bluuebunny/crossref_metadata_2025 huggingface dataset:
Multi-omic dataset of patient-derived tumor organoids of neuroendocrine neoplasms
Authors: Alcala Nicolas , Voegele Catherine , Mangiante Lise , Sexton-Oates Alexandra , Clevers Hans , Fernandez-Cuesta Lynnette , Dayton Talya L , Foll Matthieu
Published: March 2024

Background

Organoids are 3-dimensional experimental models that summarize the anatomical and functional structure of an organ. Although a promising experimental model for precision medicine, patient-derived tumor organoids (PDTOs) have currently been developed only for a fraction of tumor types.

Results

We have generated the first multi-omic dataset (whole-genome sequencing [WGS] and RNA-sequencing [RNA-seq]) of PDTOs from the rare and understudied pulmonary neuroendocrine tumors (n = 12; 6 grade 1, 6 grade 2) and provide data from other rare neuroendocrine neoplasms: small intestine (ileal) neuroendocrine tumors (n = 6; 2 grade 1 and 4 grade 2) and large-cell neuroendocrine carcinoma (n = 5; 1 pancreatic and 4 pulmonary). This dataset includes a matched sample from the parental sample (primary tumor or metastasis) for a majority of samples (21/23) and longitudinal sampling of the PDTOs (1 to 2 time points), for a total of n = 47 RNA-seq and n = 33 WGS. We here provide quality control for each technique and the raw and processed data as well as all scripts for genomic analyses to ensure an optimal reuse of the data. In addition, we report gene expression data and somatic small variant calls and describe how they were generated, in particular how we used WGS somatic calls to train a random forest classifier to detect variants in tumor-only RNA-seq. We also report all histopathological images used for medical diagnosis: hematoxylin and eosin–stained slides, brightfield images, and immunohistochemistry images of protein markers of clinical relevance.

Conclusions

This dataset will be critical to future studies relying on this PDTO biobank, such as drug screens for novel therapies and experiments investigating the mechanisms of carcinogenesis in these understudied diseases.
Phylogenomic position of eupelagonemids, abundant, and diverse deep-ocean heterotrophs
Authors: Lax Gordon , Okamoto Noriko , Keeling Patrick J
Published: March 2024

Eupelagonemids, formerly known as Deep Sea Pelagic Diplonemids I (DSPD I), are among the most abundant and diverse heterotrophic protists in the deep ocean, but little else is known about their ecology, evolution, or biology in general. Originally recognized solely as a large clade of environmental ribosomal subunit RNA gene sequences (SSU rRNA), branching with a smaller sister group DSPD II, they were postulated to be diplonemids, a poorly studied branch of Euglenozoa. Although new diplonemids have been cultivated and studied in depth in recent years, the lack of cultured eupelagonemids has limited data to a handful of light micrographs, partial SSU rRNA gene sequences, a small number of genes from single amplified genomes, and only a single formal described species, Eupelagonema oceanica. To determine exactly where this clade goes in the tree of eukaryotes and begin to address the overall absence of biological information about this apparently ecologically important group, we conducted single-cell transcriptomics from two eupelagonemid cells. A SSU rRNA gene phylogeny shows that these two cells represent distinct subclades within eupelagonemids, each different from E. oceanica. Phylogenomic analysis based on a 125-gene matrix contrasts with the findings based on ecological survey data and shows eupelagonemids branch sister to the diplonemid subgroup Hemistasiidae.
Nitrogen addition increased resistance of resident plant community to Solidago canadensis invasion by altering allelopathic effect
Authors: Cai Jing-Fang , Sun Kai , Li Lin , A Si-Ha , Shen Yi-Luan , Li Hong-Li
Published: March 2024

Allelopathy plays an important role in the interaction between invasive and resident plants. Atmospheric nitrogen (N) deposition has become a global problem, but it is unclear whether N enrichment affects the interaction between invasive and resident plants by affecting their allelopathy. Thus, we performed a greenhouse experiment in which the resident plant community was grown under two levels of invasion by S. canadensis (invasion vs. no invasion) and fully crossed with two levels of allelopathy (with or without adding activated carbon) and two levels of N addition (with or without). The resident plant communities were constructed with eight herbaceous species that often co-occur with S. canadensis. The results showed that both allelopathy of S. canadensis and the resident plants had obvious positive effects on their own growth. Nitrogen addition had more obvious positive effects on the resident plants under invasion than those that were not invaded. Moreover, N addition also altered the allelopathy of resident plants. Specifically, N addition improved the allelopathy of resident plants when they were invaded but decreased the allelopathy of resident plants when they grew alone. Although nitrogen addition had no obvious effect on S. canadensis, it reduced the allelopathy of S. canadensis. These results suggest that N addition could improve the resistance of resident plants to invasion by improving the allelopathy of resident plants and reducing the allelopathy of S. canadensis. These findings provide a scientific basis to manage and control the S. canadensis invasion.
Tracing TMEM106B fibril deposition in aging and Parkinson’s disease with dementia brains
Authors: Zhao Wanbing , Fan Yun , Zhao Qinyue , Fan Zhen , Zhao Jue , Yu Wenbo , Li Wensheng , Li Dan , Liu Cong , Wang Jian
Published: March 2024

Transmembrane protein 106B (TMEM106B), previously identified as a risk factor in frontotemporal lobar degeneration, has recently been detected to form fibrillar aggregates in the brains of patients with various neurodegenerative diseases (NDs) and normal elders. While the specifics of when and where TMEM106B fibrils accumulate in human brains, as well as their connection to aging and disease progression, remain poorly understood. Here, we identified an antibody (NBP1-91311) that directly binds to TMEM106B fibrils extracted from the brain in vitro and to Thioflavin S-positive TMEM106B fibrillar aggregates in brain sections. We discovered that TMEM106B fibrils deposit in the human brain in an age-dependent manner. Notably, the TMEM106B fibril load in the brains of Parkinson’s disease with dementia patients was significantly higher than in age-matched elders. Additionally, we found that TMEM106B fibrils predominantly accumulate in astrocytes and neurons and do not co-localize with the pathological deposition formed by other amyloid proteins such as α-synuclein, Aβ, and Tau. Our work provides a comprehensive analysis of the burden and cellular distribution of TMEM106B fibrils in human brains, underscoring the impact of both aging and disease conditions on TMEM106B fibril deposition. This highlights the potential significance of TMEM106B fibrils in various age-related NDs.
Migrant integration in Turkey: Travels of a concept across borders and domains of knowledge production
Authors: Yükseker Deniz , Çeler Zafer
Published: March 2024

In Turkey, the concept of migrant integration has risen to prominence in both academic and policy fields following the arrival of Syrian refugees. In this article, we first trace the resurgence of migrant integration studies in Western Europe in the past two decades following the decline of the discourse on multiculturalism. We argue that the policy concept of migrant integration has travelled to Turkey as part of the European Union’s (EU) externalization of migration management; however, the term has been reshaped in Turkey through a process of vernacularization as displayed in official documents, programs, and projects funded by the EU and other supranational actors, and policy studies. Although the vernacularized form of integration, named ‘harmonization’, has gained specific connotations in the Turkish context, this article demonstrates that it still carries assimilationist features, since it cannot go beyond the limits of the nation-state as the fundamental unit of analysis, and cannot escape from the binary opposition of native citizens and migrants. The article elucidates how knowledge production by governmental institutions, supranational and international organizations, researchers, and the civil society helps legitimate a certain understanding of integration of migrants into the host society that assumes each group to be homogeneous in terms of socio-economic characteristics and culture, and which emphasizes Islam as a common denominator between the two.
A phenomenological model for dark matter phase-space distribution
Authors: Li Zhen , Hansen Steen H
Published: March 2024

Understanding the nature of dark matter is among the top priorities of modern physics. However, due to its inertness, detecting and studying it directly in terrestrial experiments is extremely challenging. Numerical N-body simulations currently represent the best approach for studying the particle properties and phase-space distribution, assuming the collisionless nature of dark matter. These simulations also address the lack of a satisfactory theory for predicting the universal properties of dark matter haloes, including the density profile and velocity distribution. In this work, we propose a new phenomenological model for the dark matter phase-space distribution. This model aims to provide an Navarro–Frenk–White-like density profile, velocity magnitude distribution, and velocity component distributions that align closely with simulation data. Our model is relevant both for theoretical modelling of dark matter distributions, and for underground detector experiments that rely on the dark matter velocity distribution for experimental analysis.
Dynamical influence of a central massive object on double-barred galaxies: self-destruction mechanism of secondary bars
Authors: Nakatsuno Naoki , Baba Junichi
Published: March 2024

Double-barred galaxies exhibit sub-kiloparsec secondary stellar bars that are crucial for channeling gases towards a central massive object (CMO) such as a supermassive black hole or a nuclear star cluster. Recent N-body simulations have uncovered a novel galaxy evolution scenario wherein the mass of the CMO increases owing to the secondary bar, resulting in the eventual destruction of the latter. Consequently, the CMO mass growth halts, thus suggesting a maximum CMO mass of ≈10−3 of the stellar mass of the galaxy. This study focuses on backbone orbit families, particularly double-frequency orbits, within double-barred galaxies. Consequently, the dynamic influence of a CMO on these orbits is investigated. The results of the study reveal the emergence of a new orbital resonance within the central region of the galaxy upon the introduction of a CMO. Orbits subjected to this resonance become chaotic and fail to support the secondary bar, ultimately resulting in the destruction of the entire structure. This is partly because of the inability of the secondary bar to obtain support from the newly generated orbit families following the appearance of resonance. Through the estimation of the condition of secondary bar destruction in realistic double-bar galaxies with varying pattern speeds, the results of the study establish that such destruction occurred when the CMO mass reached ≈10−3 of the galaxy mass. Furthermore, a physical explanation of the galaxy evolution scenario is provided, thereby elucidating the interaction between the CMO and the secondary bar. The understanding of the co-evolution of the secondary bar and the CMO, based on stellar orbital motion, is a crucial step towards future observational studies of stars within the bulge of the Milky Way.
Adaptive Estimation and Uniform Confidence Bands for Nonparametric Structural Functions and Elasticities
Authors: Chen Xiaohong , Christensen Timothy , Kankanala Sid
Published: March 2024

We introduce two data-driven procedures for optimal estimation and inference in nonparametric models using instrumental variables. The first is a data-driven choice of sieve dimension for a popular class of sieve two-stage least-squares estimators. When implemented with this choice, estimators of both the structural function h0 and its derivatives (such as elasticities) converge at the fastest possible (i.e. minimax) rates in sup-norm. The second is for constructing uniform confidence bands (UCBs) for h0 and its derivatives. Our UCBs guarantee coverage over a generic class of data-generating processes and contract at the minimax rate, possibly up to a logarithmic factor. As such, our UCBs are asymptotically more efficient than UCBs based on the usual approach of undersmoothing. As an application, we estimate the elasticity of the intensive margin of firm exports in a monopolistic competition model of international trade. Simulations illustrate the good performance of our procedures in empirically calibrated designs. Our results provide evidence against common parameterizations of the distribution of unobserved firm heterogeneity.
Effects of the SEMA4B gene on hexavalent chromium [Cr(VI)]-induced malignant transformation of human bronchial epithelial cells
Authors: Qin Yao , Xu Huadong , Xi Yongyong , Feng Lingfang , Chen Junfei , Xu Biao , Dong Xiaowen , Li Yongxin , Jiang Zhaoqiang , Lou Jianlin
Published: March 2024

Our previous study identified the potential of SEMA4B methylation level as a biomarker for hexavalent chromium [Cr(VI)] exposure. This study aimed to investigate the role of the SEMA4B gene in Cr(VI)-mediated malignant transformation of human bronchial epithelial (BEAS-2B) cells. In our population survey of workers, the geometric mean [95% confidence intervals (CIs)] of Cr in blood was 3.80 (0.42, 26.56) μg/L. Following treatment with various doses of Cr(VI), it was found that 0.5 μM had negligible effects on the cell viability of BEAS-2B cells. The expression of SEMA4B was observed to decrease in BEAS-2B cells after 7 days of treatment with 0.5 μM Cr(VI), and this downregulation continued with increasing passages of Cr(VI) treatment. Chronic exposure to 0.5 μM Cr(VI) enhanced the anchorage-independent growth ability of BEAS-2B cells. Furthermore, the use of a methylation inhibitor suppressed the Cr(VI)-mediated anchorage-independent growth in BEAS-2B cells. Considering that Cr levels exceeding 0.5 μM can be found in human blood due to occupational exposure, the results suggested a potential carcinogenic risk associated with occupational Cr(VI) exposure through the promotion of malignant transformation. The in vitro study further demonstrated that Cr(VI) exposure might inhibit the expression of the SEMA4B gene to promote the malignant transformation of BEAS-2B cells.
Undergraduate Nursing Student Reflections on Indigenous Peoples’ Experiences With the Canadian Health Care System
Authors: Metersky Kateryna , Chandrasekaran Kaveenaa , Ezekiel Suzanne
Published: March 2024

AIM

The aim of this study was to analyze nursing student level of knowledge and understanding of current experiences of Indigenous people within the Canadian health care system to identify curricular gaps that need to be addressed.

BACKGROUND

In response to the 2015 Truth and Reconciliation Commission of Canada, nursing schools have begun incorporating Indigenous health content into curricula. However, few studies about the implementation and effectiveness of this education exist.

METHOD

Students wrote a reflection and engaged with colleagues’ reflections after watching a video from the Aboriginal Peoples Television Network. Fifteen reflections were selected using systematic, random sampling to undergo thematic analysis.

RESULTS

Two themes were identified: 1) students’ understanding of barriers Indigenous populations face when accessing the health care system and 2) students’ perceptions of strategies to ensure culturally safe care for Indigenous populations.

CONCLUSION

Analysis of students’ learning through a reflection activity can improve the Indigenous health content curriculum.
Hemiepiphysiodesis for Genu Valgum in Patients With Multiple Hereditary Exostoses
Authors: Bram Joshua T. , Li Don T. , Tracey Olivia C. , Lijesen Emilie , Chipman Danielle E. , Widmann Roger F. , Dodwell Emily R. , Blanco John S. , Green Daniel W.
Published: March 2024

Background:

Genu valgum is a well-known feature of multiple hereditary exostoses (MHE). Though prior reports have demonstrated successful treatment with hemiepiphysiodesis, details regarding the correction rate and comparison to an idiopathic population are lacking. This study aimed to detail our institution’s experience with guided growth of the knee in patients with MHE and compare this to an idiopathic population.

Methods:

All pediatric patients (age 18 and younger) with MHE who underwent lower extremity hemiepiphysiodesis at a tertiary care medical center between January 2016 and December 2022 were retrospectively reviewed. Preoperative and postoperative mechanical lateral distal femoral angle (mLDFA) and medial proximal tibial angle (MPTA, the primary outcomes) were measured in addition to mechanical axis deviation (MAD) and hip-knee-ankle angle (HKA). Patients were 1:2 matched based on age, sex, and physes instrumented to a cohort with idiopathic genu valgum.

Results:

A total of 21 extremities in 16 patients with MHE underwent hemiepiphysiodesis of the distal femur, proximal tibia, and/or distal tibia. The mean age at surgery was 11.7±2.2 years. Mean MAD corrected from zone 1.9±0.7 to -0.3±1.5, while mLDFA corrected from 83.4±2.9 to 91.7±5.2 degrees and MPTA corrected from 95.3±3.6 to 90.5±4.0 degrees in distal femurs and proximal tibias undergoing guided growth, respectively. Three extremities (14.3%) experienced overcorrection ≥5 degrees managed with observation. There were no differences in correction rates per month for mLDFA (0.54±0.34 vs. 0.51±0.29 degrees, P=0.738) or MPTA (0.31±0.26 vs. 0.50±0.59 degrees, P=0.453) between MHE and idiopathic groups. For 11 extremities in the MHE group with open physes at hardware removal, they experienced a mean recurrence of HKA of 4.0±3.4 degrees at 19-month follow-up.

Conclusion:

Hemiepiphysiodesis corrects lower extremity malalignment in patients with MHE at a similar rate compared with an idiopathic coronal plane deformity population. Rebound deformity of 4 degrees at 19 months after hardware removal in patients with remaining open growth plates should make surgeons conscious of the remaining growth potential when planning deformity correction.

Level of Evidence:

Level III.
Disparities in Patient-reported Outcome Measure Completion Rates and Baseline Function in Newly Presenting Spine Patients
Authors: Johnson Andrea H. , Brennan Jane C. , Rana Parimal , Turcotte Justin J. , Patton Chad
Published: March 2024

Study Design.

Retrospective review.

Objective.

The purpose of this study was to evaluate disparities in patient-reported outcome measures (PROM) completion rates and baseline function scores among newly presenting spine patients.

Summary of Background Data.

Prior studies have demonstrated that minority patients and those of low socioeconomic status may present with worse physical and mental health on PROMs. As PROMs are increasingly used in clinical care, research, and health policy, accurate assessment of health status among populations relies on the successful completion of PROM instruments.

Methods.

A retrospective review of 10,803 consecutive new patients presenting to a single multidisciplinary spine clinic from June 2020 to September 2022 was performed. Univariate statistics were performed to compare demographics between patients who did and did not complete PROMs. Multivariable analysis was used to compare PROM instrument completion rates by race, ethnicity, and Social Vulnerability Index (SVI) and baseline scores among responders.

Results.

A total of 68.4% of patients completed PROMs at the first clinic visit. After adjusting for age, sex, body mass index, and diagnosis type, patients of non-White race (OR=0.661, 95% CI=0.599–0.729, P<0.001), Hispanic ethnicity (OR=0.569, 95% CI=0.448–0.721, P<0.001), and increased social vulnerability (OR=0.608, 95% CI=0.511–0.723, P<0.001) were less likely to complete PROMs. In the multivariable models, patients of non-White race reported lower levels of physical function (β=−6.5, 95% CI=−12.4 to −0.6, P=0.032) and higher levels of pain intensity (β=0.6, 95% CI=0.2–1.0, P=0.005). Hispanic ethnicity (β=1.5, 95% CI=0.5–2.5, P=0.004) and increased social vulnerability (β=1.1, 95% CI=0.4–1.8, P=0.002) were each associated with increased pain intensity.

Conclusions.

Among newly presenting spine patients, those of non-White race, Hispanic ethnicity, and with increased social vulnerability were less likely to complete PROMs. As these subpopulations also reported worse physical function or pain intensity, additional strategies are needed to better capture patient-reported health status to avoid bias in clinical care, outcomes research, and health policy.

Level of Evidence.

4.
A Rare Midfoot Injury Case Report: Complete Dislocation of the Navicular With Dislocation of the Cuboid
Authors: Beraún-Coronel Luis , Beraún-Coronel José , Chamorro-Robles Fredy
Published: March 2024

Injuries of the midfoot are rare and they usually occur as a result of high-energy trauma. The navicular and cuboid, bones that belong to the midfoot, are fundamental structures in stabilizing the medial and lateral columns of the foot respectively, so they require an adequate treatment. We present a 26-year-old man with a complete tarsal navicular bone dislocation without associated navicular fracture, and a complete cuboid dislocation after sustaining a 4 meters fall, it was also accompanied by fracture of the lateral cuneiform and the base of the fourth metatarsal. The patient was treated successfully with open reduction and fixation with screw and Kirschner wires. At 18 months follow-up, we considered the patient’s outcome was good obtaining 90 (90/100) points in American Orthopedic Foot and Ankle Society Midfoot Score.

Level of Evidence:

Diagnostic Level V.
A phase 1 study of regorafenib and sildenafil in adults with advanced solid tumors
Authors: Poklepovic Andrew S. , Gordon Sarah W. , Kothadia Sejal , McGuire William P. , Thacker Leroy R. , Deng Xiaoyan , Tombes Mary Beth , Shrader Ellen , Hudson Daniel , Bandyopadhyay Dipankar , Ryan Alison A. , Kmieciak Maciej , Smith Steven , Dent Paul
Published: March 2024

The purpose of this study is to establish the recommended phase 2 dose for regorafenib in combination with sildenafil for patients with advanced solid tumors. Secondary outcomes included identification of antitumor effects of regorafenib and sildenafil, toxicity of the combination, determination of PDE5 expression in tumor samples, and the impact of sildenafil on the pharmacokinetics of regorafenib. This study was a phase 1, open-label single-arm dose-escalation trial using a 3 + 3 design. Additional patients were enrolled at the maximum tolerated dose (MTD) until a total of 12 patients were treated at the MTD. A total of 29 patients were treated in this study. The median duration of treatment was 8 weeks. The recommended phase 2 doses determined in this study are regorafenib 160 mg daily with sildenafil 100 mg daily. The most common toxicities included palmar-plantar erythrodysesthesia syndrome (20 patients, 69%) and hypophosphatemia (18 patients, 62%). Two patients (7%) experienced grade 4 lipase increase. Objective responses were not observed; however, 14 patients (48%) had a period of stable disease during the study. Stable disease for up to 12 months was observed in patients with ovarian cancer as well as up to 20 months for a patient with cervical cancer. The combination of regorafenib and sildenafil at the recommended phase 2 dose is safe and generally well tolerated. Disease control in patients with gynecologic malignancies was especially encouraging. Further evaluation of the combination of regorafenib and sildenafil in gynecologic malignancies is warranted. Clinical Trial Registration Number: NCT02466802.
Positive modulation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors differentially alters spatial learning and memory in juvenile rats younger and older than three weeks
Authors: Mill Nicholas R. , Ogoe Richard H. , Valibeigi Nazanin , Chen Diyi , Kimbal Carmen L. , Yoon Stanley J. , Ganju Shaunak , Perdomo Josue A. , Sardana Anjali , McHail Daniel G. , Gonzalez Diego A. , Dumas Theodore C.
Published: March 2024

Remarkable performance improvements occur at the end of the third postnatal week in rodents tested in various tasks that require navigation according to spatial context. While alterations in hippocampal function at least partially subserve this cognitive advancement, physiological explanations remain incomplete. Previously, we discovered that developmental modifications to hippocampal glutamatergic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in juvenile rats was related to more mature spontaneous alternation behavior in a symmetrical Y-maze. Moreover, a positive allosteric modulator of AMPA receptors enabled immature rats to alternate at rates seen in older animals, suggesting an excitatory synaptic limitation to hippocampal maturation. We then validated the Barnes maze for juvenile rats in order to test the effects of positive AMPA receptor modulation on a goal-directed spatial memory task. Here we report the effects of the AMPA receptor modulator, CX614, on spatial learning and memory in the Barnes maze. Similar to our prior report, animals just over 3 weeks of age display substantial improvements in learning and memory performance parameters compared to animals just under 3 weeks of age. A moderate dose of CX614 enabled immature animals to move more directly to the goal location, but only after 1 day of training. This performance improvement was observed on the second day of training with drug delivery or during a memory probe trial performed without drug delivery after the second day of training. Higher doses created more search errors, especially in more mature animals. Overall, CX614 provided modest performance benefits for immature rats in a goal-directed spatial memory task.
The Role of Psychiatry for Transgender and Gender Diverse Adults
Authors: Beazer Maggie , Breiger Micah , Keuroghlian Alex S.
Published: March 2024

Since the inclusion of gender identity disorder in the third edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-III), psychiatry and the broader medical field have made substantial alterations in their recognition of and respect for transgender and gender diverse (TGD) identities. As this recognition continues to expand, psychiatrists should be aware of both historical harm and current best care practices, especially in light of psychiatric morbidity in TGD populations relative to the general population. This article contextualizes the history of psychiatry’s engagement with TGD patients and presents the gender minority stress and resilience model to frame the mental health disparities experienced by TGD people. We envision a role for psychiatry that goes beyond gatekeeping gender-affirming hormone therapy and surgeries. Instead, we should invest in equitable care across the continuum of mental health needs. We provide an overview of existing literature to help characterize psychiatric epidemiology for this population, with the goal of offering guidance on how psychiatrists can deliver responsive and high-quality care for TGD people. Some key areas of proposed clinical improvement include culturally tailoring interventions for substance use disorders, reducing medical trauma in acute psychiatric care settings, and better understanding the interplay of psychopharmacology and gender-affirming hormone therapy.
PEMBROLIZUMAB-RELATED BILATERAL OCULAR HYPOTONY ASSOCIATED WITH CILIARY DETACHMENTS AND MACULA OEDEMA: A TREATMENT-RESISTANT SIDE EFFECT.
Authors: Bec Louise , Khouri Charles , Chiquet Christophe
Published: March 2024

Purpose:

To report of a case of bilateral ocular hypotony associated with ciliary detachments and macula edema as an uncommon troublesome side-effect of pembrolizumab (an immune checkpoint inhibitor) treatment.

Methods:

A 56-year-old man with a history of metastatic axillary melanoma (bone, lung, spleen and lymph node lesions) treated with pembrolizumab complained of visual deterioration at his first-year anti-PD1 follow-up visit. Visual acuity in both eyes was 20/32. The patient presented bilateral ocular hypotony (7 mmHg in the right eye, 3mmHg in the left eye), ciliary detachments and macula edema. Several treatments were sequentially tried including systemic steroid therapy, subconjunctival injections of triamcinolone, an intravitreal dexamethasone implant, and leaving some cohesive viscoelastic agent during cataract surgery.

Results:

None of the treatments tried were effective in reducing the ocular hypotony and stopping pembrolizumab was not an option due to its efficacy in controlling the cancer.

Conclusion:

Pembrolizumab treatment carries a risk of ocular hypotony which can be bilateral, presenting a challenging risk – benefit dilemma, particularly if pembrolizumab is effective in controlling the cancer.
Digging deeper into pain: an ethological behavior assay correlating well-being in mice with human pain experience
Authors: Pattison Luke A. , Cloake Alexander , Chakrabarti Sampurna , Hilton Helen , Rickman Rebecca H. , Higham James P. , Meng Michelle Y. , Paine Luke W. , Dannawi Maya , Qiu Lanhui , Ritoux Anne , Bulmer David C. , Callejo Gerard , Smith Ewan St. John
Published: March 2024

The pressing need for safer, more efficacious analgesics is felt worldwide. Preclinical tests in animal models of painful conditions represent one of the earliest checkpoints novel therapeutics must negotiate before consideration for human use. Traditionally, the pain status of laboratory animals has been inferred from evoked nociceptive assays that measure their responses to noxious stimuli. The disconnect between how pain is tested in laboratory animals and how it is experienced by humans may in part explain the shortcomings of current pain medications and highlights a need for refinement. Here, we survey human patients with chronic pain who assert that everyday aspects of life, such as cleaning and leaving the house, are affected by their ongoing level of pain. Accordingly, we test the impact of painful conditions on an ethological behavior of mice, digging. Stable digging behavior was observed over time in naive mice of both sexes. By contrast, deficits in digging were seen after acute knee inflammation. The analgesia conferred by meloxicam and gabapentin was compared in the monosodium iodoacetate knee osteoarthritis model, with meloxicam more effectively ameliorating digging deficits, in line with human patients finding meloxicam more effective. Finally, in a visceral pain model, the decrease in digging behavior correlated with the extent of disease. Ultimately, we make a case for adopting ethological assays, such as digging, in studies of pain in laboratory animals, which we believe to be more representative of the human experience of pain and thus valuable in assessing clinical potential of novel analgesics in animals.
Comparison of the mesodermal differentiation potential between embryonic stem cells and scalable induced pluripotent stem cells
Authors: Tsai En-Tung , Tseng Huan-Chin , Liu Yu-Hao , Wu You-Ren , Peng Shih-Yuan , Lai Wei-Yi , Lin Yi-Ying , Chen Shih-Pin , Chiou Shih-Hwa , Yang Yi-Ping , Chien Yueh
Published: March 2024

Background:

Mesenchymal stem cells (MSCs) have promising potential in clinical application, whereas their limited amount and sources hinder their bioavailability. Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have become prominent options in regenerative medicine as both possess the ability to differentiate into MSCs.

Methods:

Recently, our research team has successfully developed human leukocyte antigen (HLA)-homozygous iPSC cell lines with high immune compatibility, covering 13.5% of the Taiwanese population. As we deepen our understanding of the differences between these ESCs and HLA-homozygous iPSCs, our study focused on morphological observations and flow cytometry analysis of specific surface marker proteins during the differentiation of ESCs and iPSCs into MSCs.

Results:

The results showed no significant differences between the two pluripotent stem cells, and both of them demonstrated the equivalent ability to further differentiate into adipose, cartilage, and bone cells.

Conclusion:

Our research revealed that these iPSCs with high immune compatibility exhibit the same differentiation potential as ESCs, enhancing the future applicability of highly immune-compatible iPSCs.
Model-Based Estimation of Active and Passive Muscle Forces Using MRE in Forearm Muscles During 2-DOF Wrist Tasks
Authors: Helm Cody A , Sergi Fabrizio
Published: March 2024

Magnetic resonance elastography (MRE)-based muscle force estimation methods have been proposed to estimate individual muscle forces based on measurements of shear wave speed and joint torque in multiple postures. To estimate both the slope and offset parameters of the relationship between shear wave speed and muscle force, it is necessary to collect measurements in a plethora of postures in case of substantial muscle redundancy. However, anisotropic MRE requires a structural and diffusion-tensor imaging scan in each posture, which is infeasible given the time constraints of MRI imaging. The objectives of this work were to develop a muscle force estimator with sufficient accuracy that would only require a limited set of postures, and to evaluate its effectiveness under a variety of measurement conditions. We developed a novel MRE-based muscle force estimator, which decouples shear wave speed into its active and passive components and solves for the slope and offset parameters, independently. We assessed the effectiveness of the proposed estimator under different simulated measurement conditions, with varying levels of noise, and compared it to the original MRE-based estimator. The proposed estimator results in a reduction in the estimation error for the offset parameter, for all muscles, without significant degradation in the estimation error for the slope parameter. However, the proposed muscle force estimator does not improve the goodness-of-fit or the cross-validation error compared to the original estimator. In conclusion, the proposed MRE-based muscle force estimator improves the estimation of muscle-specific parameters and may yield increased muscle force estimation performance.
The evolution of antibiotic resistance islands occurs within the framework of plasmid lineages
Authors: Wang Yiqing , Dagan Tal
Published: March 2024

Bacterial pathogens carrying multidrug resistance (MDR) plasmids are a major threat to human health. The acquisition of antibiotic resistance genes (ARGs) in plasmids is often facilitated by mobile genetic elements that copy or translocate ARGs between DNA molecules. The agglomeration of mobile elements in plasmids generates resistance islands comprising multiple ARGs. However, whether the emergence of resistance islands is restricted to specific MDR plasmid lineages remains understudied. Here we show that the agglomeration of ARGs in resistance islands is biased towards specific large plasmid lineages. Analyzing 6,784 plasmids in 2,441Escherichia,Salmonella,andKlebsiellaisolates, we quantify that 84% of the ARGs in MDR plasmids are found in resistance islands. We furthermore observe rapid evolution of ARG combinations in resistance islands. Most regions identified as resistance islands are shared among closely related plasmids but rarely among distantly related plasmids. Our results suggest the presence of barriers for the dissemination of ARGs between plasmid lineages, which are related to plasmid genetic properties, host range and the plasmid evolutionary history. The agglomeration of ARGs in plasmids is attributed to the workings of mobile genetic elements that operate within the framework of existing plasmid lineages.
Meta-analysis of the acoustic adaptation hypothesis reveals no support for the effect of vegetation structure on acoustic signalling across terrestrial vertebrates
Authors: Freitas Bárbara , D'Amelio Pietro B. , Milá Borja , Thébaud Christophe , Janicke Tim
Published: March 2024

Acoustic communication plays a prominent role in various ecological and evolutionary processes involving social interactions. The properties of acoustic signals are thought to be influenced not only by the interaction between signaller and receiver but also by the acoustic characteristics of the environment through which the signal is transmitted. This conjecture forms the core of the so-called "acoustic adaptation hypothesis" (AAH), which posits that vegetation structure affects frequency and temporal parameters of acoustic signals emitted by a signaller as a function of their acoustic degradation properties. Specifically, animals in densely vegetated 'closed habitats' are expected to produce longer acoustic signals with lower repetition rates and lower frequencies (minimum, mean, maximum, and peak) compared to the ones inhabiting less vegetated 'open habitats'. To date, this hypothesis has received mixed results, with the level of support depending on the taxonomic group and the methodology used. We conducted a systematic literature search of empirical studies testing for an effect of vegetation structure on acoustic signalling and assessed the generality of the AAH using a meta-analytic approach based on 371 effect sizes from 75 studies and 57 taxa encompassing birds, mammals and amphibians. Overall, our results do not provide consistent support for the AAH, neither in within-species comparisons (suggesting no overall phenotypically plastic response of acoustic signalling to vegetation structure) nor in among-species comparisons (suggesting no overall evolutionary response). However, when considering birds only, we found a weak support for the AAH in within-species comparisons, which was mainly driven by studies that measured frequency bandwidth, suggesting that this variable may exhibit a phenotypically plastic response to vegetation structure. For among-species comparisons in birds, we also found support for the AAH, but this effect was not significant after excluding comparative studies that did not account for phylogenetic non-independence. Collectively, our synthesis does not support a universal role of vegetation structure in the evolution of acoustic communication. We highlight the need for more empirical work on currently under-studied taxa such as amphibians, mammals, and insects. Furthermore, we propose a framework for future research on the AAH. We specifically advocate for a more detailed and quantitative characterization of habitats to identify frequencies with the highest detection probability and to determine if frequencies with greater detection distances are preferentially used. Finally, we stress that empirical tests of the AAH should focus on signals which are selected for increased transmission distance.
Living with rheumatic fever and rheumatic heart disease in Victoria, Australia: a qualitative study
Authors: Oliver Jane , Fualautoalasi-Lam Loudeen , Ferdinand Angeline , Tiatia Ramona , Jones Bryn , Engelman Daniel , Gibney Katherine B. , Steer Andrew C.
Published: March 2024

Background

In Victoria, Australia, children with Pacific Islander (‘Pacific’) ethnicities are overrepresented in acute rheumatic fever (ARF) and rheumatic heart disease (RHD). In June 2023, a Victorian RHD control program was initiated. To inform public health and clinical practice, we described young Pacific patients’ and their caregivers’ understandings and experiences of ARF/RHD, and identified possible ways to improve the delivery of clinical care.

Methods

We established a project reference group including local Pacific people to guide this research. Pacific patients who attended an ARF/RHD clinic at The Royal Children’s Hospital, Melbourne, were invited to participate, as were their caregivers. A Samoan researcher conducted qualitative ‘talanoa’ (conversational) interviews with patients and caregivers. A second researcher conducted semi-structured interviews with treating clinicians and other stakeholders. Interview transcripts underwent thematic analysis guided by the Tuilaepa Youth Mentoring Services Pacific Youth Wellbeing Framework.

Results

We interviewed 27 participants. This included nine patients and nine caregivers, all of whom were Samoan. These 18 participants expressed a desire to learn more about ARF/RHD and connect with other affected people. While some shared their experiences of having well-liked and trusted healthcare providers, patients often struggled to have two-way clinical conversations. The need to support clinicians working with high-risk populations to improve their awareness of ARF was identified. Receiving treatment on time was a top priority for affected families, despite injection pain, inconvenience and financial costs. The need to support continuity of care for young adult patients was raised by participants.

Conclusions

Pacific people living with ARF/RHD and their families require additional support to receive high quality management in Victoria. Introducing a patient register and a specialist RHD nurse would enhance access to treatment, as would removing cost barriers, improving clinical awareness of ARF/RHD and creating Victoria-specific patient resources.
LDL-Binding IL-10 Reduces Vascular Inflammation in Atherosclerotic Mice
Authors: Volpatti Lisa R. , de Matos Salvador Norton , Borjas Gustavo , Reda Joseph , Watkins Elyse A. , Zhou Zhengjie , Nguyen Mindy , Solanki Ani , Fang Yun , Hubbell Jeffrey A.
Published: March 2024

Atherosclerosis is a chronic inflammatory disease associated with the accumulation of low-density lipoprotein (LDL) in arterial walls. Higher levels of the anti-inflammatory cytokine IL-10 in serum are correlated with reduced plaque burden. However, cytokine therapies have not translated well to the clinic, partially due to their rapid clearance and pleiotropic nature. Here, we engineered IL-10 to overcome these challenges by hitchhiking on LDL to atherosclerotic plaques. Specifically, we constructed fusion proteins in which one domain is IL-10 and the other is an antibody fragment (Fab) that binds to protein epitopes of LDL. In murine models of atherosclerosis, we show that systemically administered Fab-IL-10 constructs bind circulating LDL and traffic to atherosclerotic plaques. One such construct, 2D03-IL-10, significantly reduces aortic immune cell infiltration to levels comparable to healthy mice, whereas non-targeted IL-10 has no therapeutic effect. Mechanistically, we demonstrate that 2D03-IL-10 preferentially associates with foamy macrophages and reduces pro-inflammatory activation markers. This platform technology can be applied to a variety of therapeutics and shows promise as a potential targeted anti-inflammatory therapy in atherosclerosis.
Persistent Interruption in Parvalbumin Positive Inhibitory Interneurons: Biophysical and Mathematical Mechanisms
Authors: Upchurch Carol M , Knowlton Christopher J , Chamberland Simon , Canavier Carmen C
Published: March 2024

Persistent activity in principal cells is a putative mechanism for maintaining memory traces during working memory. We recently demonstrated persistent interruption of firing in fast-spiking parvalbumin-expressing interneurons (PV-INs), a phenomenon which could serve as a substrate for persistent activity in principal cells through disinhibition lasting hundreds of milliseconds. Here, we find that hippocampal CA1 PV-INs exhibit type 2 excitability, like striatal and neocortical PV-INs. Modelling and mathematical analysis showed that the slowly inactivating potassium current Kv1 contributes to type 2 excitability, enables the multiple firing regimes observed experimentally in PV-INs, and provides a mechanism for robust persistent interruption of firing. Using a fast/slow separation of times scales approach with the Kv1 inactivation variable as a bifurcation parameter shows that the initial inhibitory stimulus stops repetitive firing by moving the membrane potential trajectory onto a co-existing stable fixed point corresponding to a non-spiking quiescent state. As Kv1 inactivation decays, the trajectory follows the branch of stable fixed points until it crosses a subcritical Hopf bifurcation then spirals out into repetitive firing. In a model describing entorhinal cortical PV-INs without Kv1, interruption of firing could be achieved by taking advantage of the bistability inherent in type 2 excitability based on a subcritical Hopf bifurcation, but the interruption was not robust to noise. Persistent interruption of firing is therefore broadly applicable to PV-INs in different brain regions but is only made robust to noise in the presence of a slow variable.

Significance Statement

Persistent activity in neuronal networks is thought to provide a substrate for multiple forms of memory. The architecture of neuronal networks across many brain regions involves a small number of inhibitory neurons that control many principal neurons. We propose that persistent silencing of fast-spiking parvalbumin-expressing inhibitory interneurons (PVINs) can result in persistent activity of principal neurons. We use a mathematical approach and computer simulations to investigate the mechanisms governing persistent interruption of firing in hippocampal and cortical PV-INs. We show how a slowly changing state of a particular ion channel controls the long-lasting silence imposed by persistent interruption. Overall, our results provide a conceptual framework that positions the persistent interruption of PV-INs firing as a potential mechanism for persistent activity in principal cells.
Nucleolar stress induced the formation of a nucleolar stress body via the NOSR-1/NUMR-1 axis inCaenorhabditis elegans
Authors: Hong Minjie , Zhou Xiaotian , Zeng Chenming , Xu Demin , Xu Ting , Liao Shimiao , Wang Ke , Zhu Chengming , Shan Ge , Huang Xinya , Chen Xiangyang , Feng Xuezhu , Guang Shouhong
Published: March 2024

Environmental stimuli not only alter gene expression profiles but also induce structural changes in cells. How distinct nuclear bodies respond to cellular stress is poorly understood. Here, we identified a new subnuclear organelle named the nucleolar stress body (NoSB), the formation of which was induced by the inhibition of rRNA transcription or inactivation of rRNA processing and maturation inC. elegans. NoSB did not colocalize with other previously described subnuclear organelles. We conducted forward genetic screening and identified a new bZIP transcription factor, namednucleolarstress response-1 (NOSR-1), that is required for NoSB formation. The inhibition of rRNA transcription or inactivation of rRNA processing and maturation increasednosr-1expression. By using transcriptome analysis of wild-type animals subjected to different nucleolar stress conditions andnosr-1mutants, we identified that the SR-like protein NUMR-1 (nuclear localized metal responsive) is the target of NOSR-1. Interestingly, NUMR-1 is a component of NoSB and itself per se is required for the formation of NoSB. We concluded that the NOSR-1/NUMR-1 axis likely responds to nucleolar stress and mediates downstream stress-responsive transcription programs and subnuclear morphology alterations inC. elegans.