bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeting Nrf2/KEAP1 signaling pathway using bioactive compounds to combat mastitis
Authors: Khan Muhammad Zahoor , Li Liangliang , Zhan Yandong , Binjiang Huang , Liu Xiaotong , Kou Xiyan , Khan Adnan , Qadeer Abdul , Ullah Qudrat , Alzahrani Khalid J. , Wang Tongtong , Wang Changfa , Zahoor Muhammad
Published: February 2025

Mastitis is a common inflammation of mammary glands that has a significantly impact on dairy production and animal health, causing considerable economic burdens worldwide. Elevated reactive oxygen species (ROS) followed by oxidative stress, apoptosis, inflammatory changes and suppressed immunity are considered the key biomarkers observed during mastitis. The Nrf2/KEAP1 signaling pathway plays a critical role in regulating antioxidant responses and cellular defense mechanisms. When activated by bioactive compound treatment, Nrf2 translocates to the nucleus and induces the expression of its target genes to exert antioxidant responses. This reduces pathogen-induced oxidative stress and inflammation by inhibiting NF-kB signaling in the mammary glands, one of the prominent pro-inflammatory signaling pathway. Here, we summarize recent studies to highlight the therapeutic potential of Nrf2/KEAP1 pathway in the prevention and treatment of mastitis. Collectively this review article aims to explore the potential of bioactive compounds in mitigating mastitis by targeting the Nrf2/KEAP1 signaling pathway.
Contribution of cuproptosis and immune-related genes to idiopathic pulmonary fibrosis disease
Authors: Jin Chengji , Li Jia , Li Qiaoyu , Zhang Lipeng , Zheng Shaomao , Feng Qiong , Li Yongjie , Zheng Yu , Nie Qiuli , Liang Jin , Wang Jing
Published: February 2025

Background

Idiopathic pulmonary fibrosis (IPF) is a degenerative respiratory condition characterized by significant mortality rates and a scarcity of available treatment alternatives. Cuproptosis, a novel form of copper-induced cell death, has garnered attention for its potential implications. The study aimed to explore the diagnostic value of cuproptosis-related hub genes in patients with IPF. Additionally, multiple bioinformatics analyses were employed to identify immune-related biomarkers associated with the diagnosis of IPF, offering valuable insights for future treatment strategies.

Methods

Four microarray datasets were selected from the Gene Expression Omnibus (GEO) collection for screening. Differentially expressed genes (DEGs) associated with IPF were analyzed. Additionally, weighted gene coexpression network analysis (WGCNA) was employed to identify the DEGs most associated with IPF. Ultimately, we analyzed five cuproptosis-related hub genes and assessed their diagnostic value for IPF in both the training and validation sets. Additionally, four immune-related hub genes were screened using a protein–protein interaction (PPI) network and evaluated through the receiver operating characteristic (ROC) curve. Lastly, single-cell RNA-seq was employed to further investigate differential gene distribution.

Results

We identified a total of 92 DEGs. Bioinformatics analysis highlighted five cuproptosis-related genes as candidate biomarkers, including three upregulated genes (CFH, STEAP1, and HDC) and two downregulated genes (NUDT16 and FMO5). The diagnostic accuracy of these five genes in the cohort was confirmed to be reliable. Additionally, we identified four immune-related hub genes that demonstrated strong diagnostic performance for IPF, with CXCL12 showing an AUROC of 0.90. We also examined the relationship between these four genes and immune cells. CXCL12 was significantly negatively associated with neutrophils, while CXCR2 was associated exclusively with neutrophils, consistent with our single-cell sequencing results. CTSG showed a primarily positive association with follicular helper T, and SPP1 was most strongly associated with macrophages. Finally, our single-cell sequencing data revealed that in patients with IPF, CXCL12 was highly expressed in the endothelial cell subset (ECs), while SPP1 exhibited high expression in multiple cellular populations. The expression of the CTSG showed statistically significant differences in monocyte macrophages.

Conclusion

The research methodically depicted the intricate interplay among five cuproptosis-related genes, four immune-related hub genes, and IPF, offering new ideas for diagnosing and treating patients with IPF.
Multi-omics analysis reveals the sensitivity of immunotherapy for unresectable non-small cell lung cancer
Authors: Wu Rui , Wei Kunchen , Huang Xingshuai , Zhou Yinge , Feng Xiao , Dong Xin , Tang Hao
Published: February 2025

Background

To construct a prediction model consisting of metabolites and proteins in peripheral blood plasma to predict whether patients with unresectable stage III and IV non-small cell lung cancer can benefit from immunotherapy before it is administered.

Methods

Peripheral blood plasma was collected from unresectable stage III and IV non-small cell lung cancer patients who were negative for driver mutations before receiving immunotherapy. Then we classified samples according to the follow-up results after two courses of immunotherapy and non-targeted metabolomics and proteomics analyses were performed to select different metabolites and proteins. Finally, potential biomarkers were picked out by applying machine learning methods including random forest and stepwise regression and prediction models were constructed by logistic regression.

Results

The presence of metabolites and proteins in peripheral blood plasma was causally associated with both non-small cell lung cancer and PD-L1/PD-1 expression levels. A total of 2 differential metabolites including 5-sulfooxymethylfurfural and Anthranilic acid and 2 differential proteins including Immunoglobulin heavy variable 1-45 and Microfibril-associated glycoprotein 4 were selected as reliable biomarkers. The area under the curve (AUC) of the prediction model built on clinical risks was merely 0.659. The AUC of metabolomics prediction model was 0.977 and the AUC of proteomics was 0.875 while the AUC of the integrative-omics prediction model was 0.955.

Conclusions

Metabolic and protein biomarkers in peripheral blood both have high efficacy and reliability in the prediction of immunotherapy sensitivity in unresectable stage III and IV non-small cell lung cancer, but validation in larger population-based cohorts is still needed.
Single-cell RNA sequencing of circulating immune cells supports inhibition of TNFAIP3 and NFKBIA translation as psoriatic arthritis biomarkers
Authors: Garrido Ameth N. , Machhar Rohan , Cruz-Correa Omar F. , Ganatra Darshini , Crome Sarah Q. , Wither Joan , Jurisica Igor , Gladman Dafna D.
Published: February 2025

Objective

To identify biomarkers that distinguish psoriatic arthritis (PsA) from cutaneous psoriasis without arthritis (PsC) and healthy controls (HC) using single cell RNA sequencing (scRNA-seq).

Method

Peripheral blood mononuclear cell samples from three patients with PsA fulfilling CASPAR criteria, three patients with PsC and two HC were profiled using scRNA-seq. Differentially expressed genes (DEGs) identified through scRNA-seq were validated on classical monocytes, and CD4+ and CD8+ T cell subsets derived from an independent cohort of patients using the NanoString nCounter® platform. Protein expression was measured in CD4+ and CD8+ T cells by immunoblotting.

Results

A total of 18 immune cell population clusters were identified. Across 18 cell clusters, we identified 234 DEGs. NFKBIA and TNFAIP3 were overexpressed in PsA vs HC and PsC patients. Immunoblotting of the proteins encoded in these genes (IκBα and A20, respectively) showed higher levels in PsA CD4+ T cells compared to HC. Conversely, lower levels were observed in PsA CD8+ T cell lysates compared to HC for both proteins.

Conclusion

These results suggest that translation of TNFAIP3 and NFKBIA may be inhibited in PsA CD8+ T cells. This study provides insight into the cellular heterogeneity of PsA, showing that non-cell type specific expression of genes associated with the disease can be dysregulated through different mechanisms in distinct cell types.
Effects of neutrophil granule proteins on sepsis-associated lymphopenia and their relationship with CD4+ T-cell pyroptosis
Authors: Mao Jia-yu , Xie Ya-wen , Lei Xian-li , Zhang Jia-hui , Cheng Wei , Cui Na
Published: February 2025

Background

Neutrophil acts as a double-edged sword in the immune system. We hypothesized that an elevated neutrophil granule protein level is associated with sepsis-associated lymphopenia (SAL).

Methods

We enrolled 61 patients with sepsis admitted to the Department of Critical Care Medicine of Peking Union Medical College Hospital between May 2022 and October 2023 in this study. Clinical and immunological parameters were recorded. Levels of neutrophil granule proteins, including myeloperoxidase (MPO) and neutrophil elastase (NE), and pyroptosis factors were examined.

Results

Levels of neutrophil granule proteins (MPO, 82.9 vs. 175.3, p < 0 <.0001; NE, 56.3 vs. 144.2, p < 0.0001) were significantly higher in patients with sepsis with lymphopenia. Neutrophil granule protein levels were independently associated with SAL risk (MPO: OR = 1.0841, 95% CI, 1.0020–1.1730; NE: OR = 1.0540, 95% CI, 1.0040–1.1065). The area under the curve of MPO levels predicting SAL occurrence was 0.939 (95% CI, 0.846–0.984), and that of NE was 0.950 (95% CI, 0.862–0.989). Furthermore, neutrophil granule proteins were significantly correlated with CD4+ T cell and its pyroptosis [MPO and CD4+ T cells (r = −0.4039, p < 0.0001), CD4+NLRP3 (r = 0.4868, p < 0.0001), NE and CD4+ T cells (r = −0.5140, p < 0.0001), and CD4+NLRP3 (r = 0.6513, p < 0.0001)].

Conclusion

Increased levels of neutrophil granule proteins were significantly associated with SAL incidence, and a significant relationship between neutrophil granule proteins and the pyroptosis pathway of CD4+ T cells was revealed.

Clinical trial registration

chictr.org.cn identifier ChiCTR-ROC-17010750.
Adjuvanted subunit intranasal vaccine reduces SARS-CoV-2 onward transmission in hamsters
Authors: Sui Yongjun , Kar Swagata , Chawla Bhavna , Hoang Tanya , Yu YuanKai , Wallace Shannon M. , Andersen Hanne , Berzofsky Jay A.
Published: February 2025

Introduction

Most COVID-19 vaccine trials have focused on recipient protection, not protection of their contacts, a critical need. As a subunit intranasal COVID-19 vaccine reduced nasopharyngeal virus more than did an intramuscular (IM) vaccine, we hypothesized that this vaccine might reduce onward transmission to others.

Methods

We vaccinated hamsters with either the IM-administrated licensed mRNA vaccine twice or one dose of mRNA IM followed by adjuvanted subunit intranasal vaccine. 24 hours after SARS-CoV-2 challenge, these animals were housed with naïve recipients in a contactless chamber that allows airborne transmission.

Results

Onward airborne transmission was profoundly blocked: the donor and recipients of the intranasal vaccine-boosted group had lower oral and lung viral loads (VL), which correlated with mucosal ACE2 inhibition activity. Notably, in this head-to-head comparison of COVID-19 booster vaccines on SARS-CoV-2 onward transmission, we found that statistically significant viral reduction in the lung tissues and oral swabs was observed only in the intranasal S1 nanoparticle vaccine-boosted group, but not in the systemic mRNA vaccine-boosted group, suggesting the superior protection of this intranasal vaccine, which could act as an attractive vaccine booster candidate to complement the current licensed systemic vaccines.

Discussion

Overall, our study strongly supports the use of the intranasal vaccine as a boost to protect not only the vaccinated person, but also people exposed to the vaccinated person, a key public health goal.
Bradykinin B1 receptor signaling triggers complement activation on endothelial cells
Authors: Lopatko Fagerström Ingrid , Gerogianni Alexandra , Wendler Markus , Arvidsson Ida , Tontanahal Ashmita , Kristoffersson Ann-Charlotte , Qadri Fatimunnisa , Bader Michael , Karpman Diana
Published: February 2025

Introduction

The complement and kallikrein-kinin systems (KKS) are both activated during vascular inflammation, and there are many known interactions between the two systems. This study investigated if KKS activation induced complement activation on endothelial cells, and if activation was dependent on bradykinin B1 receptor (B1R) signaling.

Methods

KKS was activated in normal human serum by kaolin or activated factor XII (FXIIa). ADP-preactivated primary glomerular endothelial cells (PGECs) were incubated with serum, with or without kaolin or FXIIa, and with or without the B1R antagonist (R715) or the inositol triphosphate receptor (IP3R) inhibitor 2-aminoethoxydiphenyl borate (2-APB). Complement factors C3a, factor Ba and C5b-9 were evaluated by ELISA or immunoblotting. B1/B2 receptor double knock-out and wild-type mice were injected with lipopolysaccharide from E. coli B5:O55, to induce KKS activation.

Results

Supernatants from PGECs incubated with serum exposed to kaolin or FXIIa exhibited higher levels of Ba and C5b-9, which were significantly reduced in the presence of the B1R antagonist. Complement activation induced by FXIIa was also reduced in the presence of the IP3R inhibitor. Likewise, cell lysates showed higher levels of C3a and C5b-9 in the presence of kaolin and FXIIa, and complement activation was significantly reduced in the presence of the B1R antagonist. B1/B2 receptor double knock-out mice exhibited less C3 and C5b-9 deposition in glomeruli compared to wild-type mice.

Conclusion

This study demonstrates that KKS activation contributes to complement activation on the endothelium by B1R signaling. Blocking the B1R may have a role in reducing complement deposition and its effects on the endothelium.
Acupuncture for somatosensory deficits after stroke: a systematic review and meta-analysis
Authors: Ren Shumeng , Chen Yuhang , Liu Yu , Lv Qiuyi , Peng Jing , Song Lei , Zou Yihuai , Zhang Hua , Chen Xing
Published: February 2025

Objective

This meta-analysis aimed to evaluate the randomized controlled trials (RCTs) of acupuncture for somatosensory deficits after stroke to provide the current best evidence for clinical practice.

Methods

A systematic search was performed for eligible articles on the acupuncture for somatosensory deficits after stroke based on 14 databases. Two reviewers independently screened the RCTs, extracted data, and evaluated the methodological quality. A meta-analysis of RCTs was conducted using STATA 11.0 software.

Results

A total of 57 RCTs were included. Meta-analysis results showed that compared with the control group, the acupuncture group had a higher effective rate [risk ratio (RR) = 1.21, 95% CI (1.17, 1.24), I2 = 10.6%, P < 0.001] and a better sensory disturbance score [mean difference (MD) = 5.37, 95%CI (3.81, 6.92), I2 = 93.9%, P < 0.001]. The Visual Analog Scale in the acupuncture group was lower [MD = −1.44, 95%CI (−1.81, −1.07), I2 = 94.5%, P < 0.001]. The acupuncture also showed an improvement in the ability of daily living [MD = 12.19, 95% CI (8.50, 15.87), I2 = 97.2%, P < 0.001] and the symptoms of neurological deficit [Standardized Mean Difference (SMD) = −1.53, 95%CI (−2.04, −1.03), I2 = 89.7%, P < 0.001].

Conclusions

The current best evidence shows that acupuncture has advantages in raising the effective rate, alleviating sensory disturbance, relieving pain, enhancing the ability of daily living, and improving the symptoms of neurological deficits for somatosensory deficits after stroke compared with the control group. And the adverse reactions in acupuncture group were acceptable. However, further well-designed high-quality and multicenter international studies are needed to verify the effectiveness and safety of acupuncture for somatosensory deficits after stroke.

Systematic review registration

https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020186040.
Severe soft tissue injuries in multiple trauma patients—a challenge we can meet? A matched-pair analysis from the TraumaRegister DGU®
Authors: Kirsten Nora , Franke Georg Maximilian , Lefering Rolf , Klüter Tim , Weuster Matthias , Müller Michael , Lippross Sebastian , Seekamp Andreas ,   TraumaRegister DGU®, Fitschen-Oestern Stefanie
Published: February 2025

Introduction

Despite tremendous clinical efforts over the past few decades, the treatment of severely injured patients remains still challenging. Concomitant soft tissue injuries represent a particular challenge, as they can lead to complications at any time of trauma care, hold a high risk of infection and often require multiple surgical interventions and interdisciplinary collaboration.

Methods

This retrospective, multicentric study used the TraumaRegister DGU® to examine the effect of open fractures and severe soft tissue injuries on outcome of multiple trauma patients. Primary admitted multiple trauma patients at the age of 16 to 70 years, treated from 2010 to 2021, were included. A Matched pair analysis was performed for better comparability of trauma patients with and without open fractures and/or severe soft tissue injuries.

Results

After applying the matching criteria, 5,795 pairs were created and analyzed. The group with sustained soft tissue injuries/open fractures was found to have a higher ISS ([mean ± SD] 22.1 ± 10.4 vs. 20.6 ± 10.2, p < 0.001). Endotracheal tube insertion (27.7% vs. 30.4%, p = 0.003), catecholamine administration (6.0% vs. 8.4%, p < 0.001) and cardio-pulmonary resuscitation (1.6% vs. 2.1%, p = 0.027) were more frequent in the group with sustained soft tissue injury. Both groups were equally frequent admitted to the intensive care unit (ICU) and length of stay (LOS) at the ICU (median (quartiles) 3 (1–9) versus 3 (1–9)) did not differ significantly. However, total LOS at the hospital was longer for the group with sustained soft tissue injury (median (quartiles) 18 (11–29) versus 17 (10–27)). Sepsis occurred more often in patients with soft tissue injury (4.3% vs. 5.2%, p = 0.034). There was no significant difference in prevalence of multi organ failure, 24 h-mortality (2.1% vs. 2.5%, p = 0.151) and overall-mortality (3.6% vs. 3.9%, p = 0.329) between both groups.

Conclusion

Due to database analysis and revision of guidelines, the treatment of severely injured patients has steadily improved in recent years. Patients with severe soft tissue injuries/open fractures required more medical interventions and length of stay at the hospital was longer. In this study, we were able to show that although concomitant severe soft tissue injuries required more ICU interventions and led to a longer length of stay, 24-h and all-cause mortality were not significantly increased.
Annual cycle variations in the gut microbiota of migratory black-necked cranes
Authors: Zhang Yujia , Ma Ruifeng , Suolangduoerji  , Ma Shujuan , Nuertai Akebota , He Ke , Liu Hongyi , Zhu Ying
Published: February 2025

Introduction

Migratory birds exhibit unique annual cycles that complicate their gut microbiota. However, the annual dynamics of gut microbiota in migratory birds remain unclear, hindering our understanding of their environmental adaptation.

Methods

Here, we collected fecal samples from black-necked cranes (Grus nigricollis) across four seasons at their breeding grounds and used wintering ground data from databases to characterize their gut microbial compositions throughout the year.

Results and discussion

The results showed that the gut microbiota was clustered by season (Bray-Curtis: R2 = 0.348, p < 0.001; UniFrac: R2 = 0.352, p < 0.001). And the summer samples exhibited higher alpha (Simpson and Shannon), beta diversity (Bray-Curtis and UniFrac) and more diverse functions in gut microbiota compared to other seasons. Furthermore, in summer, the gut microbiota exhibited several balanced relative abundances at the family level, whereas Lactobacillaceae family dominated during the other seasons. Thirty-six ASVs were identified by random forest analysis to distinguish samples from distinct seasons. Despite having greater diversity, the summer gut microbiota had a simpler network structure than the other seasons (fewer edges and nodes). The dispersal limitation during random processes also significantly influenced gut microbial community assembly. Overall, the gut microbiota of the black-necked crane undergoes dynamic adjustments to adapt to seasonal environmental changes, which may be associated with the variations in diet across seasons. These results enhance our understanding of the gut microbiota of wild migratory birds and support further research on black-necked cranes.
Higher systemic immune-inflammation index is associated with increased risk of Parkinson’s disease in adults: a nationwide population-based study
Authors: Zhao Jiayu , Wu Zhipeng , Cai Fengyin , Yu Xuejv , Song Zhenyu
Published: February 2025

Background

This study aimed to explore the association between a new inflammatory marker, systemic immune-inflammation index (SII), and the risk of Parkinson’s disease (PD) in adult population.

Methods

A cross-sectional design was used, participants were recruited from the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2020. Three logistic regression models were used to explore the association between SII and the risk of PD, and subgroup analysis and sensitivity analysis were used. In addition, the restricted cubic spline (RCS) was used to explore the dose-response relationship between SII and PD. Receiver operating characteristic (ROC) curves was used to explore the diagnostic value of SII for PD.

Results

A total of 54,027 adults (mean age 35 years) were included in this study. The results of logistic regression showed that after adjusted for all covariates, compared with the Q1 group (lowest quartile in SII), the risk of PD in the Q3 group (OR = 1.82, 95%CI = 1.20–2.82, p < 0.001) and the Q4 group increased (OR = 2.49, 95%CI = 1.69–3.77, p < 0.001), with p-trend < 0.001. After excluding individuals with any missing values, sensitivity analysis also found a positive association between SII and PD. Subgroup analysis showed that this association was more significant in women, younger than 60 years old, non-smokers, alcohol drinkers, non-obese, and without a history of stroke, diabetes, or coronary heart disease. In addition, there was a positive dose-response relationship between SII and PD, and SII had an acceptable diagnostic value for PD (AUC = 0.72).

Conclusion

SII is positively correlated with the prevalence of PD in the adult population, and SII can help differentiate between PD and non-PD cases.
Association between carotid artery hemodynamics and neurovascular coupling in cerebral small vessel disease: an exploratory study
Authors: Zeng Peng , Zeng Bang , Wang Xiaohua , Yin Feiyue , Li Binglan , Nie Lisha , Tian Lin , Luo Dan , Li Yongmei
Published: February 2025

Background

Recent studies have linked disrupted cerebral hemodynamics, including pulsatility index (PI) and wall shear stress (WSS), with neuroimaging features of cerebral small vessel disease (CSVD). Cerebral neurovascular coupling (NVC) dysfunction is an important pathophysiological mechanism of CSVD. However, evidence linking the features of carotid artery hemodynamics to cerebral NVC is still lacking.

Objective

This study is aimed to explore the impact of PI and WSS on NVC and cognitive performance in CSVD patients using neuroimaging.

Methods

This study included 52 CSVD patients and 41 healthy controls. Carotid artery PI and WSS were measured using 4D flow magnetic resonance imaging (MRI). NVC was assessed through voxel-wise correlations between cerebral blood flow and the amplitude of low-frequency fluctuations. Multiple linear regression was used to investigate correlations between them.

Results

CSVD patients showed elevated PI in the C2 and C4 segments of the internal carotid artery and reduced WSS in the common carotid artery compared to controls. NVC measurements were significantly diminished in CSVD patients. Multiple linear regression analysis indicated significant correlations between reduced WSS and impaired NVC as well as between reduced PI and impaired NVC, but not between PI, WSS, and cognitive scores.

Conclusion

Reduced WSS and PI in CSVD patients are associated with impaired NVC. These findings provide insights into the mechanisms underlying CSVD and suggest that hemodynamic abnormalities may serve as indicators of neurovascular dysfunction in early-stage CSVD.
Development of the early fetal human thalamus: from a protomap to emergent thalamic nuclei
Authors: Alhesain Maznah , Alzu’bi Ayman , Sankar Niveditha , Smith Charles , Kerwin Janet , Laws Ross , Lindsay Susan , Clowry Gavin J.
Published: February 2025

Introduction

Most of what is known about thalamic development comes from rodent studies, however, the increased proportion of human association cortex has co-evolved with increased thalamocortical connectivity. Higher order thalamic nuclei, relaying information between cortical regions and important in higher cognitive function, are greatly expanded.

Methods

This study mapped the emergence of thalamic nuclei in human fetal development (8–16 post conceptional weeks; PCW) by revealing gene expression patterns using in situ hybridization and immunohistochemistry for previously established thalamic development markers.

Results

In the proliferative thalamic ventricular zone, OLIG3 and NR2F1 immunoreactivity marked the extent of the thalamus, whereas PAX6 and NR2F2 were expressed in gradients, suggesting an early protomap. This was also the case for post-mitotic transcription factors ZIC4, GBX2, FOXP2 and OTX2 which marked thalamic boundaries but also exhibited opposing gradients with ZIC4 expression higher anterior/lateral, and GBX2, FOXP2 and OTX2 higher in posterior/medial. Expression patterns became increasingly compartmentalized as development progressed and by 14 PCW recognizable thalamic nuclei were observed with, for instance, the centromedian nucleus being characterized by high FOXP2 and absent GBX2 expression. SP8-like immunoreactivity was expressed in distinct thalamic locations other than the reticular formation which has not been previously reported. Markers for GABAergic neurons and their precursors revealed the location of the prethalamus and its development into the reticular formation and zona incerta. No GAD67+ neurons were observed in the thalamus at 10 PCW, but by 14 PCW the medial posterior quadrant of the thalamus at various levels was infiltrated by GAD67+/ SOX14+ cells of presumed pretectal/midbrain origin. We compared expression of the neurodevelopmental disease susceptibility gene CNTNAP2 to these patterns. It was highly expressed by glutamatergic neurons in many thalamic regions by 14 PCW, sometimes but not always in conjunction with its upstream expression regulator FOXP2.

Conclusion

In human discrete thalamic nuclei exhibiting discrete gene expression patterns emerge relatively early from a protomap of gene expression. The migration of GABAergic neurons into the thalamus occurs over a protracted period, first from the midbrain. Disruption of CNTNAP2 activity and function could be hypothezised to have a variety of effects upon thalamic development.
Pivotal roles of melanopsin containing retinal ganglion cells in pupillary light reflex in photopic conditions
Authors: Bohl Jeremy Matthew , Hassan Abdul Rhman , Sharpe Zachary J. , Kola Megi , Shehu Angela , Beaudoin Deborah Langrill , Ichinose Tomomi
Published: February 2025

The pupillary light reflex (PLR) is crucial for protecting the retina from excess light. The intrinsically photosensitive retinal ganglion cells (ipRGCs) in the retina are neurons that are critical to generating the PLR, receiving rod/cone photoreceptor signals and directly sensing light through melanopsin. Previous studies have investigated the roles of photoreceptors and ipRGCs in PLR using genetically-modified mouse models. Herein, we acutely ablated photoreceptors using N-nitroso-N-methylurea (MNU) to examine the roles of ipRGCs in the PLR. We conducted PLR and multiple electrode array (MEA) recordings evoked by three levels of light stimuli before and 5 days after MNU intraperitoneal (i.p..) injection using C57BL6/J wildtype (WT) mice. We also conducted these measurements using the rod & cone dysfunctional mice (Gnat1–/– & Cnga3–/–:dKO) to compare the results to published studies in which mutant mice were used to show the role of photoreceptors and ipRGCs in PLR. PLR pupil constriction increased as the light stimulus intensified in WT mice. In MNU mice, PLR was not induced by the low light stimulus, suggesting that photoreceptors induced the PLR at this light intensity. By contrast, the high light stimulus fully induced PLR, similar to the response in WT mice. In dKO mice, no PLR was evoked by the low-light stimulus and a slow-onset PLR was evoked by the high-light stimulus, consistent with previous reports. Ex vivo MEA recording in the MNU tissue revealed a population of ipRGCs with a fast onset and peak time, suggesting that they drove the fast PLR response. These results suggest that ipRGCs primarily contribute to the PLR at a high light intensity, which does not agree with the previous results shown by mutant mouse models. Our results indicate that the melanopsin response in ipRGCs generate fast and robust PLR when induced by high light.
Neurological sequelae of long COVID: a comprehensive review of diagnostic imaging, underlying mechanisms, and potential therapeutics
Authors: Talkington Grant McGee , Kolluru Paresh , Gressett Timothy E. , Ismael Saifudeen , Meenakshi Umar , Acquarone Mariana , Solch-Ottaiano Rebecca J. , White Amanda , Ouvrier Blake , Paré Kristina , Parker Nicholas , Watters Amanda , Siddeeque Nabeela , Sullivan Brooke , Ganguli Nilesh , Calero-Hernandez Victor , Hall Gregory , Longo Michele , Bix Gregory J.
Published: February 2025

One lingering effect of the COVID-19 pandemic created by SARS-CoV-2 is the emergence of Long COVID (LC), characterized by enduring neurological sequelae affecting a significant portion of survivors. This review provides a thorough analysis of these neurological disruptions with respect to cognitive dysfunction, which broadly manifest as chronic insomnia, fatigue, mood dysregulation, and cognitive impairments with respect to cognitive dysfunction. Furthermore, we characterize how diagnostic tools such as PET, MRI, EEG, and ultrasonography provide critical insight into subtle neurological anomalies that may mechanistically explain the Long COVID disease phenotype. In this review, we explore the mechanistic hypotheses of these neurological changes, which describe CNS invasion, neuroinflammation, blood-brain barrier disruption, and gut-brain axis dysregulation, along with the novel vascular disruption hypothesis that highlights endothelial dysfunction and hypoperfusion as a core underlying mechanism. We lastly evaluate the clinical treatment landscape, scrutinizing the efficacy of various therapeutic strategies ranging from antivirals to anti-inflammatory agents in mitigating the multifaceted symptoms of LC.
The use of low-density EEG for the classification of PPA and MCI
Authors: Chriskos Panteleimon , Neophytou Kyriaki , Frantzidis Christos A. , Gallegos Jessica , Afthinos Alexandros , Onyike Chiadi U. , Hillis Argye , Bamidis Panagiotis D. , Tsapkini Kyrana
Published: February 2025

Objective

Dissociating Primary Progressive Aphasia (PPA) from Mild Cognitive Impairment (MCI) is an important, yet challenging task. Given the need for low-cost and time-efficient classification, we used low-density electroencephalography (EEG) recordings to automatically classify PPA, MCI and healthy control (HC) individuals. To the best of our knowledge, this is the first attempt to classify individuals from these three populations at the same time.

Methods

We collected three-minute EEG recordings with an 8-channel system from eight MCI, fourteen PPA and eight HC individuals. Utilizing the Relative Wavelet Entropy method, we derived (i) functional connectivity, (ii) graph theory metrics and extracted (iii) various energy rhythms. Features from all three sources were used for classification. The k-Nearest Neighbor and Support Vector Machines classifiers were used.

Results

A 100% individual classification accuracy was achieved in the HC-MCI, HC-PPA, and MCI-PPA comparisons, and a 77.78% accuracy in the HC-MCI-PPA comparison.

Conclusion

We showed for the first time that successful automatic classification between HC, MCI and PPA is possible with short, low-density EEG recordings. Despite methodological limitations of the current study, these results have important implications for clinical practice since they show that fast, low-cost and accurate disease diagnosis of these disorders is possible. Future studies need to establish the generalizability of the current findings with larger sample sizes and the efficient use of this methodology in a clinical setting.
Risk prediction models for dysphagia after radiotherapy among patients with head and neck cancer: a systematic review and meta-analysis
Authors: Pu You , Yang Jin , Shui Lian , Tang Qianlong , Zhang Xianqin , Liu Guangguo
Published: February 2025

Background

Predictive models can identify patients at risk and thus enable personalized interventions. Despite the increasing number of prediction models used to predict the risk of dysphagia after radiotherapy in patients with head and neck cancer (HNC), there is still uncertainty about the effectiveness of these models in clinical practice and about the quality and applicability of future studies. The aim of this study was to systematically evaluate and analyze all predictive models used to predict dysphagia in patients with HNC after radiotherapy.

Methods

PubMed, Cochrane Library, EMbase and Web of Science databases were searched from database establishment to August 31, 2024. Data from selected studies were extracted using predefined tables and the quality of the predictive modelling studies was assessed using the PROBAST tool. Meta-analysis of the predictive performance of the model was performed using the “metafor” package in R software.

Results

Twenty-five models predicting the risk of dysphagia after radiotherapy in patients with HNC were included, covering a total of 8,024 patients. Common predictors include mean dose to pharyngeal constrictor muscles, treatment setting, and tumor site. Of these models, most were constructed based on logistic regression, while only two studies used machine learning methods. The area under the receiver operating characteristic curve (AUC) reported values for these models ranged from 0.57 to 0.909, with 13 studies having a combined AUC value of 0.78 (95% CI: 0.74-0.81). All studies showed a high risk of bias as assessed by the PROBAST tool.

Conclusion

Most of the published prediction models in this study have good discrimination. However, all studies were considered to have a high risk of bias based on PROBAST assessments. Future studies should focus on large sample size and rigorously designed multicenter external validation to improve the reliability and clinical applicability of prediction models for dysphagia after radiotherapy for HNC.

Systematic review registration

https://www.crd.york.ac.uk/prospero, identifier CRD42024587252.
Late-onset and relapsed cytokine release syndrome after nivolumab treatment in a patient with head and neck squamous cell carcinoma: a case report
Authors: Otsuka Tomoyuki , Kojitani Yoshiki , Imamura Fumio , Fukutake Junko , Nishio Minako , Fujii Takashi , Kudo Toshihiro
Published: February 2025

Nivolumab, an anti-programmed death-1 (PD-1) receptor monoclonal antibody, has proven effective in treating platinum-resistant metastatic head and neck squamous cell carcinoma. Immune-related adverse events (irAEs) are well-known complications of PD-1 inhibitors. Meanwhile, cytokine release syndrome (CRS), a life-threatening immune-related adverse event, rarely develops due to nivolumab monotherapy. Here, we report a case of a 65-year-old man with squamous cell head and neck carcinoma of an occult primary origin who developed nivolumab-associated late-onset CRS that recurred. The patient was admitted with symptoms of fatigue, fever, hypotension, and respiratory distress. The diagnosis of CRS was supported by the elevated serum levels of interleukin-6 and ferritin, and the patient responded well to high-dose methylprednisolone. CRS recurred during steroid tapering, coinciding with an increased tumor burden; however, it was successfully managed with increased steroid dosing. Early detection and treatment with steroids are essential for the management of CRS.
Expression and prognostic significance of the m6A RNA methylation regulator HNRNPC in HNSCC
Authors: Zhang Yulin , Wang Yixu , Peng Jilin , Zhao Kun , Li Ling , Zhang Yuan , Zhai Ziyu , Yuan Sijie , Li Shichao , Ye Fanglei , Wang Le
Published: February 2025

Background

N6-methyladenosine (m6A) RNA modification is crucial for tumor development and progression; however, which m6A regulators play a pivotal role in head and neck squamous cell carcinoma (HNSCC) remains ambiguous.

Methods

Utilizing the Cancer Genome Atlas (TCGA) database, the expression levels of m6A regulators in HNSCC were examined, which led to the identification of heterogeneous nuclear ribonucleoprotein C (HNRNPC) as a key gene. Further experiments were performed in patient samples, stable cell lines, and a murine xenograft tumor model.

Results

A reliable survival risk model of m6A was constructed based on the TCGA database. Gene Expression Omnibus (GEO), normal and tumor tissue microarrays (TMA), and tumor tissue samples from patients with HNSCC were observed that a high level of HNRNPC expression was closely linked to a poor prognosis among patients. Knockdown of HNRNPC in the HNSCC cell lines HSC-3 and CAL-27 resulted in a significant decrease in proliferation, invasion, and malignant transformation abilities. RNA sequencing (RNA-seq) and methylated RNA immunoprecipitation and sequencing (MeRIP-seq) data revealed that HNRNPC is involved in cell differentiation, cell migration and apoptosis. The mouse xenograft model elucidated that HNRNPC can promote tumorigenesis and progression of HNSCC.

Conclusions

HNRNPC can serve as a valuable predictor of tumor progression and prognosis in patients with HNSCC.
Research trends in glioma chemoradiotherapy resistance: a bibliometric analysis (2003–2023)
Authors: Yu Shishi , Wu Jinya , Jing Yuan , Lin Ping , Lang Lang , Xiong Yifan , Chen Wangzhong , Liu Wenhua , Sun Changpeng , Lu Yuntao
Published: February 2025

Background

Glioma is the most aggressive primary malignant tumor of the central nervous system, characterized by high recurrence rates and resistance to chemoradiotherapy, making therapeutic resistance a major challenge in neuro-oncology. Recent research emphasizes the role of the tumor microenvironment (TME) and immune modulation in glioma progression and resistance. Despite these advances, a comprehensive bibliometric analysis of research trends in glioma chemoradiotherapy resistance over the past two decades is lacking. This study aims to systematically evaluate the research landscape, identify emerging hotspots, and provide guidance for future investigations.

Methods

Articles on glioma chemoradiotherapy resistance published between 2003 and 2023 were retrieved from the Web of Science Core Collection, resulting in 4,528 publications. Bibliometric tools, including VOSviewer, CiteSpace, and R packages such as bibliometrix and ggplot2, were used to analyze co-authorship networks, keyword evolution, and citation bursts to identify collaboration patterns, thematic developments, and influential contributions.

Results

Publication output increased significantly between 2013 and 2022, peaking at 650 articles in 2022. Over 1,000 institutions from 88 countries contributed to this research. The United States, Switzerland, and Germany showed the highest citation impact, while China led in publication volume but demonstrated relatively lower citation influence. The research focus has shifted from traditional topics such as the “MGMT gene” to emerging areas including the “tumor microenvironment,” “immune infiltration,” and “nanoparticles.” The androgen receptor was identified as a promising but underexplored therapeutic target.

Conclusions

Research on glioma chemoradiotherapy resistance has seen substantial growth, with increasing emphasis on immune modulation, the tumor microenvironment, and novel therapeutic targets such as the androgen receptor. This study represents the first comprehensive bibliometric analysis of this field, providing a detailed overview of research trends and potential directions for future studies. The findings highlight the need for strengthened international collaboration and multidisciplinary approaches to address the challenges of therapeutic resistance in glioma.
Does pregabalin offer potential as a first-line therapy for generalized anxiety disorder? A meta-analysis of efficacy, safety, and cost-effectiveness
Authors: Cardoner Narcis , Gutiérrez-Rojas Luis , Saiz Pilar , Lahera Guillermo , Álvarez-Mon Miguel Ángel , Alonso Ortega Pino , Pérez-Páramo María
Published: February 2025

Introduction

Generalized Anxiety Disorder (GAD) is a mental health condition with a recent increase in prevalence. GAD is often underdiagnosed, leading to negative consequences for individuals, healthcare systems, and society. The economic burden and impaired quality of life associated with GAD underscores the need for effective treatment. Pregabalin has shown promise in reducing anxiety symptoms; however, further research is needed to evaluate its efficacy and compare it with other treatment options. This study aimed to assess the efficacy, safety, and optimal pregabalin dosage for the treatment of GAD.

Methods

This meta-analysis followed PRISMA guidelines. Pregabalin-treated patients comprised the intervention group, whereas the comparator group received benzodiazepines, SSRIs, SNRIs, or placebo. Efficacy and safety were evaluated using various scales and adverse events (AEs). Randomized clinical trials were included in the study. Four major databases were used for this study. Outcome measures included the Hamilton Anxiety Rating Scale (HAM-A), Clinical Global Impression Improvement Scale (CGI-I), discontinuation rates, costs, and quality-adjusted life-years (QALYs). Meta-analyses were conducted using Review Manager 5.4 software, employing odds ratios (ORs) and mean differences (MDs) with 95% confidence intervals (CIs). Subgroup and sensitivity analyses were performed based on follow-up and dosage.

Results

Fourteen studies involving 4,822 patients were analyzed. Pregabalin demonstrated superior efficacy in reducing HAM-A global scores at 2 weeks (MD −1.23, 95% CI −1.79 to −0.66), 4 weeks (MD −1.12, 95% CI −1.60 to −0.63), 8 weeks (MD −2.50, 95% CI −4.21 to −0.79), 12 weeks (MD 0.99, 95% CI 0.35–1.63), and 6 months to 1 year (MD −3.31, 95% CI −4.30 to −2.31). Pregabalin also showed a higher response rate to HAM-A (OR 1.51, 95% CI 1.31 1.75). CGI-I scores favored pregabalin (MD −0.25, 95% CI −0.38 to −0.12), with a higher response rate (OR 1.33, 95% CI 1.15–1.55). The discontinuation rates were lower with pregabalin (OR 0.80, 95% CI 0.70, 0.91). Adverse events favored pregabalin over SSRIs/SNRIs and benzodiazepines at different doses. Pregabalin was associated with higher cost-effectiveness (MD 0.02, 95% CI 0.01, 0.03).

Conclusion

Pregabalin is an effective and well-tolerated treatment for generalized anxiety disorder, showing superior efficacy and safety compared with first-line medications.

Systematic Review Registration

PROSPERO CRD42024556152.
Anti-TNBC effects of Lappaol F by targeting epithelial-mesenchymal transition via regulation of GSK-3β/YAP/β-catenin and PI3K/AKT pathways
Authors: Meng Qiqi , Li Zhiping , He Xiaofeng , Hu Yuanhao , Wu Guiyun , Huang Jiawen , Luo Zhuohui , Hu Yingjie , Shen Xiaoling
Published: February 2025

Purpose

Lappaol F (LAF), a lignan extracted from Fructus Arctii, has a wide spectrum of anti-tumor effects, including inhibition of TNBC cell growth. However, the pharmacological mechanism of LAF targeting epithelial-mesenchymal transition (EMT) to inhibit Triple-negative breast cancer (TNBC) growth remains poorly understood. The present study aimed to reveal the potential mechanism of LAF against TNBC by in vivo and in vitro experiments.

Methods

In situ, transplantation-induced MDA-MB-231 solid tumor model in NCG mice and cultured MDA-MB-231 and Hs-578T cells were used to evaluate the anti-TNBC effect of LAF. Flow cytometry, wound healing, transwell assay, western blot, RT-PCR, and immunofluorescence analysis were carried out to investigate the pharmacological mechanism of LAF against TNBC.

Results

LAF significantly inhibited the growth of MDA-MB-231 tumors, with downregulated tumor level of vimentin and upregulated level of ZO-1. In MDA-MB-231 and Hs-578T cells, LAF markedly suppressed cell proliferation, migration and invasion, and promoted apoptosis. Similarly, LAF increased the expression of ZO-1 and occludin proteins in MDA-MB-231 cells, and inhibited the expression of vimentin, snail and slug proteins in MDA-MB-231 and Hs-578T cells, as well as the expression of N-caderin in Hs-578T cells. Moreover, LAF also inhibited the phosphorylation of GSK-3β, thereby inhibited the downstream nuclear translocation of β-catenin and the expression of YAP. Furthermore, LAF significantly inhibited the expression of PI3K and AKT, and the phosphorylation of downstream mTOR.

Conclusion

LAF showed anti-TNBC effect both in vitro and in vivo. Reversal of EMT by inhibiting GSK-3β/YAP/β-catenin signaling and PI3K/AKT/mTOR signaling contributes to the effect.
Natural bioactive compounds form herbal medicine in Alzheimer’s disease: from the perspective of GSK-3β
Authors: Wang Mei , Huang Wendi , Huang Juan , Luo Yong , Huang Nanqu
Published: February 2025

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and memory loss. Glycogen synthase kinase 3β (GSK-3β) plays a pivotal role in AD pathogenesis, particularly in tau protein hyperphosphorylation. Natural bioactive compounds have a wide range of sources, and medicinally valuable active compound can be extracted from plants, animals, and microorganisms. Currently, studies have found that various natural bioactive compounds from plants have the potential to improve AD symptoms, such as resveratrol and berberine. Therefore, this review examines the potential of natural bioactive compounds to modulate GSK-3β activity and inhibit the hyperphosphorylation of tau, offering a promising therapeutic strategy for AD. We summarize the current understanding of alkaloids, phenols, flavonoids, terpenoids and other natural compounds, highlighting their mechanisms of action and preclinical efficacy.