bluuebunny/crossref_metadata_2025 huggingface dataset:
Caste and Kinship
Authors: Abraham Janaki
Published: January 2024

This essay explores the way caste and kinship are mutually constituted by focusing on three critical themes. The first section looks at both kinship among castes through theories of origin, and at kin-like relationships across castes. The second section looks at hypergamy and endogamy as central to the reproduction of caste and outlines changes in these through a discussion of changing rural and urban landscapes and aspirations. The third and last section looks at contentious marriages / relationships and stresses that the very idea of what is ‘contentious’ shifts over time. This essay then highlights the importance of looking at temporal shifts in understanding the entangled nature of kinship and caste.
Community structure and distribution pattern of appendicularians in the Kuroshio–Oyashio transitional zone during summer
Authors: Sato Riki , Kodama Taketoshi , Hidaka Kiyotaka
Published: January 2024

The Kuroshio–Oyashio transitional zone (KOTZ), constituting the complex water–mass structure surrounding the oceanfront system, is one of the most important fisheries grounds in the western North Pacific. It serves as spawning and nursery sites among several commercially important fish species that consume appendicularians, particularly during the larval stages. In the present study, we investigated the species composition, abundance and biomass of appendicularian assemblages at 20 stations in the KOTZ in the summer of 2018. Appendicularian communities, including 24 species belonging to 7 genera—the highest record for the western North Pacific—were divided into three groups, corresponding to the anticyclonic eddy, a trough between the eddy and the Kuroshio Extension, and the rest of the study area. Statistically, the temperature within the surface layer and strength of water turbulence appear to strongly affect the quantitative and qualitative characteristics of the appendicularian community structure in the KOTZ. This relationship could be attributed to the effect of temperature on the population size and species coexistence, potentially offering an advantage for appendicularians in the future warming ocean scenario and the role of water turbulence in the predatory impact exerted by carnivores on appendicularians.
The persuasive effects of political microtargeting in the age of generative artificial intelligence
Authors: Simchon Almog , Edwards Matthew , Lewandowsky Stephan
Published: January 2024

The increasing availability of microtargeted advertising and the accessibility of generative artificial intelligence (AI) tools, such as ChatGPT, have raised concerns about the potential misuse of large language models in scaling microtargeting efforts for political purposes. Recent technological advancements, involving generative AI and personality inference from consumed text, can potentially create a highly scalable “manipulation machine” that targets individuals based on their unique vulnerabilities without requiring human input. This paper presents four studies examining the effectiveness of this putative “manipulation machine.” The results demonstrate that personalized political ads tailored to individuals’ personalities are more effective than nonpersonalized ads (studies 1a and 1b). Additionally, we showcase the feasibility of automatically generating and validating these personalized ads on a large scale (studies 2a and 2b). These findings highlight the potential risks of utilizing AI and microtargeting to craft political messages that resonate with individuals based on their personality traits. This should be an area of concern to ethicists and policy makers.
Quantum Euler angles and agency-dependent space-time
Authors: Amelino-Camelia G , D’Esposito V , Fabiano G , Frattulillo D , Höhn P A , Mercati F
Published: January 2024

Quantum gravity is expected to introduce quantum aspects into the description of reference frames. Here we begin exploring how quantum gravity induced deformations of classical symmetries could modify the transformation laws among reference frames in an effective regime. We invoke the quantum group SUq(2) as a description of deformed spatial rotations and interpret states of a representation of its algebra as describing the relative orientation between two reference frames. This leads to a quantization of one of the Euler angles and to an aspect of agency dependence: space is reconstructed as a collection of fuzzy points, exclusive to each agent, which depends on their choice of reference frame. Each agent can choose only one direction in which points can be sharp, while points in all other directions become fuzzy in a way that depends on this choice. Two agents making different choices will thus observe the same points with different degrees of fuzziness.
Steps toward developing a comprehensive fatigue monitoring and mitigation solution: perspectives from a cohort of United States Naval Surface Force officers
Authors: LaGoy Alice D , Kubala Andrew G , Seech Todd R , Jameson Jason T , Markwald Rachel R , Russell Dale W
Published: January 2024

Study Objectives

This study analyzed fatigue and its management in US Naval Surface Force warships, focusing on understanding current practices and barriers, and examining the influence of organizational and individual factors on managing chronic fatigue. Furthermore, this study explored the impact of organizational and individual factors on fatigue management.

Methods

As part of a larger study, 154 naval officers (mean ± standard deviation; 31.5 ± 7.0 years; 8.8 ± 6.8 years of service; 125 male, and 29 female) completed a fatigue survey. The survey addressed (1) self-reported fatigue, (2) fatigue observed in others, (3) fatigue monitoring strategies, (4) fatigue mitigation strategies, and (5) barriers to fatigue mitigation. Logistic and ordinal regressions were performed to examine the effect of individual (i.e. sleep quality and years in military service) and organizational (i.e. ship-class) factors on fatigue outcomes.

Results

Fatigue was frequently experienced and observed by 23% and 54% of officers, respectively. Of note, officers often monitored fatigue reactively (i.e. 65% observed others nodding off and 55% observed behavioral impairments). Still, officers did not frequently implement fatigue mitigation strategies, citing few operationally feasible mitigation strategies (62.3%), being too busy (61.7%), and not having clear thresholds for action (48.7%). Fatigue management varies across organizational factors, which must be considered when further developing fatigue management strategies.

Conclusions

Fatigue remains a critical concern aboard surface force ships and it may be better addressed through development of objective sleep and fatigue monitoring tools that could inform leadership decision-making.
Disease Modulation Versus Modification: A Call for Revised Outcome Metrics in the Treatment of Thyroid Eye Disease
Authors: North Victoria S. , Dolman Peter J. , Garrity James A. , Kazim Michael
Published: January 2024

Purpose:

This perspective introduces the concepts of disease-modulating and -modifying therapy for thyroid eye disease and offers novel metrics for therapeutic outcomes.

Methods:

A focused literature review was performed.

Results:

Modulators are treatments that suppress disease symptoms whereas modifiers alter the natural history of a disease. Though many drugs are capable of exhibiting both effects, consideration of a drug’s primary effect is useful when considering therapeutic options. For thyroid eye disease, corticosteroids and teprotumumab are effective at modulating many signs and symptoms of the disease, particularly those related to soft tissue inflammation. Orbital radiotherapy and rituximab have demonstrated effectiveness at durably modifying the natural history of thyroid eye disease.

Conclusions:

Outcome metrics should reflect the unique therapeutic objectives associated with disease modulation and modification. This conceptual framework should guide treatment of thyroid eye disease.
Correlation Between Radiologic and Histopathologic Features of Orbital Epidermoid and Dermoid Cysts
Authors: Yun Hee Jee , Kim Jeong Hee , Woo Kyung In , Kim Yoon-Duck
Published: January 2024

Purpose:

Epidermoid cysts (EC) and dermoid cysts (DC) typically appear as well-circumscribed lesions on CT. This study aimed to clarify the radiologic and histopathologic characteristics of orbital EC and DC and to determine the correlations between them.

Methods:

The medical records of 69 patients who underwent surgery for orbital DC or EC at Samsung Medical Center between January 2001 and August 2016 were retrospectively reviewed. The size and location of the cysts, rim enhancement, homogeneity of contents, presence of hemorrhagic or calcific components, radiodensity of contents, and extent of bony remodeling were evaluated using CT. Additionally, the cyst lining and contents were examined histopathologically.

Results:

Among patients with orbital cysts, EC and DC were diagnosed in 10 (14.5%) and 59 (85.5%) patients, respectively. Further, 50.0% of EC and 79.7% of DC were located in the superotemporal quadrant of the orbit. On orbital CT, the average radiodensity of EC and DC was 18.9 ± 56.2 and −67.9 ± 63.3 HU, respectively. The cystic contents were more frequently homogeneous than heterogeneous in both EC and DC; however, the radiodensity of cysts differed significantly, which may be attributed to sebaceous gland activity. Focal bony notching, bone remodeling under pressure, and bony changes from dumbbell-shaped cysts were observed more frequently in DC than in EC.

Conclusions:

Radiological and histopathological features are correlated in orbital EC and DC. Therefore, orbital EC and DC can be preoperatively differentiated using CT, based on the average radiodensity and bony remodeling.
A Case of Idiopathic Orbital Inflammation With Elevated Anti-Mumps Immunoglobulin M Antibody
Authors: Han Jiyeon , Woo Kyung In
Published: January 2024

A 21-year-old female presented with periocular swelling, diplopia, and painful ophthalmoplegia in the OS. Orbital magnetic resonance imaging revealed an enhanced soft tissue mass involving the left medial rectus muscle. Laboratory test results revealed leukocytosis, elevated reactive C-reactive protein, and positive serum levels of anti-mumps immunoglobulin M (IgM) antibody without systemic manifestations of mumps infection. The clinical course was refractory, and the patient showed a poor response to high-dose steroids. An incisional biopsy revealed stromal fibrosis with focal lymphoid aggregates, indicating sclerosing inflammation. Myopathy of the medial rectus progressed to superior, inferior, and lateral recti involvement of the left orbit. Immunosuppressive agents, including steroids, were administered for 22 months after disease onset. The mumps IgM antibody level was positive for over 5 months and became negative upon testing performed 1 year after the first visit.
Hemorrhage Following Muller’s Muscle Conjunctival Resection: Description and Case-Control Study
Authors: Gu David , Cohen Liza M. , Jung JooYeon , Rootman Daniel B.
Published: January 2024

Purpose:

The purpose of this study was to report a series of patients with postoperative hemorrhage after Muller’s muscle conjunctival resection surgery and compare risk factors and outcomes with a control population.

Methods:

In this case-control study, records of patients who underwent Muller’s muscle conjunctival resection over 5 years were reviewed for a history of postoperative hemorrhage occurring >24 hours after surgery. A 4:1 control population was matched for age and sex. Clinical data collected included demographics, medical history, medications, and subsequent surgery. Preoperative and 3-month postoperative marginal reflex distance 1 were measured digitally using ImageJ. The hemorrhage and control groups were compared using Fisher’s exact tests for categorical variables and independent samples t tests for continuous variables.

Results:

The hemorrhage group contained 10 patients (mean age 66.4 ± 18.5 years). The control group consisted of 40 age and sex-matched controls. Of 350 charts reviewed, there were 10 cases of postoperative hemorrhage (incidence 2.9%). Hemorrhage occurred a mean of 4.2 ± 1.3 (range 2–7) days after surgery and lasted for a mean of 29.3 ± 19.1 (range 12–72) hours. In all 10 cases, the bleeding resolved with conservative measures. There was no difference between the hemorrhage and control groups in terms of medical conditions, blood thinners, and surgical revision. Preoperative, postoperative, and change in marginal reflex distance 1 did not differ between the hemorrhage and control groups.

Conclusions:

Hemorrhage occurs approximately 4–5 days postoperatively in a small percentage of patients undergoing Muller’s muscle conjunctival resection surgery. This investigation did not identify any consistent risk factors, and outcomes in this patient population appear no different than controls.
The geography of arthritis-attributable pain outcomes: a county-level spatial analysis
Authors: Sun Feinuo , Zajacova Anna , Grol-Prokopczyk Hanna
Published: January 2024

Research on the geographic distribution of pain and arthritis outcomes, especially at the county level, is limited. This is a high-priority topic, however, given the heterogeneity of subnational and substate regions and the importance of county-level governments in shaping population health. Our study provides the most fine-grained picture to date of the geography of pain in the United States. Combining 2011 Behavioral Risk Factor Surveillance System data with county-level data from the Census and other sources, we examined arthritis and arthritis-attributable joint pain, severe joint pain, and activity limitations in US counties. We used small area estimation to estimate county-level prevalences and spatial analyses to visualize and model these outcomes. Models considering spatial structures show superiority over nonspatial models. Counties with higher prevalences of arthritis and arthritis-related outcomes are mostly clustered in the Deep South and Appalachia, while severe consequences of arthritis are particularly common in counties in the Southwest, Pacific Northwest, Georgia, Florida, and Maine. Net of arthritis, county-level percentages of racial/ethnic minority groups are negatively associated with joint pain prevalence, but positively associated with severe joint pain prevalence. Severe joint pain is also more common in counties with more female individuals, separated or divorced residents, more high school noncompleters, fewer chiropractors, and higher opioid prescribing rates. Activity limitations are more common in counties with higher percentages of uninsured people. Our findings show that different spatial processes shape the distribution of different arthritis-related pain outcomes, which may inform local policies and programs to reduce the risk of arthritis and its consequences.
Disruption of mitochondrial pyruvate oxidation in dorsal root ganglia drives persistent nociceptive sensitization and causes pervasive transcriptomic alterations
Authors: Haque Md Mamunul , Kuppusamy Panjamurthy , Melemedjian Ohannes K.
Published: January 2024

Metabolism is inextricably linked to every aspect of cellular function. In addition to energy production and biosynthesis, metabolism plays a crucial role in regulating signal transduction and gene expression. Altered metabolic states have been shown to maintain aberrant signaling and transcription, contributing to diseases like cancer, cardiovascular disease, and neurodegeneration. Metabolic gene polymorphisms and defects are also associated with chronic pain conditions, as are increased levels of nerve growth factor (NGF). However, the mechanisms by which NGF may modulate sensory neuron metabolism remain unclear. This study demonstrated that intraplantar NGF injection reprograms sensory neuron metabolism. Nerve growth factor suppressed mitochondrial pyruvate oxidation and enhanced lactate extrusion, requiring 24 hours to increase lactate dehydrogenase A and pyruvate dehydrogenase kinase 1 (PDHK1) expression. Inhibiting these metabolic enzymes reversed NGF-mediated effects. Remarkably, directly disrupting mitochondrial pyruvate oxidation induced severe, persistent allodynia, implicating this metabolic dysfunction in chronic pain. Nanopore long-read sequencing of poly(A) mRNA uncovered extensive transcriptomic changes upon metabolic disruption, including altered gene expression, splicing, and poly(A) tail lengths. By linking metabolic disturbance of dorsal root ganglia to transcriptome reprogramming, this study enhances our understanding of the mechanisms underlying persistent nociceptive sensitization. These findings imply that impaired mitochondrial pyruvate oxidation may drive chronic pain, possibly by impacting transcriptomic regulation. Exploring these metabolite-driven mechanisms further might reveal novel therapeutic targets for intractable pain.
Parental experience of neonatal pain research while participating in the Parental touch trial (Petal)
Authors: van der Vaart Marianne , Hauck Annalisa G.V. , Mansfield Roshni , Adams Eleri , Bhatt Aomesh , Cobo Maria M. , Crankshaw Daniel , Dhami Amraj , Hartley Caroline , Monk Vaneesha , Evans Fry Ria , Moultrie Fiona , Robinson Shellie , Yong Jean , Poorun Ravi , Baxter Luke , Slater Rebeccah
Published: January 2024

Parental involvement in neonatal comfort care is a core component of family-centred care. Yet, parents experience a range of positive and negative feelings when providing pain-relieving interventions for their infants. Parents of infants who participated in the Parental touch trial (Petal), a multicentre randomised controlled trial investigating the impact of gentle parental touch on neonatal pain, were asked to complete an anonymous survey. This survey aimed to (1) explore parent-reported motivations in deciding to participate in the Petal trial; (2) understand parent-reported experiences related to trial participation; (3) understand parents' willingness to participate in future studies; and (4) evaluate parent-reported feelings while they were delivering a gentle touch intervention either before or after a clinically necessary blood test. One hundred six parents (1 parent per infant) took part in the survey. Primary motivators for participation were altruistic. Parents most frequently reported that they wanted their child to take part in the research because it has a potential benefit to babies in the future and because they wanted to improve scientific understanding. Parents reported that providing gentle touch to their children during painful procedures was associated with positive emotions, such as feeling “useful” (64%) and “reassured” (53%). Furthermore, nearly all parents (98%) were pleased to have participated in the Petal trial and would consider, or maybe consider, participating in further research studies. These results underscore the importance of structuring trials around parental involvement and providing opportunities for parents to be involved in providing comfort to their infants during necessary painful clinical procedures.
Latina Mothers' Infant Feeding Experiences During the 2022 Formula Shortage
Authors: Channell Doig Amara
Published: January 2024

Background:

Mothers report feeling immense pressure to breastfeed their infants, and not doing so can be associated with stigma, shame, and judgment. Many Latina mothers struggle to meet their breastfeeding goals and substitute formula earlier than planned. During 2022, an infant formula recall caused a shortage and made acquiring formula difficult or impossible in many areas of the United States. This study explores Latina mothers' experiences with infant feeding during the time of the formula shortage.

Methods:

In-depth interviews (N = 7) were conducted with Latina mothers who formula-fed during the shortage. Interviews were analyzed using reflexive thematic analysis. Mean maternal age was 29.7 years, and mean infant age was 10.3 months. Three mothers were born in the United States, and 4 were immigrants.

Results:

Thematic analysis generated 3 themes: (1) Fighting to breastfeed; (2) Breastfeeding is not the only way to be a “good” mother; and (3) No formula on the shelves. Participants described their determination to continue breastfeeding despite challenges before realizing that it limited their ability to care for their children. They discussed the emotional toll of the formula shortage and strategies for finding formula.

Conclusions:

The findings emphasize the need for additional structural support for infant feeding in the United States to prevent future formula shortages and for better lactation care and mental health support for mothers who want to breastfeed.
A case report of molybdenum cofactor deficiency type A: the first case diagnosed in Syria
Authors: Kardah Haidara , Al-zoubi Hamza , Odeh Zahra , Joumaa Ranim , Alasmar Diana
Published: January 2024

Introduction:

Molybdenum cofactor deficiency (MoCD) type A, a rare mitochondrial disorder with characteristic clinical presentation and imaging findings, is one of the forms of molybdenum cofactor deficiency. It presents with seizures, psychomotor delay, and breastfeeding difficulties. Seizures are especially prominent in patients with MoCD.

Case presentation:

A 3-month-old girl presented with refractory generalized tonic-clonic seizures since the third day of life. Her parents were third-degree relatives. On physical examination, she demonstrated psychomotor delay, breastfeeding difficulties, seizures, doll-like facial features, and other neurological abnormalities. Her brain MRI scan revealed cortical and white matter atrophy of the cerebral hemispheres. Metabolic workup revealed elevated levels of liver enzymes, lactic acid, and ammonia. These results were inconclusive. She received anticonvulsants and vitamin therapy to manage her seizures. Based on a suspicion of mitochondrial disease, genetic analysis was performed, revealing a homozygous variant of uncertain significance in the MOCS1 gene associated with autosomal recessive molybdenum cofactor deficiency type A.

Conclusion:

MoCD is a rare disease. Early diagnosis should be considered based on the patient’s medical history and MRI findings, after excluding other possible diagnoses. The definitive diagnosis relies on genetic testing results.
Trapdoor Deformity Correction Post Nasal Bilobed Flaps for Basal Cell Carcinoma Reconstruction With Multiple Laser Modalities
Authors: Chuang Chun-Fang , Chang Chang-Cheng , Huang Yung-Hsueh , Liao Che-Chi , Teng Yu-Tung
Published: January 2024

In case of excision of nasal basal cell carcinoma (BCC), bilobed flaps are considered the criterion standard of reconstruction for defect less than 15 mm in size. However, there is still a risk of trapdoor deformity formation, of which its treatment is less discussed. A 44-year-old woman who was diagnosed with nasal BCC and underwent tumor excision with bilobed flap reconstruction presented with trapdoor deformity postoperatively. The computed Vancouver Scar Scale was 7. After early intervention of multiple laser modalities, including 2 sessions of 585-nm pulsed dye laser with a fluence of 9 J/cm2, pulse duration of 6 milliseconds, and spot size of 6 mm, 2940-nm Er-yttrium aluminum garnet (YAG) laser with a pulse energy of 800–900 mJ, repetition rate of 8–9 Hz, and laser spot size of 3–7 mm, and 5 sessions of 1064-nm Nd:YAG fractional picosecond laser with a pulse energy of 2.30–2.70 mJ, repetition rate of 8 Hz, and laser spot size of 6 mm from 5 to 23 weeks postoperatively, the Vancouver Scar Scale score improved to 1, with significant reduction of trapdoor scar erythema and puffiness. Although BCC is often curable, tumor excision causes unsatisfactory appearance satisfaction problem, owing to the apparent location of the lesion. Factors, such as sebaceous tissue thickness, reconstruction over multiple aesthetic subunits of nose, and damage to nasal cartilage framework structure during tumor removal, may increase the risk of trapdoor formation. Early intervention with multiple laser treatment can significantly revise the deformity.
Contemporary management and outcomes of blunt traumatic American Association for the Surgery of Trauma Organ Injury Scale grades III and IV pancreatic injuries in children: A Trauma Quality Improvement Program analysis
Authors: Rauh Jessica L. , Neff Lucas P. , Forssten Maximilian Peter , Ribeiro Marcelo A. F. , Sarani Babak , Mohseni Shahin
Published: January 2024

BACKGROUND

The Trauma Quality Improvement Program (TQIP) database has delineated management strategies and outcomes for adults with American Association for the Surgery of Trauma Organ Injury Scale grades III and IV pancreatic injuries and suggests that nonoperative management (NOM) is a viable option for these injuries. However, management strategies vary for children following significant pancreatic injuries and outcomes for these intermediate/high-grade injuries have not been sufficiently studied. Our aim was to describe the management and outcomes for grades III and IV pancreatic injuries using TQIP. We hypothesize that pediatric patients with intermediate/high-grade injuries can be safely managed with NOM.

METHODS

All pediatric patients (younger than 18 years) registered in TQIP between 2013 and 2021 who suffered a grade III or IV pancreatic injury due to blunt trauma were included in the current study. Patient demographics, clinical characteristics, complications, and in-hospital mortality were compared between the different treatment strategies for pancreatic injury: NOM versus drainage and/or pancreatic resection.

RESULTS

A total of 580 patients meeting the inclusion criteria were identified. A total of 416 pediatric patients suffered a grade III pancreatic injury; 79% (n = 332) were NOM, 7% (n = 27) received a drain, and 14% (n = 57) underwent a pancreatic resection. A further 164 patients suffered a grade IV pancreatic injury; 77% (n = 126) were NOM, 11% (n = 18) received a drain, and 12% (n = 20) underwent a pancreatic resection. No differences in overall injury severity or demographical data were observed between the treatment groups. No difference in in-hospital mortality was detected between the different management strategies. Patients who received a drain had a longer hospital length of stay.

CONCLUSION

The majority of children with American Association for the Surgery of Trauma Organ Injury Scale grades III and IV pancreatic injuries are managed nonoperatively. Nonoperative management is a reasonable strategy for these injuries and results in equivalent in-hospital adverse outcome profiles as pancreatic drainage or resection with a shorter hospital length of stay.

LEVEL OF EVIDENCE

Therapeutic/Care Management; Level IV.
Interaction of Alzheimer Disease and Traumatic Brain Injury on Cortical Thickness
Authors: D’Souza Gina M. , Churchill Nathan W. , Guan Dylan X. , Khoury Marc A. , Graham Simon J. , Kumar Sanjeev , Fischer Corinne E. , Schweizer Tom A.
Published: January 2024

Introduction:

Traumatic brain injury (TBI) is associated with an accelerated course of dementia, although biological relationships are incompletely understood.

Methods:

The study examined 1124 participants, including 343 with Alzheimer disease (AD), 127 with AD with TBI, 266 cognitively normal adults with TBI, and 388 cognitively normal adults without TBI. Cortical thickness was quantified from T1-weighted magnetic resonance imaging data. Multiple linear regression was used to determine the interaction between AD and TBI on cortical thickness.

Results:

Among those with AD, TBI was associated with an earlier age of AD onset but, counterintuitively, less cortical thinning in frontotemporal regions relative to non-AD controls.

Discussion:

AD with TBI represents a distinct group from AD, likely with distinct pathologic contributions beyond gray matter loss. This finding has important implications for the diagnosis and treatment of AD in the presence of TBI and indicates that models of AD, aging, and neural loss should account for TBI history.
Nocardia otitidiscaviarum causing pulmonary nocardiosis: a case report and its review of literature
Authors: SRIVASTAVA SAUMYA , SAMADDAR ARGHADIP , KHAN SALMAN , Tak Vibhor , Bohra Gopal Krishna , Sharma Deepak , GHOSH ARNAB , NAG VIJAYA LAKSHMI
Published: January 2024

Background: Infections caused by Nocardia spp. can occur in immunocompromised as well as immunocompetent individuals. Although nocardiosis is rare, it is being increasingly recognized owing to the rise in occurrence rate over the years. The documentation of pleural involvement in nocardiosis is rare in India.
Case: We report a case of pulmonary nocardiosis in an immunocompromised individual caused by Nocardia otitidiscaviarum.  
Discussion: Pulmonary nocardiosis caused by Nocardia otitidiscaviarum may go unnoticed without clinical suspicion. Correct and timely identification is the key to proper patient management.
Conclusion: Coordination between clinicians and microbiologists is necessary for early diagnosis and appropriate management of nocardiosis.
Epidermal ZBP1 stabilizes mitochondrial Z-DNA to drive UV-induced IFN signaling in autoimmune photosensitivity
Authors: Klein Benjamin , Reynolds Mack B. , Xu Bin , Gharaee-Kermani Mehrnaz , Gao Yiqing , Berthier Celine C. , Henning Svenja , Loftus Shannon N. , McNeely Kelsey E. , Victory Amanda M. , Dobry Craig , Hile Grace A. , Ma Feiyang , Turnier Jessica L. , Gudjonsson Johann E. , O’Riordan Mary X. , Michelle Kahlenberg J.
Published: January 2024

Photosensitivity is observed in numerous autoimmune diseases and drives poor quality of life and disease flares. Elevated epidermal type I interferon (IFN) production primes for photosensitivity and enhanced inflammation, but the substrates that sustain and amplify this cycle remain undefined. Here, we show that IFN-induced Z-DNA binding protein 1 (ZBP1) stabilizes ultraviolet (UV)B-induced cytosolic Z-DNA derived from oxidized mitochondrial DNA. ZBP1 is significantly upregulated in the epidermis of adult and pediatric patients with autoimmune photosensitivity. Strikingly, lupus keratinocytes accumulate extensive cytosolic Z-DNA after UVB, and transfection of keratinocytes with Z-DNA results in stronger IFN production through cGAS-STING activation compared to B-DNA. ZBP1 knockdown abrogates UV-induced IFN responses, whereas overexpression results in a lupus-like phenotype with spontaneous Z-DNA accumulation and IFN production. Our results highlight Z-DNA and ZBP1 as critical mediators for UVB-induced inflammation and uncover how type I IFNs prime for cutaneous inflammation in photosensitivity.

One Sentence Summary:ZBP1 and mitochondrial Z-DNA drive autoimmune photosensitivity via cGAS-STING activation.
Dual-targeted nanoparticulate drug delivery systems for enhancing triple-negative breast cancer treatment
Authors: Zheng Shunzhe , Li Meng , Xu Wenqian , Zhang Jiaxin , Li Guanting , Xiao Hongying , Liu Xinying , Shi Jianbin , Xia Fengli , Tian Chutong , Kamei Ken-ichiro
Published: January 2024

The efficacy of DNA-damaging agents, such as the topoisomerase I inhibitor SN38, is often compromised by the robust DNA repair mechanisms in tumor cells, notably homologous recombination (HR) repair. Addressing this challenge, we introduce a novel nano-strategy utilizing binary tumor-killing mechanisms to enhance the therapeutic impact of DNA damage and mitochondrial dysfunction in cancer treatment. Our approach employs a synergistic drug pair comprising SN38 and the BET inhibitor JQ-1. We synthesized two prodrugs by conjugating linoleic acid (LA) to SN38 and JQ-1 via a cinnamaldehyde thioacetal (CT) bond, facilitating co-delivery. These prodrugs co-assemble into a nanostructure, referred to as SJNP, in an optimal synergistic ratio. SJNP was validated for its efficacy at both the cellular and tissue levels, where it primarily disrupts the transcription factor protein BRD4. This disruption leads to downregulation of BRCA1 and RAD51, impairing the HR process and exacerbating DNA damage. Additionally, SJNP releases cinnamaldehyde (CA) upon CT linkage cleavage, elevating intracellular ROS levels in a self-amplifying manner and inducing ROS-mediated mitochondrial dysfunction. Our results indicate that SJNP effectively targets murine triple-negative breast cancer (TNBC) with minimal adverse toxicity, showcasing its potential as a formidable opponent in the fight against cancer.
Integrative single-cell multi-omics of CD19-CARposand CARnegT cells suggest drivers of immunotherapy response in B-cell neoplasias
Authors: Guerrero-Murillo Mercedes , Rill-Hinarejos Aina , Trincado Juan L. , Bataller Alex , Ortiz-Maldonado Valentín , Benitez-Ribas Daniel , Español Marta , González Europa Azucena , Martinez-Cibrian Nuria , Marchese Doménica , Martín-Martín Lourdes , Garcia-Sancho Alejandro Martin , Heyn Holger , Juan Manel , Urbano-Ispizúa Álvaro , Delgado Julio , Orfao Alberto , Mereu Elisabetta , Bueno Clara , Menendez Pablo
Published: January 2024

How phenotypic, clonal, and functional heterogeneity of CAR-T-cells impact clinical outcomes remain understudied. Here, we integrated clonal kinetics with transcriptomic heterogeneity resolved by single-cell omics to explore cellular dynamics response of both non-transduced (CARneg) and transduced (CARpos)T-cells. CARnegand CARposT-cells were longitudinally interrogated in the manufactured infusion product (IP) andin-vivoat CAR-T cell expansion peak in five B-ALL patients treated with CD19CAR-T-cells (varni-cel). Significant differences were found in the cellular dynamics between CARposand CARnegT-cells in response to therapy. CARposT-cells in the IP exhibited a significant higher CD4:CD8 ratio than CARnegT-cells, and the CD4:CD8 CARposT-cell composition impacted therapy outcome as confirmed in a larger cohort of 24 varni-cel-treated B-ALL patients. Conversely, an inverted trend in the CD4:CD8 CARposT-cell ratio was consistently observed at the expansion peak, with clonally expanding CD8+effector memory and cytotoxic T-cells being the most abundant populations. Expanded cytotoxic CARposγδT cells emerged at the expansion peak, and the extent of theirin-vivoexpansion positively correlated with treatment efficacy, which was validated in a large cohort of B-ALL patients (n=18) treated with varni-cell and B-cell lymphoma patients (n=58) treated with either lisa-cel or axi-cel. Our data provide insights into the complexity and diversity of T-cell responses following CAR-T cell therapy and suggest drivers of immunotherapy response.
Genome-Wide Profiling of Soybean WRINKLED1 Transcription Factor Binding Sites Provides Insight into Seed Storage Lipid Biosynthesis
Authors: Jo Leonardo , Pelletier Julie M. , Goldberg Robert B. , Harada John J.
Published: January 2024

Understanding the regulatory mechanisms controlling storage lipid accumulation will inform strategies to enhance seed oil quality and quantity in crop plants. The WRINKLED1 transcription factor (WRI1 TF) is a central regulator of lipid biosynthesis. We characterized the genome-wide binding profile of soybean (Gm)WRI1 and show that the TF directly regulates genes encoding numerous enzymes and proteins in the fatty acid and triacylglycerol biosynthetic pathways. GmWRI1 binds primarily to regions downstream of target gene transcription start sites. We showed that GmWRI1 bound regions are enriched for the canonical WRI1 DNA binding element, the AW Box (CNTNGNNNNNNNCG), and another DNA motif, the CNC Box (CNCCNCC). Functional assays showed that both DNA elements mediate transcriptional activation by GmWRI1. We also show that GmWRI1 works in concert with other TFs to establish a regulatory state that promotes fatty acid and triacylglycerol biosynthesis. In particular, comparison of genes targeted directly by GmWRI1 and by GmLEC1, a central regulator of the maturation phase of seed development, reveals that the two TFs act in a positive feedback subcircuit to control fatty acid and triacylglycerol biosynthesis. Together, our results provide new insights into the genetic circuitry in which GmWRI1 participates to regulate storage lipid accumulation during seed development.

Significance Statement

We report the genome-wide profiling of DNA sequences bound by and the genes directly- regulated by soybean WRINKLED1, a central regulator of storage lipid accumulation in oilseed plants. The information offers new insights into the mechanisms by which WRINKLED1 regulates genes encoding lipid biosynthetic enzymes and establishes a regulatory environment that promotes oil accumulation, and it may aid in the design of strategy to alter storage lipid accumulation in oilseeds.
Integrated genomic analysis of NF1-associated peripheral nerve sheath tumors: an updated biorepository dataset
Authors: Banerjee Jineta , Lyu Yang , Makri Stavriani C. , Scott Alexandra J. , Zhang Lindy , Calizo Ana , Pollard Kai , Yang Kuangying , Gross John M. , Wang Jiawan , Levin Adam S. , Belzberg Allan J. , Romo Carlos G. , Allaway Robert J. , Blakeley Jaishri O. , Hirbe Angela C. , Pratilas Christine A.
Published: January 2024

Neurofibromatosis type 1 (NF1) is an inherited neurocutaneous condition that predisposes to the development of peripheral nerve sheath tumors (PNST) including cutaneous neurofibromas (CNF), plexiform neurofibromas (PNF), atypical neurofibromatous neoplasms with unknown biological potential (ANNUBP), and malignant peripheral nerve sheath tumors (MPNST). The successful advancement of therapeutic development for NF1-associated PNST necessitates the systematic acquisition and analysis of human tumor specimens and their corresponding model systems. RNA sequencing (RNAseq) and whole exome sequencing (WES) data were generated from 73 and 114 primary human tumor samples, respectively. These pre-processed data, standardized for immediate computational analysis, are accessible through the NF Data Portal, allowing immediate interrogation. This analysis combines new and previously released samples, offering a comprehensive view of the entire cohort sequenced. As a dedicated effort to systematically bank tumor samples from people with NF1, in collaboration with molecular geneticists and computational biologists to advance understanding of NF1 biology, the Johns Hopkins NF1 biospecimen repository offers access to samples and genomic data to promote advancement of NF1-related therapies.
Quantifying the impact of pre-vaccination titre and vaccination history on influenza vaccine immunogenicity
Authors: Hodgson David , Sánchez-Ovando Stephany , Carolan Louise , Liu Yi , Hadiprodjo A. Jessica , Fox Annette , Sullivan Sheena G. , Kucharski Adam J.
Published: January 2024

Epidemiological studies suggest that heterogeneity in influenza vaccine antibody response is associated with host factors, including pre-vaccination immune status, age, gender, and vaccination history. However, the pattern of reported associations varies between studies. To better understand the underlying influences on antibody responses, we combined host factors and vaccine-induced in-host antibody kinetics from a cohort study conducted across multiple seasons with a unified analysis framework. We developed a flexible individual-level Bayesian model to estimate associations and interactions between host factors, including pre-vaccine HAI titre, age, sex, vaccination history and study setting, and vaccine-induced HAI titre antibody boosting and waning. We applied the model to derive population-level and individual effects of post-vaccine antibody kinetics for vaccinating and circulating strains for A(H1N1) and A(H3N2) influenza subtypes. We found that post-vaccine HAI titre dynamics were significantly influenced by pre-vaccination HAI titre and vaccination history and that lower pre-vaccination HAI titre results in longer durations of seroprotection (HAI titre equal to 1:40 or higher). Consequently, for A(H1N1), our inference finds that the expected duration of seroprotection post-vaccination was 171 (95% Posterior Predictive Interval[PPI] 128–220) and 159 (95% PPI 120–200) days longer for those who are infrequently vaccinated (<2 vaccines in last five years) compared to those who are frequently vaccinated (2 or more vaccines in the last five years) at pre-vaccination HAI titre values of 1:10 and 1:20 respectively. In addition, we found significant differences in the empirical distributions that describe the individual-level duration of seroprotection for A(H1N1) circulating strains. In future, studies that rely on serological endpoints should include the impact of pre-vaccine HAI titre and prior vaccination status on seropositivity and seroconversion estimates, as these significantly influence an individual’s post-vaccination antibody kinetics.
The α4 nicotinic acetylcholine receptor is necessary for the initiation of organophosphate-induced neuronal hyperexcitability
Authors: Andrew Peter M. , Feng Wei , Calsbeek Jonas J. , Antrobus Shane P. , Cherednychenko Gennady A. , MacMahon JA Jeremy A. , Bernardino Pedro N. , Liu Xiuzhen , Harvey Danielle J. , Lein Pamela J. , Pessah Isaac N.
Published: January 2024

Acute intoxication with organophosphorus (OP) cholinesterase inhibitors can produce seizures that rapidly progress to life-threateningstatus epilepticus. Significant research effort has been invested investigating the involvement of muscarinic acetylcholine receptors (mAChRs) in OP-induced seizure activity. In contrast, there has been far less effort focused on nicotinic AChRs (nAChRs) in this context. Here, we address this data gap using a combination ofin vitroandin vivomodels. Pharmacological antagonism and genetic deletion of α4, but not α7, nAChR subunits prevented or significantly attenuated OP-induced electrical spike activity in acute hippocampal slices and seizure activity in mice, indicating that α4 nAChR activation is necessary for neuronal hyperexcitability triggered by acute OP exposures. These findings not only suggest that therapeutic strategies for inhibiting the α4 nAChR subunit warrant further investigation as prophylactic and acute treatments for acute OP-induced seizures, but also provide mechanistic insight into the role of the nicotinic cholinergic system in seizure generation.
SMAC mimetics overcome apoptotic resistance in ovarian cancer through MSLN-TNF alpha axis
Authors: Coelho Ricardo , Seashore-Ludlow Brinton , Schütz Sarah , Christopher Lombardo Flavio , Moussaud-Lamodière Elisabeth , Casanova Ruben , Ficek-Pascual Joanna , Brunhilde Labrosse Kathrin , Hensler Michal , Lopez-Nunez Monica , Rimmer Natalie , Fedier Andre , Lima Renata , Montavon Sartorius Céline , Kurzeder Christian , Singer Franziska , Bertolini Anne ,   Tumor Profiler Consortium, Fucikova Jitka , Rätsch Gunnar , Bodenmiller Bernd , Kallioniemi Olli , Östling Päivi , David Leonor , Heinzelmann-Schwarz Viola , Jacob Francis
Published: January 2024

Resistance to chemotherapy and PARPi inhibitors remains a critical challenge in the treatment of epithelial ovarian cancer, mainly due to disabled apoptotic responses in tumor cells. Given mesothelin’s pivotal role in ovarian cancer and its restricted expression in healthy tissues, we conducted a drug-screening discovery analysis across a range of genetically modified cancer cells to unveil mesothelin’s therapeutic impact. We observed enhanced cell death in cancer cells with low mesothelin expression when exposed to a second mitochondria-derived activator of caspases (SMAC) mimetics, and demonstrated a compelling synergy when combined with chemotherapy inex vivopatient-derived cultures and zebrafish tumor xenografts. Mechanistically, the addition of the SMAC mimetics drug birinapant to either carboplatin or paclitaxel triggered the activation of the Caspase 8-dependent apoptotic program facilitated by TNFLJ signaling. Multimodal analysis of neoadjuvant-treated patient samples further revealed an association between tumor-associated macrophages and the activation of TNFLJ-related pathways. Our proposed bimodal treatment shows promise in enhancing the clinical management of patients by harnessing the potential of SMAC mimetics alongside conventional chemotherapy.
Dynamic Profiling and Prediction of Antibody Response to Booster Inactivated Vaccines by Microsample-driven Biosensor and Machine Learning
Authors: Bian Sumin , Shang Min , Tao Ying , Wang Pengbo , Xu Yankun , Wang Yao , Shen Zhida , Sawan Mahamad
Published: January 2024

Knowledge on the antibody response to inactivated vaccines in third dose is crucial because it is one of the primary global vaccination programs. This study integrated microsampling with optical biosensors to profile neutralizing antibodies (NAbs) in fifteen vaccinated healthy donors, followed by application of machine learning to predict antibody response at given timepoints. Over a nine-month duration, microsampling and venipuncture were conducted at seven individual timepoints. A refined iteration of fiber optic-biolayer interferometry (FO-BLI) biosensor was designed, enabling rapid multiplexed biosensing of NAbs towards both wild-type and Omicron variants in minutes. Findings revealed a strong correlation (Pearson r of 0.919, specificity of 100%) between wild-type NAbs levels in microsamples and sera. Following the third dose, Sera NAbs levels for wide-type increased by 2.9-fold after seven days and 3.3-fold within a month, subsequently waning and becoming undetectable in three months. Considerable but incomplete escape of the latest omicron subvariants from booster vaccine elicited NAbs was confirmed, although a higher number of binding antibodies (BAbs) was identified by another rapid FO-BLI biosensor in minutes. Significantly, FO-BLI highly correlated with a pseudovirus neutralization assay in identifying neutralizing capacities (Pearson r of 0.983). Additionally, machine learning demonstrated exceptional accuracy in predicting antibody levels with an error of <5% for both NAbs and BAbs across multiple timepoints. Microsample-driven biosensing enables individuals to access their results within hours after self-collection, while precise models could guide personalized vaccination strategies. The technology’s innate adaptability positions its potential for effective translation in diseases prevention and vaccines development.