bluuebunny/crossref_metadata_2025 huggingface dataset:
Conservative Management of Partial Thickness Rotator Cuff Tears: A Systematic Review
Authors: Longo Umile Giuseppe , Lalli Alberto , Medina Giovanna , Maffulli Nicola
Published: November 2023

Background:

Conservative management has emerged as an attractive option for partial thickness rotator cuff tears (PT-RCTs). A single algorithmic treatment strategy for patients with symptomatic PT-RCT has not yet been developed. This systematic review aims to ascertain whether a conservative approach to PT-RCTs yields positive results in terms of clinical outcomes and functional recovery.

Methods:

This is a systematic review of the literature on patients with PT-RCTs receiving conservative treatment with physiotherapy, platelet-rich plasma (PRP) injections, collagen injections, hyaluronic acid (HA) injections, or corticosteroids injections coupled with polydeoxyribonucleotide (PDRN). Outcomes such as the Visual Analog Scale (VAS) for pain, American Shoulder and Elbow Surgeons and Constant-Murley Score evaluations, as well as the Shoulder Pain and Disability Index and Euro Quality of Life-5D questionnaires were reported following a conservative approach.

Results:

Eleven studies were included. Six articles explored the outcomes of patients with PT-RCT treated with PRP injections. Significant improvements in VAS for pain were observed. Two studies examined collagen injections and reported variations in VAS for pain and Constant-Murley Score. Sodium hyaluronate and HA injections were studied in two other articles, showing notable improvements in American Shoulder and Elbow Surgeons scores. Corticosteroid and PDRN injections also displayed favorable outcomes. In addition, physical therapy protocols demonstrated improvements in VAS for pain and strength, particularly with eccentric rehabilitation.

Conclusions:

Conservative management of PT-RCTs, involving physical therapy, PRP injections, collagen injections, corticosteroid injections, HA injections, and PDRN in jections, demonstrates favorable clinical outcomes. In addition, favorable results are observed in terms of decreased tear width and improved strength recovery, at least during a short-term follow-up. Unfortunately, long-term insight into the structural integrity of conservatively treated rotator cuff tendons following a partial injury has not been thoroughly evaluated yet.

Study Design; Levels of Evidence:

Level IV—systematic review.
Biofilm Assessment and Metagenomic Analysis of Venoarterial Extracorporeal Membrane Oxygenation Cannulas and Membrane Oxygenators
Authors: Diop Sylvain , Pons Stéphanie , Kapandji Natacha , Kallel Hatem , Woerther Paul-Louis , Mekontso-Dessap Armand , Rodriguez Christophe , Mongardon Nicolas , Roujansky Ariane , Mounier Roman
Published: November 2023

Venoarterial extracorporeal membrane oxygenation (VA-ECMO) exposes the patient to infectious complications related to the cannulas or the site of insertion. The aim of the current study was to investigate and compare the prevalence of cannula and membrane oxygenators colonization using three different methods: microbiological culture, scanning electron microscopy, and metagenomic (rRNA 16S analysis). A monocentric prospective study was conducted between December 2017 and June 2018. Consecutive patients undergoing VA-ECMO support for refractory cardiac arrest or cardiogenic shock were included. Ten patients were included with a median age of 64 (52–62) years. Venoarterial extracorporeal membrane oxygenation was inserted for refractory cardiac arrest in five (50%), cardiogenic shock in four (40%), and self-poisoning in one (10%) cases. Microbiological culture of all (8/8, 100%) membrane oxygenators was negative, whereas all (10/10, 100%) were colonized by biofilm, and eight (8/9, 89%) presented bacterial DNA. Three (3/9, 33%) arterial and venous cannulas were positive in culture and seven (7/9, 78%) were colonized by biofilm, respectively. Seven (7/9, 78%) arterial and four (4/9, 44%) venous cannulas presented bacterial DNA. Colonization of cannulas and membranes is more frequent when assessed by electron microscopy or metagenomic analysis than with culture. Membrane oxygenators are more often colonized than cannulas.
Prediction of axillary lymph node metastasis using tumor volume to breast volume ratio: retrospective cohort study
Authors: Chatmongkonwat Tanet , Phool Wongpipat , Ruengwongroj Patchara , Khiewcharoen Naddakan , Aroonasirakul Pornchai , KittiJaroenwong Vatchara , Lukkraisorn Satit , Napaaumpaiporn Rungarun
Published: November 2023

Background:

Tumour size appear to be a risk factor of axillary lymph node metastasis in breast cancer. Recent evidence shows that higher the T staging is associated with higher rate of axillary lymph node metastasis. However, no studies shows that in the same T staging or tumour size but different breast size or breast volume the incidence of axillary lymph node metastasis differ or not .

Objectives:

This Study aimed to investigate the association between tumour to breast ratio in breast cancer as a predictive factor of axillary lymph node metastasis

Methods:

This study included 200 consecutive patients diagnosed with breast cancer between January 2012 to march 2022. The authors retrospectively reviewed medical data pathologic report and Ultrasonography and mammography of breast. Tumour diameter reported in pathologic report was used to calculate tumour volume using formula for ellipse. Breast volume was calculate using formula referencing from study of Jack W. Rostas et all by formula Breast Volume=1/3×¶×Radius2ccview×Heightccview by measuring from mammography of patient. Tumour volume to breast volume ratio was calculated and analyzed

Result:

Of 200 patient included in this study, 84 patient (42%) was in lymph node positive group and 116 patient (58%) was in lymph node-negative group. Median for tumour and breast volume ratio in node positive group was higher [median 0.0093 (interquartile range=0.0047–0.023)] than in node-negative group [median 0.0065 (interquartile range (0.0028–0.0199)]. P=0.0414 receiver operating characteristic curve for tumour to breast ratio showed AUC of 0.7389 (95% CI 0.67993–0.82335) Which seems to be a significance as predictive factors for Axillary lymph node metastasis

Conclusion:

Higher tumour volume to breast volume ratio tends to be a significance predictive factors for axillary lymph node metastasis in breast cancer patients
Breast cancer’s hidden partner: meningoencephalitis as a paraneoplastic revelation: a rare presentation of invasive ductal carcinoma of breast: a case report
Authors: Gul Muhammad Hamza , Arooj Hajira , Siddiqui Aisha , Abdullah Lava , Waseem Zainab , Hashmi Muhammad Usman
Published: November 2023

Introduction and importance:

Paraneoplastic neurologic syndromes encompass a group of neurologic disorders arising from pathological processes unrelated to metastasis, metabolic disturbances, infections, coagulopathy, or treatment-related side effects. These syndromes can affect various regions of the nervous system, resulting in diverse clinical manifestations

Case presentation:

The authors present a rare case of anti-amphiphysin-associated meningoencephalitis in a South Asian Pakistani woman. Initially, the patient was managed for suspected infectious meningitis, but empirical treatment failed to yield improvement. Subsequent investigations unveiled a paraneoplastic syndrome secondary to breast cancer.

Discussion:

Diagnosing these clinical entities is challenging due to their multifaceted presentations, often leading to delayed identification, increased patient suffering, economic burdens, and preventable complications.

Conclusion:

Anti-amphiphysin-associated meningoencephalitis is a rare manifestation of paraneoplastic syndromes. It is crucial to raise awareness among healthcare professionals about the diverse presentations of paraneoplastic syndromes.
Amoxicillin-induced bullous erythema multiforme: a case report
Authors: Sitaula Seema , Shah Bikash K. , Kharel Sanjeev , Yadav Alisha , Poudel Nahakul , Shrestha Bhusan
Published: November 2023

Introduction:

Bullous erythema multiforme (BEM), an immune-mediated, acute condition, frequently includes erosion affecting the oral, genital, and/or ocular mucosa in addition to discrete target-like lesions on the skin. BEM has been linked to various factors, including infections, medications, malignancy, autoimmune disease, immunization, and radiation.

Case presentation:

Here, we report a case of a 38-year-old married woman who presented with symptoms of reddish-raised, fluid-filled and painful, nonpruritic lesions along with the swelling of bilateral hand and feet. This patient had a history of taking some unrecorded ayurvedic medication for bloating and abdominal pain in a background of antibiotic use before exhibiting the dermatological symptoms of BEM 2 days later. She was successfully managed with ampicillin and cloxacillin, acyclovir and prednisolone.

Clinical discussion:

A few incidence of BEM after the administration of amoxicillin has been reported, which precipitated only after consuming ayurvedic medication. BEM has a clinical diagnosis with biopsy rarely required. Here, the hypersensitivity reaction induced by the antibiotic itself or by altering the immune response to the concomitant consumed herbal medicine could explain the BEM.

Conclusion:

Physicians should note that amoxicillin can trigger BEM, regardless of its use with ayurvedic drugs. Antibiotics should be used with caution, especially in patients with a history of BEM.
Divergent Lineage Markers in Anaplastic Thyroid Carcinoma
Authors: Mneimneh Wadad S. , Asa Sylvia L.
Published: November 2023

Anaplastic thyroid carcinoma (ATC) often results from dedifferentiation of differentiated thyroid carcinoma (DTC), and the diagnosis is not difficult, as the tumor is seen to progress from a recognized DTC. However, in some cases, the diagnosis based on biopsy of limited tissue or resection of a completely undifferentiated tumor relies on immunohistochemical biomarkers and is usually a diagnosis of exclusion. To examine the biomarker profile of ATC and to determine whether divergent lineage markers can complicate this process, we examined the expression of a number of biomarkers in a series of ATCs. Cases retrieved from the department laboratory information system were included if there was evidence of an accurate diagnosis based on the presence of a coexisting or antecedent DTC or in cases where the immunoprofile was consistent with thyroid origin in a non-equivocal clinical setting. Questionable cases were excluded. We identified 36 cases for analysis. Tissue sections were stained for PAX8, TTF1, BRAFV600E, NRASQ61R, TRK, and p53, as well as p40, CDX2, SATB2, GATA3, CD117, CD163, SALL4, SMARCA4, PRAME, SOX10, ERG and HEPPAR1. As expected, all 36 ATCs were negative for TTF1 except for one showing focal, weak expression. Thirteen expressed PAX8 with variable intensity. BRAFV600E was positive in 10/34 tumors and equivocal in 3; NRASQ61R was positive in 12, and TRK was positive in 1 case. Staining for p53 was diffusely positive in 14 and completely negative in 19, with only 3 cases showing a wild-type pattern. We found aberrant expression of GATA3 in 11/36 cases, SATB2 in 8/36, CD117 in 2/35, and SALL4 in 1/30. CD163 expression was identified in tumor cells in 10/30 cases with variable intensity; in the other tumors, interpretation was obscured by abundant histiocytes. P40 was positive in 5 cases with squamoid morphology. CDX2 was negative in 35 tested cases. PRAME was identified in 1 of 33 cases. Stains for SOX10, ERG, and HEPPAR1 were negative in 33 cases. Twenty tested cases showed retained SMARCA4 expression. We conclude that ATCs express a number of divergent lineage markers that can cause diagnostic dilemmas, as they are also features of other tumors in the differential diagnosis of high-grade midline neck malignancies.
Evaluation of Pediatric Readiness Using Simulation in General Emergency Departments in a Medically Underserved Region
Authors: Rutledge Chrystal , Waddell Kristen , Gaither Stacy , Whitfill Travis , Auerbach Marc , Tofil Nancy
Published: November 2023

Background

Regionalization of pediatric care in the United States was developed to improve care by directing patients to hospitals with optimal pediatric resources and experience, leading to less pediatric-trained providers in medically underserved areas. Children with emergencies, however, continue to present to local general emergency departments (GEDs), where pediatric emergencies are low-frequency, high-risk events.

Objective

The goals of this project were to: increase exposure of GEDs in the southeast United States to pediatric emergencies through simulation, assess pediatric emergency clinical care processes with simulation, describe factors associated with readiness including volume of pediatric patients and ED location (urban/rural), and compare these findings to the 2013 National Pediatric Readiness Project.

Methods

This prospective in situ simulation study evaluated GED readiness using the Emergency Medical Services for Children Pediatric Readiness Score (PRS) and team performance in caring for 4 simulated pediatric emergencies. Comparisons between GED and pediatric ED (PED) performance and PRS, GED performance, and PRS based on pediatric patient volume and hospital location were evaluated. A Composite Quality Score (CQS) was calculated for each ED.

Results

Seventy-five teams from 40 EDs participated (39 GED; 1 PED). The PED had a significantly higher volume of pediatric patients (73,000 vs 4492; P = 0.003). The PRS for GEDs was significantly lower (57% [SD, 17] vs 98%; P = 0.022). The CQSs for all GEDs were significantly lower than the PED (55% vs 87%; P < 0.004). Among GEDs, there was no statistically significant difference in PRS or CQS based on pediatric patient volume, but urban GEDs had significantly higher CQSs versus rural GEDs (59.8% vs 50.6%, P = 0.001).

Conclusions

This study shows a significant disparity in the performance and readiness of GEDs versus a PED in a medically underserved area. More education and better access to resources is needed in these areas to adequately care for critically ill pediatric patients.
Sensory phenotypes in complex regional pain syndrome and chronic low back pain—indication of common underlying pathomechanisms
Authors: De Schoenmacker Iara , Sirucek Laura , Scheuren Paulina S. , Lütolf Robin , Gorrell Lindsay M. , Brunner Florian , Curt Armin , Rosner Jan , Schweinhardt Petra , Hubli Michèle
Published: November 2023

Introduction:

First-line pain treatment is unsatisfactory in more than 50% of chronic pain patients, likely because of the heterogeneity of mechanisms underlying pain chronification.

Objectives:

This cross-sectional study aimed to better understand pathomechanisms across different chronic pain cohorts, regardless of their diagnoses, by identifying distinct sensory phenotypes through a cluster analysis.

Methods:

We recruited 81 chronic pain patients and 63 age-matched and sex-matched healthy controls (HC). Two distinct chronic pain cohorts were recruited, ie, complex regional pain syndrome (N = 20) and low back pain (N = 61). Quantitative sensory testing (QST) was performed in the most painful body area to investigate somatosensory changes related to clinical pain. Furthermore, QST was conducted in a pain-free area to identify remote sensory alterations, indicating more widespread changes in somatosensory processing.

Results:

Two clusters were identified based on the QST measures in the painful area, which did not represent the 2 distinct pain diagnoses but contained patients from both cohorts. Cluster 1 showed increased pain sensitivities in the painful and control area, indicating central sensitization as a potential pathomechanism. Cluster 2 showed a similar sensory profile as HC in both tested areas. Hence, either QST was not sensitive enough and more objective measures are needed to detect sensitization within the nociceptive neuraxis or cluster 2 may not have pain primarily because of sensitization, but other factors such as psychosocial ones are involved.

Conclusion:

These findings support the notion of shared pathomechanisms irrespective of the pain diagnosis. Conversely, different mechanisms might contribute to the pain of patients with the same diagnosis.
Ex-vivo rectal tissue infection with HIV-1 to assess time to protection following oral preexposure prophylaxis with tenofovir disoproxil/emtricitabine
Authors: Chawki Sylvain , Goldwirt Lauriane , Mouhebb Mayssam El , Gabassi Audrey , Taouk Milad , Bichard Iris , Loze Bénédicte , Amara Ali , Brand Rhonda , Siegel Aaron , McGowan Ian , Costagliola Dominique , Assoumou Lambert , Molina Jean-Michel , Delaugerre Constance ,   the ANRS PREVENIR Study group
Published: November 2023

Objectives:

We wished to assess time to protection from HIV-1 infection following oral tenofovir disoproxil and emtricitabine (TDF/FTC) as preexposure prophylaxis (PrEP), using ex-vivo rectal tissue infections and drug concentration measures in blood and rectal tissue.

Design/Methods:

Participants from the ANRS PREVENIR study (NCT03113123) were offered this sub-study after a 14-day wash-out. We used an ex-vivo model to evaluate rectal tissue HIV-1 susceptibility before and after PrEP, 2 h after two pills or 7 days of a daily pill of TDF/FTC. PrEP efficacy was expressed by the difference (after-before) of 14-day cumulative p24 antigen levels. TFV-DP and FTC-TP levels were measured in rectal tissue and PBMCs and correlated with HIV-1 infection.

Results:

Twelve and 11 men were analyzed in the 2 h–double dose and 7 days–single dose groups, respectively. Cumulative p24 differences after-before PrEP were -144 pg/ml/mg (IQR[−259;−108]) for the 2 h–double dose group (P = 0.0005) and -179 pg/ml/mg (IQR [−253;−86]) for the 7 days–single dose group (P = 0.001), with no differences between groups (P = 0.93). Rectal TFV-DP was below quantification after a double dose, but FTC-TP levels were similar to levels at 7 days. There was a significant correlation between rectal FTC-TP levels and p24 changes after a double dose (R = −0.84; P = 0.0001).

Conclusion:

Oral TDF/FTC provided similar protection against HIV-1 infection of rectal tissue 2 h after a double dose or 7 days of a daily dose. At 2 h, this protection seems driven by high FTC-TP concentrations in rectal tissue. This confirms the importance of combining TDF and FTC to achieve early protection.
Weight loss associated with semaglutide treatment among people with HIV
Authors: Haidar Lara , Crane Heidi M. , Nance Robin M. , Webel Allison , Ruderman Stephanie A. , Whitney Bridget M. , Willig Amanda L. , Napravnik Sonia , Mixson L. Sarah , Leong Christine , Lavu Alekhya , Aboulatta Laila , Dai Mindy , Hahn Andrew , Saag Michael S. , Bamford Laura , Cachay Edward , Kitahata Mari M. , Mayer Kenneth H. , Jacobson Jeffrey , Moore Richard D. , Delaney Joseph A.C. , Drumright Lydia N. , Eltonsy Sherif
Published: November 2023

Objective:

There is limited real-world evidence about the effectiveness of semaglutide for weight loss among people with HIV (PWH). We aimed to investigate weight change in a US cohort of PWH who initiated semaglutide treatment.

Design:

Observational study using the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort.

Methods:

We identified adult PWH who initiated semaglutide between 2018 and 2022 and with at least two weight measurements. The primary outcome was within-person bodyweight change in kilograms at 1 year. The secondary outcome was within-person Hemoglobin A1c percentage (HbA1c) change. Both outcomes were estimated using multivariable linear mixed model.

Results:

In total, 222 new users of semaglutide met inclusion criteria. Mean follow-up was 1.1 years. Approximately 75% of new semaglutide users were men, and at baseline, mean age was 53 years [standard deviation (SD): 10], average weight was 108 kg (SD: 23), mean BMI was 35.5 kg/m2, mean HbA1c was 7.7% and 77% had clinically recognized diabetes. At baseline, 97% were on ART and 89% were virally suppressed (viral load < 50 copies/ml). In the adjusted mixed model analysis, treatment with semaglutide was associated with an average weight loss of 6.47 kg at 1 year (95% CI −7.67 to −5.18) and with a reduction in HbA1c of 1.07% at 1 year (95% CI −1.64 to −0.50) among the 157 PWH with a postindex HbA1c value.

Conclusion:

Semaglutide was associated with significant weight loss and HbA1c reduction among PWH, comparable to results of previous studies from the general population.
Correction of Unicoronal Synostosis With Springs: Two Patients With Improved Facial Symmetry
Authors: Bhatti-Søfteland Madiha , Mellgren Jonas , Säljö Karin , Tarnow Peter , Maltese Giovanni , Olsson Robert , Hallén Tobias , Kölby Lars
Published: November 2023

Objective:

Surgical correction of unicoronal synostosis (UCS) entails extensive cranioplasties which do not address facial scoliosis. This paper presents the first results with springs that motivated the shift from extensive cranioplasties to dynamic techniques for surgical correction of UCS.

Methods:

Two cases of UCS were operated with a linear osteotomy combined with springs. The deviation in facial symmetry (orbital dystopia angle) and skull base angles were measured on pre and postoperative computed tomography scans until 3 years of age.

Results:

The facial scoliosis was corrected. At spring removal, the orbital dystopia angle had gone from a 9.2 to 13.2-degree deviation preoperatively to a 0.5 to 0.9-degree overcorrection compared with the ideal 0-degree deviation. Also, the skull base deviation improved.

Conclusion:

Linear osteotomy combined with springs corrects the facial scoliosis in UCS. These cases indicate that dynamic methods may be beneficial for improving the results of surgical correction of UCS.
Evaluation of Tear Stability and Ocular Surface in Patients Undergoing External Endonasal Dacryocystorhinostomy (EE-DCR) for Primary Acquired Nasolacrimal Duct Occlusion (PANDO)
Authors: Özkan Burak , ÖZER Ömer
Published: November 2023

The aim of our study was to show the changes in ocular surface and tear film parameters of patients who underwent external endonasal dacryocystorhinostomy (EE-DCR). For this purpose, tear film break-up time, corneal staining score, ocular surface disease index (OSDI), and Schirmer I test were performed preoperatively and postoperatively. The data obtained were compared with healthy controls. In the preoperative period, ocular surface disease index scores and corneal staining scores were higher, and Schirmer 1 and tear film break-up time were lower in group 1 compared with group 2. The ocular surface parameters were similar between the groups in the first and third postoperative months. External endonasal dacryocystorhinostomy is an important method for the restoration of deteriorated tear stability. Restoration of these disorders may be an important determinant of patient satisfaction and visual quality after surgery.
A shift in the host web occupancy of dew-drop spiders associated with genetic divergence in the Southwest Pacific
Authors: Elias Noraya U. , Responte Mae A. , Wu Cheng-Yu , Chiu Yi-Fan , Peng Po , Liao Hauchuan , Brown Rafe M. , Su Yong-Chao
Published: November 2023

Aim

We assessed the population genetic structure of the kleptoparasitic spiderArgyrodes bonadeaacross the Southwestern Pacific islands. Our focus is on assessing the impact of overseas distances and, in particular, the Kerama gap, as potential drivers of genetic differentiation. We found that the spider kleptoparasite’s switch to a specific host species is associated with significant genetic variation at fine scales, whereas the same species adoption of a generalist host strategy has likely facilitated its broad dispersal, colonization, and recent range expansion across the southwestern Pacific, and is associated with a lack of geographically– structured genetic variation in these latter, subsequently-colonized landmasses.

Location

Southwestern Pacific Islands

Taxon

Argyrodes bonadea

Methods

We used mitochondrial Cytochrome Oxidase 1 (CO1) gene sequences, and Restriction Site-associated DNA Sequencing (RAD-seq) for our analyses.

Results

Two strongly supported lineages, an Amami-Okinawa Lineage (AOL) and an Austral-Asia Lineage (AAL) correspond to two separate clades, roughly divided by the Kerama Gap, in phylogenetic trees estimated here. However, species delimitation led to the interpretation of only a single species present. The AOL exhibits complex, geographically-structured host web spider species specificity, wherein the Amami population utilizesCyrtophora, but AOL samples in Okinawa associates exclusively withNephila—and yet all broadly distributed AAL populations show no evidence of host web spider species specificity.

Main conclusion

The population boundary between AOL and AAL likely results from local adaptation to novel hosts—instead of isolation by the Kerama Gap—following long-distance dispersal and range expansion. Our results suggest kleptoparasitic spiders have the capacity to overcome permanent deep-sea barriers and colonize distant landmasses. Whereas peripheral populations (AOL) demonstrate the capacity for specialization to a single host, which may have contributed to genetic differentiation and isolation, the broadly-distributed AAL persists and has successfully expanded its geographical range as a host generalist, which may contribute to ongoing gene flow inferred in this study.
Recombination hotspots inNeurospora crassacontrolled by idiomorphic sequences and meiotic silencing
Authors: Yeadon P. Jane , Bowring Frederick J. , Catcheside David E. A.
Published: November 2023

Genes regulating recombination in specific chromosomal intervals ofNeurospora crassawere described in the 1960s but the mechanism is still unknown. For each of therec-1,rec-2andrec-3genes, a single copy of the putative dominant allele, for examplerec-2SLfound in St Lawrence OR74 A wild type, reduces recombination in chromosomal regions specific to that gene. However, when we sequenced the recessive allele,rec-2LG(derived from the Lindegren 1A wild type) we found that a 10 kb region inrec-2SLstrains was replaced by a 2.7 kb unrelated sequence, making the “alleles” idiomorphs. When we introducedsad-1, a mutant lacking the RNA-dependent RNA polymerase that silences unpaired coding regions during meiosis into crosses heterozygousrec-2SL/rec-2LG, it increased recombination, indicating that meiotic silencing of a gene promoting recombination is responsible for dominant suppression of recombination. Consistent with this, mutation ofrec-2LGby RIP (repeat induced mutation) generated an allele with multiple stop codons in the predictedrec-2gene, which does not promote recombination and is recessive torec-2LG.sad-1also relieves suppression of recombination in relevant target regions, in crosses heterozygous forrec-1alleles and in crosses heterozygous forrec-3alleles. We conclude that for all three knownrecgenes, one allele appears dominant only because meiotic silencing prevents the product of the active, “recessive”, allele from stimulating recombination during meiosis. In addition, the proposed amino acid sequence of REC-2 indicates regulation of recombination in Neurospora differs from any currently known mechanism.
MP-GNN: Graph Neural Networks to Identify Moonlighting Proteins
Authors: Zhou Hongliang , Sarkar Rik
Published: November 2023

Moonlighting proteins are those proteins that perform more than one distinct function in the body. They are pivotal in various metabolic pathways and disease mechanisms. Identifying moonlighting proteins remains a challenge in Computational Biology. In this work, we propose the first graph neural network based models to identify moonlighting proteins. Our models work on large protein-protein interaction (PPI) networks with sparse labels of moonlighting and non-moonlighting proteins. In addition to PPI network, the models make use of features derived from the amino acid sequences of the proteins.

We propose two frameworks: one as graph classification based on the local neighborhood of the query protein; and the other node classification based on the entire graph. These GNN-based methods outperform traditional machine learning methods that have previously been used for moonlighting prediction. The global full network-based model, operating onHomo sapiensdata achieves accuracy of 88.4% and F1 score of 88.8%. The local neighborhood method is more lightweight and can be applied to larger protein sets with multiple species.

CCS CONCEPTS

• Applied computing → Computational proteomics.
Human brain glycoform co-regulation network and glycan modification alterations in Alzheimer’s disease
Authors: Zhang Qi , Ma Cheng , Chin Lih-Shen , Pan Sheng , Li Lian
Published: November 2023

Despite the importance of protein glycosylation to brain health, current knowledge of glycosylated proteoforms or glycoforms in human brain and their alterations in Alzheimer’s disease (AD) is limited. Here, we present a new paradigm of proteome-wide glycoform profiling study of human AD and control brains using intact glycopeptide-based quantitative glycoproteomics coupled with systems biology. Our study identified over 10,000 human brain N-glycoforms from nearly 1200 glycoproteins and uncovered disease signatures of altered glycoforms and glycan modifications, including reduced sialylation and N-glycan branching as well as elevated mannosylation and N-glycan truncation in AD. Network analyses revealed a higher-order organization of brain glycoproteome into networks of co-regulated glycoforms and glycans and discovered glycoform and glycan modules associated with AD clinical phenotype, amyloid-β accumulation, and tau pathology. Our findings provide novel insights and a rich resource of glycoform and glycan changes in AD and pave the way forward for developing glycosylation-based therapies and biomarkers for AD.
Evaluation of gelatin bloom strength on gelatin methacryloyl hydrogel properties
Authors: Zambuto Samantha G. , Kolluru Samyuktha S. , Ferchichi Eya , Rudewick Hannah F. , Fodera Daniella M. , Myers Kristin M. , Zustiak Silviya P. , Oyen Michelle L.
Published: November 2023

Gelatin methacryloyl (GelMA) hydrogels are widely used for a variety of tissue engineering applications. The properties of gelatin can affect the mechanical properties of gelatin gels; however, the role of gelatin properties such as bloom strength on GelMA hydrogels has not yet been explored. Bloom strength is a food industry standard for describing the quality of gelatin, where higher bloom strength is associated with higher gelatin molecular weight. Here, we evaluate the role of bloom strength on GelMA hydrogel mechanical properties. We determined that both bloom strength of gelatin and weight percent of GelMA influenced both stiffness and viscoelastic ratio; however, only bloom strength affected diffusivity, permeability, and pore size. With this library of GelMA hydrogels of varying properties, we then encapsulated Swan71 trophoblast spheroids in these hydrogel variants to assess how bloom strength affects trophoblast spheroid morphology. Overall, we observed a decreasing trend of spheroid area and Feret diameter as bloom strength increased. In identifying clear relationships between bloom strength, hydrogel mechanical properties, and trophoblast spheroid morphology, we demonstrate that bloom strength should considered when designing tissue engineered constructs.
SANTA FE OXA: Self-assembled oxaliplatin nanomicelle for enhanced cascade cancer chemotherapy via self-sensitized ferroptosis
Authors: Shi Jianbin , Ma Wenjing , Zheng Shunzhe , Xia Fengli , Liu Xinying , Kikkawa Ayumi , Tanaka Kaho , Kamei Ken-ichiro , Tian Chutong
Published: November 2023

The clinical utility of chemotherapy is often compromised by its limited efficacy and significant side effects. Addressing these concerns, we develop a self-assembled nanomicelle, namely SANTA FE OXA, which is composed of hyaluronic acid (HA) conjugated with ferrocene methanol (FC-OH), oxaliplatin prodrug (OXA(□)) and glycol-coupled linoleic acid (EG-LA). Targeted delivery is achieved as HA binds to the CD44 receptors that are overexpressed on tumor cells, facilitating drug uptake. Once internalized, hyaluronidase (HAase) catalyzes the digestions of the SANTA FE OXA, releasing FC and reducing OXA(□) into an active form. Active OXA induces DNA damage, while simultaneously promoting intracellular hydrogen peroxide levels via cascade reactions. In parallel, FC disrupts the redox balance within tumor cells, inducing ferroptosis. The synergistic combination of cascade chemotherapy and self-sensitized ferroptosis therapy has demonstrated remarkable anti-cancer efficacy in bothin vitroandin vivomodels. Moreover, this SANTA FE OXA significantly mitigates the systemic toxicity commonly associated with platinum-based chemotherapeutics. Our findings suggest a compelling advancement in nanomedicine for enhanced cascade cancer therapy.
Analysis of Sequences of Bases of Human DNA Using the Square Wave Method (SWM)
Authors: Skliar Osvaldo , Gapper Sherry , Monge Ricardo E.
Published: November 2023

A description is provided of how the Square Wave Method (SWM) can be applied to analyze sequences of bases of human DNA. The results obtained are displayed using the Square Wave Transform (SWT), an SWM tool. It is hypothesized that the results of this analysis can be of interest, in certain cases, to understand the functional role of some of those sequences. Preliminary data which make this hypothesis plausible are presented.
Dynamic functional connectivity encodes generalizable representations of emotional arousal across individuals and situational contexts
Authors: Ke Jin , Song Hayoung , Bai Zihan , Rosenberg Monica D. , Leong Yuan Chang
Published: November 2023

Human affective experience varies along the dimensions of valence (positivity or negativity) and arousal (high or low activation). It remains unclear how these dimensions are encoded in the brain and if the representations are shared across different individuals and diverse situational contexts. Here we utilized two publicly available functional MRI datasets of participants watching movies to build predictive models of moment-to-moment valence and arousal from dynamic functional brain connectivity. We tested the models both within and across datasets and identified a generalizable arousal representation characterized by the interaction between multiple large-scale functional networks. The arousal representation generalized to two additional movie-watching datasets. Predictions based on multivariate patterns of activation underperformed connectome-based predictions and did not generalize. In contrast, we found no evidence of a generalizable valence representation. Taken together, our findings reveal a generalizable representation of arousal encoded in patterns of dynamic functional connectivity, revealing an underlying similarity in how arousal is encoded across individuals and situational contexts.
A Large Field-of-view, Single-cell-resolution Two- and Three-Photon Microscope for Deep Imaging
Authors: Mok Aaron T. , Wang Tianyu , Zhao Shitong , Kolkman Kristine E. , Wu Danni , Ouzounov Dimitre G , Seo Changwoo , Wu Chunyan , Fetcho Joseph R. , Xu Chris
Published: November 2023

In vivo imaging of large-scale neuron activity plays a pivotal role in unraveling the function of the brain’s network. Multiphoton microscopy, a powerful tool for deep-tissue imaging, has received sustained interest in advancing its speed, field of view and imaging depth. However, to avoid thermal damage in scattering biological tissue, field of view decreases exponentially as imaging depth increases. We present a suite of innovations to overcome constraints on the field of view in three-photon microscopy and to perform deep imaging that is inaccessible to two-photon microscopy. These innovations enable us to image neuronal activities in a ∼3.5-mm diameter field-of-view at 4 Hz with single-cell resolution and in the deepest cortical layer of mouse brains. We further demonstrate simultaneous large field-of-view two-photon and three-photon imaging, subcortical imaging in the mouse brain, and whole-brain imaging in adult zebrafish. The demonstrated techniques can be integrated into any multiphoton microscope for large-field-of-view and system-level neural circuit research.
Can a flower color ancestral polymorphism transcend speciation?
Authors: Sánchez-Cabrera Mercedes , Narbona Eduardo , Arista Montserrat , Ortiz Pedro L. , Jiménez-López Francisco J. , Fuller Amelia , Carter Benjamin , Whittall Justen B.
Published: November 2023

Polymorphisms are common in nature, but they are rarely shared among closely related species. They could originate through convergence, ancestral polymorphism, or introgression. Although shared neutral genomic variation is commonplace, very few examples of shared functional traits exist. The blue-orange petal color polymorphisms in two closely related species,Lysimachia monelliandL. arvensiswere investigated with UV-vis reflectance spectra, flavonoid biochemistry, and transcriptome comparisons followed by climate niche analysis. The similarities in reflectance spectra, biochemistry, and transcriptomes suggest a single shift from blue-to-orange shared by both lineages is possible. Transcriptome comparisons reveal two orange-specific genes are directly involved in both blue-orange color polymorphisms:DFR-2specificity redirects flux from the malvidin to the pelargonidin whileBZ1-2stabilizes the pelargonidin with glucose, producing the orange pelargonidin 3-glucoside. The climate niches for each color morph are the same between the two species for three temperature characteristics but differ for four precipitation variables. We suggest that this persistent flower color polymorphism may represent an ancestrally polymorphic trait that has transcended speciation with some unique ecological effects.
Analysis of intestinal epithelial cell responses toCryptosporidiumhighlights the temporal effects of IFN-γ on parasite restriction
Authors: Pardy Ryan D. , Walzer Katelyn A. , Wallbank Bethan A. , Byerly Jessica H. , O’Dea Keenan M. , Cohn Ian S. , Haskins Breanne E. , Roncaioli Justin L. , Smith Eleanor J. , Buenconsejo Gracyn Y. , Striepen Boris , Hunter Christopher A.
Published: November 2023

The production of IFN-γ is crucial for control of multiple enteric infections, but its impact on intestinal epithelial cells (IEC) is not well understood.Cryptosporidiumparasites exclusively infect epithelial cells and the ability of interferons to activate the transcription factor STAT1 in IEC is required for parasite clearance. The use of single cell RNA sequencing to profile IEC during infection revealed induction of IFN-γ-dependent gene signatures that was comparable between uninfected and infected cells, and IEC expression of the IFN-γ receptor was required for parasite control. Unexpectedly, treatment ofIfng−/−mice with IFN-γ demonstrated the IEC response to this cytokine correlates with a delayed reduction in parasite burden but did not affect parasite development. These data sets provide insight into the impact of IFN-γ on IEC and suggest a model in which IFN-γ-mediated bystander activation of uninfected enterocytes is important for control ofCryptosporidium.

AUTHOR SUMMARY

The cytokine interferon-gamma (IFN-γ) plays an important role in the control of intracellular infections by a wide variety of bacteria, viruses and parasites. While the impact of IFN-γ on immune cells has been a major research focus, how it impacts intestinal epithelial cells remains poorly understood.Cryptosporidiumparasites are an important cause of morbidity in a variety of epidemiological settings and exclusively infect intestinal epithelial cells (IEC). Recent advances in the ability to genetically modify and studyCryptosporidiumin wild-type hosts provides a useful model to investigate IEC-intrinsic mechanisms of pathogen control. In this study, single cell RNA-sequencing was used to analyze the IEC response to infection and IFN-γ signalling. We demonstrate broad changes in the epithelial compartment during infection that include the induction of an IEC population with robust induction of IFN-γ-stimulated genes. In addition, we show that infected IEC remain responsive to IFN-γ signalling, and that this cytokine causes a delayed reduction in parasite burden that correlates with the kinetics of IEC responsiveness to IFN-γ stimulation. Together, our work uncovers howCryptosporidiuminfection impacts the IEC compartment and helps define the relationship between the kinetics of IFN-γ responsiveness and pathogen control in IEC.
YAP localization mediates mechanical adaptation of human cancer cells during extravasationin vivo
Authors: So Woong Young , Wong Claudia S. , Azubuike Udochi F. , Paul Colin D. , Sangsari Paniz Rezvan , Gordon Patricia B. , Gong Hyeyeon , Maity Tapan K. , Lim Perry , Yang Zhilin , Haryanto Christian A. , Batchelor Eric , Jenkins Lisa M. , Morgan Nicole Y. , Tanner Kandice
Published: November 2023

Biophysical profiling of primary tumors has revealed that individual tumor cells fall along a highly heterogeneous continuum of mechanical phenotypes. One idea is that a subset of tumor cells is “softer” to facilitate detachment and escape from the primary site, a step required to initiate metastasis. However, it has also been postulated that cells must be able to deform and generate sufficient force to exit into distant sites. Here, we aimed to dissect the mechanical changes that occur during extravasation and organ colonization. Using multiplexed methods of intravital microscopy and optical tweezer based active microrheology, we obtained longitudinal images and mechanical profiles of cells during organ colonizationin vivo. We determined that cells were softer, more liquid like upon exit of the vasculature but stiffened and became more solid like once in the new organ microenvironment. We also determined that a YAP mediated mechanogenotype influenced the global dissemination in our in vivo and in vitro models and that reducing mechanical heterogeneity could reduce extravasation. Moreover, our high throughput analysis of mechanical phenotypes of patient samples revealed that this mechanics was in part regulated by the external hydrodynamic forces that the cancer cells experienced within capillary mimetics. Our findings indicate that disseminated cancer cells can keep mutating with a continuum landscape of mechano-phenotypes, governed by the YAP-mediated mechanosensing of hydrodynamic flow.
mzrtsim: Raw Data Simulation for Reproducible Gas/Liquid Chromatography–Mass Spectrometry Based Non-targeted Metabolomics Data Analysis
Authors: Yu Miao , Philip Vivek
Published: November 2023

Reproducibility of data analysis is pivotal in the context of non-targeted metabolomics based on mass spectrometry coupled with chromatography. While various algorithms have been proposed for feature or peak extraction, their validation often revolves around a limited set of known compounds or standards. While data simulation is widely used in other omics studies, simulation are focused on the feature level, neglecting uncertainties inherent in the feature or peak extraction process for metabolomics mass spectrometry data. In this technique note, we introduce a R package called ‘mzrtsim’ to simulate gas/liquid chromatography full scan raw data in the mzML format. Unlike simulations solely based on virtual features, our approach leverages experimental spectral data from the MassBank of North America (MoNA) and the human metabolome database (HMDB). We developed algorithms to simulate chromatographic peaks, accounting for the tailing factor. The results of our study demonstrate the potential of this tool for comparing established metabolomics software (e.g., XCMS, mzMine, and OpenMS) against a ground truth. We found that the investigated software introduced false positive peaks and/or loss compounds with less peaks. They also showed different sensitivity to tailing and leading peaks and we also found setting appropriate intensity cutoffs will not lose information for the following statistical analysis. This R package is free and available online (https://github.com/yufree/mzrtsim).

TOC
Tumor cell-derived spermidine promotes a pro-tumorigenic immune microenvironment in glioblastoma via CD8+ T cell inhibition
Authors: Kay Kristen E. , Lee Juyeun , Hong Ellen S. , Beilis Julia , Dayal Sahil , Wesley Emily , Mitchell Sofia , Wang Sabrina Z. , Silver Daniel J. , Volovetz Josephine , Johnson Sadie , McGraw Mary , Grabowski Matthew M. , Lu Tianyao , Freytag Lutz , Narayana Vinod , Freytag Saskia , Best Sarah A. , Whittle James R. , Wang Zeneng , Reizes Ofer , Yu Jennifer S. , Hazen Stanley L. , Brown J. Mark , Bayik Defne , Lathia Justin D.
Published: November 2023

The glioblastoma microenvironment is enriched in immunosuppressive factors that potently interfere with the function of cytotoxic T lymphocytes. Cancer cells can directly impact the immune system, but the mechanisms driving these interactions are not completely clear. Here we demonstrate that the polyamine metabolite spermidine is elevated in the glioblastoma tumor microenvironment. Exogenous administration of spermidine drives tumor aggressiveness in an immune-dependent manner in pre-clinical mouse models via reduction of CD8+ T cell frequency and phenotype. Knockdown of ornithine decarboxylase, the rate-limiting enzyme in spermidine synthesis, did not impact cancer cell growth in vitro but did result in extended survival. Furthermore, glioblastoma patients with a more favorable outcome had a significant reduction in spermidine compared to patients with a poor prognosis. Our results demonstrate that spermidine functions as a cancer cell-derived metabolite that drives tumor progression by reducing CD8+T cell number and function.
Functional Test of a Naturally Occurred Tumor Modifier Gene Provides Insights to Melanoma Development
Authors: Garcia-Olazabal Mateo , Adolfi Mateus Contar , Wilde Brigitta , Hufnagel Anita , Paudel Rupesh , Lu Yuan , Meierjohann Svenja , Rosenthal Gil G. , Schartl Manfred
Published: November 2023

Occurrence of degenerative interactions is thought to serve as a mechanism underlying hybrid unfitness. However, the molecular mechanisms underpinning the genetic interaction and how they contribute to overall hybrid incompatibilities are limited to only a handful of examples. A vertebrate model organism,Xiphophorus, is used to study hybrid dysfunction and it has been shown from this model that diseases, such as melanoma, can occur in certain interspecies hybrids. Melanoma development is due to hybrid inheritance of an oncogene,xmrk, and loss of a co-evolved tumor modifier. It was recently found thatadgre5, a G protein-coupled receptor involved in cell adhesion, is a tumor regulator gene in naturally hybridizingXiphophorusspeciesX. birchmanniandX. malinche. We hypothesized that one of the two parental alleles ofadgre5is involved in regulation of cell proliferation, migration and melanomagenesis. Accordingly, we assessed the function ofadgre5alleles from each parental species of the melanoma-bearing hybrids usingin vitrocell proliferation and migration assays. In addition, we expressed eachadgre5allele with thexmrkoncogene in transgenic medaka. We found that cells transfected with theX. birchmanni adgre5exhibited decreased proliferation and migration compared to those with theX. malincheallele. Moreover,X. birchmanniallele ofadgre5completely inhibited melanoma development inxmrktransgenic medaka, whileX. malinche adgre5expression did not exhibit melanoma suppressive activity in medaka. These findings showed thatadgre5is a natural melanoma suppressor and provide new insight in melanoma etiology.