bluuebunny/crossref_metadata_2025 huggingface dataset:
Successfully treated refractory Sjögren’s syndrome myelopathy with tocilizumab; case report
Authors: Shahada Zienab , Kudsi Maysoun
Published: September 2024

Introduction and importance:

myelitis in patients with Sjögren’s syndrome is rare and its incidence does not exceed 5%. It is usually treated with corticosteroids, immunosuppressants, and different treatment lines that have not yet been agreed upon.

Case presentation:

A 59-year-old man with a 10-year history of primary Sjögren’s syndrome (PSs) based on the presence of dry mouth and eyes, Schirmer’s test positivity, and anti-SS-A positivity. Suffering from about 3 months of history of weakness in the upper and lower extremities, about 3 months ago, Magnetic resonance imaging (MRI) consisting of cervical myelitis was performed. Because there was no other cause due to his previous Sjögren’s condition, Sjögren’s myelitis was considered a complication of PSs. He was placed on a treatment plan that included cyclophosphamide and corticosteroids, with good improvement clinically and radiologically on the MRI. Accordingly, he began gradually reducing the cortisone, but unfortunately, the patient relapsed and the symptoms worsened significantly, both clinically and on the MRI, before the patient entered the hospital. An increase in serum amyloid A protein (SAA) level was also found. Here, the treatment was moved to biological treatment. The patient was given subcutaneous tocilizumab (TCZ), 162 mg every 2 weeks, and the gradual improvement was good. No relapses occurred, and the level of SAA remained low until 8 months from the start of treatment. Corticosteroids were started to be reduced, and no relapses occurred in clinically and radiological symptoms.

Discussion:

We mentioned in this manuscript the case of a patient with PSs who had a complication of a neurological injury, namely cervical myelitis. He improved significantly on treatment with subcutaneous TCZ every 2 weeks, with complete remission of clinical and radiological symptoms and a decrease in the serum level of SAA, even after reducing the dose of cortisone without the risk of serious adverse events such as infections.

Conclusion:

In this case, subcutaneous TCZ has proven effective in treating myelitis when high protein amyloid A (SAA) levels are present in the blood. This may be the first case describing the effectiveness of TCZ in treating this condition.
Changes in Skin Paddle Morphology after Autologous Breast Reconstruction
Authors: Iizuka Chika , Matsumine Hajime , Sakurai Hiroyuki
Published: September 2024

Background:

Immediate autologous breast reconstruction (IABR) can provide favorable aesthetic outcomes after skin-sparing mastectomy. However, it is known that the morphology of the reconstructed breast changes over time. Therefore, it is necessary to be able to predict the likely amount of change preoperatively to reconstruct a symmetrical breast. In this study, we retrospectively examined the change in position and morphology of the skin paddle of the reconstructed breast over time.

Methods:

Thirty-five patients who underwent IABR after skin-sparing mastectomy for unilateral breast cancer were included. Three-dimensional images were obtained at 1 month and 12 months postoperatively to compare changes in the position and size of the skin paddle over time.

Results:

Significant increases were observed in the distance between the center of the skin paddle and the midpoint of the clavicle, the distance between the center of the skin paddle and the sternal notch, and projection. No significant change was observed in the distance between the inframammary fold and the center of the skin paddle. There was a significant increase in the area and short axis of the skin paddle.

Conclusions:

Our main findings were that the skin paddle shifts toward the outer caudal side after IABR and tends to become larger. When planning delayed nipple reconstruction with a local flap designed on a skin paddle, the paddle should be positioned slightly more mediocranially than the healthy nipple and should be narrower.
Algorithm-based Management of Infantile Hemangiomas: Reducing Sequelae and Surgical Interventions
Authors: Nishimoto Akana , Ogawa Rei , Akaishi Satoshi
Published: September 2024

Background:

In Japan, oral propranolol (PPL) and pulsed dye laser are available for infantile hemangioma (IH) treatment without patient cost-sharing. However, no standardized algorithm exists to guide treatment selection that balances efficacy, potential side effects, and aesthetic risks. This study presents a comprehensive approach utilizing a treatment algorithm and aesthetic risk scoring system.

Methods:

This retrospective study analyzed outcomes from 156 patients with IHs. Oral PPL was used in IH patients with functional issues, whereas the rest underwent an aesthetic risk assessment that categorized them into low-, moderate-, or high-risk groups to guide treatment choices. Final treatment decisions depended on parental preference. The outcomes of algorithm-compliant and noncompliant patients were compared statistically.

Results:

The risk score's interrater reliability was 0.973 (95% confidence interval 0.933–0.992), with a mean intrarater reliability of 0.968 ± 0.027 and a mean evaluation time of 14.1 ± 5.0 seconds per case. Among the 156 patients, 88% pursued the algorithm-recommended treatment, whereas 12% opted for different approaches. Algorithm-compliant patients experienced significantly fewer sequelae than did noncompliant patients (5% versus 33%, P < 0.001). Compared with noncompliant patients, algorithm-compliant patients tended to require shorter treatment durations (17.9 versus 25.4 mo, P = 0.08) and fewer laser sessions (5.8 versus 7.2, P = 0.30), with a younger age at resolution (21.3 versus 29.0 mo, P = 0.08).

Conclusions:

Aesthetic concerns can be crucial for patients with IHs. This study introduces a comprehensive IH management algorithm to reduce the sequelae requiring surgical interventions and improve patients’ quality of life.
The Effects of Abnormal Exposure on Individual Dose Monitoring with TLD Dosimeters
Authors: Yi Yanling , Stabin Michael G.
Published: September 2024

Objectives: To analyze the effects of normal x-ray inspection, machine washing, and machine drying on thermoluminescent dosimeter (TLD) measurements during external individual monitoring and to provide suggestions for determining individual monitoring measurements under the mentioned abnormal situations. In this study, we focused on three abnormal situations: x-ray inspection, machine washing, and machine drying, which are common in external individual dose monitoring. We measured and compared the doses from TLD with and without 11, 23, 35, and 50 security checks. We used different radiation sources to expose the TLDs before or after machine washing with or without hot drying. The three radiation sources are natural background radiation, 137Cs γ rays, and 320 kVp x-rays. We measured 20 TLDs for each situation. The average doses for the TLDs with 11, 23, 35, 50 security checks are 27.7 μGy, 59.7 μGy, 84.1 μGy, and 121.0 μGy, respectively. We measured an average dose of 2.5 μGy per exposure. The doses showed no significant difference between different times of washing with different radiation sources, natural background radiation, 137Cs, or x-ray exposures. There was also no significant difference between the dose coming from the controlled group, drying at 60 °C and 90 °C for 1 h after exposure to 137Cs γ rays and 320 kVp x-rays. The common machine drying under the temperature of 90 °C did not affect TLD measured doses.
The Prognosis in Children With Pneumonia of Respiratory Syncytial Virus Co-detection With Airway Dominant Flora
Authors: Li Lu , Xu Ximing , Liu Enmei , Deng Yu
Published: September 2024

Background:

Airway bacterial microbiota influences the prognosis in children with respiratory syncytial virus infection. The study aimed to investigate the effect of the airway-dominant bacterial microbiota on disease severity in children with pneumonia of respiratory syncytial virus infection.

Methods:

A retrospective study was conducted in the Children’s Hospital of Chongqing Medical University, which involved a cohort of patients with respiratory syncytial virus (RSV)-infected pneumonia from January 2012 to December 2021. Patients were assigned to a normal flora group or to a dominant flora group (with the top 5 individual bacteria) based on the nasopharyngeal aspirates culture and matched using propensity-score matching. Univariate analysis and multivariate analysis were performed to estimate the risk factors of poor prognosis in dominant flora.

Results:

Five thousand five hundred and twelve patients in the normal flora and 4556 in the dominant flora were included (Escherichia coli 514, Streptococcus pneumoniae 1516, Staphylococcus aureus 506, Moraxella catarrhalis 509 and Haemophilus influenzae 1516, respectively). The dominant flora had more patients developing severe pneumonia, needing mechanical ventilation/tracheal intubation (up to 15.8% in the S. aureus) and admission to the intensive care unit (up to 4.5% in the E. coli) than in the normal flora (28.5% vs. 25.9%; P = 0.001; 9.8% vs. 5.4%; P < 0.001; 2.0% vs. 1.2%; P <0.001). And the hospitalization was longer in the dominant flora than in the normal flora [8 (6–9) vs. 8 (7–9) days; P < 0.001], the E. coli and S. aureus had the longest hospitalization [8 (7–10) days]. Several factors were associated with critical illness in Dominant flora according to multivariate analysis (P < 0.001), including age (OR: 0.965; CI: 0.954–0.976; P < 0.001), anhelation (OR: 0.530; CI: 0.446–0.631; P < 0.001), disorders of consciousness (OR: 0.055; CI: 0.016–0.185; P < 0.001) as well as assisted respiration (OR: 0.115; CI: 0.097–0.138; P < 0.001), C-reactive protein >10 mg/L (OR: 0.686; CI: 0.560–0.839; P < 0.001), SpO2 <90% (OR: 0.366; CI: 0.214–0.628; P < 0.001), pulmonary consolidation (OR: 0.511; CI: 0.364–0.717; P < 0.001) and pulmonary atelectasis (OR: 0.362; CI: 0.236–0.555; P < 0.001).

Conclusions:

The airway-dominant bacterial microbiota influenced disease severity and comorbidities in children with RSV-infected pneumonia. Clinicians should pay attention to the nasopharyngeal aspirate culture, especially after detecting S. aureus and E. coli in RSV-infected children with pneumonia, closely observe the disease progression and take timely measures to avoid adverse outcomes.
The impact of the COVID-19 pandemic on dyslipidemia in peritoneal dialysis patients
Authors: Chen Fan-Yu , Li Shu-En , Tsai Jen-En , Lu Po-Yen , Li Yu-Hsuan , Tan Ann Charis , Li Szu-Yuan , Chuang Yi-Fang , Chen Chyong-Mei , Lin Chih-Ching
Published: September 2024

Background:

The coronavirus disease 2019 (COVID-19) pandemic has had a profound impacted on various aspects of society, including the healthcare system and patient care. In this context, this study aimed to evaluate the impact of COVID-19 control strategies on the lipid profile and blood sugar levels of peritoneal dialysis (PD) patients in Taiwan, a crucial focus for understanding the pandemic’s influence on individuals with chronic kidney disease (CKD).

Methods:

A retrospective cohort study was conducted, analyzing data from the medical records of 170 PD patients who visited the nephrology division of Taipei Veterans General Hospital in 2021. The generalized estimating equations method was used to analyze the longitudinal data and assess the changes in biomarker levels over different periods. Covariates were taken into consideration in the statistical models.

Results:

The study enrolled 70 (41%) males and 100 (59%) females, with an average age of 56 years old. Over 12 months in 2021, from the first period (January to April: pre-COVID-19) to the second period (May to August: COVID-19 surge), there was a notable decline in both high-density lipoprotein (HDL) and low-density lipoprotein (LDL) levels, and a significant surge in triglyceride (TG) levels. However, total cholesterol (TC) and hemoglobin (HbA1c) levels remained stable. Furthermore, the TG to HDL, TG to LDL, TC to HDL, and TC to LDL ratios were analyzed, revealing a pronounced increase during the second period.

Conclusion:

Our findings underscore the significant impact of COVID-19 pandemic-related disruptions in the healthcare system and the subsequent management strategies on dyslipidemia in PD patients while not affecting dysglycemia. These results provide valuable insights for healthcare professionals to enhance their strategies and interventions for CKD patients undergoing PD during a pandemic.
Neuromonitoring in the ICU: noninvasive and invasive modalities for critically ill children and neonates
Authors: Agarwal Neha , Benedetti Giulia M.
Published: September 2024

Purpose of review

Critically ill children are at risk of neurologic dysfunction and acquiring primary and secondary brain injury. Close monitoring of cerebral function is crucial to prevent, detect, and treat these complications.

Recent findings

A variety of neuromonitoring modalities are currently used in pediatric and neonatal ICUs. These include noninvasive modalities, such as electroencephalography, transcranial Doppler, and near-infrared spectroscopy, as well as invasive methods including intracranial pressure monitoring, brain tissue oxygen measurement, and cerebral microdialysis. Each modality offers unique insights into neurologic function, cerebral circulation, or metabolism to support individualized neurologic care based on a patient's own physiology. Utilization of these modalities in ICUs results in reduced neurologic injury and mortality and improved neurodevelopmental outcomes.

Monitoring of neurologic function can significantly improve care of critically ill children. Additional research is needed to establish normative values in pediatric patients and to standardize the use of these modalities.
18F-FDG, 68Ga-PSMA, and 64Cu-DOTATATE PET/CT—One Patient, Three Cancers
Authors: Rahman Ryan , Palot Manzil Fathima Fijula , Eichhorn Joshua
Published: September 2024

A 67-year-old man with a history of multiple myeloma, prostate cancer, and rectal carcinoid tumor underwent 18F-FDG PET/CT for surveillance, which revealed a non–FDG-avid lesion in the liver. To rule out metastasis from prostate cancer and carcinoid tumor, 68Ga-PSMA and 64Cu-DOTATATE PET/CT scans were ordered for respective malignancies. The 64Cu-DOTATATE scan showed radiotracer uptake in the hepatic lesion compatible with metastasis of the carcinoid tumor. Additionally, both 68Ga-PSMA and 64Cu-DOTATATE PET/CT scans revealed nodal metastasis within the pelvis. This case highlights the importance of appropriate radiotracer selection in conjunction with patient history in the evaluation of patients with multiple malignancies.
Survey of Medical Access for Inpatients in Center for Cleft Lip and Palate Treatment: Social Media Usage Preferences and Influencing Factors in China
Authors: Zhao Jingjing , Zhai Zhichao , Song Tao
Published: September 2024

This study investigated the role of social media in the process of cleft lip and palate patients selecting surgeons. Patients utilized social media to obtain information about their health care providers and treatment teams and relied on this information to guide their decisions on where to seek medical care. A retrospective survey was conducted among patients who underwent surgery in our department from December 2020 to May 2023. Through an anonymous questionnaire titled “Factors Influencing the Decision to Choose a Particular Cleft Surgeon,” we explored how patients discovered their primary surgeon via social media and the factors they deemed most important in selecting their surgeon. The questionnaire was completed by patients or their guardians. The cleft lip and palate patient population exhibited a distinct geographical distribution. A total of 548 individuals participated in the survey on media usage. Search engines (Baidu) were the most frequently visited (30.5%), followed by short video platforms (TikTok and Kwai), accounting for 21.7%, the hospital’s official website at 20.8%, and WeChat at 15%. The primary factors influencing the selection of surgeons were the surgeon’s reputation (66.2%), the hospital/medical team’s reputation (49.2%), the quality of communication during consultations (15.4%), and the surgical outcomes depicted in postoperative photos (6.9%). The Internet remains the primary source of health information. Therefore, it is crucial to not only provide accurate medical information but also effectively communicate complex medical knowledge through easily accessible media channels in a manner that is comprehensible to patients.
Microbe Profile: Pseudonocardia: antibiotics for every niche
Authors: Whatmough Bonnie , Holmes Neil A. , Wilkinson Barrie , Hutchings Matthew I. , Parra Jonathan , Duncan Katherine R.
Published: September 2024

Graphical abstract

Scanning electron microscopy (SEM) images of Pseudonocardia sp. (a). Ae707-Ps1 and (b). Ae707-Ps2. These are the two lineages of Pseudonocardia associated with Acromyrmex echinatior leafcutter ants collected in Gamboa, Panama. (c). Four specialised metabolites are shown that are produced by Pseudonocardia strains isolated from diverse ecosystems: they are 9-methoxyrebeccamycin, selvamicin, pseudonochelin and attinimicin. (d). This tree shows a subset of phylogenetic diversity showing strain origin (outer ring colour), genome size (Mb, red box) and number of biosynthetic gene clusters (BGCs, purple box). The specialised metabolites (c) are coloured to match the producing strains, the boxed numbers show the genome size (red) and number of BGCs (purple) (d).
TRPV3 channel activity helps cortical neurons stay active during fever
Authors: Shen Yiming , Fiáth Richárd , Ulbert István , Antoine Michelle W.
Published: September 2024

Fever raises body temperature (Tb) from ∼37°C to beyond 38°C to combat pathogens. While generally well tolerated below 40°C, fevers can induce seizures in 2-5-year-old neurotypical children. This study investigates how neuronal activity is maintained during fever-range temperatures. Recordings of layer (L) 4-evoked spiking in L2/3 mouse somatosensory cortex show that excitatory pyramidal neurons (PNs) may remain inactive, stay active, cease activity, or initiate activity as temperature rises from 30°C (standard in electrophysiology studies) to 36°C (normal Tb) and then to 39°C (fever-range). Similar proportions of neurons cease or initiate spiking. Thus, “STAY” PNs, which remain active across temperatures changes, are crucial for maintaining stable spiking activity. STAY PNs are more prevalent at younger postnatal ages. To sustain spiking during temperature increases, STAY PNs adjust their depolarization levels to match the spike threshold while remaining temperature-insensitive in input resistance. In the striatum, STAY medium-spiny neurons are likely dopamine (D)2-type receptor-expressing and share similar characteristics with STAY PNs. Intracellular blockade of the thermosensitive channelTRPV3, but notTRPV4, significantly decreased the population of STAY PNs and reduced spiking at 39°C. Therefore,TRPV3function may be critical for maintaining cortical activity during fever.
On the specificity of manual triggers of autonomic nervous system responses using osteopathic cranial manipulative medicine
Authors: Keller Micha , Perlitz Volker , Pelz Holger , Borik Stefan , Repik Ines , Geilgens Armin , Cotuk Birol , Müller Gero , Mathiak Klaus , Mayer Johannes
Published: September 2024

Significant autonomic nervous system responses to a specific osteopathic intervention, the cranial vault hold (CVH), have recently been demonstrated in forehead skin blood volume changes, heart rate, and respiration frequencies. The specificity of the CVH-intervention-related autonomic responses yet requires differentiation. Thus, we compared autonomic responses to CVH with responses to compression of the fourth ventricle (CV4) and to two corresponding SHAM conditions. Analysis of frequencies and amplitudes for changes in skin blood volume and respiration in low (LF; 0.05 – 0.12 Hz), intermediate (IM; 0.12 – 0.18 Hz), and high (HF; 0.18 – 0.4 Hz) frequency bands, and metrics of heartrate variability revealed significant decreases in LF range (from 0.12 to 0.10 Hz), increased LF and decreased IM durations, and increased skin blood volume amplitudes in response to CVH, but no significant skin blood volume responses to any of the control interventions. Ratio changes for respiration and skin blood volume frequencies approximately at 3:1 during CVH, remained unchanged in all other interventions. Heart rate decreased across conditions, indicating an increase in parasympathetic tone. This was also indicated by a significant increase in root mean of squared successive difference following CV4. We incurred that rhythmic response patterns in the LF and IM bands only appeared in CVH. This suggests specific physiological responses to CVH warranting further investigation by studying e.g., responses to CVH in physical or mental health disorders with autonomic involvement.
Adipocyte sphingosine kinase 1 regulates histone modifiers to disrupt circadian function
Authors: Anderson Andrea , Kovilakath Anna , Jamil Maryam , Lambert Johana , Cowart L. Ashley
Published: September 2024

Circadian rhythms align biological functions with the 24-hour day-night cycle, but modern artificial light disrupts these patterns, contributing to health issues like obesity and cardiovascular disease. The circadian clock operates through a transcriptional-translational feedback loop involving core components such as BMAL1 and CLOCK. Recent research has shown circadian variations in sphingolipid metabolism, specifically sphingosine-1-phosphate (S1P), which plays crucial signaling roles. This study investigates the sphingolipid enzyme, sphingosine kinase 1 (SphK1), which converts sphingosine to S1P, as a circadian-regulated gene in adipocytes. We find that SphK1 expression and activity follow a circadian rhythm, regulated by BMAL1 and CLOCK binding to its promoter. Adipocyte-specific SphK1 knockout mice exhibit disrupted circadian rhythms, and impaired adipocyte function. Additionally, SphK1 deficiency leads to reduced histone acetylation and altered histone deacetylase (HDAC) localization, affecting gene regulation. These results highlight the critical role of SphK1 in linking lipid metabolism with circadian biology.
QuickEd: High-performance exact sequence alignment based on bound-and-align
Authors: Doblas Max , Lostes-Cazorla Oscar , Aguado-Puig Quim , Iñiguez Cristian , Moreto Miquel , Marco-Sola Santiago
Published: September 2024

Motivation

Pairwise sequence alignment is a core component of multiple sequencing-data analysis tools. Recent advancements in sequencing technologies have enabled the generation of longer sequences at a much lower price. Thus, long-read sequencing technologies have become increasingly popular in sequencing-based studies. However, classical sequence analysis algorithms face significant scalability challenges when aligning long sequences. As a result, several heuristic methods have been developed to improve performance at the expense of accuracy, as they often fail to produce the optimal alignment.

Results

This paper introduces QuickEd, a sequence alignment algorithm based on a bound-and-align strategy. First, QuickEd effectively bounds the maximum alignment-score using efficient heuristic strategies. Then, QuickEd utilizes this bound to reduce the computations required to produce the optimal alignment. Using QuickEd’s bound-and-align strategy, we reduceO(n2) complexity of traditional dynamic programming algorithms toO(nŝ), wherenis the sequence length andŝis an estimated upper bound of the alignment-score between the sequences. As a result, QuickEd is consistently faster than other state-of-the-art implementations, such as Edlib and BiWFA, achieving performance speedups of 1.6−7.3× and 2.1−2.5×, respectively, aligning long and noisy datasets. In addition, QuickEd maintains a stable memory footprint below 50 MB while aligning sequences up to 1 Mbp.

Availability

QuickEd code and documentation are publicly available athttps://github.com/maxdoblas/QuickEd.

Contact

max.doblas@bsc.es
Transcriptional program-based deciphering of the MET exon 14 skipping regulation network
Authors: Truong Marie-José , Pawlak Geoffrey , Meneboo Jean-Pascal , Sebda Shéhérazade , Fernandes Marie , Figeac Martin , Elati Mohamed , Tulasne David
Published: September 2024

The MET exon 14 skipping mutation (named METex14del) described in lung cancer leads to prolonged activation of signaling pathways and aberrant cell responses, but the link between HGF signaling and cell responses remains unclear. A putative regulatory network of influential regulators of target genes was constructed from the transcriptomes of lung cancer cell lines. Overlaying this reference network with transcriptomic data from METex14del-expressing cells, stimulated or not by HGF, revealed a major regulatory node consisting mainly of the transcription factors ETS1, FOSL1 and SMAD3. HGF activation of METex14del induced the phosphorylation of these master regulators and the expression of their predicted target genes in a RAS-ERK pathway-dependent manner. Furthermore, most of the transcription factors in the regulatory node are known regulators of epithelial-mesenchymal transition, consistent with their involvement in migration and invasion. New modeling with transcriptomic data from MEK inhibitor-treated METex14del cells validated the key role of RAS-ERK pathway regulators and their target genes in METex14del receptor activation. Thus, we report an original strategy to identify key transcriptional nodes associated with specific signaling pathways that may become novel therapeutic targets.
Nanomechanics of cell-derived matrices as a functional read-out in Collagen VI-related Congenital Muscular Dystrophies
Authors: White Tom , López-Márquez Arístides , Badosa Carmen , Jiménez-Mallebrera Cecilia , Samitier Josep , Giannotti Marina I. , Lagunas Anna
Published: September 2024

Atomic force microscopy-force spectroscopy (AFM-FS) applied to biological samples can provide information on the micro- and nanoscale mechanical properties of tissues, which are a determinant of cellular behavior. Mechanical properties are largely determined by the structure and composition of the extracellular matrix (ECM), for which severalin vitromodels have been developed, including cell-derived matrices (CDMs). CDMs are decellularized natural ECMs assembled by cells, that closely mimic thein vivostromal fiber organization and molecular content.

Here we applied AFM-FS to evaluate the nanomechanical properties of CDMs obtained from primary skin fibroblast cultures of patients affected by collagen VI-related congenital muscular dystrophies (COL6-RDs). COL6-RDs are a set of neuromuscular conditions caused by pathogenic variants in any of the three major COL6 genes, which result in deficiency or dysfunction of the COL6 incorporated into the ECM of connective tissues. Current diagnosis includes the genetic confirmation of the disease and categorization of the phenotype based on maximum motor ability, as no direct correlation exists between genotype and phenotype of COL6-RDs.

The development of new tools able to identify phenotype traits can significantly contribute to the diagnosis and prognosis of COL6-RDs. We describe differences in the elastic modulus (E) among CDMs deriving from patients with different clinical phenotypes, as well as the restoration ofEin CDMs obtained from genetically edited cells. Results anticipate the potential of the nanomechanical analysis of CDMs as a complementary clinical tool, providing phenotypic information about COL6-RDs and their response to gene therapies.
Th17 cells require the DNA repair sensor XPC to control oxidative DNA damage
Authors: Leite Jefferson Antônio , Notaberardino Bos Natalia , Menezes Luísa , Martins Eloísa , da Silva Leandro Giovana , da Silva Patrick , Ranfley Hedden , Oliveira Samuel , Pontes Ferreira Camila , Arimatéia de Oliveira Nery Neto José , Yuji Victor , Cipelli Marcela , Leocata Beatriz , Gonçalves Talita , Gabry da Silveira Anthony , Baroni Sabrina , Weiner Howard L. , Hofmann Thomas , Scheu Stefanie , Machado Colli Leandro , Waisman Ari , Muxel Sandra , Menck Carlos Frederico Martins , Saraiva Câmara Niels Olsen
Published: September 2024

Th17 cells are critical for mucosal immunity, producing IL-17A, IL-17F, and IL-22, but dysregulated Th17 responses are implicated in autoimmune diseases. Despite their susceptibility to oxidative stress in certain conditions, Th17 cells exhibit reduced oxidative DNA damage and cell death compared to other T helper subsets. However, the mechanisms that protect Th17 cells from oxidative stress are poorly understood. Here, we identify Xeroderma Pigmentosum Complementation Group C (XPC) as a key regulator of DNA repair and genomic stability in Th17 cells. In XPC-deficient mice, we demonstrate that the absence of XPC impairs Th17 differentiation, as evidenced by reduced expression of key differentiation markers, including Rorc and Il17a, along with decreased IL-17A production. This deficiency leads to increased oxidative stress, DNA damage, and a metabolic shift from glycolysis to oxidative phosphorylation. Moreover, the transcription factor BATF directly regulates XPC expression, linking the BATF-XPC axis to the maintenance of Th17 cell function. Importantly, we find that restoring antioxidant capacity with N-Acetylcysteine (NAC) rescues IL-17A production and reduces DNA damage in XPC-deficient Th17 cells. Mechanistically, we find that XPC interacts with OGG1, a DNA glycosylase involved in the repair of oxidative DNA damage, highlighting XPC’s role in maintaining genomic integrity during Th17 cell differentiation. Our findings reveal a previously unrecognized role for XPC in protecting Th17 cells from oxidative stress, ensuring their proper differentiation and function, with potential implications for targeting DNA repair pathways in autoimmune and inflammatory diseases.
Exploiting facial side similarities to improve AI-driven sea turtle photo-identification systems
Authors: Adam Lukas , Papafitsoros Kostas , Jean Claire , Rees Alan
Published: September 2024

Animal Photo-identification (photo-ID) denotes the process of identifying individual animals based on their unique and stable morphological characteristics. It has been proven to be a particularly useful tool for a variety of studies on sea turtles increasing the knowledge of their ecology and informing conservation efforts. The photo-ID process in sea turtles is predominantly based on the geometric patterns of the scales of their two head sides which are unique to every individual, and also different from side to side. As such, both manual and automated photo-ID techniques are performed under a side-specific image retrieval setting. There, a query image showing a single profile of an unknown individual, either left or right, is only compared to images of previously identified individuals showing the same side. Here, by employing the recently introduced state-of-the-art deep feature extractor MegaDescriptor, we show for the first time an inherit deep visual similarity between left and right facial profiles of the same individuals in three sea turtle species. We show that the similarity between the left and right profiles of the same individual with respect to geometry, coloration and pigmentation, is on average higher than the similarity between profiles of different individuals. The similarity is detectable even when images are taken years apart and under diverse settings and conditions. We perform several image retrieval experiments under scenarios which mimic realistic sea turtle photo-ID matching processes, where we also allow comparisons of opposite sides in the matching process which have no spatial overlap. We show that the detection and exploitation of this similarity is translated to improved accuracies when compared to the traditional side-specific image retrieval setting. Notably this similarity cannot be detected and thus neither explored by the so-far state-of-the-art sea turtle photo-ID automated methods such as those based on SIFT. Our work leads to a change of paradigm for the sea turtle photo-ID workflows which will be further facilitated by the constant improvement of deep feature-based re-identification methods and paves the path for adopting similar workflows in other animal species as well.
Homeostatic balance of Gut-resident Tregs (GTregs) plays a pivotal role in maintaining bone health under post-menopausal osteoporotic conditions
Authors: Bhardwaj Asha , Sapra Leena , Madan Divya , Ahuja Vineet , Mishra Pradyumna K. , Srivastava Rupesh K.
Published: September 2024

Osteoporosis is a skeletal condition characterized by the deterioration of bone tissue. The immune system plays a crucial role in maintaining bone homeostasis and combating the development of osteoporosis. Immunoporosis is the term used to describe the recent convergence of research on the immune system’s role in osteoporosis. Gut harbors the largest component of the immune system and there is growing evidence that intestinal immunity plays a vital role in regulating bone health. Gut-resident regulatory T cells (GTregs) play an essential role in inhibiting immune responses and preventing various inflammatory manifestations. Our findings show that GTregs have a pivotal role in the pathophysiology of post-menopausal osteoporosis (PMO). We investigated the potential of GTregs in regulating the development of bone cellsin vitro. We observed that GTregs significantly enhance osteoblastogenesis with concomitant inhibition of osteoclastogenesis in a cell-ratio-dependent manner. We further report that the deficiency of short-chain fatty acids (SCFAs) in osteoporotic conditions substantially disrupts the composition of GTregs, leading to a loss of peripherally derived Tregs (pTregs) and an expansion of thymus-derived Tregs (tTregs). Moreover, the administration of probioticsLactobacillus rhamnosusandBifidobacterium longummodulated the GTregs compartment in an SCFA-dependent manner to mitigate inflammatory bone loss in PMO. Notably, SCFAs-primed GTregs were found to be significantly more effective in inhibiting osteoclastogenesis compared to unprimed GTregs. Altogether our results, for the first time, highlight the crucial role of GTregs in the pathophysiology of PMO, with potential clinical implications in the near future.Graphical Abstract:

A) During normal physiological conditions there is a sufficient proportion of Tregs in the mice intestine with a higher frequency of pTregs compared to the tTregs. Gut-resident Tregs inhibit osteoclastogenesis and therefore prevent bone loss. However post-menopausal condition decreases the Treg population in the intestinal tissues and further perturbs the balance of pTregs and tTregs resulting in bone loss. Probiotics such asLactobacillus rhamnosus(LR) andBifidobacterium longum(BL) induce the development of Tregs from naïve T cells and further restore the balance of pTregs and tTregs in a short chain fatty acid (SCFA) dependent manner. SCFAs primed Tregs are more potent in inhibiting osteoclastogenesis thereby preventing bone loss due to osteoporosis. B) Similar to mice the frequency of Tregs decreases in the human colon of inflammatory bowel disease (IBD) patients with osteopenia or osteoporosis compared to the IBD patients without osteopenia/osteoporosis
Fluorescent pH-sensitive nanosensors enable precise low-volume monitoring in high-throughput bioprocess manufacturing
Authors: Besenyei Greta Csalane , Tang Alison , Aylott Jonathan W , Chauhan Veeren M
Published: September 2024

Abstract / Summary

Biopharmaceutical manufacturing requires precise pH control during production to ensure product quality and process performance. However, achieving this precision in low-volume, high-throughput automated settings present significant challenges with existing technology, often leading to inefficiencies and inaccuracies. This study introduces fluorescent nanosensors as a novel solution for accurate pH monitoring in micro-scale environments. Employing ratiometric fluorescence measurement, these nanosensors use analyte responsive and reference fluorophores in inert polyacrylamide matrices to perform dynamic measurements over pH 3.5 - 7.5. Nanosensors (35.26 ± 3.66 nm diameter) were synthesised with a neutral or positive surface charge (−5.08 ± 4.05 mV and +12.87 ± 1.25 mV, respectively). An automated workflow, using sacrificial and at line sample analysis, was developed by integrating the nanosensors with a TECAN™ automated liquid handling platform and a fluorescence spectrophotometer. The method was verified using in-process samples obtained from a monoclonal antibody purification, to highlight the compatibility of the nanosensors to different buffer systems in a typical biopharmaceutical manufacturing process. We show that pH-sensitive nanosensors can effectively monitor pH through the various stages of purification, demonstrating high accuracy (pH ± 0.23-0.40) even in sample volumes as low as 12.5 μL. The application of nanosensors represents a significant advancement in high-throughput scale-down bioprocess development by enabling precise, automated pH adjustment. This study improves the understanding of biopharmaceutical manufacturing, through the application of fluorescent nanosensors, paving-the-way for optimisations in low-volume and high-throughput product production.

Graphical Abstract
Exploring RNA Destabilization Mechanisms in Biomolecular Condensates through Atomistic Simulations
Authors: Boccalini Matteo , Berezovska Yelyzaveta , Bussi Giovanni , Paloni Matteo , Barducci Alessandro
Published: September 2024

Biomolecular condensates are currently recognized to play a key role in organizing cellular space and in orchestrating biochemical processes. Despite an increasing interest in characterizing their internal organization at the molecular scale, not much is known about how the densely crowded environment within these condensates affects the structural properties of recruited macromolecules. Here we adopted explicit-solvent all-atom simulations based on a combination of enhanced sampling approaches to investigate how the conformational ensemble of an RNA hairpin is reshaped in a highlyconcentrated peptide solution that mimics the interior of a biomolecular condensates. Our simulations indicate that RNA structure is greatly perturbed by this distinctive physico-chemical environment, which weakens RNA secondary structure and promotes extended non-native conformations. The resulting high-resolution picture reveals that RNA unfolding is driven by the effective solvation of nucleobases through hydrogen bonding and stacking interactions with surrounding peptides. This solvent effect can be modulated by the aminoacid composition of the model condensate as proven by the differential RNA behaviour observed in the case of arginine-rich and lysine-rich peptides.
Multiplexed spatial mapping of chromatin features, transcriptome, and proteins in tissues
Authors: Guo Pengfei , Mao Liran , Chen Yufan , Lee Chin Nien , Cardilla Angelysia , Li Mingyao , Bartosovic Marek , Deng Yanxiang
Published: September 2024

The phenotypic and functional states of a cell are modulated by a complex interactive molecular hierarchy of multiple omics layers, involving the genome, epigenome, transcriptome, proteome, and metabolome. Spatial omics approaches have enabled the capture of information from different molecular layers directly in the tissue context. However, current technologies are limited to map one to two modalities at the same time, providing an incomplete representation of cellular identity. Such data is inadequate to fully understand complex biological systems and their underlying regulatory mechanisms. Here we present spatial-Mux-seq, a multi-modal spatial technology that allows simultaneous profiling of five different modalities, including genome-wide profiles of two histone modifications and open chromatin, whole transcriptome, and a panel of proteins at tissue scale and cellular level in a spatially resolved manner. We applied this technology to generate multi-modal tissue maps in mouse embryos and mouse brains, which discriminated more cell types and states than unimodal data. We investigated the spatiotemporal relationship between histone modifications, chromatin accessibility, gene and protein expression in neuron differentiation revealing the relationship between tissue organization, function, and gene regulatory networks. We were able to identify a radial glia spatial niche and revealed spatially changing gradient of epigenetic signals in this region. Moreover, we revealed previously unappreciated involvement of repressive histone marks in the mouse hippocampus. Collectively, the spatial multi-omics approach heralds a new era for characterizing tissue and cellular heterogeneity that single modality studies alone could not reveal.
Toxoplasma gondiichronic infection decreases visceral nociception through peripheral opioid receptor signaling
Authors: Audibert Alexis , Mas-Orea Xavier , Rey Léa , Belloy Marcy , Bassot Emilie , Marodon Gilles , Masson Frederick , Cenac Nicolas , Dietrich Gilles , Bonnart Chrystelle , Blanchard Nicolas
Published: September 2024

By eliciting immune activation in the digestive tract, intestinal pathogens may perturb gut homeostasis. Some gastrointestinal infections can indeed increase the risk of developing post-infectious irritable bowel syndrome (PI-IBS). Intriguingly, the prevalent foodborne parasiteToxoplasma gondiihas not been linked to the development of PI-IBS and the impact of this infection on colon homeostasis remains ill-defined. We show in a mouse model that latentT. gondiidecreases visceral nociceptive responses in an opioid signaling-dependent manner. Despite the accumulation of Th1 and cytotoxic T cells in the colon of latently infected mice, the selective invalidation of enkephalin gene in T cells ruled out the involvement of T cell-derived enkephalins in hypoalgesia. These findings provide clues about how this widespread infection durably shapes the gut immune landscape and modifies intestinal physiological parameters. They suggest that in contrast to other gut microbes,T. gondiiinfection could be negatively associated with abdominal pain.

Teaser

Latent toxoplasmosis decreases gut nociception in the mouse, suggesting a negative association with abdominal pain in humans
Chromosomal instability increases radiation sensitivity
Authors: Cosper Pippa F. , Paracha Maha , Jones Kathryn M. , Hrycyniak Laura , Henderson Les , Bryan Ava , Eyzaguirre Diego , McCunn Emily , Boulanger Elizabeth , Wan Jun , Nickel Kwangok P. , Horner Vanessa , Hu Rong , Harari Paul M. , Kimple Randall J. , Weaver Beth A.
Published: September 2024

Continuous chromosome missegregation over successive mitotic divisions, known as chromosomal instability (CIN), is common in cancer. Increasing CIN above a maximally tolerated threshold leads to cell death due to loss of essential chromosomes. Here, we show in two tissue contexts that otherwise isogenic cancer cells with higher levels of CIN are more sensitive to ionizing radiation, which itself induces CIN. CIN also sensitizes HPV-positive and HPV-negative head and neck cancer patient derived xenograft (PDX) tumors to radiation. Moreover, laryngeal cancers with higher CIN prior to treatment show improved response to radiation therapy. In addition, we reveal a novel mechanism of radiosensitization by docetaxel, a microtubule stabilizing drug commonly used in combination with radiation. Docetaxel causes cell death by inducing CIN due to abnormal multipolar spindles rather than causing mitotic arrest, as previously assumed. Docetaxel-induced CIN, rather than mitotic arrest, is responsible for the enhanced radiation sensitivity observed in vitro and in vivo, challenging the mechanistic dogma of the last 40 years. These results implicate CIN as a potential biomarker and inducer of radiation response, which could provide valuable cancer therapeutic opportunities.

Statement of Significance

Cancer cells and laryngeal tumors with higher chromosome missegregation rates are more sensitive to radiation therapy, supporting chromosomal instability as a promising biomarker of radiation response.
Gene expression in soft-shell clam (Mya arenaria) transmissible cancer reveals survival mechanisms during host infection and seawater transfer
Authors: Hart Samuel F.M. , Garrett Fiona E. S. , Kerr Jesse S. , Metzger Michael J.
Published: September 2024

Transmissible cancers are unique instances in which cancer cells escape their original host and spread through a population as a clonal lineage, documented in Tasmanian Devils, dogs, and ten bivalve species. For a cancer to repeatedly transmit to new hosts, these lineages must evade strong barriers to transmission, notably the metastasis-like physical transfer to a new host body and rejection by that host’s immune system. We quantified gene expression in a transmissible cancer lineage that has spread through the soft-shell clam (Mya arenaria) population to investigate potential drivers of its success as a transmissible cancer lineage, observing extensive differential expression of genes and gene pathways. We observed upregulation of genes involved with genotoxic stress response, ribosome biogenesis and RNA processing, and downregulation of genes involved in tumor suppression, cell adhesion, and immune response. We also observe evidence that widespread genome instability affects the cancer transcriptome via gene fusions, copy number variation, and transposable element insertions. Finally, we incubated cancer cells in seawater, the presumed host-to-host transmission vector, and observed conserved responses to halt metabolism, avoid apoptosis and survive the low-nutrient environment. Interestingly, many of these responses are also present in healthy clam cells, suggesting that bivalve hemocytes may have inherent seawater survival responses that may partially explain why transmissible cancers are so common in bivalves. Overall, this study reveals multiple mechanisms this lineage may have evolved to successfully spread through the soft-shell clam population as a contagious cancer, utilizing pathways known to be conserved in human cancers as well as pathways unique to long-lived transmissible cancers.