyas Paresh
Published: December 2024

Acquired resistance to targeted non-intensive therapies is common in myeloid malignancies. Yet, key questions remain as to how rapidly resistant clones are selected by treatment and in which hematopoietic cell compartments clonal selection occurs. To address this gap, we studied clonal responses to ivosidenib + venetoclax +/- azacitidine combination therapy in 8 patients with IDH1-mutant myeloid malignancy. Whilst all 8 patients initially responded to treatment, 6 relapsed and 2 remained in sustained remission for > 4 years. To study longitudinal clonal dynamics through hematopoietic differentiation, we performed high-sensitivity single-cell genotyping in index-sorted sequential patient samples. In all patients who relapsed, therapy-resistant clones were selected rapidly, within 1-3 treatment cycles, at times when hematopoiesis was still largely sustained by either normal or pre-leukemic cells. Selection of therapy-resistant clones preceded overt treatment failure by months or even years. Relapse was associated either with clones harboring newly-detected myeloid driver mutations or expansion of minor pre-existing clones that had reduced fitness prior to treatment. In both cases, resistant clones were selected within immature cell populations previously shown to contain leukemic stem cell (LSC) potential, preceding malignant expansion of these compartments by immunophenotyping. In contrast, in both patients remaining in remission, leukemic clones were eradicated and rapidly replaced by clonal and wild-type hematopoiesis. These observations suggest that, in patients treated with non-intensive ivosidenib combination therapy, rapid clonal selection occurs in populations with LSC potential, where failure to eliminate either genetically evolved or persistent leukemic clones ultimately leads to relapse.
Computational Disruption of Paired Helical Filaments (PHFs) Assembly Using Milk Lactalbumin-derived Peptides Against Alzheimer’s Disease
Authors: Pourmand Saeed , Zareei Sara , Jozi Mohanna , Massahi Shokoufeh
Published: December 2024

Peptides show great potential in diagnosing and treating Alzheimer’s disease (AD), particularly by targeting amyloid-beta plaques and neurofibrillary tangles (NFTs) formed by hyperphosphorylated tau proteins. This study focuses on designing peptide inhibitors from bovine milk alpha-lactalbumin to reduce tau aggregation in AD. Using computational techniques, such as docking, molecular dynamics simulations, and mutagenesis, we evaluated the binding and stability of these peptides against the paired helical filament (PHF) core. Our results identified promising inhibitors, with p136 emerging as the most effective. It significantly altered the PHF core’s structure, preventing further aggregation by blocking additional subunits. Additionally, p76 displayed strong binding against straight filaments (SFs). These findings highlight the potential of peptides derived from bovine milk alpha-lactalbumin as diagnostic and therapeutic tools for AD, with p136 standing out as a promising candidate for disrupting tau aggregation.
The role of local and long-range stresses in cephalic furrow formation in theDrosophila melanogasterembryo
Authors: Niloy Redowan A. , Gao Guo-Jie J. , Holcomb Michael C. , Thomas Jeffrey H. , Blawzdziewicz Jerzy
Published: December 2024

Cephalic furrow (CF) is a transient epithelial invagination that forms during early gastrulation in theDrosophila melanogasterembryo. The initial stage of cephalic furrow formation (CFF) involves a shortening of initiator cells, generation of a localized asymmetric protrusion inwards, and then subsequent descent of cells into the yolk sac area. We present an analysis of how local forces associated with cell-membrane tensions and cell pressures interact with the long-range tensile stress developing along the furrow to generate the invagination. We propose two numerical models which capture different aspects of CFF. First, we formulate a force-center model of CF to show how the spatiotemporal heterogeneity of initiator-cell activation observedin vivois a result of tensile-stress-feedback-based intercellular coordination. We also argue that this kind of mechanical stress-based activation mechanism likely contributes to robustness of the overall process. Second, we use our multi-node lateral vertex model to analyze the mechanical dynamics of the anterior–posterior cross-section of CF. This approach allows us to quantify the balance between cortical membrane tension forces, cellular pressures, and the inward force produced by the tension along the curved apical surface of the embryo. Comparing our simulations to experimental images, we discuss the crucial and indispensable role of the tension-induced inward force, especially during the initial stages of CFF where the localized asymmetric protrusion is formed. We argue that without this inward force the initial descent of the initiator cells into the furrow would not be possible, and that at later stages the inward force provides redundancy to this process and thus aids CFF robustness.
Analysis of mouse lens morphological and proteomic abnormalities following depletion of βB3-crystallin
Authors: Rayêe Danielle , Wilmarth Phillip A. , VanSlyke Judy K. , Zientek Keith , Reddy Ashok P. , Musil Linda S. , David Larry L. , Cvekl Ales
Published: December 2024

Crystallin proteins serve as both essential structural and as well as protective components of the ocular lens and are required for the transparency and light refraction properties of the organ. The mouse lens crystallin proteome is represented by αA-, αB-, βA1-, βA2-, βA3-, βA4-, βB1-, βB2-, βB3-, γA-, γB-, γC-, γD-, γE, γF-, γN-, and γS-crystallin proteins encoded by 16 genes. Their mutations are responsible for lens opacification and early onset cataract formation. While many cataract-causing missense and nonsense mutations are known for these proteins, including the human CRYBB3 gene, the mammalian loss-of function model of theCrybb3gene remains to be established. Herein, we generated the first mouse model via deletion of the Crybb3 promoter that abolished expression of the βB3-crystallin. Histological analysis of lens morphology using newborn βB3-crystallin-deficient lenses revealed disrupted lens morphology with early-onset phenotypic variability. In-depth lens proteomics at four time points (newborn, 3-weeks, 6-weeks, and 3-months) showed both down- and up-regulation of various proteins, with the highest divergence from control mice observed in 3-months lenses. Apart from the βB3-crystallin, another protein Smarcc1/Baf155 was down-regulated in all four samples. In addition, downregulation of Hspe1, Pdlim1, Ast/Got, Lsm7, Ddx23, and Acad11 was found in three time points. Finally, we show that the βB3-crystallin promoter region, which contains multiple binding sites for the transcription factors AP-2α, c-Jun, c-Maf, Etv5, and Pax6 is activated by FGF2 in primary lens cell culture experiments. Together, these studies establish the mouseCrybb3loss-of-function model and its disrupted crystallin and non-crystallin proteomes.
Bipolar and schizophrenia risk geneAKAP11encodes an autophagy receptor coupling the regulation of PKA kinase network homeostasis to synaptic transmission
Authors: Lee You-Kyung , Xiao Cong , Zhou Xiaoting , Wang Le , McReynolds Meghan G. , Wu Zhiping , Purisic Eric , Kim Henry , Li Xianting , Pang Zhiping , Dai Jinye , Peng Junmin , Yang Nan , Yue Zhenyu
Published: December 2024

Human genomic studies have identified protein-truncating variants inAKAP11associated with both bipolar disorder and schizophrenia, implicating a shared disease mechanism driven by loss-of-function. AKAP11, a protein kinase A (PKA) adaptor, plays a key role in degrading the PKA-RI complex through selective autophagy. However, the neuronal functions of AKAP11 and the impact of its loss-of-function remains largely uncharacterized. Through multi-omics approaches, cell biology, and electrophysiology analysis in mouse models and human induced neurons, we delineated a central role of AKAP11 in coupling PKA kinase network regulation to synaptic transmission. Loss of AKAP11 distorted PKA activity and impaired cellular functions that significantly overlap with pathways associated with the psychiatric diseases. Moreover, we identified interactions between AKAP11, the PKA-RI adaptor SPHKAP, and the ER-resident autophagy-related proteins VAPA/B, which co-adapt and mediate PKA-RI complex degradation in neurons. Notably, AKAP11 deficiency impaired neurotransmission, providing key insights into the mechanism underlyingAKAP11-associated psychiatric diseases.
RNAGenesis: Foundation Model for Enhanced RNA Sequence Generation and Structural Insights
Authors: Zhang Zaixi , Chao Linlin , Jin Ruofan , Zhang Yikun , Zhou Guowei , Yang Yujie , Yang Yukang , Huang Kaixuan , Yang Qirong , Xu Ziyao , Zhang Xiaoming , Cong Le , Wang Mengdi
Published: December 2024

RNA molecule plays an essential role in a wide range of biological processes. Gaining a deeper understanding of their functions can significantly advance our knowledge of life’s mechanisms and drive the development of drugs for various diseases. Recently, advances in RNA foundation models have enabled new approaches to RNA engineering, yet existing methods fall short in generating novel sequences with specific functions. Here, we introduce RNAGenesis, a foundation model that combines RNA sequence understanding and de novo design through latent diffusion. With a Bert-like Transformer encoder with Hybrid N-Gram tokenization for encoding, a Query Transformer for latent space compression, and an autoregressive decoder for sequence generation, RNAGenesis reconstructs RNA sequences from learned representations. Specifically for the generation, a score-based denoising diffusion model is trained to capture the latent distribution of RNA sequences. RNAGenesis outperforms current methods in RNA sequence understanding, achieving the best results in 9 of 13 benchmarks (especially in RNA structure prediction), and further excels in designing natural-like aptamers and optimized CRISPR sgRNAs with desirable properties. Our work establishes RNAGenesis as a powerful tool for RNA-based therapeutics and biotechnology.
Central cholinergic degeneration in prodromal and early manifest Parkinsons disease: relation to cognition, clinical phenotype, and future conversion
Authors: Eisenstein Tamir , Groenewald Karolien , van Hillegondsberg Ludo , Al Hajraf Falah , Zerenner Tanja , Lawton Michael A , Ben-Shlomo Yoav , Griffanti Ludovica , Hu Michele T , Klein Johannes C
Published: December 2024

The neuropathological process in Parkinson’s disease (PD) and Lewy body disorders has been shown to extend well beyond the degeneration of the dopaminergic system, affecting other neuromodulatory systems in the brain which play crucial roles in the clinical expression and progression of these disorders.

Here, we investigate the role of the macrostructural integrity of the nucleus basalis of Meynert (NbM), the main source of cholinergic input to the cerebral cortex, in cognitive function, clinical manifestation, and disease progression in non-demented subjects with PD and individuals with isolated REM sleep behaviour disorder (iRBD).

Using structural MRI data from 393 early PD patients, 128 iRBD patients, and 186 controls from two longitudinal cohorts, we found significantly lower NbM grey matter volume in both PD (β=-12.56,p=0.003) and iRBD (β=-16.41,p=0.004) compared to controls. In PD, higher NbM volume was associated with better higher-order cognitive function (β=0.12,p=0.012), decreased non-motor (β=-0.66,p=0.026) and motor (β=-1.44,p=0.023) symptom burden, and lower risk of future conversion to dementia (Hazard ratio (HR)<0.400,p<0.004). Higher NbM volume in iRBD was associated with decreased future risk of phenoconversion to PD or dementia with Lewy bodies (DLB) (HR<0.490,p<0.016). However, despite similar NbM volume deficits to those seen in PD, associations between NbM structural deficits and current disease burden or clinical state were less pronounced in iRBD.

These findings identify NbM volume as a potential biomarker with dual utility: predicting cognitive decline and disease progression in early PD, while also serving as an early indicator of phenoconversion risk in prodromal disease. The presence of structural deficits before clear clinical correlates in iRBD suggests complex compensatory mechanisms may initially mask cholinergic dysfunction, with subsequent failure of these mechanisms potentially contributing to clinical conversion.
Targeting AML Resistance with LY3009120-Sapanisertib and Ruxolitinib-Ulixertinib Combinations Demonstrate Superior Efficacy inFLT3,TP53,andMUC4mutations
Authors: Gholizadeh Elham , Zangene Ehsan , Parsons Alun , Kontro Mika , Heckman Caroline A. , Jafari Mohieddin
Published: December 2024

Acute myeloid leukemia (AML) is a genetically heterogeneous malignancy characterized by the clonal expansion of myeloid precursor cells. Advances in genomic profiling have enhanced our understanding of AML pathogenesis, leading to the identification of recurrent mutations, includingTP53, FLT3, MUC4, RAS,andIDH1/2. These mutations significantly influence treatment response and prognosis, withTP53mutations conferring poor outcomes and resistance to conventional therapies. Despite the advent of venetoclax-based regimens, resistance mechanisms persist, necessitating the development of novel therapeutic strategies. This study aims to investigate the efficacy of drug combinations for the treatment of AML using bothin vitroAML cell lines and anin vivozebrafish embryo xenograft model. Specifically, we focus on two drug combinations; the pan-RAF inhibitor LY3009120 combined with the mTOR inhibitor sapanisertib (designated as LS), and the JAK1/2 inhibitor ruxolitinib combined with the ERK inhibitor ulixertinib (designated as RU). The study integrates real-time cell viability assays, xenograft imaging, and genomic analyses to assess drug efficacy and explore correlations between treatment responses and mutational profiles, particularlyTP53, FLT3, and MUC4mutations. Both combinations, LS and RU, demonstrated superior efficacy compared to venetoclax-based treatments in reducing cell viability across AML cell lines. The LS combination showed significant reductions in cell viability in MOLM16 and SKM cells, while RU exhibited comparable efficacy with lower toxicity profiles. In zebrafish embryos, the LS combination effectively inhibited the proliferation of xenografted human AML cells, as evidenced by decreased fluorescence signals, indicating cell death. The RU combination also disrupted survival signaling pathways, showing promise as a therapeutic strategy. Furthermore, a correlation was identified between drug response and mutational profiles, withTP53, FLT3 and MUC4mutations significantly influencing sensitivity to the LS and RU combinations. These findings support the further development of LS and RU as effective alternatives to current clinical regimens, with implications for personalized AML treatment.
scRepertoire 2: Enhanced and Efficient Toolkit for Single-Cell Immune Profiling
Authors: Yang Qile , Safina Ksenia R. , Borcherding Nicholas
Published: December 2024

Single-cell adaptive immune receptor repertoire sequencing (scAIRR-seq) and single-cell RNA sequencing (scRNA-seq) provide a transformative approach to profiling immune responses at unprecedented resolution across diverse pathophysiologic contexts. This work presents scRepertoire 2, a substantial update to our R package for analyzing and visualizing single-cell immune receptor data. This new version introduces an array of features designed to enhance both the depth and breadth of immune receptor analysis, including improved workflows for clonotype tracking, repertoire diversity metrics, and novel visualization modules that facilitate longitudinal and comparative studies. Additionally, scRepertoire 2 offers seamless integration with contemporary single-cell analysis frameworks like Seurat and SingleCellExperiment, allowing users to conduct end-to-end immune profiling with transcriptomic data. Performance optimizations in scRepertoire 2 substantially reduce computational time and memory usage, addressing the demands of the ever-increasing size and scale of single-cell studies. This release marks an advancement in single-cell immunogenomics, equipping researchers with a robust toolset to uncover immune dynamics in health and disease.
Shear and bulk viscosity of the quark-gluon plasma with Gribov gluons and quasiparticle quarks
Authors: Madni Sadaf , Mukherjee Arghya , Jaiswal Amaresh , Haque Najmul
Published: December 2024

In this study, we analyze the transport properties of the quark-gluon plasma (QGP), focusing on bulk (ζ) and shear (η) viscosities at vanishing chemical potential. To describe the QGP, we employ a quasiparticle model for quarks along with Gribov’s prescription for gluons, which effectively captures nonperturbative dynamics. The Gribov parameter γG and the dynamical mass mg are obtained by solving the one-loop gap equation in the MS¯ renormalization scheme and further using lattice QCD data for the equation of state (EOS) of pure gluonic matter. The interaction between quarks and gluons is reflected in the quark quasimass mq, again obtained using lattice EOS data for (2+1)-flavor QCD. Our primary goal is to investigate the influence of quasiquarks on the transport coefficients of QGP. Interestingly, we find a substantial decrease in the scaled transport coefficients with rising temperatures within the range (1≤T/Tc≤3.5).

Published by the American Physical Society
2024
Randomized low-rank decompositions of nuclear three-body interactions
Authors: Tichai A. , Arthuis P. , Hebeler K. , Heinz M. , Hoppe J. , Miyagi T. , Schwenk A. , Zurek L.
Published: December 2024

First-principles simulations of many-fermion systems are commonly limited by the computational requirements of processing large data objects. As a remedy, we propose the use of low-rank approximations of three-body interactions, which are the dominant such limitation in nuclear physics. We introduce a randomized decomposition technique to handle the excessively large matrix dimensions and study the sensitivity of low-rank properties to interaction details. The developed low-rank three-nucleon interactions are benchmarked in simulations of few- and many-body systems. Exploiting low-rank properties provides a promising route to extend the microscopic description of atomic nuclei to large systems where storage requirements exceed the computational capacities of the most advanced high-performance computing facilities.

Published by the American Physical Society
2024
Unconventional Coherence Peak in Cuprate Superconductors
Authors: Li Zheng , Mu Chao , Li Pengfei , Wu Wei , Hu Jiangping , Xiang Tao , Jiang Kun , Luo Jianlin
Published: December 2024

The Hebel-Slichter coherence peak, observed in the spin-lattice relaxation rate 1/T1 just below the critical temperature Tc, serves as a crucial experimental validation of the Bardeen-Cooper-Schrieffer pairing symmetry in conventional superconductors. However, no coherence peak in 1/T1 has been observed in unconventional superconductors like cuprates. In this study, an unconventional coherence peak is identified for the first time using nuclear quadrupole resonance on YBa2Cu4O8, pointing to a distinctive pairing symmetry. The spin-lattice relaxation rate in nuclear quadrupole resonance and nuclear magnetic resonance with nuclear spin I>1/2 comprises the magnetic relaxation rate 1/T1mag, which probes magnetic fluctuations, and the quadrupole relaxation rate 1/T1quad, which probes charge fluctuations. By utilizing Cu63 and Cu65 isotopes, we successfully distinguish 1/T1mag and 1/T1quad of YBa2Cu4O8 and reveal the presence of the coherence peak in 1/T1quad but not in 1/T1mag, in contrast to conventional superconductors. Our finding demonstrates that unconventional superconductors do not exhibit a coherence peak in 1/T1 when the relaxation is due to fluctuations of the hyperfine field. Conversely, a coherence peak is expected when the relaxation is caused by electric field gradient fluctuations, due to the different coherence factors between charge and magnetic fluctuations. Our successful measurements of 1/T1 for the chains of YBa2Cu4O8 suggest that, should the conditions for predominant quadrupole relaxation be satisfied, this phenomenon could provide a novel approach to exploring the unconventional nature of the pairing mechanism in other superconductors.

Published by the American Physical Society
2024
Sparse Probabilistic Synthesis of Quantum Operations
Authors: Koczor Bálint
Published: December 2024

Successful implementations of quantum technologies require protocols and algorithms that use as few quantum resources as possible. However, many important quantum operations, such as continuous rotation gates in quantum computing or broadband pulses in NMR or magnetic resonance imaging (MRI) applications, can only be implemented approximately using finite quantum resources. This work develops an approach that, on average—at the cost of a modestly increased measurement repetition rate—enables exact implementations. One proceeds by first building a library of a large number of different approximations to the desired gate operation; by randomly selecting these operations according to a preoptimized probability distribution, one can on average implement the desired operation with a rigorously controllable approximation error. The approach relies on sophisticated tools from convex optimization to efficiently find optimal probability distributions. A diverse spectrum of applications are demonstrated as (a) exactly synthesizing rotations in fault-tolerant quantum computers using only low T-count circuits and (b) synthesizing broadband and band-selective pulses of superior performance in quantum optimal control with (c) further applications in NMR or MRI. The approach is very general and a broad spectrum of practical applications in quantum technologies are explicitly demonstrated.

Published by the American Physical Society
2024
Impact pathways: walking a tightrope—unveiling the paradoxes of adopting artificial intelligence (AI) in sales and operations planning
Authors: Jazairy Amer , Shurrab Hafez , Chedid Fabienne
Published: December 2024

Purpose

This research aims to examine the potential tensions and management strategies for adopting artificial intelligence (AI) within Sales and Operations Planning (S&OP) environments.

Design/methodology/approach

We conducted in-depth interviews with eight S&OP professionals from different manufacturing firms, supplemented by interviews with AI solutions experts and secondary document analysis of various S&OP processes, to scrutinize the paradoxes associated with AI adoption in S&OP.

Findings

We revealed 12 sub-paradoxes associated with AI adoption in S&OP, culminating in 5 overarching impact pathways: (1) balancing immediate actions with long-term AI-driven strategies, (2) navigating AI adoption via centralized systems, process redesign and data unification, (3) harmonizing AI-driven S&OP identities, collaboration and technology acceptance, (4) bridging traditional human skills with innovative AI competencies and (5) managing the interrelated paradoxes of AI adoption in S&OP.

Practical implications

The findings provide a roadmap for firms to proactively address the possible tensions associated with adopting AI in S&OP, balancing standardization with flexibility and traditional expertise with AI capabilities.

Originality/value

This research offers (1) a nuanced understanding of S&OP-specific paradoxes in AI adoption, contributing to the broader literature on AI within operations management and (2) an extension to Paradox Theory by uncovering distinct manifestations at the AI–S&OP intersection.
Employee demand–ability fit and promotability ratings: a moderated mediation model of task performance and political skill
Authors: Chen Hsien Chun , Ng Chin Tung Stewart , Chen I-Heng , Chen Yi-Ting , Polacek Michal , Liang Ying-Lun
Published: December 2024

Purpose

The study explores the mechanism between employee demand–ability fit and promotability ratings. Moreover, we examine whether political skill moderates the relationship above.

Design/methodology/approach

The present study received 260 effective supervisor-rated questionnaires from various industries in Taiwan.

Findings

The results reveal that employee demand–ability fit positively relates to promotability ratings, and task performance mediates the above relationship. In addition, political skill positively moderates the relationship between employee demand–ability fit and task performance.

Originality/value

We used the supervisor rating for our variables to test the hypotheses.