bluuebunny/crossref_metadata_2025 huggingface dataset:
Modulating Sympathetic Nervous System With the Use of SGLT2 Inhibitors: Where There Is Smoke, There Is Fire?
Authors: Dimitriadis Kyriakos , Pitsiori Daphne , Alexiou Polyxeni , Pyrpyris Nikolaos , Sakalidis Athanasios , Beneki Eirini , Iliakis Panagiotis , Tatakis Fotis , Theofilis Panagiotis , Tsioufis Panagiotis , Konstantinidis Dimitrios , Aggeli Konstantina , Tsioufis Konstantinos
Published: October 2024

Heart failure (HF) has become even more prevalent in recent years, because of improved diagnostics and an increase in the risk factors predisposing to its pathology. Sodium–glucose cotransporter 2 inhibitors (SGLT2i) emerged as one of the key pharmacotherapy options for both reduced and preserved ejection fraction, providing cardio- and renoprotection and improving mortality and cardiovascular (CV) outcomes. The pleiotropism of SGLT2i has led to multiple efforts to understand their distinct pathophysiologic interactions with various pathways, including microcirculation, endothelial dysfunction, and inflammation. More recently, the role of SGLT2i on the sympathetic nervous system (SNS) is starting to be recognized, especially because observations of retained or reduced heart rate despite volume contraction have been noted by investigators in the large clinical trials testing the safety and efficacy of these agents. Both preclinical and clinical studies have been performed, with conflicting results. Interestingly, in both settings, although there are indications of SNS modulation by SGLT2i, other studies contradict such findings, without showing, however, worsening of the autonomic homeostasis. Given the importance of neuromodulation in HF, in both pharmacologic and interventional therapies, in this review, we aim to describe the role of SNS in CV disease, focusing on HF, analyze preclinical and clinical data regarding the efficacy of SGLT2i in modulating autonomic dysfunction by examining various markers of SNS activation, and provide the most plausible theoretical backgrounds on the mechanism of benefit of SNS from the inhibition of SGLT2 receptors.
Liquid Chromatography–Tandem Mass Spectrometry Method for Therapeutic Drug Monitoring of Dalbavancin in Plasma of Pediatric and Young Adult Patients
Authors: Cafaro Alessia , Mariani Marcello , Pigliasco Federica , Baiardi Giammarco , Barco Sebastiano , Biondi Margherita , Mesini Alessio , Russo Chiara , Saffioti Carolina , Mattioli Francesca , Castagnola Elio , Cangemi Giuliana
Published: October 2024

Background:

Dalbavancin, an antimicrobial lipoglycopeptide, is authorized in Europe for treating acute bacterial infections of the skin and skin structures in adults and pediatric patients aged 3 months and older. However, off-label dosing regimens have been proposed for various indications beyond acute bacterial infections of the skin and skin structures. This study presents a novel bioanalytical method using liquid chromatography–tandem mass spectrometry to quantify dalbavancin in low-volume plasma samples (50 μL).

Methods:

The method underwent validation in accordance with international guidelines for bioanalytical method validation and was applied to 9 clinical samples obtained from pediatric and young adult patients undergoing dalbavancin therapy. Liquid chromatography–tandem mass spectrometry analyses were conducted at the G. Gaslini Institute in Genoa, Italy, utilizing an Ultimate 3000 ultra high performance liquid chromatography system coupled to a TSQ Quantiva Triple Quadrupole system (Thermo Fisher Scientific, Milan, Italy). The analytical procedure involved the addition of deuterated dalbavancin as internal standard and a rapid extraction from 50 µL of human plasma, followed by chromatographic separation on a Thermo Scientific Accucore Polar Premium column. Accurate quantification of the analyte was achieved through multiple reaction monitoring detection.

Results:

The assay exhibited linearity within the concentration range of 0.66–400 mcg/mL in plasma, demonstrating accuracy and reproducibility in the absence of matrix effects. Stability testing was conducted on both quality controls and real samples to establish a robust protocol under real-life conditions.

Conclusions:

This fast and reliable dalbavancin quantitation method could improve current pediatric clinical practice by enabling data collection for future dose recommendations in special patient populations.
Hyponatremia in Critically Ill Patients Due to Continuous Venovenous Hemofiltration With Diluted Sodium Citrate
Authors: Zadek Francesco , Brunoni Beatrice , Mulazzani Francesca , Minotti Francesco , Faraldi Loredana , Tardini Francesca , Giudici Riccardo , Paccagnini Stefania , De Angelis Maria Luisa , Fumagalli Roberto , Langer Thomas
Published: October 2024

Continuous venovenous hemofiltration (CVVH) is frequently performed in critically ill patients using diluted citrate for regional anticoagulation. The impact of this renal replacement strategy on plasma sodium has not been evaluated yet. Our aim was therefore to assess the period prevalence of hyponatremia (sodium <135 mmol/L) during CVVH and discuss possible underlying mechanisms. After 48 hours of treatment, 70% of the 27 oligo-anuric critically ill patients were hyponatremic, despite the use of dialysis fluid bags (Regiocit 18/0, Phoxilium by Baxter, Deerfield, IL, and Multibic K2 by Fresenius Medical Care AG & Co. KGaA, Bad Homburg, Germany) with sodium content of 140 mmol/L. Indeed, sodium decreased from 142 ± 7 to 135 ± 3 mmol/L, p < 0.001. Sodium concentrations of employed dialysis bags were confirmed using ion chromatography. However, ionized sodium of Regiocit measured with a direct-ion selective electrode (ISE) resulted lower (~118 mmol/L), suggesting the presence of sodium-to-citrate complexes. Possible mechanisms explaining the hyponatremia development could therefore include: i) plasma water dilution; ii) a reduced Gibbs-Donnan effect, given the low albumin concentration (2.6 ± 0.8 g/dl) of our critically ill patients; iii) a negative sodium balance due to the loss of sodium-to-citrate complexes across the filter. The clinical implications of the described hyponatremia and the different contributions of the hypothesized mechanisms need to be addressed in future studies.
Pre-sacral glomangioma: a rare localization of glomus tumors: case report
Authors: Mseddi Mohamed Ali , Siala Rakia , Yaakoubi Chaima , Saad Sarra , Zeheni Kassar Alia , Nouri Takwa , Guizeni Rami , Sassi Karim , Ben Slima Mohamed
Published: October 2024

Introduction and importance:

Deep-located glomangiomas are rarely reported. Because of their scarcity, treatment strategy is hard to establish. Herein, the authors report the first case to our knowledge of pre-sacral glomangioma.

Case presentation:

A 34-year-old female patient, with no previous medical history, consulted for 2-month-old pelvic abdominal pain, vomiting and delayed menstruation. Her physical and biological parameters were with no abnormalities. MRI of the pelvis demonstrated a 14 cm mixed heterogeneous pre-sacral lesion pushing the rectum anteriorly. She was operated on via a laparoscopic approach. Division of Douglas’ pouch and pelvic peritoneum laterally to the bladder showcased a cystic lesion of 13×8 cm occupying the pelvis while deviating the rectum anteriorly. Its content was aspirated and left membrane was extracted in a sac. The postoperative course was uneventful.

Discussion:

Pre-sacral masses are hard to treat because of their large heterogeneity. Surgical resection should be tempted to retrieve the definitive histological diagnosis and relieve the patient. However, the surgical route is controversial as each approach has its advantages. Thus, the surgical route should take into consideration the lesion’s size, height and surrounding contacts, the patient’s functional state and surgeon’s expertise.

Conclusion:

Pre-sacral glomangiomas carries a low malignant pattern but should be resected to offer histological diagnosis. The surgical route remains at the surgeon’s decision, with the main objective to totally resect the encountered lesion without causing functional and sexual complications or harm to surrounding viscera.
Hodgkin lymphoma in pre-existing thymoma: a case report
Authors: AbuKhalaf Rahaf M. , Zeer Zahraa M. M. , Abu Harb Zahra Hosam , Kamal Nazmi , Alseedat Yasmin , Sughayer Maher A.
Published: October 2024

Introduction:

Thymus is a primary lymphoid organ which has an important role in humoral and cellular immunity. It can be a site for various neoplasms including thymomas.

Case presentation:

The authors report a case of a 55-year-old patient presenting with weight loss, night sweats and sensation of heat. After thorough evaluation his histopathology analysis revealed the rare presence of Hodgkin lymphoma in a background of type B2 thymoma.

Discussion:

Thymoma is one of the well-known thymic tumors that is encountered in clinical practice. It has diverse associations with other autoimmune diseases and malignancies. The concurrent diagnosis of thymoma with thymic Hodgkin lymphoma is extremely rare.

Conclusion:

Although this association is very rare, it is crucial to distinguish between thymic Hodgkin lymphoma and thymoma and manage them appropriately.
Identification of potential immune-related genes and infiltrations in temporomandibular joint osteoarthritis
Authors: Zhu Mengjiao , Xing Min , Sun Ruinan , Li Minhui , Qian Wenhao , Fan Mingyue
Published: October 2024

Objective:

The aim of this study was to investigate the potential inflammatory cytokines and chemokines markers for temporomandibular joint osteoarthritis (TMJOA) diagnosis using a bioinformatics analysis.

Methods:

The differentially expressed genes of mRNA (DEGs) and transcripts of lncRNA (DETs) were identified between TMJOA samples and normal controls curated from GSE205389 by the “DESeq. 2” R package. KEGG and GO were conducted using the R package “ggplot2” and “clusterProfiler”. A PPI network was constructed to identify hub genes by using the STRING and Cytoscape. The co-expression network was constructed between mRNA and lncRNA to check the potential regulation and function of lncRNA on protein-coding genes. Finally, the immune cell infiltration analysis was conducted with CIBERSORTx and confirmed with xCells.

Results:

The authors identified 171 DEGs and DETs, of which the DEGs were closely related to immune response, T-cell activation, cytokine-cytokine-receptor interaction, and the muscle system process. PPI network of the DEGs screened the top 10 hub genes, including IL6, IL1B, IL10, CCL2, CCL5, CXCL1, CXCL10, ICAM1, CSF1 and MMP1. Additionally, the immune cell infiltration analysis showed that CD8+ T cells, M1 macrophage and B cells infiltration were increased in TMJOA samples. Finally, the authors demonstrated that the co-expression between mRNA and lncRNA was mainly enriched in inflammatory and muscle-related pathways.

Conclusions:

The authors found that immune and muscle system-related pathways as well as the immune infiltration played a significant role in the TMJOA development. Additionally, inflammatory cytokines and chemokines could be crucial markers for early-stage TMJOA diagnosis and personalized treatment strategies.
Significance of Image Reconstruction Parameters for Future Lung Cancer Risk Prediction Using Low-Dose Chest Computed Tomography and the Open-Access Sybil Algorithm
Authors: Simon Judit , Mikhael Peter , Graur Alexander , Chang Allison E.B. , Skates Steven J. , Osarogiagbon Raymond U. , Sequist Lecia V. , Fintelmann Florian J.
Published: October 2024

Purpose

Sybil is a validated publicly available deep learning–based algorithm that can accurately predict lung cancer risk from a single low-dose computed tomography (LDCT) scan. We aimed to study the effect of image reconstruction parameters and CT scanner manufacturer on Sybil's performance.

Materials and Methods

Using LDCTs of a subset of the National Lung Screening Trial participants, which we previously used for internal validation of the Sybil algorithm (test set), we ran the Sybil algorithm on LDCT series pairs matched on kilovoltage peak, milliampere-seconds, reconstruction interval, reconstruction diameter, and either reconstruction filter or axial slice thickness. We also evaluated the cumulative effect of these parameters by combining the best- and the worst-performing parameters. A subanalysis compared Sybil's performance by CT manufacturer. We considered any LDCT positive if future lung cancer was subsequently confirmed by biopsy or surgical resection. The areas under the curve (AUCs) for each series pair were compared using DeLong's test.

Results

There was no difference in Sybil's performance between 1049 pairs of standard versus bone reconstruction filter (AUC at 1 year 0.84 [95% confidence interval (CI): 0.70–0.99] vs 0.86 [95% CI: 0.75–0.98], P = 0.87) and 1961 pairs of standard versus lung reconstruction filter (AUC at 1 year 0.98 [95% CI: 0.97–0.99] vs 0.98 [95% CI: 0.96–0.99], P = 0.81). Similarly, there was no difference in 1288 pairs comparing 2-mm versus 5-mm axial slice thickness (AUC at 1 year 0.98 [95% CI: 0.94–1.00] vs 0.99 [95% CI: 0.97–0.99], P = 0.68). The best-case scenario combining a lung reconstruction filter with 2-mm slice thickness compared with the worst-case scenario combining a bone reconstruction filter with 2.5-mm slice thickness uncovered a significantly different performance at years 2–4 (P = 0.03). Subanalysis showed no significant difference in performance between Siemens and Toshiba scanners.

Conclusions

Sybil's predictive performance for future lung cancer risk is robust across different reconstruction filters and axial slice thicknesses, demonstrating its versatility in various imaging settings. Combining favorable reconstruction parameters can significantly enhance predictive ability at years 2–4. The absence of significant differences between Siemens and Toshiba scanners further supports Sybil's versatility.
Fixel-Based Analysis of White Matter Alterations in Facial Palsy
Authors: Wang Yan-fang , Wang Wei , Ma Hao , Zhang Chen-hao , Lu Ye-chen
Published: October 2024

Predicting individual prognosis is difficult despite various risk factor studies, due to the complex recovery involving peripheral nerve restoration and cerebral plasticity. This study uses fixel-based analysis (FBA) to better understand neural pathway alterations, hypothesizing that FBA can effectively link functional outcomes with diffusion metrics in the process of rehabilitation. The authors recruited 50 participants including 30 patients and 20 healthy controls into the study. All of them underwent assessment 3 months and 6 months after injury. Both whole-brain fixel-based analysis and tract of interest analysis were performed. The authors observed multiple regions including the superior corona radiata, posterior limb of the internal capsule, and cerebral peduncle displaying significant changes of FD (fiber density), FC (fiber-bundle cross-section), and FDC (fiber density and cross-section). Patients with unfavorable outcomes showed increased FD in the ipsilesional side and decreased FD in the contralesional side compared with patients with favorable outcomes. In addition, FD values of the contralesional side exhibited positive correlations with differences in FGS at 3 months and 6 months. Conversely, FD values in the ipsilesional side showed a negative correlation. Our findings suggest that FD metrics within the corticobulbar tract could serve as predictive biomarkers for symmetry outcomes. Thus, FBA holds promise for early estimation of behavioral outcomes in facial palsy, guiding more targeted interventions.
Prospective Multicenter Comprehensive Survey on Male Sexual Dysfunction following Laparoscopic, Robotic, and Transanal Approaches for Rectal Cancer (the LANDMARC Study)
Authors: Numata Masakatsu , Yamaguchi Tomohiro , Shiomi Akio , Inada Ryo , Shiozawa Manabu , Kazama Keisuke , Hotchi Masanori , Yamamoto Daisuke , Hasegawa Suguru , Miguchi Masashi , Ohnuma Shinobu , Uehara Kay , Munakata Koji , Kinugasa Yusuke , Horie Hisanaga , Yamaguchi Shigeki , Takeshima Teppei , Hida Koya , Akagi Tomonori , Kagawa Hiroyasu , Oyamada Shunsuke , Rino Yasushi , Sakai Yoshiharu , Watanabe Masahiko , Naitoh Takeshi ,   LANDMARC Collaborative Study Group of the Japan Society of Laparoscopic Colorectal Surgery
Published: October 2024

Objective:

To investigate the incidence of male sexual dysfunction (SD) including erectile dysfunction (ErD) and ejaculatory dysfunction (EjD) after minimally invasive rectal cancer surgery.

Background:

Male SD significantly affects post-rectal cancer surgery quality of life (QOL). Current assessments using the International Index of Erectile Function-5 are unsuitable for patients with reduced postoperative sexual activity, because it assumes sexual intercourse. This study addresses this gap using the Erection Hardness Score (EHS) and custom ejaculatory questionnaires.

Methods:

This prospective multicenter open-label phase II trial enrolled 399 patients who underwent laparoscopic (Lap), robotic (Ro), or transanal (Ta) rectal cancer surgery. EHS and custom ejaculatory questionnaires assessed ErD, EjD, and potency impairment at 3, 6, and 12 months postoperatively. The rates were assessed in the full analysis set and compared between the Lap and Ro groups after propensity score matching.

Results:

At 12 months, the overall incidences of ErD and EjD were 34.7% and 29.8%, respectively. The Ro group showed a significantly lower EjD rate (25.0%) than the Lap group (40.9%), with no significant difference in ErD. Potency impairment was lower in the Ro group at 6 months (32.7% vs. 22.3%) and 12 months (29.0% vs. 17.8%) postoperatively. The Ta group showed relatively high ErD and EjD at 3 months, with some recovery at 12 months.

Conclusions:

Minimally invasive rectal cancer surgery commonly results in ErD, EjD, and potency impairment. Robotic surgery provides lower EjD rates and less potency impairment. Comprehensive sexual function assessments are essential to inform patients and improve QOL outcomes.
Reconstructing the invention of the wheel using computational structural analysis and design
Authors: Alacoque Lee R. , Bulliet Richard W. , James Kai A.
Published: October 2024

The invention of the wheel is widely credited as a pivotal moment in human history, yet the details surrounding its discovery are shrouded in mystery. There remains no scholarly consensus on key questions such as where, how and by whom this technology was originally invented. In this study, we employ state-of-the-art techniques from computational structural mechanics to shed light on this long-standing puzzle. Based on this analysis, we propose a probable path along which the wheel evolved via a sequence of three major innovations. We also introduce an original computational design algorithm that autonomously generates a wheel-and-axle system using an evolutionary process that offers insight into the way in which the first wheels likely evolved nearly 6000 years ago. Our analysis provides new supporting evidence for the recently advanced theory that the wheel was invented by Neolithic miners harvesting copper ore from the Carpathian Mountains as early as 3900 BC. Moreover, we show how the discovery of the wheel was made possible by the unique physical features of the mine environment, whose impact was analogous to the selective environmental pressures that drive biological evolution.
The Pvc15 ATPase selectively associates effector proteins with the
Photorhabdus
virulence cassette
Authors: Evans Rhys , Waterfield Nicholas R.
Published: October 2024

The
Photorhabdus
virulence cassette (PVC) is an extracellular contractile injection system. In the producing bacterium, N-terminal signal peptides enable effector ‘payloads’ to be loaded into the PVC’s hollow tube—facilitated by the ‘
A
TPases
a
ssociated with diverse cellular
a
ctivities’ (AAA) ATPase, Pvc15—ready for injection of the toxin or virulence factor into eukaryotic cytosols. Pvc15’s function and its interaction with the signal peptide were unclear. This study describes the signal peptide diversity in extracellular contractile injection system clades and interrogates the Pvc15–signal peptide interaction using ATPase assays, cell respiratory assays and western blot quantification of
Escherichia coli
lysates and co-purifications of PVCs with their payloads. This study found that extracellular contractile injection system signal peptides can be grouped according to sequence alignment, owing to potentially homologous loading mechanisms. Pvc15 contains three domains, including tandem AAA domains D1 and D2. By constructing Pvc15 mutants, we found that while each domain is necessary for PVC-payload loading, domain D2 is the sole bioactive ATPase domain and rescues unstable payloads via the signal peptide. Finally, truncating the signal peptide abolishes Pvc15-dependent PVC loading and has varying effects on payload stability. This study provides crucial insights into extracellular contractile injection system effector loading mechanisms and their ATPase chaperones, and suggests that these devices could be bioengineered for injection of therapeutic proteins into human cells.
Spherical image potentials for an N-charged particle system
Authors: Randazzo Juan M. , Della Picca Renata , Sarsa Antonio J. , Ancarani Lorenzo Ugo
Published: October 2024

The potential energy interaction between a system of

N

-charged particles and a spherical conducting surface is obtained by means of direct integration of the electrostatic energy density. Making use of the image charge method, we show that the full potential can be split into a sum of one-body central potentials and two-body contributions related to particle–particle and particle–sphere interactions. Analytical expressions are provided for all contributions. The spherical surface of radius

R

can be considered to correspond to a cavity inside a conductor or a metallic ball, with two different electric conditions, namely the grounded and isolated charged cases. By taking the limit

R
→
∞

of the spherical case, one recovers the image potential for an

N

-charged particle system interacting with a planar conductor. While the final results for the potential do not appear as unexpected, the provided analytical expressions should help in diverse physical applications modelled by a number of charged particles interacting close to a spherical surface.
Oxygen loss compromises growth and cognition of cuttlefish newborns
Authors: Court Melanie , Macau Marta , Ranucci Maddalena , Marquês Tânia , Repolho Tiago , Lopes Vanessa Madeira , Rosa Rui , Paula José Ricardo
Published: October 2024

Ocean deoxygenation and standing levels of hypoxia are shrinking fundamental niches, particularly in coastal areas, yet documented repercussions on species development and behaviour are limited. Here, we tackled the impacts of deoxygenation (7 mg O
2
l
−1
), mild hypoxia (nocturnal 5 mg O
2
l
−1
) and severe hypoxia (nocturnal 2 mg O
2
l
−1
) on cuttlefish (
Sepia officinalis
) development (hatching success, development time, mantle length), cognition (ability to learn individually and socially) and behaviour (ability to camouflage and to explore its surroundings spatially). We found that hypoxia yielded lower survival rates, smaller body sizes and inhibited predatory (increased latency to attack the prey) and anti-predator (camouflage) behaviours. Acute and chronic exposure to low oxygen produced similar effects on cognition (inability to socially learn, increased open-field activity levels, no changes in thigmotaxis). It is thus expected that, although cuttlefish can withstand oxygen limitation to a certain degree, expanding hypoxic zones will diminish current habitat suitability.
Environmental complexity and regularity shape the evolution of cognition
Authors: Turner Cameron Rouse , Morgan Thomas J. H. , Griffiths Thomas L.
Published: October 2024

The environmental complexity hypothesis suggests that cognition evolves to allow animals to negotiate a complex and changing environment. By contrast, signal detection theory suggests cognition exploits environmental regularities by containing biases (e.g. to avoid dangerous predators). Therefore, two significant bodies of theory on cognitive evolution may be in tension: one foregrounds environmental complexity, the other regularity. Difficulty in reconciling these theories stems from their focus on different aspects of cognition. The environmental complexity hypothesis focuses on the reliability of sensors in the origin of cognition, while signal detection theory focuses on decision making in cognitively sophisticated animals. Here, we extend the signal detection model to examine the joint evolution of mechanisms for detecting information (sensory systems) and those that process information to produce behaviour (decision-making systems). We find that the transition to cognition can only occur if processing compensates for unreliable sensors by trading-off errors. Further, we provide an explanation for why animals with sophisticated sensory systems nonetheless disregard the reliable information it provides, by having biases for particular behaviours. Our model suggests that there is greater nuance than has been previously appreciated, and that both complexity and regularity can promote cognition.
Single-Trial Characterisation of Frontal Theta and Parietal Alpha Oscillatory Episodes during Spatial Navigation in Humans
Authors: Cuello Mireia Torralba , Marti-Marca Angela , Pápai Márta Szabina , Soto-Faraco Salvador
Published: October 2024

Theoretical proposals and empirical findings both highlight the relevance of theta brain oscillations in human Spatial Navigation. However, whilst the general assumption is that the relevant theta band activity is purely oscillatory, most empirical studies fail to disentangle oscillatory episodes from wide band activity. In addition, experimental approaches often rely on averaged activity across trials and subjects, disregarding moment-to-moment fluctuations in Theta activity, contingent on key aspects of the task. Here, we used novel oscillation detection approaches to investigate the dynamics of theta and alpha episodes in human subjects performing a spatial navigation task in a Virtual Reality environment, resolved at single-trial level. The results suggest that bouts of theta oscillatory activity are related to task difficulty and access to previously encoded information, across different timescales. alpha episodes, instead, seem to anticipate successful navigational decisions and could be related to shifts in internal attention.
Mu and Delta Opioid Receptors Modulate Inhibition within the Prefrontal Cortex Through Dissociable Cellular and Molecular Mechanisms
Authors: Cole Rebecca H. , Joffe Max E.
Published: October 2024

Aberrant signaling within cortical inhibitory microcircuits has been identified as a common signature of neuropsychiatric disorders. Interneuron (IN) activity is precisely regulated by neuromodulatory systems that evoke widespread changes in synaptic transmission and principal cell output. Cortical interneurons express high levels of Mu and Delta opioid receptors (MOR and DOR), positioning opioid signaling as a critical regulator of inhibitory transmission. However, we lack a complete understanding of how MOR and DOR regulate prefrontal cortex (PFC) microcircuitry. Here, we combine whole-cell patch-clamp electrophysiology, optogenetics, and viral tools to provide an extensive characterization MOR and DOR regulation of inhibitory transmission. We show that DOR activation is more effective at suppressing spontaneous inhibitory transmission in the prelimbic PFC, while MOR causes a greater acute suppression of electrically-evoked GABA release. Cell type-specific optogenetics revealed that MOR and DOR differentially regulate inhibitory transmission from parvalbumin, somatostatin, cholecystokinin, and vasoactive intestinal peptide-expressing INs. Finally, we demonstrate that DOR regulates inhibitory transmission through pre- and postsynaptic modifications to IN physiology, whereas MOR function is predominantly observed in somato-dendritic or presynaptic compartments depending on cell type.

Significance Statement

The endogenous opioid system regulates behaviors that rely on prefrontal cortex (PFC) function. Previous studies have described Mu and Delta opioid receptor expression within cortical GABAergic interneurons, but a detailed understanding of how opioids regulate different interneuron subtypes and cortical microcircuits has not been reported. We use whole-cell patch-clamp electrophysiology, genetically engineered mice, and optogenetics to assess MOR and DOR regulation of PFC inhibitory transmission, demonstrating that MOR and DOR inhibition of interneurons display qualitative and quantitative variation across GABAergic circuits within mouse prelimbic PFC.
Cancer-associated adipocytes mediate CD8+T cell dysfunction via FGF21-driven lipolysis
Authors: Dalangood Sumiya , Hu Cegui , Yuan Chenwei , Li Xiang , Qiao Wen , Li Hanjun , Zhang Rongyu , Li Luying , Li Peng , Yu Xiang , Yin Wenjin , Lu Jinsong , Gui Jun
Published: October 2024

Cancer-associated adipocytes (CAAs) reprogram metabolic status of tumor microenvironment (TME). The metabolic crosstalk between CAAs and CD8+T cells in TME remains unclear. Here we report that CAAs undergo lipolysis, releasing free fatty acids that promote lipid peroxidation and disturb mitochondrial homeostasis in CD8+T cells, leading to their functional exhaustion. Importantly, we uncover that fibroblast growth factor 21 (FGF21) autocrinally drives CAA lipolysis through upregulating adipose triglyceride lipase (ATGL) via FGFR1/KLB-p38 signaling. FGF21 deletion in adipose tissue or ATGL inhibition impedes CAA lipolysis, mitigates lipid peroxidation, normalizes mitochondrial dynamics of CD8+T cells, and restores their effector function, consequently blunting tumor growth. Moreover, combining ATGL inhibitor with anti-PD-1 therapy synergistically enhances the antitumor activity of CD8+T cells, yielding greater therapeutic efficacy. Our findings highlight the pivotal role of CAA lipol ysis in CD8+T cell dysfunction within TME, suggesting that targeting CAA lipolysis represents a valuable avenue for improving cancer immunotherapy.
Basal EFNA3 Facilitates Luminal-Driving Mammary Epithelial Migration and Cancer Metastasis by Promoting OXPHOS
Authors: Chen Jing , ma Rongze , Feng Deyi , Deng Zhixuan , Lu Yunzhe , Xia Kun , Klein Ophir D. , Lu Pengfei
Published: October 2024

Collective migration is essential for tissue development, repair, and cancer metastasis. However, the mechanisms by which different cell types coordinate to facilitate cohesive movement remain poorly understood. Here, we report distinct migratory behaviors in luminal and basal cells during collective migration of the mammary epithelium. We show that luminal cells are leaders of directional migration. However, basal cells also play a central role in promoting collective migration by producing EFNA3, which targets luminal cells and enhances oxidative phosphorylation and energy production. This promotion of epithelial migration and branching morphogenesis is confirmed in vivo. Importantly, EFNA3 is a prognostic marker for breast cancer metastasis, with high expression correlating with increased metastasis. Conversely, inhibition of EFNA3 significantly slows metastasis. These findings reveal a novel mechanism of epithelial migration that is critical for organogenesis and identify EFNA3 as a potential therapeutic target for cancer metastasis.
Modeling Electrocardiogram (ECG) Waveforms Using Group Theory and Symmetry Elements
Authors: Frueh Samuel J.
Published: October 2024

We present a what we believe to be a novel approach for generating electrocardiogram (ECG) waveforms using group theory and the algebraic structure of abstract symmetry elements from point groups up to order 10. Unlike traditional ECG modeling, which relies on physiological simulation or differential equations with predefined boundary conditions, our approach uses algebraic structures without predefined boundary conditions. This method allows us to explore the underlying algebraic symmetry of ECG signals, offering a perspective on biological signal representation. The flexibility and abstract nature of this framework opens potential applications for interdisciplinary research in mathematical biology, signal processing, and computational biology.
p-ClustVal: A Novelp-adic Approach for Enhanced Clustering of High-Dimensional Single Cell RNASeq Data
Authors: Sharma Parichit , Mishra Sarthak , Kurban Hasan , Dalkilic Mehmet
Published: October 2024

This paper introducesp-ClustVal, a novel data transformation technique inspired byp-adic number theory that significantly enhances cluster discernibility in genomics data, specifically Single Cell RNA Sequencing (scRNASeq). By leveragingp-adic-valuation,p-ClustVal integrates with and augments widely used clustering algorithms and dimension reduction techniques, amplifying their effectiveness in discovering meaningful structure from data. The transformation uses a data-centric heuristic to determine optimal parameters, without relying on ground truth labels, making it more user-friendly.p-ClustVal reduces overlap between clusters by employing alternate metric spaces inspired byp-adic-valuation, a significant shift from conventional methods. Our comprehensive evaluation spanning 30 experiments and over 1400 observations, shows thatp-ClustVal improves performance in 91% of cases, and boosts the performance of classical and state of the art (SOTA) methods. This work contributes to data analytics and genomics by introducing a unique data transformation approach, enhancing downstream clustering algorithms, and providing empirical evidence ofp-ClustVal’s efficacy. The study concludes with insights into the limitations ofp-ClustVal and future research directions.
Real-Time Visualization of Protein Microenvironment Changes with High Spatial Resolution in Live Cells via Site-Specific Incorporation of Rotor-Based Fluorescent Noncanonical Amino Acids
Authors: Yang Shudan , Jin Shikai , Zhang Mengxi , Chen Yuda , Guo Yiming , Hu Yu , Wolynes Peter G. , Xiao Han
Published: October 2024

Traditional methods, such as the use of fluorescent protein fusions and environment-sensitive fluorophores, have limitations when studying protein microenvironment changes at the finest spatial resolution. These techniques often rely on bulky proteins or tags restricted to the N- or C-terminus, which can disrupt the natural behavior of the target protein and dramatically limit the ability of their method to investigate noninvasively microenvironment effects. To overcome these challenges, we have developed an innovative strategy to visualize microenvironment changes of protein substructures in real-time by genetically incorporating environment-sensitive noncanonical amino acids (ncAAs) containing rotor-based fluorophores (RBFs) at specific positions within a protein of interest. Through computational redesign of aminoacyl-tRNA synthetase, we successfully incorporated these rotor-based ncAAs into various proteins in mammalian cells. By site-specifically placing these ncAAs in distinct regions of proteins, we detected microenvironmental changes of several different protein domains during events such as aggregation, clustering, aggregation disassembly, and cluster dissociation.
Generative AI for Drug Discovery: A GPT-2 and LSTM Based Models for Designing EGFR Inhibitors
Authors: Dasser Omar , Benaceur Othman Filali , Fadel Salma
Published: October 2024

The design of novel EGFR inhibitors is a critical focus in cancer drug discovery. This study leverages generative AI models, specifically fine-tuned GPT-2 and LSTM architectures, to generate new chemical structures targeting the Epidermal Growth Factor Receptor (EGFR). The models were trained on a curated dataset of approximately 500,000 bioactive ligands from the ChEMBL database, with SMILES strings as input. After generating a batch of 1,000 molecules, post-generation filtering was applied based on Lipinski’s rule of five, Quantitative Estimate of Drug-likeness (QED), and Synthetic Accessibility Scores (SAS) to ensure drug-like properties. Molecular docking studies were performed using PyRx with AutoDock Vina, focusing on the crystal structure of EGFR (PDB ID: 1M17). The LSTM model outperformed GPT-2, achieving a higher validity rate (90.98% vs. 52.27%) and similar uniqueness rates, while also producing molecules with stronger binding affinities, ranging from -9.4 to -10.4 kcal/mol. The results indicate that the LSTM model is more effective for generating chemically valid EGFR inhibitors, offering promising candidates for further experimental validation. This study demonstrates the potential of generative AI to accelerate the identification of effective cancer therapeutics.
Key contribution of prefrontal inhibition to passive coping behaviour: chronic stress and fast-acting antidepressant
Authors: Fong Tsz Hei , Li Tianxiang , Ma Xiaoyan , Cai Xiang , Zhou Qiang
Published: October 2024

Persistent passive coping behaviour is a hallmark feature in major depression and is reversed by fast-acting antidepressants (such as ketamine). This behaviour is regulated by a specific cortico-midbrain circuit. However, whether the prefrontal cortex (PFC), especially inhibition in PFC, contributes to the modulation of passive coping, and whether this modulation is important for mediating the impacts of chronic stress and/or fast-acting antidepressants, are poorly understood. Here, we found that rostral prelimbic cortex (rPL) bidirectionally controls the occurrence of passive coping behaviour where excitatory and inhibitory neurons play opposite roles. Chronic stress leads to reduced excitation/inhibition (E/I) ratio, reflected as alterations inin vivospiking rate, synaptic inputs and intrinsic excitability of both excitatory and inhibitory neurons. A fast-acting antidepressant, (2R, 6R)-hydroxynorketamine (HNK), reduced passive coping behaviour, restored rPL E/I ratio and partially reversed altered properties in rPL neurons, in chronically stressed mice. Importantly, chronic stress and HNK mostly affected fast-spiking/parvalbumin inhibitory neurons instead of other inhibitory neurons, indicating the important role of this subtype of inhibitory neurons in the above processes. These findings demonstrate the importance of rPL E/I balance in regulating passive coping, which can be modulated by chronic stress and rapidly restored by fast-acting antidepressant.
Impact of transportation on the suitability of corneal lenticule for implantation
Authors: Soo Jenetta Y. W. , Tan Gabriel , Han Evelina , Boey Kenny P. Y. , Liu Yu-Chi , Mehta Jodhbir S. , Riau Andri K.
Published: October 2024

Background

Corneal lenticules can be banked and retrieved for vision-restoring surgeries. Extended transportation logistic delays from the lenticule bank to the clinic could be a concern. This study investigated the effects of transportation on the lenticules.

Methods

Lenticules were cryopreserved at a Ministry of Health-licensed lenticule bank for 1 year and were transported at 4°C. The transparency was measured daily until significant degradation was notable, compared to fresh lenticules from donor corneas (n=3). The molecular and ultrastructural integrity of lenticules after 1 day in transport (n=3) and on the day of transparency deterioration (n=3) was evaluated by histochemistry and transmission electron microscopy (TEM). In addition, 6 rabbits were implanted with these lenticules to assess the difference in postoperative outcomes by corneal imaging, immunofluorescence staining, and TEM.

Results

Lenticules showed a significant transparency reduction after 6 days in transit (p=0.002). The change was not caused by molecular alterations but by a greater distribution shift in the interfibrillar distance (IFD) (Z=4.419; p<0.001) and fibrillar diameter (FD) (Z=6.435; p<0.001). Post-implantation, day 6 lenticules exhibited greater haze and slower recovery of clarity compared to fresher lenticules, despite corneal imaging and immunofluorescence staining showing no fibrosis, inflammation, or vascularization in either group. With TEM, the discrepancy was revealed due to the difference in the recovery of IFD and FD distribution.

Conclusions

Banked lenticules can maintain transparency for up to 5 days of transportation at 4°C. Further delays compromise their ultrastructural integrity and postoperative clarity, emphasizing the need to factor in transportation in lenticule banking logistics.
Integrative Transcriptomic Profiling of NK Cells and Monocytes: Advancing Diagnostic and Therapeutic Strategies for COVID-19
Authors: Loukman Salma , Ben Mrid Reda , Bouchmaa Najat , Hboub Hicham , El Fatimy Rachid , Benhida Rachid
Published: October 2024

In this study, we use integrated transcriptomic datasets from the GEO repository with the purpose of investigating immune dysregulation in COVID-19. Thus, in this context, we decided to be focused on NK cells and CD14+ monocytes gene expression, considering datasets GSE165461 and GSE198256, respectively. Other datasets with PBMCs, lung, olfactory, and sensory epithelium and lymph were used to provide robust validation for our results. This approach gave an integrated view of the immune responses in COVID-19, pointing out a set of potential biomarkers and therapeutic targets with special regard to standards of physiological conditions. IFI27, MKI67, CENPF, MBP, HBA2, TMEM158, THBD, HBA1, LHFPL2, SLA, and AC104564.3 were identified as key genes from our analysis that have critical biological processes related to inflammation, immune regulation, oxidative stress, and metabolic processes. Consequently, such processes are important in understanding the heterogeneous clinical manifestations of COVID-19—from acute to long-term effects now known as ‘long COVID’. Subsequent validation with additional datasets consolidated these genes as robust biomarkers with an important role in the diagnosis of COVID-19 and the prediction of its severity. Moreover, their enrichment in key pathophysiological pathways presented them as potential targets for therapeutic intervention.The results provide insight into the molecular dynamics of COVID-19 caused by cells such as NK cells and other monocytes. Thus, this study constitutes a solid basis for targeted diagnostic and therapeutic development and makes relevant contributions to ongoing research efforts toward better management and mitigation of the pandemic.
Humans are resource-rational predictors in a sequence learning task
Authors: Ferdinand Vanessa , Yu Amy , Marzen Sarah
Published: October 2024

Organisms can solve complex tasks despite having limited cognitive resources when those resources are used optimally. Doing so optimally makes an organism “resource-rational”. In this paper, we show for the first time that humans are resource-rational at prediction. In a novel sequence learning experiment, participants predict data generated from hidden Markov models (HMMs) and receive online feedback via clicker training. We compute the predictive rateaccuracy (PRA) curve for each HMM to solve for the highest accuracy achievable for a given cognitive capacity, or “rate”, quantified as the mutual information between participants’ predictions and the underlying causal state of the sequence being predicted. We found that the majority of participants achieve near-optimal prediction with various cognitive capacities, despite performing well below the maximum predictive accuracy on the task overall. We also show that this information-theoretic approach to measuring cognitive capacity can be grounded in the established psychological science concept of working memory: participants who extracted higher quantities of mutual information in the sequence learning task showed significantly higher working memory in a complex digit span test. This research provides new avenues for assessing smart behavior in difficult prediction tasks, provides a new methodology for assessing resource-rationality, and provides evidence that humans are resource-rational predictors.
Induction of orbital currents and Kapitza stabilization in superconducting circuits with Laguerre-Gaussian microwave beams
Authors: Yerzhakov Hennadii , Yeh Tien-Tien , Balatsky Alexander
Published: October 2024

We investigate the effects of a Laguerre-Gaussian (LG) beam on the superconducting state. We show that the vortex angular momentum of a LG beam affects the superconducting state and induces currents. The induction of the current by microwave radiation is illustrated on a Josephson loop and SQUID devices. In particular, we establish that coupling a dc SQUID to the ac magnetic flux of a LG beam can stabilize the π phase in the SQUID. This can happen via developing a global or local minimum in the effective potential at π. In the latter case, this happens via the Kapitza mechanism.

Published by the American Physical Society
2024
Numerical simulation of a two-dimensional Blume-Capel ferromagnet in an oscillating magnetic field with a constant bias
Authors: Mendes Celeste , Buendía Gloria M. , Rikvold Per Arne
Published: October 2024

We perform a numerical study of the kinetic Blume-Capel (BC) model to find if it exhibits the metamagnetic anomalies previously observed in the kinetic Ising model for supercritical periods [P. Riego , ; G. M. Buendía , ]. We employ a heat-bath Monte Carlo (MC) algorithm on a square lattice in which spins can take values of ±1,0, with a nonzero crystal field, subjected to a sinusoidal oscillating field in conjunction with a constant bias. In the ordered region, we find an equivalent hysteretic response of the order parameters with its respective conjugate fields between the kinetic and the equilibrium model. In the disordered region (supercritical periods), we observed two peaks, symmetrical with respect to zero bias, in the susceptibility and scaled variance curves, consistent with the numerical and experimental findings on the kinetic Ising model. This behavior does not have a counterpart in the equilibrium model. Furthermore, we find that the peaks occur at higher values of the bias field and become progressively smaller as the density of zeros, or the amplitude of the oscillating field, increases. Using nucleation theory, we demonstrate that these fluctuations, as in the Ising model, are not a critical phenomenon, but that they are associated with a crossover between a single-droplet (SD) and a multidroplet (MD) magnetization switching mechanism. For strong (weak) bias, the SD (MD) mechanism dominates. We also found that the zeros concentrate on the droplets' surfaces, which may cause a reduced interface tension in comparison with the Ising model [M. Schick , ]. Our results suggest that metamagnetic anomalies are not particular to the kinetic Ising model, but rather are a general characteristic of spin kinetic models, and provide further evidence that the equivalence between dynamical phase transitions and equilibrium ones is only valid near the critical point.

Published by the American Physical Society
2024