bluuebunny/crossref_metadata_2025 huggingface dataset:
Survival Impact of Inflammation-based Prognostic Scores in Metastatic or Unresectable Esophageal Cancer Treated With Pembrolizumab Plus Chemotherapy
Authors: Sugase Takahito , Kanemura Takashi , Takeoka Tomohira , Matsuura Norihiro , Masuike Yasunori , Shinno Naoki , Hara Hisashi , Kitakaze Masatoshi , Kubo Masahiko , Mukai Yosuke , Sueda Toshinori , Hasegawa Shinichiro , Akita Hirofumi , Nishimura Junichi , Wada Hiroshi , Yasui Masayoshi , Omori Takeshi , Miyata Hiroshi
Published: June 2024

Pembrolizumab plus chemotherapy has been indicated as the first-line treatment for metastatic or unresectable locally advanced esophageal cancer. However, pretreatment biomarkers for predicting clinical outcomes remain unclear. We investigated the predictive value of inflammation-based prognostic scores in patients treated with pembrolizumab and chemotherapy. The Prognostic Nutritional Index (PNI), C-reactive protein/albumin ratio (CAR), neutrophil-to-lymphocyte ratio (NLR), and platelet-to-lymphocyte ratio (PLR) were calculated before initial treatment in 65 eligible patients with metastatic or unresectable locally advanced esophageal cancer receiving pembrolizumab plus CF therapy, and the relationship between these biomarkers and clinical outcomes was analyzed. The objective response rate (ORR) and progression disease (PD) were observed in 51% and 21% of all patients. Patients with PNI<39 have significantly worse treatment responses than those with PNI≥39 (ORR; 28% vs. 60%, PD; 44% vs. 13%, P=0.020). Progression-free survival (PFS) is significantly associated with the PNI and CAR (P<0.001 and P=0.004, respectively). Overall survival (OS) is associated with PNI, CAR, and PLR (P<0.001, P=0.008, and P=0.018, respectively). The PNI cutoff value of 39 is identified as an independent factor for PFS (odds ratio=0.27, 95% CI: 0.18–0.81, P=0.012) and OS (odds ratio=0.22, 95% CI: 0.08–0.59, P=0.003). Patients with PNI<39 have significantly worse 6-month PFS and 1-year OS than those with PNI≥39 (27.8% vs. 66.7%, 27.2% vs. 81.1%, respectively). In conclusion, inflammation-based prognostic scores are associated with survival in patients treated with pembrolizumab plus CF therapy. Pretreatment PNI is a promising candidate for predicting treatment response and survival.
Percutaneous renal denervation in the management of hypertension: Chinese expert scientific statement
Authors: Li Yueping , Lu Chengzhi , Jiang Xiongjing , Yu Jing , Ma Wei , Hu Jialu , Zhang Yi , Zhou Yujie , Sun Ningling , Huo Yong , Ge Junbo , Chen Xiaoping , Chen Yundai , Jiang Hong , Kong Xiangqing , Li Nanfang , Ma Likun , Shen Li , Su Xi , Wang Jie , Wang Jingfeng , Yin Yuehui , Zhang Yuqing
Published: June 2024

Hypertension constitutes a critical risk factor for cardio-cerebrovascular disease. Despite the effectiveness of lifestyle adjustments and medications in blood pressure (BP) management, the hypertension control rates remain inadequate. Percutaneous renal denervation (RDN) has emerged as a forward-looking and evidence-supported interventional modality for the improvement of BP regulation and enhancement of hypertension control. Comprehensive evidence from randomized, sham-controlled clinical trials supports the sustained the efficacy and satisfactory safety profile of RDN in lowing BP. This scientific statement, endorsed by Chinese authorities, aims to provide a comprehensive overview of global and national clinical evidence on RDN. It seeks to highlight the therapeutic advancements of RDN, articulate expert consensus and recommendations for its utilization in hypertension management. Through the promotion of structured, safe, and standardized incorporation of RDN into clinical practice, this statement strives to optimize hypertension treatment within the Chinese medical community.
Cardiac intima sarcoma: a rapid review of case reports
Authors: Awoyemi Toluwalase , Gwira-Tamattey Edwin , Oluwole Abib , Ezekwueme Francis , Odeyinka Oladipo , Guzman Rocio Barriga , Obarombi Joshua , Chima-Kalu Roseline , Anuforo Anderson
Published: June 2024

Background and purpose:

Cardiac intimal sarcoma (CIS) is a rare and often misdiagnosed clinical entity with notably high morbidity and mortality rates. Urgent efforts are required to comprehensively the disease and establish evidence-based management guidelines. Given the relative scarcity of data and the imperative for consensus on management strategies, this review assumes critical importance. Through a rapid review approach, we aims to synthesize and consolidate information gleaned from published case reports, thereby offering an up-to-date resource for CIS’s natural history.

Methods:

Utilizing inductive content analysis, we systematically searched for and synthesized case reports and series. Keywords related to CIS guided our search on Medline via Ovid, Scopus, and Web of Science from inception until March 17, 2024.

Results:

Our review identified 79 CIS, characterized by a mean age of 52 years, predominantly male (58%), with left-sided lesions. Approximately one-third of the patients presented with cardiovascular symptoms, and transthoracic echocardiography emerged as the preferred initial diagnostic modality in most cases. Fluorescence in situ hybridization (FISH) analysis on pre-operative tissue biopsies found murine double minute 2 (MDM2) amplification in 95% of cases tested. While surgery remained the cornerstone of treatment, recurrence occurred in 14% of cases postoperatively, with 28% succumbing to the disease despite therapeutic interventions.

Conclusions:

This synthesis of published case reports and series provides updated insights into the clinical profile CIS. Our findings highlight the need for increased clinical awareness, precise data collection, and further research to enhance diagnostic accuracy, treatment approaches, and patient outcomes in CIS.
IL-17 signaling in primary sclerosing cholangitis patient-derived organoids
Authors: Garcia Moreno Ana S. , Guicciardi Maria E. , Wixom Alexander Q. , Jessen Erik , Yang Jingchun , Ilyas Sumera I. , Bianchi Jackie K. , Pinto e Vairo Filippo , Lazaridis Konstantinos N. , Gores Gregory J.
Published: June 2024

Background:

The pathogenesis of primary sclerosing cholangitis (PSC) is unclear, although studies implicate IL-17A as an inflammatory mediator in this disease. However, a direct assessment of IL-17 signaling in PSC cholangiocytes is lacking. In this study, we aimed to investigate and characterize the response of PSC extrahepatic cholangiocyte organoids (ECO) to IL-17A stimulation.

Methods:

Cholangiocytes obtained from patients with PSC and without PSC by endoscopic retrograde cholangiography were cultured as ECO. The ECO were treated with vehicle or IL-17A and assessed by transcriptomics, secretome analysis, and genome sequencing.

Results:

Unsupervised clustering of all integrated single-cell RNA sequencing data identified 8 cholangiocyte clusters that did not differ between PSC and non-PSC ECO. However, PSC ECO cells demonstrated a robust response to IL-17 treatment, as noted by an increased number of differentially expressed genes by transcriptomics and more abundant chemokine and cytokine expression and secretion. After rigorous filtering, genome sequencing identified candidate somatic variants shared among PSC ECO from unrelated individuals. However, no candidate rare variants in genes regulating the IL-17 pathway were identified, but rare variants regulating the MAPK signaling pathway were present in all PSC ECO.

Conclusions:

PSC and non-PSC patient-derived ECO respond differently to IL-17 stimulation, implicating this pathway in the pathogenesis of PSC.
Prostate health index density aids the diagnosis of prostate cancer detected using magnetic resonance imaging targeted prostate biopsy in Taiwanese multicenter study
Authors: Chang Ching-Hsin , Yu Ping-Hsuan , Hsieh Po-Fan , Hong Jian-Hua , Chiang Chih-Hung , Cheng Hao-Min , Wu Hsi-Chin , Huang Chao-Yuan , Lin Tzu-Ping
Published: June 2024

Background:

Multiparametric magnetic resonance imaging (mpMRI) followed by MRI-targeted prostate biopsy is the current standard for diagnosing prostate cancer (PCa). However, studies evaluating the value of biomarkers, including prostate health index (PHI) and its derivatives using this method are limited. We aimed to investigate the efficacy of PHI density (PHID) in guiding MRI-targeted prostate biopsies to identify clinically significant PCas (csPCa).

Methods:

The multicenter prospectively registered prostate biopsy database from three medical centers in Taiwan included patients with PHI and MRI-targeted and/or systematic prostate biopsies. We assessed the required values of prostate-specific antigen (PSA), prostate volume, PHI, PHID, and Prostate Imaging Reporting & Data System (PI-RADS) score using multivariable analyses, receiver operating characteristic curve analysis, and decision curve analyses (DCA). csPCa was defined as the International Society of Urological Pathology Gleason group ≥2 PCa, with an emphasis on reducing unwarranted biopsies.

Results:

The study cohort comprised 420 individuals. Diagnoses of PCa and csPCa were confirmed in 62.4% and 47.9% of the participants, respectively. The csPCa diagnosis rates were increased with increasing PI-RADS scores (20.5%, 44.2%, and 73.1% for scores 3, 4, and 5, respectively). Independent predictors for csPCa detection included PHI, prostate volume, and PI-RADS scores of 4 and 5 in multivariable analyses. The area under the curve (AUC) for csPCa of PHID (0.815) or PHI (0.788) was superior to that of PSA density (0.746) and PSA (0.635) in the entire cohort, and the superiority of PHID (0.758) was observed in PI-RADS 3 lesions. DCA revealed that PHID achieved the best net clinical benefit in PI-RADS 3-5 and 4/5 cases. Among PI-RADS 3 lesions, cutoff values of PHID 0.70 and 0.43 could eliminate 51.8% and 30.4% of omitted biopsies, respectively.

Conclusion:

PHI-derived biomarkers, including PHID, performed better than other PSA-derived biomarkers in diagnosing PCa in MRI-detected lesions.
Multiobjective Optimization of Rotodynamic Blood Pumps: The Use Case of a Cavopulmonary Assist Device
Authors: Escher Andreas , Miric Spasoje , Thamsen Bente , Giuffrida Rosario , Schmidt Pascal , Weinhold Benjamin , Hübler Michael , Zimpfer Daniel , Kolar Johann Walter , Granegger Marcus
Published: June 2024

Comprehensive optimization of rotodynamic blood pumps (RBPs) requires the consideration of three partially conflicting objectives: size, hemocompatibility, and motor efficiency. Optimizing these individual objectives independently, the potential of multiobjective optimizations often remains untapped. This study aimed at the multiobjective optimization of an RBP for cavopulmonary support accounting for all three objectives simultaneously. Hydraulic and electromagnetic design spaces were characterized using computational fluid dynamics and computational electromagnetics, respectively. Design variables included secondary flow gap widths, impeller diameters, and stator heights. The size objective encompassed the RBP widths and heights, the hemocompatibility objective was a weighted composite measure of well-established metrics, and the motor objective was determined by motor losses. Multiobjective optimization was performed through Pareto analysis. 81 designs were considered, and 21 Pareto-optimal designs were identified. The Pareto analysis indicated that hemocompatibility performance could be improved by 72.4% with a concomitant 1.5% reduction in the baseline pump volume. This, however, entailed an increase in motor losses by 0.2 W, while still meeting design requirements, with maximum local temperature rises remaining below 0.4 K. The multiobjective optimization led to a Pareto front, demonstrating the feasibility to improve hemocompatibility at reduced pump volume, however, at the cost of a diminished yet still acceptable motor performance.
Mechanical Preload Reduction: Harnessing a Cornerstone of Heart Failure Management to Improve Clinical Outcomes
Authors: Kapur Navin K. , Kanwar Manreet K. , Yousefzai Rayan , Bhimiraj Arvind , Farber Harrison , Esposito Michele L. , Kiernan Michael S. , John Kevin J. , Burkhoff Daniel
Published: June 2024

Decongestion is a cornerstone therapeutic goal for those presenting with decompensated heart failure. Current approaches to clinical decongestion include reducing cardiac preload, which is typically limited to diuretics and hemofiltration. Several new technologies designed to mechanically reduce cardiac preload are in development. In this review, we discuss the pathophysiology of decompensated heart failure; the central role of targeting cardiac preload; emerging mechanical preload reduction technologies; and potential application of these devices.
Subgroups of mild cognitive impairment based on cognitive function among Chinese older adults
Authors: Zhou Yi , Yan Yuan-jiao , Lin Rong , Luo Yu-ting , Cai Zhen-zhen , Zhu Kai-yan , Huang Chen-shan , Wang Yun-xian , Xu Yi-fei , Chao Yueqi , Zhang Chu-fan , Chen Ming-feng , Li Hong
Published: June 2024

Background:

Due to the heterogeneity of mild cognitive impairment (MCI), the key points for nonpharmaceutical therapies cannot be determined. Examining impairment characteristics among different MCI subgroups would therefore be beneficial to the development of nonpharmaceutical therapies.

Objective:

To characterize the subgroups of older Chinese with MCI and examine factors associated with the membership of distinct subgroups.

Methods:

This cross-sectional study was conducted between October 2018 and June 2022 in Fujian, East China, with 1017 older adults with MCI deemed eligible. Exclusion criteria included any diagnosis of other neurological or psychiatric conditions that could affect cognition. Participants underwent a neuropsychological test that assessed memory, language, attention, and executive function(s) and completed a questionnaire collecting their socioeconomic and clinical variables. Neuropsychological test scores were transformed into z-scores, which were then examined using latent class analysis. Associations between socioeconomic and clinical variables, and MCI subgroups were assessed using multinomial logistic regression analysis.

Results:

Three MCI subgroups were identified: G1 “Minimally impairment” (56.64%), G2 “Moderate impairment” (36.28%), and G3 “Worst impairment” (7.08%). Age, place of residence, marriage status, living status, and participation in intellectual activities differed significantly across the 3 MCI subgroups (P<0.05). Compared with the minimally impairment group, participants with the worst impairment were less likely to participate in intellectual activity and more likely to live in a nursing home.

Conclusion:

Cognitive function is a suitable foundation for establishing classifications among individuals with MCI. Nonpharmalogical therapies may target older adults at higher risk of moderate or worst impairment.
A Novel Treponema pallidum Subspecies pallidum Strain Associated With a Painful Oral Lesion Is a Member of a Potentially Emerging Nichols-Related Subgroup
Authors: Velasquez Maria Rosa , De Lay Bridget D. , Edmondson Diane G. , Wormser Gary P. , Norris Steven J. , Cafferky Kaitlin , Munzer Eric , Rizk Ciril-Christian , Keller Marina
Published: June 2024

Background

Early syphilitic lesions are typically painless; however, several recent case studies have included patients with tender lesions and no evidence of concurrent infections. Here we present the manifestations and serological and molecular findings of a patient from New York State with a painful tongue lesion.

Methods

The diagnosis of syphilis was based on a combination of physical examination, serologic, pathologic, and immunohistochemical findings. DNA obtained from a formalin-fixed, paraffin-embedded biopsy was used to characterize the infecting pathogen using polymerase chain reaction, multilocus sequence typing, and whole-genome sequencing methods.

Results

Polymerase chain reaction and multilocus sequence typing of the biopsy specimen confirmed infection with T. pallidum subspecies pallidum (T. pallidum) of the Nichols cluster. Whole-genome sequencing analysis of this strain (herein called NYMC01) showed that it contained 17 unique single nucleotide variations and 4 more complex genetic differences; this novel genotype matched only 2 specimens, both from a patient in Seattle, Washington. The presence of this rare genotype in 2 geographically distinct locations suggests the potential emergence and spread of a new subgroup of the Nichols cluster.

Conclusions

To our knowledge, this is the first genomic sequence obtained from a T. pallidum strain linked to a painful lesion, and the third description of whole-genome sequencing of T. pallidum from formalin-fixed, paraffin-embedded tissue. Analysis of additional specimens may reveal that the NYMC01-related genotype represents an emerging T. pallidum subgroup and may also aid in determining whether the painful clinical presentation of primary syphilis is related to specific T. pallidum genotypes.
Current Trends for Children With Spina Bifida: A Survey of Pediatric Physical Therapists
Authors: Flores Megan B. , Ardolino Elizabeth M. , J. Manella Kathleen
Published: June 2024

Purpose:

To describe contemporary physical therapy practice and management of children with spina bifida (SB) in the context of the International Classification of Functioning, Disability, and Health (ICF) framework.

Methods:

A descriptive, cross-sectional electronic survey was sent to US pediatric physical therapy clinics and posted in the American Physical Therapy Association Pediatrics newsletter. Data were analyzed using content analysis. Codes were compared, refined, and condensed into categories.

Results:

A total of 163 participants were included. Most assessments evaluated the ICF Activity component. Most frequently reported ICF components: impairments = decreased strength (17.9%), activity limitations = limited walking (22.5%), and participation restrictions = restricted socializing/playing with peers or siblings (22.6%). The most prevalent intervention was strength training.

Conclusions:

Physical therapists (PTs) in the United States are performing assessments and interventions supported by available evidence; however, knowledge translation and more research are needed to support best practices in PT management of children with SB.
A Scoping Review of Health Equity Interventions in Governmental Public Health
Authors: Martin Skky , Dill Janette , Demeritte Denisha , Geressu Hannah , Dahal Roshani , Kirkland Chelsey , Hunt Shanda , Parikh Romil
Published: June 2024

Context:

Despite major efforts in research, practice, and policy, racial and ethnic disparities in health and health care persist in the United States. Interventions in collaboration with governmental public health may provide ways to address these persistent racial and ethnic health and health care disparities and improve health outcomes.

Objective:

To conduct a comprehensive review of health equity interventions performed in collaboration with public health agencies.

Design:

This scoping review includes intervention studies from Ovid MEDLINE, PsycINFO, and Academic Search Premier, published between 2017 and 2023. The search strategy used terminology focused on 4 concepts: race/ethnicity, equity, health departments, and epidemiologic studies.

Eligibility Criteria:

The following inclusion criteria were determined a priori: (1) intervention tailored to reduce racial/ethnic health disparities, (2) public health department involvement, (3) health outcome measures, (4) use of epidemiologic study methods, (5) written in English, (6) implemented in the United States, (7) original data (not a commentary), and (8) published between January 2017 and January 2023.

Main Outcome Measure(s):

This review focused primarily on 4 dimensions of racial health equity interventions including intervention components, intervention settings, intervention delivery agents, and intervention outcomes.

Results:

This review indicated that health equity interventions involving public health agencies focused on the following categories: (1) access to care, (2) health behavior, (3) infectious disease testing, (4) preventing transmission, and (5) cancer screening. Critical strategies included in interventions for reaching racial/ethnic minoritized people included using community settings, mobile clinics, social media/social networks, phone-based interventions, community-based workers, health education, active public health department involvement, and structural/policy change.

Conclusions:

This scoping review aims to provide an evidence map to inform public health agencies, researchers, and funding agencies on gaps in knowledge and priority areas for future research and to identify existing health equity interventions that could be considered for implementation by public health leaders.
Quantitative sensory testing in notalgia paresthetica reveals small fiber-type–specific differences in non-pruritic sensitivity: a pilot study
Authors: Harper Daniel , Chu Lena , Mustin Danielle , Cole Emily
Published: June 2024

Introduction:

Notalgia paresthetica (NP) is a chronic condition characterized by pruritus and other unpleasant dysesthetic sensations unilaterally on the subscapular back. Its specific underlying mechanisms are largely unknown, though hypothesized to be neuropathic. Determination of possible somatosensory contributors to the condition could pave the way for novel treatments.

Objectives:

Given the potential involvement of non-pruritic mechanisms in NP, our objective was to broadly characterize the somatosensory function in NP-affected and unaffected skin using methods that have been standardized in pain-free controls and painful neuropathic disorders. We hypothesized that if NP is caused by neuropathic mechanisms not targeted directly to pruritoceptors in the skin, somatosensory abnormalities would not be itchspecific. Second, given the lack of symptoms on the contralateral side of the back, we hypothesized that this region would be normally sensitive.

Methods:

In this study, quantitative sensory testing (QST) was used to comprehensively assess the somatosensory function in 15 adult patients with NP. Standardized QST metrics were performed in the NP-affected region and compared with the contralateral asymptomatic skin and itch-free individuals using an age, gender, and site-matched reference data set.

Results:

There were no significant differences in sensitivity between symptomatic and asymptomatic skin, except for increased mechanical-evoked itch on the itchy side. However, reference data set comparisons revealed bilateral hyposensitivity to innocuous cold and noxious pinprick and higher temporal summation of pain in patients with NP. In addition, compared with reference data, patients with NP demonstrated decreased sensitivity to cold and pinprick, presence of paradoxical heat sensations, and increased wind-up of pain.

Conclusion:

These results suggest a role for Aδ fiber pathways and central sensitization in NP-associated itch. More research is needed to determine whether sensory differences extend beyond the NP-affected dermatomal level and what might cause neuropathy specifically targeting Aδ fibers.
Comparison of Speech Outcomes Between Speech Therapy Only and Double-Opposing Z-Plasty Combined With Speech Therapy in Patients With Submucous Cleft Palate
Authors: Jeon Sungmi , Park Jin Sol , Han Mira , Oh Albert K. , Kim Byung Jun , Chung Jee Hyeok , Baek Seung-Hak , Kim Sukwha
Published: June 2024

The purpose of this study was to compare speech outcomes in patients with submucous cleft palate (SMCP) between speech therapy alone and double-opposing Z-plasty (DOZ) combined with speech therapy. The subjects were 67 patients with SMCP (overt type, 45 males, 22 females), who were divided into the observation group (n=18), the speech therapy group (n=24; duration, 17.8 mo), and the DOZ and speech therapy (DOZ-speech therapy) group (n=25; median age at DOZ, 5.3 years, duration, 18.6 mo). The median age at initial and final speech assessments were 3 and 5 years. After age, sex, syndromic status, duration of speech therapy, surgery timing, and speech outcomes were investigated, statistical analysis was performed. After tailored interventions, both isolated and non-isolated SMCP patients experienced significant improvements in speech outcomes, including nasal emission, hypernasality, compensatory articulation, and unintelligible speech. Since comparable improvements were observed, there were no significant differences in the final assessments regardless of initial speech issues between the speech therapy group and the DOZ-speech therapy group (all P>0.05). In the DOZ-speech therapy group, the rate of achieving “socially acceptable” speech was 92.3% in isolated cases and 90% in non-isolated cases. Multivariate analysis revealed that DOZ showed a tendency to reduce hypernasality, compensatory articulation, and “unintelligible” speech; syndromic or developmental conditions influenced outcomes in nasal emission and hypernasality; and initial hypernasality and compensatory articulation were correlated with outcomes. Therefore, DOZ surgery could be recommended to resolve hypernasality and compensatory articulation in SMCP patients before speech issues worsen.
Tyrosinase deficiency impairs social novelty preference in mice
Authors: Aizawa Shu , Yamamuro Yutaka
Published: June 2024

Objective

Tyrosinase is a rate-limiting enzyme for the biosynthesis of melanin pigment in peripheral tissues, such as skin and the retina. We recently reported the expression and enzymatic activity of tyrosinase as well as its protective effects against oxidative stress-induced protein damage in the mouse brain. The functional role of tyrosinase in the central nervous system, however, remains largely unknown. In the present study, we investigated the involvement of tyrosinase in social behavior in mice.

Methods

Pigmented C57BL/10JMsHir (B10) and tyrosinase-deficient albino B10.C-Tyrc
/Hir (B10-c) mice were subjected to the three-chamber sociability test to assess sociability and social novelty preference. In addition, we measured the mRNA expression of genes involved in catecholamine metabolism in the hippocampus by real-time quantitative PCR analysis.

Results

The results obtained showed that tyrosinase deficiency impaired social novelty preference, but not sociability in mice. We also found that the hippocampal expression of genes involved in catecholamine metabolism, such as monoamine oxidase A and catechol-O-methyltransferase, were significantly decreased in tyrosinase-deficient B10-c mice.

Conclusion

These results suggest that tyrosinase activity is functionally involved in the phenotypic expression of social behavior, particularly social novelty preference, in mice. The present study will advance our understanding of the functional role of tyrosinase in the central nervous system.
Optical projection tomography implemented for accessibility and low cost (
OPTImAL
)
Authors: Darling C. , Kumar S. , Alexandrov Y. , de Faye J. , Almagro Santiago J. , Rýdlová A. , Bugeon L. , Dallman M. J. , Behrens A. J. , French P. M. W , McGinty J.
Published: June 2024

Optical projection tomography (OPT) is a three-dimensional mesoscopic imaging modality that can use absorption or fluorescence contrast, and is widely applied to fixed and live samples in the mm–cm scale. For fluorescence OPT, we present OPT implemented for accessibility and low cost, an open-source research-grade implementation of modular OPT hardware and software that has been designed to be widely accessible by using low-cost components, including light-emitting diode (LED) excitation and cooled complementary metal-oxide-semiconductor (CMOS) cameras. Both the hardware and software are modular and flexible in their implementation, enabling rapid switching between sample size scales and supporting compressive sensing to reconstruct images from undersampled sparse OPT data, e.g. to facilitate rapid imaging with low photobleaching/phototoxicity. We also explore a simple implementation of focal scanning OPT to achieve higher resolution, which entails the use of a fan-beam geometry reconstruction method to account for variation in magnification.

This article is part of the Theo Murphy meeting issue 'Open, reproducible hardware for microscopy'.
Clearing-enabled light sheet microscopy as a novel method for three-dimensional mapping of the sensory innervation of the mouse knee
Authors: Ko Frank C. , Fullam Spencer , Lee Hoomin , Ishihara Shingo , Adamczyk Natalie S. , Obeidat Alia M. , Soorya Sarah , Miller Richard J. , Malfait Anne-Marie , Miller Rachel E.
Published: June 2024

A major barrier that hampers our understanding of the precise anatomic distribution of pain sensing nerves in and around the joint is the limited view obtained from traditional two dimensional (D) histological approaches. Therefore, our objective was to develop a workflow that allows examination of the innervation of the intact mouse knee joint in 3D by employing clearing-enabled light sheet microscopy. We first surveyed existing clearing protocols (SUMIC, PEGASOS, and DISCO) to determine their ability to clear the whole mouse knee joint, and discovered that a DISCO protocol provided the most optimal transparency for light sheet microscopy imaging. We then modified the DISCO protocol to enhance binding and penetration of antibodies used for labeling nerves. Using the pan-neuronal PGP9.5 antibody, our protocol allowed 3D visualization of innervation in and around the mouse knee joint. We then implemented the workflow in mice intra-articularly injected with nerve growth factor (NGF) to determine whether changes in the nerve density can be observed. Both 3D and 2D analytical approaches of the light sheet microscopy images demonstrated quantifiable changes in midjoint nerve density following 4 weeks of NGF injection in the medial but not in the lateral joint compartment. We provide, for the first time, a comprehensive workflow that allows detailed and quantifiable examination of mouse knee joint innervation in 3D.
Computer vision guided open-source active commutator for neural imaging in freely behaving animals
Authors: Oladepo Ibrahim , Saxena Kapil , Surinach Daniel , Lehman Malachi , Kodandaramaiah Suhasa B.
Published: June 2024

Recently developed miniaturized neural recording devices that can monitor and perturb neural activity in freely behaving animals have significantly expanded our knowledge neural underpinning of complex behaviors. Most miniaturized neural interfaces require a wired connection for external power and data acquisition systems. The wires are required to be commutated through a slip ring to accommodate for twisting of the wire or tether and alleviate torsional stresses. The increased trend towards long term continuous neural recordings have spurred efforts to realize active commutators that can sense the torsional stress and actively rotation the slip ring to alleviate torsional stresses. Current solutions however require addition of sensing modules. Here we report on an active translating commutator that uses computer vision (CV) algorithms on behavioral imaging videos captured during the experiment to track the animal’s position and heading direction in real-time and uses this information to control the translation and rotation of a slipring commutator to accommodate for accumulated mouse heading orientation changes and position. The CV guided active commutator has been extensively tested in three separate behavioral contexts and we show reliable cortex-wide imaging in a mouse in an open-field with a miniaturized widefield cortical imaging device. Active commutation resulted in no changes to measured neurophysiological signals. The active commutator is fully open source, can be assembled using readily available off-the-shelf components, and is compatible with a wide variety of miniaturized neurophotonic and neurophysiology devices.
Conditional CAR T cells with specificity to oncofetal glycosaminoglycans in solid tumors
Authors: Khazamipour Nastaran , Oo Htoo Zarni , Al-Nakouzi Nader , Marzban Mona , Khazamipour Nasrin , Roberts Morgan E. , Farivar Negin , Moskalev Igor , Lo Joey , Ghaidi Fariba , Nelepcu Irina , Moeen Alireza , Truong Sarah , Dagil Robert , Choudhary Swati , Gustavsson Tobias , Zhai Beibei , Heitzender Sabine , Salanti Ali , Sorensen Poul H , Daugaard Mads
Published: June 2024

Glycosaminoglycans are often deprioritized as targets for synthetic immunotherapy due to the complexity of glyco-epitopes and limited options for obtaining specific subtype-binding. Solid tumors express proteoglycans that are modified with oncofetal chondroitin sulfate (CS), a modification normally restricted to the placenta. Here, we report the design and functionality of conditional chimeric antigen receptor (CAR) T cells with selectivity to oncofetal CS. Following expression in T cells, the CAR could be ‘armed’ with recombinant VAR2CSA lectins (rVAR2) to target tumor cells expressing oncofetal CS. While un-armed CAR T cells remained inactive in the presence of target cells, VAR2-armed CAR T cells displayed robust activation and the ability to eliminate diverse tumor cell typesin vitro. Cytotoxicity of the CAR T cells was proportional to the concentration of rVAR2 available to the CAR, offering a potential molecular handle to finetune CAR T cell activity.In vivo, armed CAR T cells rapidly targeted bladder tumors and increased survival of tumor-bearing mice. Thus, our work indicates that cancer-restricted glycosaminoglycans can be exploited as potential targets for CAR T cell therapy.
Neuronal segmentation in cephalopod arms
Authors: Olson Cassady S. , Schulz Natalie Grace , Ragsdale Clifton W.
Published: June 2024

The prehensile arms of the cephalopod are among these animals most remarkable features, but the neural circuitry governing arm and sucker movements remains largely unknown. We studied the neuronal organization of the adult axial nerve cord (ANC) ofOctopus bimaculoideswith molecular and cellular methods. The ANCs, which lie in the center of every arm, are the largest neuronal structures in the octopus, containing four times as many neurons as found in the central brain. In transverse cross section, the cell body layer (CBL) of the ANC wraps around its neuropil (NP) with little apparent segregation of sensory and motor neurons or nerve exits. Strikingly, when studied in longitudinal sections, the ANC is segmented. ANC neuronal cell bodies form columns separated by septa, with 15 segments overlying each pair of suckers. The segments underlie a modular organization to the ANC neuropil: neuronal cell bodies within each segment send the bulk of their processes directly into the adjoining neuropil, with some reaching the contralateral side. In addition, some nerve processes branch upon entering the NP, forming short-range projections to neighboring segments and mid-range projections to the ANC segments of adjoining suckers. The septa between the segments are employed as ANC nerve exits and as channels for ANC vasculature. Cellular analysis establishes that adjoining septa issue nerves with distinct fiber trajectories, which across two segments (or three septa) fully innervate the arm musculature. Sucker nerves also use the septa, setting up a nerve fiber “suckerotopy” in the sucker-side of the ANC. Comparative anatomy suggests a strong link between segmentation and flexible sucker-laden arms. In the squidDoryteuthis pealeii, the arms and the sucker- rich club of the tentacles have segments, but the sucker-poor stalk of the tentacles does not. The neural modules described here provide a new template for understanding the motor control of octopus soft tissues. In addition, this finding represents the first demonstration of nervous system segmentation in a mollusc.
Romiumeter: An Open-Source Inertial Measurement Unit-Based Goniometer for Range of Motion Measurements
Authors: Diwakarreddy Basinepalli Kothireddy Gari , Abishek S , Andrews Amal , Vasanthan Lenny , Balasubramanian Sivakumar
Published: June 2024

Range of motion (ROM) serves as a crucial metric for assessing movement impairments. Traditionally, clinicians use goniometers to measure the ROM, but this method relies on the clinician’s skill, in particular for difficult joints such as the shoulder and neck joints. Recent studies have explored the use of wearable inertial measurement units (IMUs) as an alternative. IMUs exhibit excellent agreement with goniometers, but the lack of affordable, accessible, and clinically validated tools remains an issue. This paper introduces the Romiumeter, a single IMU-based device designed to measure the ROM of the neck and shoulder movements. To validate its accuracy, the Romiumeter was tested on 34 asymptomatic individuals for shoulder and neck movements, using an optical motion capture system as the ground truth. The device demonstrated good accuracy, with a maximum absolute error of less than 5°with moderate to good reliable measurements(inter-rater reliability: 0.69 - 0.87 and intra-rater reliability: 0.76 - 0.87). Additionally, the Romiumeter underwent validation for different algorithms, including the complementary and Madgwick filters. Interestingly, no significant differences were found between the algorithms. Overall, the Romiumeter provides reliable measurements for assessing shoulder and neck ROM in asymptomatic individuals.
Oryza genome evolution through a tetraploid lens
Authors: Fornasiero Alice , Feng Tao , Al-Bader Noor , Alsantely Aseel , Mussurova Saule , Hoang Nam V. , Misra Gopal , Zhou Yong , Fabbian Leonardo , Mohammed Nahed , Rivera Serna Luis , Thimma Manjula , Llaca Victor , Parakkal Praveena , Kudrna David , Copetti Dario , Rajasekar Shanmugam , Lee Seunghee , Talag Jayson , Sobel-Sorenson Chandler , Panaud Olivier , McNally Kenneth L. , Zhang Jianwei , Zuccolo Andrea , Schranz M. Eric , Wing Rod A.
Published: June 2024

Oryza is remarkable genus - with two domesticated (i.e. Asian and African rice) and 25 diploid and tetraploid wild species, 11 extant genome types, and a ~3.4-fold genome size variation - that possesses a virtually untapped reservoir of genes that can be used for crop improvement. Here we unveil and interrogate 11 new chromosome-level assemblies of nine tetraploid and two diploid wild Oryza species in the context of ~15 million years of evolution of the genus. We show that the core Oryza (sub)genome across all genome types is only ~200 Mb and largely syntenic, while the remaining nuclear fractions, spanning ~80-600 Mb, are intermingled, extremely plastic and rapidly evolving. For the halophyte O. coarctata, we show that - despite the detection of gene fractionation in the subgenomes - homoeologous genes are expressed at higher levels in one subgenome over the other in a mosaic form, thereby showing subgenome equivalence. The integration of these 11 new ultra-high quality reference genomes with our previously published genome data sets provide a nearly complete picture of the consequences of natural and artificial selection across the evolutionary history of Oryza. This in turn opens the door to unlock their genetic potential for future crop improvement and neodomestication.
A refined human linear B cell epitope map of Outer surface protein C (OspC) from the Lyme disease spirochete,Borreliella burgdorferi
Authors: Freeman-Gallant Grace , McCarthy Kathleen , Yates Jennifer , Kulas Karen , Rudolph Michael J. , Vance David J , Mantis Nicholas J
Published: June 2024

A detailed understanding of the human antibody response toOutersurfaceprotein C (OspC) ofBorrelellia burgdorferihas important implications for Lyme disease diagnostics and vaccines. In this report, a total of 13 peptides encompassing eight reported OspC linear B cell epitopes from OspC types A, B and K, including the conserved C-terminus (residues 193-210: peptide C10), were evaluated by multiplex immunoassay (MIA) for IgG reactivity with ∼700 human serum samples confirmed positive in a two-tiered Lyme disease diagnostic assay and ∼160 post-treatment Lyme disease (PTLD) serum samples. The VlsE C6-17 peptide was included as a positive control. Diagnostic serum IgG reacted with 11 of the 13 OspC-derived peptides, significantly more than controls, with the C10 peptide being the most reactive. In the PTLD serum samples, two OspC peptides including C10 were significantly more reactive than controls. Spearman’s rank correlation matrices and hierarchical clustering indicated a strong correlation between C10 and VlsE C6-17 peptide reactivity but little demonstrable association between C10 and the other OspC peptides or recombinant OspC. OspC peptide reactivities (excluding C10) were strongly correlated with each other and were disproportionately influenced by a subset of pan-reactive samples. In the PTLD cohort, C10 clustered with the other OspC-derived peptides and was distinct from OspC and VlsE C6-17. The asynchronous serologic response to OspC, C10, and the OspC-derived peptides reveals the complexity of B cell responses toB. burgdorferiand confounds simple interpretation of antibody profiles associated with Lyme disease.

IMPORTANCE

Lyme disease is an emerging tick-borne infection caused by the spirochete,Borreliella burgdorferi. In humans, antibodies against spirochetal outer surface lipoproteins are proposed to play a role in disease resolution and in protection against reinfection. Some of those same antibodies also serve as diagnostic indicators of an active or history of Lyme disease. In this study, we sought to validate reported antibody binding sites on Outer surface protein C (OspC), a known target of both protective and diagnostic antibodies.
Negative regulation of Activation-Induced Cytidine Deaminase gene transcription in developing B cells by a PU.1-interacting intronic region
Authors: MacKenzie Allanna C. E. , Sams Mia P. , Lin Jane , Batista Carolina Reyes , Lim Michelle , Riarh Chanpreet K. , DeKoter Rodney P.
Published: June 2024

Activation-induced cytidine deaminase (AID, encoded byAicda) plays a key role in somatic hypermutation and class switch recombination in germinal center B cells. However, off-target effects of AID are implicated in human leukemia and lymphoma. A mouse model of precursor B cell acute lymphoblastic leukemia driven by deletion of the related transcription factors PU.1 and Spi-B revealed C->T transition mutations compatible with being induced by AID. Therefore, we hypothesized that PU.1 negatively regulatesAicdaduring B cell development.AicdamRNA transcript levels were increased in leukemia cells and preleukemic bone marrow pre-B cells lacking PU.1 and/or Spi-B, relative to wild type cells. Using chromatin immunoprecipitation, PU.1 was found to interact with a negative regulatory region (R2-1) within the first intron ofAicda. CRISPR-Cas9-induced mutagenesis of R2-1 in cultured pre-B cells resulted in upregulation ofAicdain response to lipopolysaccharide stimulation. Mutation of the PU.1 interaction site and neighboring sequences resulted in reduced repressive ability of R2-1 in transient transfection analysis followed by luciferase assays. These results show that a PU.1-interacting intronic region negatively regulatesAicdatranscription in developing B cells.
Multimodal Predictive Modeling: Scalable Imaging Informed Approaches to Predict Future Brain Health
Authors: Ajith Meenu , Spence Jeffrey S. , Chapman Sandra B. , Calhoun Vince D.
Published: June 2024

Background

Predicting future brain health is a complex endeavor that often requires integrating diverse data sources. The neural patterns and interactions iden-tified through neuroimaging serve as the fundamental basis and early indica-tors that precede the manifestation of observable behaviors or psychological states.

New Method

In this work, we introduce a multimodal predictive modeling approach that leverages an imaging-informed methodology to gain insights into fu-ture behavioral outcomes. We employed three methodologies for evalua-tion: an assessment-only approach using support vector regression (SVR), a neuroimaging-only approach using random forest (RF), and an image-assisted method integrating the static functional network connectivity (sFNC) matrix from resting-state functional magnetic resonance imaging (rs-fMRI) alongside assessments. The image-assisted approach utilized a partially con-ditional variational autoencoder (PCVAE) to predict brain health constructs in future visits from the behavioral data alone.

Results

Our performance evaluation indicates that the image-assisted method ex-cels in handling conditional information to predict brain health constructs in subsequent visits and their longitudinal changes. These results suggest that during the training stage, the PCVAE model effectively captures relevant in-formation from neuroimaging data, thereby potentially improving accuracy in making future predictions using only assessment data.

Comparison with Existing Methods

The proposed image-assisted method outperforms traditional assessment-only and neuroimaging-only approaches by effectively integrating neuroimag-ing data with assessment factors,

Conclusion

This study underscores the potential of neuroimaging-informed predictive modeling to advance our comprehension of the complex relationships between cognitive performance and neural connectivity.

Highlights

Multifaceted perspective for studying longitudinal brain health changes.

Showcases the versatility of methodologies through assessment-only, neuroimaging-only, and image-assisted predictive approaches.

Provides predictive insights by revealing the neural patterns corresponding to alterations in behavior.

Graphical Abstract
Emergent Metabolic Niches for Marine Heterotrophs
Authors: Reynolds Ryan , Weiss Anna CB , James Chase C , Kojima Conner Y , Weissman Jackie Lee , Thrash J. Cameron , Levine Naomi M
Published: June 2024

Ocean microbial communities are made up of thousands of diverse taxa whose metabolic demands set the rates of both biomass production and degradation. Thus, these microscopic organisms play a critical role in ecosystem dynamics, global carbon cycling, and climate. While we have frameworks for relating phytoplankton diversity to rates of carbon fixation, our knowledge of how variations in heterotrophic microbial populations drive changes in carbon cycling is in its infancy. Here, we leverage global metagenomic datasets and metabolic models to identify a set of metabolic niches with distinct growth strategies. These groupings provide a simplifying framework for describing microbial communities in different oceanographic regions and for understanding how heterotrophic microbial populations function. This framework, predicated directly on metabolic capability rather than taxonomy, enables us to tractably link heterotrophic diversity directly to biogeochemical rates in large scale ecosystem models.