bluuebunny/crossref_metadata_2025 huggingface dataset:
PM21-particle stimulation augmented with cytokines enhances NK cell expansion and confers memory-like characteristics with enhanced survival
Authors: Oyer Jeremiah L. , Croom-Perez Tayler J. , Hasan Md Faqrul , Rivera-Huertas Javier A. , Gitto Sarah B. , Mucha Joanna M. , Zhu Xiang , Altomare Deborah A. , Igarashi Robert Y. , Copik Alicja J.
Published: April 2024

NK cell therapeutics have gained significant attention as a potential cancer treatment. Towards therapeutic use, NK cells need to be activated and expanded to attain high potency and large quantities for an effective dosage. This is typically done by ex vivo stimulation with cytokines to enhance functionality or expansion for 10-14 days to increase both their activity and quantity. Attaining a robust methodology to produce large doses of potent NK cells for an off-the-shelf product is highly desirable. Notably, past reports have shown that stimulating NK cells with IL-12, IL-15, and IL-18 endows them with memory-like properties, better anti-tumor activity, and persistence. While this approach produces NK cells with clinically favorable characteristics supported by encouraging early results for the treatment of hematological malignancies, its limited scalability, variability in initial doses, and the necessity for patient-specific production hinder its broader application. In this study, stimulation of NK cells with PM21-particles derived from K562-41BBL-mbIL21 cells was combined with memory-like induction using cytokines IL-12, IL-15, and IL-18 to produce NK cells with enhanced anti-tumor function. The use of cytokines combined with PM21-particles (cytokine and particle, CAP) significantly enhanced NK cell expansion, achieving a remarkable 8,200-fold in 14 days. Mechanistically, this significant improvement over expansion with PM21-particles alone was due to the upregulation of receptors for key stimulating ligands (4-1BBL and IL-2), resulting in a synergy that drives substantial NK cell growth, showcasing the potential for more effective therapeutic applications. The therapeutic potential of CAP-NK cells was demonstrated by the enhanced metabolic fitness, persistence, and anti-tumor function both in vitro and in vivo. Finally, CAP-NK cells were amenable to current technologies used in developing therapeutic NK cell products, including CRISPR/Cas9-based techniques to generate a triple-gene knockout or a gene knock-in. Taken together, these data demonstrate that the addition of cytokines enhanced the already effective method of ex vivo generation of therapeutic NK cells with PM21-particles, yielding a superior NK cell product for manufacturing efficiency and potential therapeutic applications.
One gene to rule them all – clinical perspectives of a potent suppressor of cytokine signaling – SOCS1
Authors: Körholz Julia , Chen Lan-Sun , Strauss Timmy , Schuetz Catharina , Dalpke Alexander H.
Published: April 2024

The discovery of Suppressor of Cytokine Signaling 1 (SOCS1) in 1997 marked a significant milestone in understanding the regulation of Janus kinase/Signal transducer and activator of transcription (JAK/STAT) signaling pathways. Subsequent research deciphered its cellular functions, and recent insights into SOCS1 deficiencies in humans underscored its critical role in immune regulation. In humans, SOCS-haploinsufficiency (SOCS1-HI) presents a diverse clinical spectrum, encompassing autoimmune diseases, infection susceptibility, and cancer. Variability in disease manifestation, even within families sharing the same genetic variant, raises questions about clinical penetrance and the need for individualized treatments. Current therapeutic strategies include JAK inhibition, with promising results in controlling inflammation in SOCS1-HI patients. Hematopoietic stem cell transplantation and gene therapy emerge as promising avenues for curative treatments. The evolving landscape of SOCS1 research, emphasizes the need for a nuanced understanding of genetic variants and their functional consequences.
Lipidation of pneumococcal proteins enables activation of human antigen-presenting cells and initiation of an adaptive immune response
Authors: Paulikat Antje D. , Schwudke Dominik , Hammerschmidt Sven , Voß Franziska
Published: April 2024

Streptococcus pneumoniae remains a significant global threat, with existing vaccines having important limitations such as restricted serotype coverage and high manufacturing costs. Pneumococcal lipoproteins are emerging as promising vaccine candidates due to their surface exposure and conservation across various serotypes. While prior studies have explored their potential in mice, data in a human context and insights into the impact of the lipid moiety remain limited. In the present study, we examined the immunogenicity of two pneumococcal lipoproteins, DacB and MetQ, both in lipidated and non-lipidated versions, by stimulation of primary human immune cells. Immune responses were assessed by the expression of common surface markers for activation and maturation as well as cytokines released into the supernatant. Our findings indicate that in the case of MetQ lipidation was crucial for activation of human antigen-presenting cells such as dendritic cells and macrophages, while non-lipidated DacB demonstrated an intrinsic potential to induce an innate immune response. Nevertheless, immune responses to both proteins were enhanced by lipidation. Interestingly, following stimulation of dendritic cells with DacB, LipDacB and LipMetQ, cytokine levels of IL-6 and IL-23 were significantly increased, which are implicated in triggering potentially important Th17 cell responses. Furthermore, LipDacB and LipMetQ were able to induce proliferation of CD4+ T cells indicating their potential to induce an adaptive immune response. These findings contribute valuable insights into the immunogenic properties of pneumococcal lipoproteins, emphasizing their potential role in vaccine development against pneumococcal infections.
Independent organelle and organelle—organelle interactions: essential mechanisms for malignant gynecological cancer cell survival
Authors: Shen Ying , Chen Qiao-Chu , Li Chen-Yu , Han Feng-Juan
Published: April 2024

Different eukaryotic cell organelles (e.g., mitochondria, endoplasmic reticulum, lysosome) are involved in various cancer processes, by dominating specific cellular activities. Organelles cooperate, such as through contact points, in complex biological activities that help the cell regulate energy metabolism, signal transduction, and membrane dynamics, which influence survival process. Herein, we review the current studies of mechanisms by which mitochondria, endoplasmic reticulum, and lysosome are related to the three major malignant gynecological cancers, and their possible therapeutic interventions and drug targets. We also discuss the similarities and differences of independent organelle and organelle–organelle interactions, and their applications to the respective gynecological cancers; mitochondrial dynamics and energy metabolism, endoplasmic reticulum dysfunction, lysosomal regulation and autophagy, organelle interactions, and organelle regulatory mechanisms of cell death play crucial roles in cancer tumorigenesis, progression, and response to therapy. Finally, we discuss the value of organelle research, its current problems, and its future directions.
Households neighboring wildlife protected areas may be at a higher risk of rabies than those located further away: a community-based cross-sectional cohort study at Pian Upe game reserve, Bukedea district, Eastern Uganda
Authors: Atuheire Collins G. K. , Okwee-Acai James , Taremwa Martha , Ssajjakambwe Paul , Munyeme Musso , Kankya Clovice , Terence Odoch , Ssali Sarah N. , Mwiine Frank N. , Buhler Kayla J. , Tryland Morten
Published: April 2024

Introduction

This study examines rabies incidence and associated risk factors at the interface between wildlife and human communities near Pian-Upe game reserve in Eastern Uganda. We hypothesized that human settlements in closer proximity to the reserve would exhibit higher rabies risk compared to those located further away.

Methods

Using a standard questionnaire, households within <4, 4-14, and >14 km from the Pian Upe game reserve in Bukedea District were interviewed. Data on socio-demographic characteristics, recent rabid animal bites, and suspected human and livestock rabies cases for the past year (2023) were collected after seeking informed consent. Descriptive statistics were used to analyze socio-demographic information and incidence data, while separate binomial generalized linear models with log-link function were used to identify predictors of rabies incidence and mortality.

Results

Between January and March 2023, 302 participants were interviewed. Respondents had an average age of 44 years with 34% (n=103) being female. All households owned at least one dog, though only 47% (n=142) had vaccinated their dogs against rabies in the past year. Additionally, 39% (n=118) of respondents used dogs for hunting. Rabies annual incidence increased with decreasing distance to the game reserve (7.5 to 15.7% for humans, for the dogs, and 5.0 to 9.8% for livestock, including cows, goats and sheep). Significant factors associated with rabies in humans included primary education level (aRR=3.8, 95%CI 1.0-23.7) and grazing livestock in the reserve (aRR=5.30, 95%CI 1.0-40.3). Mortality was associated with fetching firewood from the game reserve (aRR=4.7, 95%CI 1.3-17.5).

Conclusions

This study reveals that there is an increased risk of rabies for domesticated animals and people located within proximity to the game reserve. Further efforts to prevent the spread of rabies could include increasing education and awareness for communities along with targeted dog vaccination in settlements surrounding wildlife protected areas.
COVID-19 with high-sensitivity CRP associated with worse dynamic clinical parameters and outcomes
Authors: Iam-Arunthai Kunapa , Chamnanchanunt Supat , Thungthong Pravinwan , Chinapha Anongnart , Nakhahes Chajchawan , Suwanban Tawatchai , Umemura Tsukuru
Published: April 2024

Objective

This study aimed to evaluate the relationship between high-sensitivity C-reactive protein (hsCRP) in hospitalized COVID-19 patients and their clinical outcomes, including trajectory of hsCRP changes during hospitalization.

Method and results

Patients with positive COVID-19 tests between 2021 and 2023 were admitted to two hospitals. Among 184 adult patients, approximately half (47.3%) had elevated hsCRP levels upon admission, which defined as exceeding the laboratory-specific upper limit of test (> 5.0 mg/L). Clinical outcomes included critical illness, acute kidney injury, thrombotic events, intensive care unit (ICU) requirement, and death during hospitalization. Elevated hsCRP levels had a higher risk of ICU requirement than those with normal, 39.1% versus 16.5%; adjusted odds ratio (aOR), 2.3 [95% CI, 1.05–5.01]; p = 0.036. Patients with extremely high (≥2 times) hsCRP levels had aOR, 2.65 [95% CI, 1.09–6.45]; p < 0.001. On the fifth day hospitalization, patients with high hsCRP levels associated with acute kidney injury (aOR, 4.13 [95% CI, 1.30–13.08]; p = 0.016), ICU requirement (aOR, 2.67 [95%CI, 1.02–6.99]; p = 0.044), or death (aOR, 4.24 [95% CI, 1.38-12.99]; p = 0.011). The likelihood of worse clinical outcomes increased as hsCRP levels rose; patients with elevated hsCRP had lower overall survival rate than those with normal (p = 0.02). The subset of high hsCRP patients with high viral load also had a shorter half-life compared to those with normal hsCRP level (p = 0.003).

Conclusion

Elevated hsCRP levels were found to be a significant predictor of ICU requirement, acute kidney injury, or death within 5 days after hospitalization in COVID-19 patients. This emphasized the importance of providing more intensive care management to patients with elevated hsCRP.
Antimicrobial efficacy of Punica granatum Lythraceae peel extract against pathogens belonging to the ESKAPE group
Authors: Scaglione Elena , Sateriale Daniela , Mantova Giuseppe , Di Rosario Martina , Continisio Leonardo , Vitiello Mariateresa , Pagliarulo Caterina , Colicchio Roberta , Pagliuca Chiara , Salvatore Paola
Published: April 2024

The improper use and abuse of antibiotics have led to an increase in multidrug-resistant (MDR) bacteria resulting in a failure of standard antibiotic therapies. To date, this phenomenon represents a leading public health threat of the 21st century which requires alternative strategies to fight infections such as the identification of new molecules active against MDR strains. In the last 20 years, natural extracts with biological activities attracted scientific interest. Following the One Health Approach, natural by-products represent a sustainable and promising alternative solution. Consistently, the aim of the present study was to evaluate the antimicrobial activity of hydro-alcoholic pomegranate peel extract (PPE) against MDR microorganisms belonging to Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp. “ESKAPE” group pathogens. Through semiquantitative and quantitative methods, the PPE showed effective antimicrobial activity against Gram-positive and Gram-negative MDR bacteria. The kinetics of bactericidal action of PPE highlighted that microbial death was achieved in a time- and dose-dependent manner. High concentrations of PPE exhibited antioxidant activity, providing a protective effect on cellular systems and red blood cell membranes. Finally, we report, for the first time, a significant intracellular antibacterial property of PPE as highlighted by its bactericidal action against the staphylococcal reference strain and its bacteriostatic effect against clinical resistant strain in the HeLa cell line. In conclusion, due to its characterized content of polyphenolic compounds and antioxidant activity strength, the PPE could be considered as a therapeutic agent alone or in conjunction with standard antibiotics against challenging infections caused by ESKAPE pathogens.
Analyzing molecular signatures in preeclampsia and fetal growth restriction: Identifying key genes, pathways, and therapeutic targets for preterm birth
Authors: Azmi Muhammad Bilal , Nasir Mushyeda Fatima , Asif Uzma , Kazi Mohsin , Uddin Mohammad N. , Qureshi Shamim Akhtar
Published: April 2024

Background:

Intrauterine growth restriction (IUGR) and preeclampsia (PE) are intricately linked with specific maternal health conditions, exhibit shared placental abnormalities, and play pivotal roles in precipitating preterm birth (PTB) incidences. However, the molecular mechanism underlying the association between PE and IUGR has not been determined. Therefore, we aimed to analyze the data of females with PE and those with PE + IUGR to identify the key gene(s), their molecular pathways, and potential therapeutic interactions.

Methods:

In this study, a comprehensive relationship analysis of both PE and PE + IUGR was conducted using RNA sequence datasets. Using two datasets (GSE148241 and GSE114691), differential gene expression analysis via DESeq2 through R-programming was performed. Gene set enrichment analysis was performed using ClusterProfiler, protein‒protein interaction (PPI) networks were constructed, and cluster analyses were conducted using String and MCODE in Cytoscape. Functional enrichment analyses of the resulting subnetworks were performed using ClueGO software. The hub genes were identified under both conditions using the CytoHubba method. Finally, the most common hub protein was docked against a library of bioactive flavonoids and PTB drugs using the PyRx AutoDock tool, followed by molecular dynamic (MD) simulation analysis. Pharmacokinetic analysis was performed to determine the ADMET properties of the compounds using pkCSM.

Results:

We identified eight hub genes highly expressed in the case of PE, namely, PTGS2, ENG, KIT, MME, CGA, GAPDH, GPX3, and P4HA1, and the network of the PE + IUGR gene set demonstrated that nine hub genes were overexpressed, namely, PTGS2, FGF7, FGF10, IL10, SPP1, MPO, THBS1, CYBB, and PF4. PTGS2 was the most common hub gene found under both conditions (PE and PEIUGR). Moreover, the greater (−9.1 kcal/mol) molecular binding of flavoxate to PTGS2 was found to have satisfactory pharmacokinetic properties compared with those of other compounds. The flavoxate-bound PTGS2 protein complex remained stable throughout the simulation; with a ligand fit to protein, i.e., a RMSD ranging from ∼2.0 to 4.0 Å and a RMSF ranging from ∼0.5 to 2.9 Å, was observed throughout the 100 ns analysis.

Conclusion:

The findings of this study may be useful for treating PE and IUGR in the management of PTB.
Translational pathway of a novel PFF2 respirator with chitosan nanotechnology: from the concept to the practical applications
Authors: Fleury Rosa Mário Fabrício , Santos Leonor Maria Pacheco , Grabois Gadelha Carlos Augusto , Martins de Toledo Aline , Carregaro Rodrigo Luiz , Almeida da Silva Ana Karoline , Mota da Costa Lindemberg Barreto , Ferreira da Rocha Adson , de Siqueira Rodrigues Fleury Rosa Suélia
Published: April 2024

Introduction:

Translational Health Research (THR) is a tool aimed at assisting in the transformation of basic and/or applied scientific research into a health technology ready for commercialization. The aim of this study is to present the translational pathway in wich our research group developed a Personal Protective Equipment (PPE) called VESTA® Facial Respirator with chitosan nanotechnology for protection against viruses, bacteria, and fungi. The aim of this study is to present the process of THR applied to a health technology research.

Methods:

The theoretical-methodological process of THR was applied to the Research and Development (R&D) of the respirator. This method is characterized by subsequent phases, as follow: T (0)—Concept, T (1) Pre-Clinical, T (2) Clinical, T (3) Industrial Scale Production, and T (4) Characterized by subsequent phases, as follow: Technological Evaluation.

Results:

Applying the THR process in the development and production of the Particulate Filtering Facepiece class 2 (PFF2) respirator with chitosan nanotechnology, University of Brasilia was able to transform the research idea into a respirator approved by the National Regulatory Agency for industrial-scale production within 24 months. The THR process is not a linear action; this flexibility allows essential activities for transforming research into a marketable product.

Discussion:

The integration among various stakeholders right from the genesis of research is a driving force for the effective utilization of results. The maturity of the country’s industrial sector is crucial for converting university research into a marketable product, and governments need to prioritize these products in healthcare system incorporations. The academic culture of scientific research needs to intensify the technological transfer phase of its inventions. Conclusion: In less than 24 months, the University of Brasilia translated research on a new PPE into the market by applying the THR method.
Synthetic minority over-sampling technique-enhanced machine learning models for predicting recurrence of postoperative chronic subdural hematoma
Authors: Ni Zhihui , Zhu Yehao , Qian Yiwei , Li Xinbo , Xing Zhenqiu , Zhou Yinan , Chen Yu , Huang Lijie , Yang Jianjing , Zhuge Qichuan
Published: April 2024

Objective

Chronic subdural hematoma (CSDH) is a neurological condition with high recurrence rates, primarily observed in the elderly population. Although several risk factors have been identified, predicting CSDH recurrence remains a challenge. Given the potential of machine learning (ML) to extract meaningful insights from complex data sets, our study aims to develop and validate ML models capable of accurately predicting postoperative CSDH recurrence.

Methods

Data from 447 CSDH patients treated with consecutive burr-hole irrigations at Wenzhou Medical University’s First Affiliated Hospital (December 2014-April 2019) were studied. 312 patients formed the development cohort, while 135 comprised the test cohort. The Least Absolute Shrinkage and Selection Operator (LASSO) method was employed to select crucial features associated with recurrence. Eight machine learning algorithms were used to construct prediction models for hematoma recurrence, using demographic, laboratory, and radiological features. The Border-line Synthetic Minority Over-sampling Technique (SMOTE) was applied to address data imbalance, and Shapley Additive Explanation (SHAP) analysis was utilized to improve model visualization and interpretability. Model performance was assessed using metrics such as AUROC, sensitivity, specificity, F1 score, calibration plots, and decision curve analysis (DCA).

Results

Our optimized ML models exhibited prediction accuracies ranging from 61.0% to 86.2% for hematoma recurrence in the validation set. Notably, the Random Forest (RF) model surpassed other algorithms, achieving an accuracy of 86.2%. SHAP analysis confirmed these results, highlighting key clinical predictors for CSDH recurrence risk, including age, alanine aminotransferase level, fibrinogen level, thrombin time, and maximum hematoma diameter. The RF model yielded an accuracy of 92.6% with an AUC value of 0.834 in the test dataset.

Conclusion

Our findings underscore the efficacy of machine learning algorithms, notably the integration of the RF model with SMOTE, in forecasting the recurrence of postoperative chronic subdural hematoma. Leveraging the RF model, we devised an online calculator that may serve as a pivotal instrument in tailoring therapeutic strategies and implementing timely preventive interventions for high-risk patients.
Serial ASPECTS to predict stroke-associated pneumonia after thrombolysis in patients with acute ischemic stroke
Authors: Krongsut Sarawut , Soontornpun Atiwat , Anusasnee Niyada
Published: April 2024

Background

Stroke-associated pneumonia (SAP) is a serious complication in stroke patients, significantly increasing mortality. The Alberta Stroke Program Early CT Score (ASPECTS) is a recognized predictor of acute ischemic stroke outcomes. We aimed to investigate the performance of serial ASPECTS assessments (baseline ASPECTS, 24-h ASPECTS, and change in ASPECTS) for predicting SAP in patients with thrombolyzed acute anterior circulation ischemic stroke (AACIS).

Materials

A retrospective observational cohort study of adult patients with thrombolyzed AACIS was conducted. Baseline and 24-h ASPECTS using non-contrast computed tomography (NCCT), complications of stroke, including SAP and swallowing dysfunction using the Modified Water Swallowing test, were collected. Baseline and 24-h ASPECTS were evaluated by a certified neurologist and neuroradiologist. The predictive performance was determined based on the receiver operating characteristic curve (ROC). Multivariable logistic regression analyses were employed to assess the impact of serial ASPECTS assessment on predicting SAP.

Results

Of the 345 patients with thrombolyzed AACIS in our study, 18.4% (64/345) experienced SAP. The patients’ median age was 62 years [interquartile range (IQR): 52–73], with 53.4% being male. The median NIHSS score was 11 points (IQR: 8–17). The ROC analysis revealed areas under the curve for predicting SAP with baseline ASPECTS, 24-h ASPECTS, and change in ASPECTS were 0.75 (95% CI, 0.69–0.82), 0.84 (95% CI, 0.79–0.89), and 0.82 (95% CI, 0.76–0.87), respectively. Of the three measures, 24-h ASPECTS was a better predictor of SAP (odds ratio: 5.33, 95%CI: 2.08–13.67, p < 0.001) and had a higher sensitivity (0.84 [95%CI, 0.74–0.92]) and specificity (0.79 [95%CI, 0.74–0.84]) than both baseline ASPECTS and change in ASPECTS.

Conclusion

24-h NCCT-ASPECTS outperformed both baseline ASPECTS and change in ASPECTS for predicting SAP. Notably, 24-h ASPECTS, with a cut-off value of ≤6, exhibited good predictive performance and emerged as the better predictor for SAP.
Examining the utility of near infrared light as pre-exposure therapy to mitigate temporary noise-induced hearing loss in humans
Authors: Williams Erin , Minesinger Kayla , Gallagher Hilary , Stefanson J. R. , Bridges Nathaniel , Jackson Natalie , Stark Valerie , Coto Jennifer , Rajguru Suhrud , Yankaskas Kurt , Rogers Rick , Hoffer Michael E.
Published: April 2024

Introduction

This study sought to determine the effect of Occupational Safety and Health Administration (OSHA) compliant noise on auditory health and assess whether pre-noise near infrared (NIR) light therapy can mitigate the effects of noise exposure.

Methods

Over four visits, participants (n = 30, NCT#: 03834714) with normal hearing completed baseline hearing health assessments followed by exposure to open ear, continuous pink noise at 94 dBA for 15 min. Immediately thereafter, post-noise hearing tests at 3000, 4000, and 6000 Hz and distortion product otoacoustic emissions (DPOAEs) were conducted along with the Modified Rhyme Test (MRT), Masking Level Difference Test (MLD), and Fixed Level Frequency Tests (FLFT) [collectively referred to as the Central and Peripheral Auditory Test Battery (CPATB)] to acquire baseline noise sensitivity profiles. Participants were then randomized to either Active or Sham NIR light therapy for 30 min binaurally to conclude Visit 1. Visit 2 (≥24 and ≤ 48 h from Visit 1) began with an additional 30-min session of Active NIR light therapy or Sham followed by repeat CPATB testing and noise exposure. Post-noise testing was again conducted immediately after noise exposure to assess the effect of NIR light therapy. The remaining visits were conducted following ≥2 weeks of noise rest in a cross-over design (i.e., those who had received Active NIR light therapy in Visits 1 and 2 received Sham therapy in Visits 3 and 4).

Results

Recovery hearing tests and DPOAEs were completed at the end of each visit. Participants experienced temporary threshold shifts (TTS) immediately following noise exposure, with a mean shift of 6.79 dB HL (±6.25), 10.61 dB HL (±6.89), and 7.30 dB HL (±7.25) at 3000, 4000, and 6000 Hz, respectively, though all thresholds returned to baseline at 3000, 4000, and 6000 Hz within 75 min of noise exposure. Paradoxically, Active NIR light therapy threshold shifts were statistically higher than Sham therapy at 3000 Hz (p = 0.04), but no other differences were observed at the other frequencies tested. An age sub-analysis demonstrated that TTS among younger adults were generally larger in the Sham therapy group versus Active therapy, though this was not statistically different. There were no differences in CPATB test results across Active or Sham groups. Finally, we observed no changes in auditory function or central processing following noise exposure, suggestive of healthy and resilient inner ears.

Conclusion

In this study, locally administered NIR prior to noise exposure did not induce a significant protective effect in mitigating noise-induced TTS. Further exploration is needed to implement effective dosage and administration for this promising otoprotective therapy.
Magnetic resonance-guided focused ultrasound thalamotomy for essential tremor patients with low skull density ratio: a case-matched analysis
Authors: Ng Patrick R. , Blitz Sarah E. , Chua Melissa M. J. , Cosgrove G. Rees
Published: April 2024

Introduction

Skull density ratio (SDR) is the ratio between the mean Hounsfield units of marrow and cortical bone, impacting energy transmission through the skull. Low SDR has been used as an exclusion criterion in major trials of magnetic resonance-guided focused ultrasound (MRgFUS) thalamotomy for medication-refractory essential tremor (ET). However, some studies have suggested that patients with low SDR can safely undergo MRgFUS with favorable outcomes. In this case-matched study, we aim to compare the characteristics, sonication parameters, lesion sizes, and clinical outcomes of patients with low SDR vs. patients with high SDR who underwent unilateral MRgFUS thalamotomy for medication-refractory ET.

Methods

Between March 2016 and April 2023, all patients (n = 270) who underwent unilateral MRgFUS thalamotomy for medication-refractory ET at a single institution were classified as low SDR (<0.40) and high SDR (≥0.40). All clinical and radiological data was prospectively collected and retrospectively analyzed using non-case-matched and 1:1 case-matched methodology.

Results

Thirty-one patients had low SDR, and 239 patients had high SDR. Fifty-six patients (28 in each cohort) were included in 1:1 case-matched analysis. There were no significant differences in baseline characteristics between the two groups in both non-case-matched and 1:1 case-matched analyses. In both analyses, compared to patients with high SDR, patients with low SDR required a significantly higher maximum sonication power, energy, and duration, and reached a lower maximum temperature with smaller lesion volumes. In the non-case-matched and case-matched analyses, low SDR patients did not have significantly less tremor control at any postoperative timepoints. However, there was a higher chance of procedure failure in the low SDR group with three patients not obtaining an appropriately sized lesion. In both analyses, imbalance was observed more often in high SDR patients on postoperative day 1 and month 3.

Discussion

ET patients with SDR <0.40 can be safely and effectively treated with MRgFUS, though there may be higher rates of treatment failure and intraoperative discomfort.
Critical review of the evidence for Vojta Therapy: a systematic review and meta-analysis
Authors: Sánchez-González Juan Luis , Sanz-Esteban Ismael , Menéndez-Pardiñas Mónica , Navarro-López Víctor , Sanz-Mengíbar José Manuel
Published: April 2024

Introduction

It is essential to link the theoretical framework of any neurophysiotherapy approach with a detailed analysis of the central motor control mechanisms that influence motor behavior. Vojta therapy (VT) falls within interventions aiming to modify neuronal activity. Although it is often mistakenly perceived as exclusively pediatric, its utility spans various functional disorders by acting on central pattern modulation. This study aims to review the existing evidence on the effectiveness of VT across a wide range of conditions, both in the adult population and in pediatrics, and analyze common therapeutic mechanisms, focusing on motor control modulation.

Aim

The goals of this systematic review are to delineate the existing body of evidence concerning the efficacy of Vojta therapy (VT) in treating a broad range of conditions, as well as understand the common therapeutic mechanisms underlying VT with a specific focus on the neuromodulation of motor control parameters.

Methods

PubMed, Cochrane Library, SCOPUS, Web of Science, and Embase databases were searched for eligible studies. The methodological quality of the studies was assessed using the PEDro list and the Risk-Of-Bias Tool to assess the risk of bias in randomized trials. Methodological quality was evaluated using the Risk-Of-Bias Tool for randomized trials. Random-effects meta-analyses with 95% CI were used to quantify the change scores between the VT and control groups. The certainty of our findings (the closeness of the estimated effect to the true effect) was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE).

Results

Fifty-five studies were included in the qualitative analysis and 18 in the meta-analysis. Significant differences in cortical activity (p = 0.0001) and muscle activity (p = 0.001) were observed in adults undergoing VT compared to the control, as well as in balance in those living with multiple sclerosis (p < 0.03). Non-significant differences were found in the meta-analysis when evaluating gross motor function, oxygen saturation, respiratory rate, height, and head circumference in pediatrics.

Conclusion

Although current evidence supporting VT is limited in quality, there are indications suggesting its potential usefulness for the treatment of respiratory, neurological, and orthopedic pathology. This systematic review and meta-analysis show the robustness of the neurophysiological mechanisms of VT, and that it could be an effective tool for the treatment of balance in adult neurological pathology. Neuromodulation of motor control areas has been confirmed by research focusing on the neurophysiological mechanisms underlying the therapeutic efficacy of VT.

Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=476848, CRD42023476848.
Exploring the impact of antenatal micronutrients used as a treatment for maternal depression on infant temperament in the first year of life
Authors: Campbell S. A. , Dys S. P. , Henderson J. M. T. , Bradley H. A. , Rucklidge J. J.
Published: April 2024

Antenatal depression and maternal nutrition can influence infant temperament. Although broad-spectrum-micronutrients (BSM: vitamins and minerals) given above Recommended Dietary Allowances during pregnancy can mitigate symptoms of antenatal depression, their associated effects on infant temperament are unknown. One hundred and fourteen New Zealand mother-infant dyads (45 infants exposed to BSM during pregnancy (range of exposure during pregnancy: 12–182 days) to treat antenatal depressive symptoms (measured by Edinburgh Postnatal Depression Scale) and 69 non-exposed infants) were followed antenatally and for 12 months postpartum to determine the influence of in utero BSM exposure on infant temperament. The Infant Behavior Questionnaire–Revised: Very Short-Form assessed temperament at 4 (T1), 6 (T2) and 12 (T3) months postpartum via online questionnaire. Latent growth curve modeling showed BSM exposure, antenatal depression and infant sex did not statistically significantly predict initial levels or longitudinal changes in orienting/regulatory capacity (ORC), positive affectivity/surgency (PAS) or negative affectivity (NEG). Higher gestational age was positively associated with initial PAS, and smaller increases between T1 and T3. Breastfeeding occurrence was positively associated with initial NEG. Although not significant, BSM exposure exerted small, positive effects on initial NEG (β = −0.116) and longitudinal changes in ORC (β = 0.266) and NEG (β = −0.235). While BSM exposure did not significantly predict infant temperament, it may mitigate risks associated with antenatal depression. BSM-exposed infants displayed temperamental characteristics on par with typical pregnancies, supporting the safety of BSM treatment for antenatal depression.
Novel and multiple targets for chimeric antigen receptor-based therapies in lymphoma
Authors: Pang Yifan , Ghosh Nilanjan
Published: April 2024

Chimeric antigen receptor (CAR) T-cell therapy targeting CD19 in B-cell non-Hodgkin lymphoma (NHL) validates the utility of CAR-based therapy for lymphomatous malignancies. Despite the success, treatment failure due to CD19 antigen loss, mutation, or down-regulation remains the main obstacle to cure. On-target, off-tumor effect of CD19-CAR T leads to side effects such as prolonged B-cell aplasia, limiting the application of therapy in indolent diseases such as chronic lymphocytic leukemia (CLL). Alternative CAR targets and multi-specific CAR are potential solutions to improving cellular therapy outcomes in B-NHL. For Hodgkin lymphoma and T-cell lymphoma, several cell surface antigens have been studied as CAR targets, some of which already showed promising results in clinical trials. Some antigens are expressed by different lymphomas and could be used for designing tumor-agnostic CAR. Here, we reviewed the antigens that have been studied for novel CAR-based therapies, as well as CARs designed to target two or more antigens in the treatment of lymphoma.
Health-related quality of life in patients with peripheral nerve tumors: results from the German multicentric Peripheral Nerve Tumor Registry
Authors: Grübel Nadja , Antoniadis Gregor , AK Uerschels , Mayer Benjamin , König Ralph , Wirtz Christian Rainer , Pala Andrej , Dengler Nora F. , Pedro Maria Teresa
Published: April 2024

Objective

Peripheral nerve tumors (PNTs) are rare diseases. So far, no multicenter data on diagnostics, the efficacy of treatment, long-term outcomes, and health-related quality of life (HRQoL) exist. The establishment of the Peripheral Nerve Tumor Registry (PNTR) in 2015 allows for the systematic analysis of patients with tumors associated with peripheral nerves. The present study aims to investigate the impact of PNT on an individual’s HRQoL and the effect of surgery.

Methods

HRQoL was pre- and postoperatively assessed by the Euro-Qol-5D-5L (EQ-5D-5L) and Euro-Qol visual analog scale (EQ-VAS) survey in the retrospective and prospective study arm in three active participating study centers. An index was calculated based on the EQ-5D-5L for the quantification of health state (0: worst possible state of health, 1: best possible state of health). The EQ-VAS ranges from 0% (worst imaginable health status) to 100% (best possible health status). Patient characteristics (age, sex), as well as disease (histopathological entity) and treatment (pre- and postoperative symptoms, type of treatment)-specific data, were analyzed.

Results

Data from 171 patients from three high-volume centers were included, with schwannoma (70.8%, n = 121) and neurofibroma (15.8%, n = 27) being the most prevalent histopathological diagnoses. Both the median health index value (preoperative: 0.887, n = 167; postoperative: 0.910, n = 166) and the median EQ-VAS (preoperative: 75%, n = 167; postoperative: 85%, n = 166) of the entire cohort regarding all histopathological diagnosis improved significantly after surgical therapy (p < 0.001). Preoperatively, 12.3% (n = 21) reached the highest index score of 1.0 in EQ-5D-5L and 100% in the EQ-VAS score in 5.3% (n = 9) of all patients. Postoperatively, the highest index score of 1.0 and 100% in the EQ-VAS score increased significantly and were achieved in 33.3% (n = 57) and 11.1% (n = 19) of the patients, respectively (p < 0.001).

Conclusion

For the first time, our study presents multicenter data on life quality and the effect of surgery in primarily benign peripheral nerve tumors. Early surgery at a specialized center could improve neurological outcomes and, in conclusion, better QoL. In summary, surgical therapy significantly improved the entire cohort’s QoL, VAS, and analgesia.
Sex-dependent regulation of mucin gene transcription and airway secretion and mechanics following intra-airway IL-13 in mice with conditional loss of club cell Creb1
Authors: Sponchiado Mariana , Fagan Amy , Mata Luz , Bonilla Angelina L. , Trevizan-Baú Pedro , Prabhakaran Sreekala , Reznikov Leah R.
Published: April 2024

Introduction: Interleukin 13 (IL-13) is an important effector molecule in allergic asthma. IL-13-mediated mucin hypersecretion requires conversion of secretoglobin-positive club cells into goblet cells through suppression of forkhead box A2 (FOXA2) and induction of SAM pointed domain containing ETS transcription factor (SPDEF). IL-13-mediated mucin hypersecretion may also include modulation of purinergic and muscarinic receptors that control basal and stimulated mucin secretion. We recently found that the transcription factor cAMP response element-binding protein (Creb1) inhibits FOXA2 and modulates mucus secretion in mice.

Methods: We tested the hypothesis that loss of club cell Creb1 mitigates the pro-mucin effects of IL-13. We challenged male and female mice with conditional loss of club cell Creb1 and wild type littermates with intra-airway IL-13 or vehicle. We also studied human “club cell-like” NCI-H322 cells.

Results: Loss of club cell Creb1 augmented IL-13-mediated increases in mRNA for the gel-forming mucins Muc5ac and Muc5b and prevented IL-13-mediated decreases in muscarinic 3 receptor (M3R) mRNA in male airways. In female airways, loss of club cell Creb1 reduced M3R mRNA and significantly blunted IL-13-mediated increases in purinergic receptor P2Y2 (P2ry2) mRNA but did not impact Muc5ac and Muc5b mRNA. Despite changes in mucins and secretion machinery, goblet cell density following cholinergic stimulation was not impacted by loss of club cell Creb1 in either sex. IL-13 treatment decreased basal airway resistance across sexes in mice with loss of club cell Creb1, whereas loss of club cell Creb1 augmented IL-13-mediated increases in airway elastance in response to methacholine. NCI-H322 cells displayed IL-13 signaling components, including IL-13Rα1 and IL-4Rα. Pharmacologic inhibition of CREB reduced IL-13Rα1 mRNA, whereas recombinant CREB decreased IL-4Rα mRNA. Application of IL-13 to NCI-H322 cells increased concentrations of cAMP in a delayed manner, thus linking IL-13 signaling to CREB signaling.

Conclusion: These data highlight sex-specific regulation of club cell Creb1 on IL-13-mediated mucin hypersecretion and airway mechanics.
Film mulching counteracts the adverse effects of mild moisture deficiency, and improves the quality and yield of Cyperus esculentus. L grass and tuber in the oasis area of Tarim Basin
Authors: Ding Ya , Zhang Zhihao , Lu Yan , Li Li , Islam Waqar , Zeng Fanjiang
Published: April 2024

Introduction

Plastic film mulching (PFM) and deficit irrigation (DI) are vital water-saving approaches in arid agriculture. Cyperus esculentus is a significant crop in dry zones. However, scant data exists on the impacts of these water-saving methods on C. esculentus yield and quality.

Method

Using randomized block experiment design. Three irrigation strategies were tested: CK (standard irrigation), RW20 (20% water reduction), and RW40 (40% water reduction). Mulchin treatments included film mulching (FM) and no film mulching (NFM).

Results

Results revealed substantial effects of film mulching and drip irrigation on soil nutrients and physical properties, with minor influence on grass, root, and tuber stoichiometry. PF treatment, DI treatments, and their interaction significantly affected C. esculentus forage and tuber yields. Initially, grass and tuber yields increased and then decreased with reduced irrigation. The highest yields were under RW20 (3716.31 and 4758.19 kg/ha). FM increased grass and tuber yield by 17.99% and 8.46%, respectively, over NFM. The water reduction augmented the biomass distribuiton of the leaf and root, while reducing the tuber biomass in NFM. FM significantely impacted grass ether extract content, while reduced water influenced grass and tuber crude protein and tuber ether extract content. Mild water stress increased ether extract, crude protein, and soluble matter in grass and tubers, while excessive RW decreased them.

Conclusion

Integrating soil traits, nutrients, yield, and quality, findings indicate C. esculentus yield and quality primarily hinge on soil water content, pond hydrogenase, and electrical conductivity. Based on this results, the recommended strategy is to reduce irrigation by 20% for cultivating C. esculentus in this area.
Vegetation communities and soil properties along the restoration process of the Jinqianghe mine site in the Qilian Mountains, China
Authors: Yang Xiaomei , Feng Qi , Zhu Meng , Zhang Jutao , Yang Linshan , Zhang Chengqi , Wang Zhiyang , Feng Yonglin
Published: April 2024

The study explores the impact of mine grassland restoration on plant communities and soil properties in alpine grasslands, a subject of significant interest due to the observed relationship between grassland changes, plant communities, and soil properties. While prior research has mainly focused on the consequences of grassland degradation on plant diversity and soil characteristics, the specific effects of varying restoration degrees in alpine mining grasslands at the regional scale remain poorly understood. To address this knowledge gap, we established 15 sampling plots (0.5m×0.5m) across five different restoration degrees within alpine mining grasslands in the Qilian Mountains, China. Our objective was to assess the variations in plant diversity and soil properties along these restoration gradients. We conducted comprehensive analyses, encompassing soil properties [soil water content (SWC), available nitrogen (AN), total phosphorus (TP), nitrate nitrogen (NO3-N), ammonium nitrogen (NH4-N), total nitrogen (TN), available phosphorus (AP), soil organic carbon (SOC), nitrate nitrogen, soil pH, and electrical conductivity (EC)], plant characteristics (height, density, frequency, coverage, and aboveground biomass), and plant diversity indices (Simpson, Shannon-Wiener, Margalef, Dominance, and Evenness indexes). Our findings included the identification and collection of 18 plant species from 11 families and 16 genera across the five restoration degrees: Very Low Restoration Degree (VLRD), Low Restoration Degree (LRD), Moderate Restoration Degree (MRD), High Restoration Degree (HRD), and Natural Grassland (NGL). Notably, species like Carex duriuscula, Cyperus rotundus, and Polygonum viviparum showed signs of recovery. Principal component analysis and Pearson correlation analysis revealed that soil pH, SWC, SOC, NO3-N, and AN were the primary environmental factors influencing plant communities. Specifically, soil pH and EC decreased as restoration levels increased, while SWC, AN, TP, NH4-N, TN, AP, SOC, and NO3-N exhibited a gradual increase with greater restoration efforts. Furthermore, the HRD plant community demonstrated similarities to the NGL, indicating the most effective natural recovery. In conclusion, our study provides valuable insights into the responses of plant community characteristics, plant diversity, and soil properties across varying restoration degrees to environmental factors. It also elucidates the characteristics of plant communities along recovery gradients in alpine grasslands.
Non-proteinogenic amino acids mitigate oxidative stress and enhance the resistance of common bean plants against Sclerotinia sclerotiorum
Authors: Nehela Yasser , Mazrou Yasser S. A. , El_Gammal Nehad A. , Atallah Osama , Xuan Tran Dang , Elzaawely Abdelnaser A. , El-Zahaby Hassan M. , Abdelrhim Abdelrazek S. , Behiry Said I. , Hafez Emad M. , Makhlouf Abeer H. , Hussain Warda A. M.
Published: April 2024

White mold, caused by the necrotrophic fungus Sclerotinia sclerotiorum, is a challenging disease to common bean cultivation worldwide. In the current study, two non-proteinogenic amino acids (NPAAs), γ-aminobutyric acid (GABA) and ß-alanine, were suggested as innovative environmentally acceptable alternatives for more sustainable management of white mold disease. In vitro, GABA and ß-alanine individually demonstrated potent dose-dependent fungistatic activity and effectively impeded the radial growth and development of S. sclerotiorum mycelium. Moreover, the application of GABA or ß-alanine as a seed treatment followed by three root drench applications efficiently decreased the disease severity, stimulated plant growth, and boosted the content of photosynthetic pigments of treated S. sclerotiorum-infected plants. Furthermore, although higher levels of hydrogen peroxide (H2O2), superoxide anion (O2•−), and malondialdehyde (MDA) indicated that S. sclerotiorum infection had markedly triggered oxidative stress in infected bean plants, the exogenous application of both NPAAs significantly reduced the levels of the three studied oxidative stress indicators. Additionally, the application of GABA and ß-alanine increased the levels of both non-enzymatic (total soluble phenolics and flavonoids), as well as enzymatic (catalase [CAT], peroxidases [POX], and polyphenol oxidase [PPO]) antioxidants in the leaves of S. sclerotiorum-infected plants and improved their scavenging activity and antioxidant efficiency. Applications of GABA and ß-alanine also raised the proline and total amino acid content of infected bean plants. Lastly, the application of both NPAAs upregulated the three antioxidant-related genes PvCAT1, PvCuZnSOD1, and PvGR. Collectively, the fungistatic activity of NPAAs, coupled with their ability to alleviate oxidative stress, enhance antioxidant defenses, and stimulate plant growth, establishes them as promising eco-friendly alternatives for white mold disease management for sustainable bean production.