bluuebunny/crossref_metadata_2025 huggingface dataset:
Current management of avascular necrosis of the metacarpal head: a comprehensive literature review
Authors: Fan Xiao-Lei , Wang Wen-Tao , Wang Jian , Xiao Rui
Published: April 2023

Background:

Avascular necrosis (AVN) of the metacarpal head is a rare disease that may lead to progressive destruction of the metacarpophalangeal joint and hand function. This study aimed to describe the epidemiology, possible risk factors, clinical presentation, diagnostic workup, and treatment of the rare condition of avascular necrosis of the metacarpal head.

Methods:

Articles were searched using the subject words “Dieterich disease”,“Mauclaire’s disease”, and “avascular necrosis of metacarpal head” in the PubMed and Scopus databases. Studies were retained for review after meeting the inclusion criteria. Those outcomes relevant to diagnose and assessing AVN of the metacarpal head and those related to curative management were extracted.

Results:

The literature search revealed 45 studies with 55 patients. Although the aetiology of osteonecrosis has not been clearly delineated, AVN of the metacarpal head most commonly arises from trauma but other risk factors may also be involved. Plain radiographs are often negative and therefore likely to be missed. Early-stage osteonecrosis of the metacarpal head was best assessed using MRI. Given the rarity of this condition, there is no clear consensus on the treatment.

Conclusions:

Avascular necrosis of the metacarpal head should be considered in the differential diagnosis of painful metacarpophalangeal joints. An early understanding of this unusual disease will provide an optimal clinical outcome, restoring joint activity, and resolving pain. Nonoperative treatment cannot cure all patients. Surgical management is based on the patient and lesion characteristics.
Milk and Dairy Consumption and Its Relationship With Abundance of Lactobacillus crispatus in the Vaginal Microbiota: Milk Intake and Vaginal Lactobacillus
Authors: B. Moura Gabriela , G. Silva Márcia , Marconi Camila
Published: April 2023

Objectives

Diet habits, such as low milk and dairy intake, have been associated with bacterial vaginosis. Thus, we compared vaginal Lactobacillus crispatus abundances in women with different molecularly defined community state types (CSTs) according to the consumption of milk and/or dairy products.

Methods

A total of 516 women from the 5 geographic regions of Brazil were included. Participants were interviewed with a structured questionnaire for assessment of milk and/or dairy intake. Vaginal samples were used for sequencing of V3-V4 regions of the 16S ribosomal RNA gene for further determination of L. crispatus relative abundance (RA) and clustering into 1 of the 5 CSTs (CSTI–CSTV), as firstly described by Ravel et al. (2011). The nonparametric Mann-Whitney test was used to compare L. crispatus RA within the most representative CSTs (L. crispatus-dominant CSTI, Lactobacillus iners-dominant CSTIII, and Lactobacillus-depleted CSTIV) in this population, according to the frequency of milk and/or dairy intake.

Results

The prevalence of CSTI was 33.3% (n = 172), CSTIII was 39% (n = 201), and CSTIV was 27.7% (n = 143). Among the participants with CSTIII, higher L. crispatus RA was observed for those who reported milk/dairy intake (median = 0.02; interquartile range = 0.01–0.09) than those with no consumption (median = 0.01; interquartile range = 0–0.03) (p = .03). Such difference was not observed for participants with CSTI and CSTIV.

Conclusions

Women with vaginal microbiota dominated by L. iners who consume milk and/or dairy present increased abundances of L. crispatus. Therefore, they could benefit from L. crispatus protective properties conferring greater temporal microbiota stability and, consequently, increased protection against infections.
Storytelling
Authors: Karlowicz Karen A.
Published: April 2023

Background:

An annual patient safety lecture is offered through a partnership with the local children's hospital. Presentations focus on the personal impact of medical errors, as told by families, patients, and care providers. The human stories of involvement with a medical error expose situations and actions that can lead to adverse clinical events.

Problem:

Nursing education strategies heighten students' awareness of patient safety policies and guidelines but may not assist students to understand the human impact of medical errors and their role in preventing them.

Approach:

Storytelling links course content to actual accounts of lived experiences involving medical errors. It promotes reflective learning by prompting students to examine beliefs, challenge assumptions, transform their understanding of concepts, and connect theory to practice.

Outcomes/Conclusion:

The annual culture of safety presentation promotes a deeper understanding of the role and responsibility that nurses have in promoting safe clinical practice.
Atypical Endometriosis: Comprehensive Characterization of Clinicopathologic, Immunohistochemical, and Molecular Features
Authors: Wepy Cindy , Nucci Marisa R. , Parra-Herran Carlos
Published: April 2023

Atypical endometriosis (A-EMS), defined by cytologic atypia and/or crowded glands resembling endometrial intraepithelial neoplasia, remains poorly understood. We aimed to refine the morphologic, immunohistochemical, and molecular features of A-EMS in an institutional series. Cases were identified through a structured search and reviewed by 2 pathologists. Immunohistochemistry and comprehensive sequencing using a panel 447-gene coverage were performed in suitable cases. A-EMS with synchronous and/or subsequent EMS-related neoplasia were compared with those without. Of 4598 EMS cases over an 11-yr period, 36 A-EMS were identified. The mean age at presentation was 46 (range 26–68) yr. Locations included the ovary (24, 66%), tubo-ovary (6, 17%), fallopian tube (3, 8%), and peritoneum (3, 8%). The mean size was 6.5 (range 0.5–40) mm. Cytologic atypia was mild in 4 (11%), moderate in 21 (58%), and severe in 11 (31%). Most lesions were partially or completely flat (28, 78%); of these, 66% showed hobnail nuclei. Crowded/cribriform and micropapillary/papillary patterns were seen in 11 (31%) and 16 (44%) A-EMS, respectively. Immunohistochemistry, performed in 33 A-EMS, showed wildtype p53 (100%) retained PMS2/MSH6 (100%), and positive estrogen receptor (97%, mean 65% cells), progesterone receptor (76%, mean 30% cells), and Napsin A (39%). Ki67 labelling was <1% to 10% (median 5%). Nine (25%) patients presented with concurrent or subsequent ipsilateral endometrioid, seromucinous, or clear cell neoplasia (4 borderline tumors and 4 carcinomas). The only A-EMS feature statistically more frequent in this subset was crowded/glands (6/9 vs. 2/27 A-EMS without, P=0.001 Fisher exact test). Sequencing showed pathogenic variants in 5 of 6 cases analyzed, involving ATM, BRCA2, KRAS, AKT, CTNNB1, PTEN, and ARID1A among other genes. In 2 cases, synchronous neoplasia showed an accumulation of additional variants. A-EMS is characterized by cytologic atypia and crowded architecture but low proliferation index, positive estrogen receptor, and normal p53 and MMR, which can be helpful in the distinction from malignancy. The prevalence of synchronous/subsequent tubo-ovarian neoplasia in our series was 25%, significantly higher than the reported 1% in conventional EMS. Moreover, A-EMS harbors genomic alterations seen in EMS-related tumors and shares pathogenic variants with synchronous ipsilateral neoplasia. Therefore, it is important to report A-EMS as currently defined and describe its architectural features, especially gland crowding as this appears to increase the risk of EMS-related epithelial neoplasia. Napsin-A is often positive in A-EMS and should be interpreted with caution.
The Revised R Status is an Independent Predictor of Postresection Survival in Pancreatic Cancer After Neoadjuvant Treatment
Authors: Leonhardt Carl-Stephan , Pils Dietmar , Qadan Motaz , Jomrich Gerd , Assawasirisin Charnwit , Klaiber Ulla , Sahora Klaus , Warshaw Andrew L. , Ferrone Cristina R. , Schindl Martin , Lillemoe Keith D. , Strobel Oliver , Fernández-del Castillo Carlos , Hank Thomas
Published: April 2023

Objective:

To investigate the oncological outcomes of patients with pancreatic ductal adenocarcinoma (PDAC) who had an R0 or R1 resection based on the revised R status (1 mm) after neoadjuvant therapy (NAT).

Background:

The revised R status is an independent prognostic factor in upfront-resected PDAC; however, the significance of 1 mm margin clearance after NAT remains controversial.

Methods:

Patients undergoing pancreatectomy after NAT for PDAC were identified from 2 prospectively maintained databases. Clinicopathological and survival data were analyzed. The primary outcomes were overall survival (OS), recurrence-free survival (RFS), and pattern of recurrence in association with R0 >1 mm and R1 ≤1 mm resections.

Results:

Three hundred fifty-seven patients with PDAC were included after NAT and subsequent pancreatic resection. Two hundred eight patients (58.3%) received FOLFIRINOX, 41 patients (11.5%) received gemcitabine-based regimens, and 299 individuals (83.8%) received additional radiotherapy. R0 resections were achieved in 272 patients (76.2%) and 85 patients (23.8%) had R1 resections. Median OS after R0 was 41.0 months, compared with 20.6 months after R1 resection (P = 0.002), and even longer after additional adjuvant chemotherapy (R0 44.8 vs R1 20.1 months; P = 0.0032). Median RFS in the R0 subgroup was 17.5 months versus 9.4 months in the R1 subgroup (P < 0.0001). R status was confirmed as an independent predictor for OS (R1 hazard ratio: 1.56, 95% CI: 1.07–2.26) and RFS (R1 hazard ratio: 1.52; 95% CI: 1.14–2.0). In addition, R1 resections were significantly associated with local but not distant recurrence (P < 0.0005).

Conclusions:

The revised R status is an independent predictor of postresection survival and local recurrence in PDAC after NAT. Achieving R0 resection with a margin of at least 1 mm should be a primary goal in the surgical treatment of PDAC after NAT.
When morphology does not fit the genomes: the case of rodent olfaction
Authors: Martinez Quentin , Courcelle Maxime , Douzery Emmanuel , Fabre Pierre-Henri
Published: April 2023

Linking genes to phenotypes has been a major question in evolutionary biology for the last decades. In the genomic era, few studies attempted to link olfactory-related genes to different anatomical proxies. However, they found very inconsistent results. This study is the first to investigate a potential relation between olfactory turbinals and olfactory receptor (OR) genes. We demonstrated that despite the use of similar methodology in the acquisition of data, OR genes do not correlate with the relative and the absolute surface area of olfactory turbinals. These results challenged the interpretations of several studies based on different proxies related to olfaction and their potential relation to olfactory capabilities.
Proof theory and non-smooth analysis
Authors: Kohlenbach Ulrich , Pischke Nicholas
Published: April 2023

We develop a general proof-theoretic framework for various classes of set-valued operators, including maximally as well as cyclically monotone and rectangular operators and we discuss a treatment for sums of set-valued operatorsA,Bin that context such that all of the previous fits into logical metatheorems on bound extractions. In particular, we introduce quantitative forms forAbeing (weakly) uniformly rectangular with witnessing moduli. Based on this, we give quantitative forms of the Brezis–Haraux theorem that use such moduli as input. It turns out that a modulus for weak uniform rectangularity, which can be extracted even from non-effective proofs of rectangularity, is sufficient while the bound gets simpler in the case of a modulus forAbeing uniform rectangular which can be extracted from semi-constructive proofs. We use our results to explain recent proof minings in the context of Bauschke’s solution to the zero displacement conjecture and its extensions to other classes of functions than metric projections as instances of logical metatheorems.

This article is part of the theme issue ‘Modern perspectives in Proof Theory’.
The uniform Kruskal theorem: between finite combinatorics and strong set existence
Authors: Freund Anton , Uftring Patrick
Published: April 2023

The uniform Kruskal theorem extends the original result for trees to general recursive data types. As shown by Freund, Rathjen and Weiermann (Freund, Rathjen, Weiermann 2022
Adv. Math.
400
, 108265 (
doi:10.1016/j.aim.2022.108265
)), it is equivalent to

Π
1
1

-comprehension, over

R
C

A
0

with the ascending descending sequence principle (

A
D
S

). This result provides a connection between finite combinatorics and abstract set existence. The present article sheds further light on this connection. Firstly, we show that the original Kruskal theorem is equivalent to the uniform version for data types that are finitely generated. Secondly, we prove a dichotomy result for a natural variant of the uniform Kruskal theorem. On the one hand, this variant still implies

Π
1
1

-comprehension over

R
C

A
0

extended by the chain antichain principle (

C
A
C

). On the other hand, it becomes weak when

C
A
C

is removed from the base theory.

This article is part of the theme issue ‘Modern perspectives in Proof Theory’.
Logics and admissible rules of constructive set theories
Authors: Iemhoff Rosalie , Passmann Robert
Published: April 2023

We survey the logical structure of constructive set theories and point towards directions for future research. Moreover, we analyse the consequences of being extensible for the logical structure of a given constructive set theory. We finally provide examples of a number of set theories that are extensible.

This article is part of the theme issue ‘Modern perspectives in Proof Theory’.
Monkeypox virus: phylogenomics, host–pathogen interactome and mutational cascade
Authors: Kumar Roshan , Nagar Shekhar , Haider Shazia , Sood Utkarsh , Ponnusamy Kalaiarasan , Dhingra Gauri Garg , Anand Shailly , Dua Ankita , Singh Mona , Kumar Roushan , Sengar Manisha , Singh Indrakant Kumar , Lal Rup
Published: April 2023

While the world is still recovering from the Covid-19 pandemic, monkeypox virus (MPXV) awaits to cause another global outbreak as a challenge to all of mankind. However, the Covid-19 pandemic has taught us a lesson to speed up the pace of viral genomic research for the implementation of preventive and treatment strategies. One of the important aspects of MPXV that needs immediate insight is its evolutionary lineage based on genomic studies. Utilizing high-quality isolates from the GISAID (Global Initiative on Sharing All Influenza Data) database, primarily sourced from Europe and North America, we employed a SNP-based whole-genome phylogeny method and identified four major clusters among 628 MPXV isolates. Our findings indicate a distinct evolutionary lineage for the first MPXV isolate, and a complex epidemiology and evolution of MPXV strains across various countries. Further analysis of the host–pathogen interaction network revealed key viral proteins, such as E3, SPI-2, K7 and CrmB, that play a significant role in regulating the network and inhibiting the host’s cellular innate immune system. Our structural analysis of proteins E3 and CrmB revealed potential disruption of stability due to certain mutations. While this study identified a large number of mutations within the new outbreak clade, it also reflected that we need to move fast with the genomic analysis of newly detected strains from around the world to develop better prevention and treatment methods.
PheWAS-based clustering of Mendelian Randomisation instruments reveals distinct mechanism-specific causal effects between obesity and educational attainment
Authors: Darrous Liza , Hemani Gibran , Smith George Davey , Kutalik Zoltán
Published: April 2023

Mendelian Randomisation (MR) is a statistical method that estimates causal effects between risk factors and common complex diseases using genetic instruments. Heritable confounders, pleiotropy and heterogeneous causal effects violate MR assumptions and can lead to biases. To tackle these, we propose an approach employing a PheWAS-based clustering of the MR instruments (PWC-MR). We apply this method to revisit the surprisingly large apparent causal effect of body mass index (BMI) on educational attainment (EDU):α= -0.19 [-0.22, -0.16].

As a first step of PWC-MR, we clustered 324 BMI-associated genetic instruments based on their association profile across 407 traits in the UK Biobank, which yielded six distinct groups. The subsequent cluster-specific MR revealed heterogeneous causal effect estimates on EDU. A cluster strongly enriched for traits related to socio-economic position yielded the largest BMI-on-EDU causal effect estimate (α= -0.49 [-0.56, -0.42]) whereas a cluster enriched for primary impact on body-mass had the smallest estimate (α= -0.09 [-0.13, - 0.05]). Several follow-up analyses confirmed these findings: (i) within-sibling MR results (α= -0.05 [-0.09, -0.01]); (ii) MR for childhood BMI on EDU (α= -0.03 [-0.06, -0.002]); (iii) step-wise multivariable MR (MVMR) (α= -0.06 [-0.09, -0.04]) where time spent watching television and past tobacco smoking (two proxies for potential confounders) were jointly modelled.

Through a detailed examination of the BMI-EDU causal relationship we demonstrated the utility of our PWC-MR approach in revealing distinct pleiotropic pathways and confounder mechanisms.
omicSynth: an Open Multi-omic Community Resource for Identifying Druggable Targets across Neurodegenerative Diseases
Authors: Alvarado Chelsea X. , Makarious Mary B. , Weller Cory A. , Vitale Dan , Koretsky Mathew J. , Bandres-Ciga Sara , Iwaki Hirotaka , Levine Kristin , Singleton Andrew , Faghri Faraz , Nalls Mike A. , Leonard Hampton L.
Published: April 2023

Treatments for neurodegenerative disorders remain rare, although recent FDA approvals, such as Lecanemab and Aducanumab for Alzheimer’s Disease, highlight the importance of the underlying biological mechanisms in driving discovery and creating disease modifying therapies. The global population is aging, driving an urgent need for therapeutics that stop disease progression and eliminate symptoms. In this study, we create an open framework and resource for evidence-based identification of therapeutic targets for neurodegenerative disease. We use Summary-data-based Mendelian Randomization to identify genetic targets for drug discovery and repurposing. In parallel, we provide mechanistic insights into disease processes and potential network-level consequences of gene-based therapeutics. We identify 116 Alzheimer’s disease, 3 amyotrophic lateral sclerosis, 5 Lewy body dementia, 46 Parkinson’s disease, and 9 Progressive supranuclear palsy target genes passing multiple test corrections (pSMR_multi< 2.95×10−6and pHEIDI> 0.01). We created a therapeutic scheme to classify our identified target genes into strata based on druggability and approved therapeutics - classifying 41noveltargets, 3knowntargets, and 115difficulttargets (of these 69.8% are expressed in the disease relevant cell type from single nucleus experiments). Ournovelclass of genes provides a springboard for new opportunities in drug discovery, development and repurposing in the pre-competitive space. In addition, looking at drug-gene interaction networks, we identify previous trials that may require further follow-up such as Riluzole in AD. We also provide a user-friendly web platform to help users explore potential therapeutic targets for neurodegenerative diseases, decreasing activation energy for the community [https://nih-card-ndd-smr-home-syboky.streamlit.app/].
Predictive links between petal color and pigment quantities in naturalPenstemonhybrids
Authors: Stevens Joshua T.E. , Wheeler Lucas C. , Williams Noah H. , Norton Alice M. , Wessinger Carolyn A.
Published: April 2023

Flowers have evolved remarkable diversity in petal color, in large part due to pollinator-mediated selection. This diversity arises from specialized metabolic pathways that generate conspicuous pigments. Despite the clear link between flower color and floral pigment production, studies determining predictive relationships between pigmentation and petal color are currently lacking. In this study, we analyze a dataset consisting of hundreds of naturalPenstemonhybrids that exhibit variation in flower color, including blue, purple, pink, and red. For each individual hybrid, we measured anthocyanin pigment content and petal spectral reflectance. We found that floral pigment quantities are correlated with hue, chroma, and brightness as calculated from petal spectral reflectance data: hue is related to the relative amounts of delphinidin vs. pelargonidin pigmentation, whereas brightness and chroma are correlated with the total anthocyanin pigmentation. We used a partial least squares regression approach to identify predictive relationships between pigment production and petal reflectance. We find that pigment quantity data provide robust predictions of petal reflectance, confirming a pervasive assumption that differences in pigmentation should predictably influence flower color. Moreover, we find that reflectance data enables accurate inferences of pigment quantities, where the full reflectance spectra provide much more accurate inference of pigment quantities than spectral attributes (brightness, chroma, and hue). Our predictive framework provides readily interpretable model coefficients relating spectral attributes of petal reflectance to underlying pigment quantities. These relationships represent key links between genetic changes affecting anthocyanin production and ecological functions of petal coloration.
Objects sharpen visual scene representations: evidence from MEG decoding
Authors: Brandman Talia , Peelen Marius V.
Published: April 2023

Real-world scenes consist of objects, defined by local information, and scene background, defined by global information. While objects and scenes are processed in separate pathways in visual cortex, their processing interacts. Specifically, previous studies have shown that scene context makes blurry objects look sharper, an effect that can be observed as a sharpening of object representations in visual cortex from around 300 ms after stimulus onset. Here, we use MEG to show that objects can also sharpen scene representations, with the same temporal profile. Photographs of indoor (closed) and outdoor (open) scenes were blurred such that they were difficult to categorize on their own but easily disambiguated by the inclusion of an object. Classifiers were trained to distinguish MEG response patterns to intact indoor and outdoor scenes, presented in an independent run, and tested on degraded scenes in the main experiment. Results revealed better decoding of scenes with objects than scenes alone and objects alone from 300 ms after stimulus onset. This effect was strongest over left posterior sensors. These findings show that the influence of objects on scene representations occurs at similar latencies as the influence of scenes on object representations, in line with a common predictive processing mechanism.
Establishment and Evaluation of Rat Models of Cervical Spondylopathy with Yin Deficiency Syndrome
Authors: Yang Wenlong , Liu Muqing , Sun Qinran , Liu Lei , Wu Wenqing , Gao Peng , Liu Fangming , Liu Zhizhen
Published: April 2023

Objective

Cervical spondylosis (CS) with Yin deficiency syndrome is an important classification of traditional Chinese medicine (TCM) symptoms of CS. However, there is no animal model for studying this TCM syndrome. This study aimes to establish and evaluate rat models of cervical spondylopathy with Yin deficiency syndrome.

Method

Thirty-six Sprague–Dawley male rats were randomly divided into the blank control (control), CS and CS with Yin deficiency syndrome (YCS) groups (n = 12 rats/group). CS was induced using cervical static–dynamic imbalance to mimic disk degeneration (except in the control group). After 30 days of the CS rat model, rats in the YCS group were subjected to sustained sleep deprivation for 168h. After different induction times, the rats in each group were observed for behavior and weight. Pain behavior was assessed by a withdrawal response to von Frey filament application, and heart rate and blood pressure were measured using a rat noninvasive sphygmomanometer. Intervertebral disc pathology sections were observed using hematoxylin and eosin staining and an electron microscope. Western blotting was used to evaluate the protein level of collagen-II, Bcl-2, Bax and Bcl-2/Bax expression in the cervical intervertebral disc. Determination of related laboratory serum indexes, cyclic adenosine monophosphate, and cyclic guanosine phosphate were conducted using enzyme-linked immunosorbent assay.

Results

The laboratory indexes in the YCS group were significantly different from those in the control and CS groups (P < 0.05), and indicators of 72-, 120-, and 178-h sleep deprivation showed varying degrees of difference from those of the CS group.

Conclusion

After establishing a model of CS, continuous sleep deprivation for 72 h was used to create a rat model of CS with Yin deficiency syndrome. The established rat models of CS with Yin deficiency syndrome met the clinical and Chinese medicine characteristics, and thus, they can be expected to become an ideal model for studying CS with Yin deficiency syndrome in the future.
A Weighted Two-stage Sequence Alignment Framework to Identify DNA Motifs from ChIP-exo Data
Authors: Li Yang , Wang Yizhong , Wang Cankun , Fennell Anne , Ma Anjun , Jiang Jing , Liu Zhaoqian , Ma Qin , Liu Bingqiang
Published: April 2023

Identifying precise transcription factor binding sites (TFBS) or regulatory DNA motifs plays a fundamental role in researching transcriptional regulatory mechanisms in cells and in helping construct regulatory networks. Current algorithms developed for motif searching focus on the analysis of ChIP-enriched peaks but are not able to integrate the ChIP signal in nucleotide resolution. We present a weighted two-stage alignment tool (TESA). Our framework implements an analysis workflow from experimental datasets to TFBS prediction results. It employs a binomial distribution model and graph searching model with ChIP-exonuclease (ChIP-exo) reads depth and sequence data. TESA can effectively measure the possibility for each position to be an actual TFBS in a given promoter sequence and predict statistically significant TFBS sequence segments. The algorithm substantially improves prediction accuracy and extends the scope of applicability of existing approaches. We apply the framework to a collection of 20 ChIP-exo datasets of E. coli from proChIPdb and evaluate the prediction performance through comparison with three existing programs. The performance evaluation against the compared programs indicates that TESA is more accurate for identifying regulatory motifs in prokaryotic genomes.
Obstructive Sleep Apnea Improves with Non-invasive Hypoglossal Nerve Stimulation using Temporal Interference
Authors: Missey Florian , Ejneby Malin Silverå , Ngom Ibrahima , Donahue Mary J. , Trajlinek Jan , Acerbo Emma , Botzanowski Boris , Cassarà Antonino M. , Neufeld Esra , Glowacki Eric D. , Shangold Lee , Hanes William M. , Williamson Adam
Published: April 2023

Background

Peripheral nerve stimulation is used in both clinical and fundamental research for therapy and exploration. At present, non-invasive peripheral nerve stimulation still lacks the penetration depth to reach deep nerve targets and the stimulation focality to offer selectivity. It is therefore rarely employed as the primary selected nerve stimulation method. We have previously demonstrated that a new stimulation technique, temporal interference stimulation, can overcome depth and focality issues.

Methods

Here, we implement a novel form of temporal interference, bilateral temporal interference stimulation, for bilateral hypoglossal nerve stimulation in rodents and humans. Pairs of electrodes are placed alongside both hypoglossal nerves to stimulate them synchronously and thus decrease the stimulation amplitude required to activate hypoglossal-nerve controlled tongue movement.

Results

Comparing bilateral temporal interference stimulation with unilateral temporal interference stimulation, we show that it can elicit the same behavioral and electrophysiological responses at a reduced stimulation amplitude. Traditional transcutaneous stimulation evokes no response with equivalent amplitudes of stimulation.

Conclusions

During first in-man studies, temporal interference stimulation was found to be well-tolerated, and to clinically reduce apnea-hypopnea events in a subgroup of female patients with obstructive sleep apnea. These results suggest a high clinical potential for the use of temporal interference in the treatment of obstructive sleep apnea and other diseases as a safe, effective, and patient-friendly approach.

Trial registration

The protocol was conducted with the agreement of the International Conference on Harmonisation Good Clinical Practice (ICH GCP), applicable United States Code of Federal Regulations (CFR) and followed the approved BRANY IRB File # 22-02-636-1279.
Male rats emit aversive 44-kHz ultrasonic vocalizations during prolonged Pavlovian fear conditioning
Authors: Olszyński Krzysztof H. , Polowy Rafał , Wardak Agnieszka D. , Łaska Izabela A. , Grymanowska Aneta W. , Puławski Wojciech , Gawryś Olga , Koliński Michał , Filipkowski Robert K.
Published: April 2023

Rats are believed to communicate their emotional state by emitting two distinct types of ultrasonic vocalizations. The first is long “22-kHz” vocalizations (>300 ms, <32 kHz) with constant frequency, signaling aversive states and the second, is short “50-kHz” calls (<150 ms, >32 kHz), often frequency-modulated, in appetitive situations. Here we describe aversive vocalizations emitted at a higher pitch by male Wistar and spontaneously hypertensive rats (SHR) in an intensified aversive state – prolonged fear conditioning. These calls, which we named “44-kHz” vocalizations, are long (>150 ms), generally at a constant frequency (usually within 35-50 kHz range) and have an overall spectrographic image similar to 22-kHz calls. Some 44-kHz vocalizations are comprised of both 22-kHz-like and 44-kHz-like elements. Furthermore, two separate clustering methods confirmed that these 44-kHz calls can be separated from other vocalizations. We observed 44-kHz calls to be associated with freezing behavior during fear conditioning training, during which they constituted up to 19.4% of all calls and most of them appeared next to each other forming uniform groups of vocalizations (bouts). We also show that some of rats’ responses to the playback of 44-kHz calls were more akin to that of aversive calls, e.g., heart rate changes, whereas other responses were at an intermediate level between aversive and appetitive calls. Our results suggest that rats have a wider vocal repertoire than previously believed, and current definitions of major call types may require reevaluation. We hope that future investigations of 44-kHz calls in rat models of human diseases will contribute to expanding our understanding and therapeutic strategies related to human psychiatric conditions.
Single-cell RNA-sequencing identifies a novel subset of CD9+reparative macrophages modulated by CCN2 derived from Nlrx1 deficient cardiomyocytes in the infarcted heart
Authors: Li Jun , He Guangxiang , Wang Linyi , Wang Haijuan , Ma Ruixue , Sun Wenjie , Hu Jintao , Liang Jun , Li Renqi , Wu Xingan , Yang Yanling , Chen Jun , Liu Rongrong , Pei Jianming
Published: April 2023

Rationale

Nlrx1, a pattern recognition receptor belonging to the NLR family, is highly expressed in the heart and is significantly increased after myocardial infarction in vivo, however, the role of Nlrx1 in post-infarction inflammation and healing is poorly understood. Although the effects of infiltrating macrophages on survival of cardiomyocytes and healing of injured hearts have been intensely studied, whether or not and how surviving cardiomyocytes might influence the phenotype and function of macrophages in the infarcted hearts was largely unexplored.

Objective

To investigate the role of Nlrx1 in post-infarction inflammation and healing and to dissect the underlying mechanism.

Methods and results

Single cell RNA-sequencing of 23,805 cells isolated from infarcted hearts revealed 7 clusters of infarct macrophages including CCR2+, Isg+, Mki67+proliferative, and LYVE1+cardiac resident macrophages, and identified a novel subset of CD9+Il1rn+macrophages, which were characterized by high expression ofCd9, Il1rn, GpnmbandSpp1,and downregulation of proinflammatory cytokines and chemokines. CD9+Il1rn+macrophages were largely found in infarcted hearts of Nlrx1KO mice, and were transcriptionally unique with reparative phenotype. Loss of Nlrx1 attenuated ventricular dysfunction and adverse remodeling, and decreased post-infarction mortality. Flow cytometry analysis showed markedly increased number of CD9+macrophages and higher mean fluorescence intensity of CD9 in Nlrx1KO mice. RNA-seq analysis revealed that CD9+macrophages of Nlrx1KO infarcted hearts exhibited a reparative and anti-inflammatory phenotype as featured by upregulation of wound healing-associated genes includingCD9, Spp1andFn1, and downregulation of proinflammatory genes. Conditioned medium from Nlrx1 deficient cardiomyocytes upon hypoxia stimulation skewed macrophage polarization towards a reparative and inflammation-suppressed phenotype. Gain-and loss-of function of Nlrx1 combined with RNA-seq analysis identified CCN2, whose expression and secretion were significantly increased in Nlrx1 deficient cardiomyocytes upon hypoxia, as a cardiomyocytes-derived mediator responsible, at least partly, for reprograming macrophage towards a reparative phenotype. In vivo, CCN2 expression was markedly elevated in Nlrx1KO infarcted hearts. Moreover, exogenous CCN2 partially mediated macrophage transition towards a reparative phenotype.

Conclusions

CD9+IL1rn+macrophages modulated by Nlrx1 deficient cardiomyocytes-derived CCN2, is a novel subset of reparative macrophages contributing to infarct healing. Inhibition of myocardial Nlrx1 and/or activation of CCN2 to boost CD9+IL1rn+reparative macrophages may represent new therapeutics for infarct healing following ischemic injury.
Effect of hexanal treatment on fruit qualities and antioxidant activities on ‘Umran’ Indian jujube fruit during cold storage
Authors: Sharma Anil , Bons Harsimrat K. , Jawandha S K , Chung Sun Woo
Published: April 2023

‘Umran’ Indian jujube is a widely grown cultivar due to its marketable quality and productivity, resulting in excellent market value. Despite its high quality, the product’s short shelf life poses a challenge for transportation, even within the domestic market. Hexanal with three concentrations (0.15%, 0.20%, and 0.25%) was applied to the fruit of ‘Umran’ Indian jujube at both pit hardening and color break stages. Harvested fruits were stored for 28 days in a cold chamber of 7.5±1°C and 90-95% RH. The changes in fruit qualities were assessed with physicochemical characteristics, bioactive compounds, and enzymatic antioxidant activities every seven days. Fruits treated with hexanal of 0.20% reduced fruit weight loss and spoilage and maintained fruit firmness, soluble solids content, carotenoid content, and antioxidant activity. The activities of cell wall degrading enzymes investigated were suppressed. Of the antioxidant activities, superoxide dismutase and peroxidase were positively activated. Therefore, these results indicated that pre-harvest application of hexanal 0.20% improved physiochemical characteristics, maintained bioactive compounds, antioxidant enzyme activities, and extended the shelf life of Indian jujube fruits up to 21 days during cold storage.
Relationship Between Donor Derived Cell-Free DNA and Tissue-Based Rejection-Related Transcripts In Heart Transplantation
Authors: Lee Dae Hyun , Usmani Ahsan , Wu Robby , Wicks Tammi , Burke Ryan , Ravichandran Vani , Wolf-Doty Theresa , Dumitru Ioana , Oliveira Guilherme H. , Berman Peter , Mackie Benjamin
Published: April 2023

Introduction

Endomyocardial biopsy (EMB)-based traditional microscopy remains the gold standard for the detection of cardiac allograft rejection, despite its limitation of inherent subjectivity leading to inter-reader variability. Alternative techniques now exist to surveil for allograft injury and classify rejection. Donor-derived cell-free DNA (dd-cfDNA) testing is now a validated blood-based assay used to surveil for allograft injury. The molecular microscope diagnostic system (MMDx) utilizes intragraft rejection-associated transcripts (RATs) to classify allograft rejection and identify injury. The use of dd-cfDNA and MMDx together provides objective molecular insight into allograft injury and rejection. The aim of this study was to measure the diagnostic agreement between dd-cfDNA and MMDx and assess the relationship between dd-cfDNA and MMDx-derived RATs which may provide further insight into the pathophysiology of allograft rejection and injury.

Methods

This is a retrospective observational study of 186 endomyocardial biopsy (EMB) evaluated with traditional microscopy and MMDx. All samples were paired with dd-cfDNA from peripheral blood prior to EMB (up to 1 month). Diagnostic agreement between traditional microscopy, MMDx, and dd-cfDNA (threshold of 0.20%) were compared for assessment of allograft injury. In addition, the relationship between dd-cfDNA and individual RAT expression levels from MMDx was evaluated.

Results

MMDx characterized allograft tissue as no rejection (NR) (64.5%), antibody-mediated rejection (ABMR) (25.8%), T-cell-mediated rejection (TCMR) (4.8%), and mixed ABMR/ TCMR (4.8%). For the diagnosis of any type of rejection (TCMR, ABMR, and mixed rejection), there was substantial agreement between MMDx and dd-cfDNA (74.7% agreement). All transcript clusters (group of gene sets designated by MMDx) and individual transcripts considered abnormal from MMDx had significantly elevated dd-cfDNA. In addition, a positive correlation between dd-cfDNA levels and certain MMDx-derived RATs was observed. Tissue transcript clusters correlated with dd-cfDNA scores, includingDSAST, GRIT, HT1, QCMAT and S4. For individual transcripts, tissueROBO4was significantly correlated with dd-cfDNA in both non-rejection and rejection as assessed by MMDx.

Conclusion

Collectively, we have shown substantial diagnostic agreement between dd-cfDNA and MMDx. Furthermore, based on the findings presented, we postulate a common pathway between the release of dd-cfDNA andROBO4(a vascular endothelial-specific gene that stabilizes the vasculature) in the setting of AMR, which may provide a mechanistic rationale for observed elevations in dd-cfDNA in AMR, compared to ACR.
Spatial-linked alignment tool (SLAT) for aligning heterogenous slices properly
Authors: Xia Chen-Rui , Cao Zhi-Jie , Tu Xin-Ming , Gao Ge
Published: April 2023

Spatially resolved omics technologies reveal the spatial organization of cells in various biological systems. Integrative and comparative analyses of spatial omics data depend on proper slice alignment, which should take both omics profiles and spatial context into account. Here we propose SLAT (Spatially-Linked Alignment Tool), a graph-based algorithm for efficient and effective alignment of spatial omics data. Adopting a graph adversarial matching strategy, SLAT is the first algorithm capable of aligning heterogenous spatial data across distinct technologies and modalities. Systematic benchmarks demonstrate SLAT’s superior precision, robustness, and speed vis à vis existing methods. Applications to multiple real-world datasets further show SLAT’s utility in enhancing cell-typing resolution, integrating multiple modalities for regulatory inference, and mapping fine-scale spatial-temporal changes during development. The full SLAT package is available athttps://github.com/gao-lab/SLAT.
A longitudinal resource for population neuroscience of school-age children and adolescents in China
Authors: Fan Xue-Ru , Wang Yin-Shan , Chang Da , Yang Ning , Rong Meng-Jie , Zhang Zhe , He Ye , Hou Xiaohui , Zhou Quan , Gong Zhu-Qing , Cao Li-Zhi , Dong Hao-Ming , Nie Jing-Jing , Chen Li-Zhen , Zhang Qing , Zhang Jia-Xin , Li Hui-Jie , Bao Min , Chen Antao , Chen Jing , Chen Xu , Ding Jinfeng , Dong Xue , Du Yi , Feng Chen , Feng Tingyong , Fu Xiaolan , Ge Li-Kun , Hong Bao , Hu Xiaomeng , Huang Wenjun , Jiang Chao , Li Li , Li Qi , Li Su , Liu Xun , Mo Fan , Qiu Jiang , Su Xue-Quan , Wei Gao-Xia , Wu Yiyang , Xia Haishuo , Yan Chao-Gan , Yan Zhi-Xiong , Yang Xiaohong , Zhang Wenfang , Zhao Ke , Zhu Liqi ,   Lifespan Brain Chart Consortium (LBCC),   Chinese Color Nest Consortium (CCNP), Zuo Xi-Nian
Published: April 2023

During the past decade, cognitive neuroscience has been calling for population diversity to address the challenge of validity and generalizability, ushering in a new era of population neuroscience. The developing Chinese Color Nest Project (devCCNP, 2013-2022), a ten-year pilot stage of the lifespan CCNP (2013-2032), is an ongoing project focusing on brain-mind development. The project aims to create and share a large-scale, longitudinal and multimodal dataset of typically developing children and adolescents (ages 6.0–17.9 at enrolment) in the Chinese population. The devCCNP houses not only phenotypes measured by demographic, biophysical, psychological and behavioural, cognitive, affective, and ocular-tracking assessments but also neurotypes measured with magnetic resonance imaging (MRI) of brain morphometry, resting-state function, naturalistic viewing function and diffusion structure. This Data Descriptor introduces the first data release of devCCNP including a total of 864 visits from 479 participants. Herein, we provided details of the experimental design, sampling strategies, and technical validation of the devCCNP resource. We demonstrate and discuss the potential of a multicohort longitudinal design to depict normative brain growth curves from the perspective of developmental population neuroscience. The devCCNP resource is shared as part of the “Chinese Data-sharing Warehouse forIn-vivoImaging Brain” in theChinese Color Nest Project (CCNP) – Lifespan Brain-Mind Development Data Community(https://www.scidb.cn/en/c/ccnp) at the Science Data Bank.

Design Types

Accelerated longitudinal design

Brain-mind development

Population imaging

Brain chart

Repeated measure

Measurements

Psychological behaviours

Biophysical and physical measures

Intelligence quotient measure

Neuroimaging

Sample Characteristic - Organism

Homo sapiens

Sample Characteristic - Environment

School- and community-based sample

Sample Characteristic - Location

Chongqing and Beijing, China

Duration

10 years (2013-2022)
PoseR - A deep learning toolbox for decoding animal behavior
Authors: Mullen Pierce N , Bowlby Beatrice , Armstrong Holly C , Zwart Maarten F
Published: April 2023

The actions of animals provide a window into how their minds work. Recent advances in deep learning are providing powerful approaches to recognize patterns of animal movement from video recordings, including markerless pose estimation models. However, tools to efficiently parse coordinates of animal position and pose into meaningful semantic behavioral labels are lacking. Here, we present PoseRecognition (PoseR), a behavioral decoder leveraging state- of-the-art action recognition models using spatio-temporal graph convolutional networks. We show that it can be used to decode animal behavior quickly and accurately from pose estimations, using zebrafish larvae and mice as model organisms. PoseR can be accessed using a Napari plugin, which facilitates efficient behavioral extraction, annotation, model training and deployment. We have simplified the workflow of behavioral analysis after pose estimation, transforming coordinates of animal position and pose into meaningful semantic behavioral labels, using methods designed for fast and accurate behavioral extraction, annotation, model training and deployment. Furthermore, we contribute a novel method for unsupervised clustering of behaviors and provide open-source access to our zebrafish datasets and models. The design of our tool ensures scalability and versatility for use across multiple species and contexts, improving the efficiency of behavioral analysis across fields.
Salt corrections for RNA secondary structures in the ViennaRNA package
Authors: Yao Hua-Ting , Lorenz Ronny , Hofacker Ivo L. , Stadler Peter F.
Published: April 2023

Background

RNA features a highly negatively charged phosphate backbone that attracts a of cloud counter-ions that reduce the electrostatic repulsion in a concentration dependent manner. Ion concentrations thus have a large influence on folding and stability of RNA structures. Despite their well-documented effects, salt effects are not handled by currently available secondary stucture prediction algorithms. Combining Debye-Hückel potentials for line charges and Manning’s counter-ion condensation theory, Einertet al. [Biophys. J.100: 2745-2753 (2011)] modeled the energetic effects contributions monovalent cations on loops and helices.

Results

The model of Einertet al. is adapted to match the structure of the dynamic programming recursion of RNA secondary structure prediction algorithms. An empirical term describing the dependence salt dependence of the duplex initiation energy is added to improve co-folding predictions for two or more RNA strands. The slightly modified model is implemented in theViennaRNApackage in such way that only the energy parameters but not the algorithmic structure is affected. A comparison with data from the literature show that predicted free energies and melting temperatures are in reasonable agreement with experiments.

Conclusion

The new feature in theViennaRNApackage makes it possible to study effects of salt concentrations on RNA folding in a systematic manner. Strictly speaking, the model pertains only to mono-valent cations, and thus covers the most important parameter, i.e., the NaCl concentration. It remains a question for future research to what extent unspecific effects of bi- and tri-valent cations can be approximated in a similar manner.

Availability

Corrections for the concentration of monovalent cations are available in theViennaRNApackage starting from version 2.6.0.
Analysis of Differential Gene Expression and Core Canonical Pathways involved in the Epithelial to Mesenchymal Transition of Triple Negative Breast Cancer Cells by Ingenuity Pathway Analysis
Authors: Bhattacharya Santanu , Ghosh Somiranjan , Banerjee Hirendra
Published: April 2023

Triple Negative Breast Cancer (TNBC) is a malignant form of cancer with very high mortality and morbidity. Epithelial to Mesenchymal Transition (EMT) is the most common pathophysiological change observed in cancer cells of epithelial origin that promotes metastasis, drug resistance and cancer stem cell formation. Since the information regarding differential gene expression in TNBC cells and cell signaling events leading to EMT is limited, this investigation was done by comparing transcriptomic data generated by RNA isolation and sequencing of a EMT model TNBC cell line in comparison to regular TNBC cells. RNA sequencing and Ingenuity Pathway Software Analysis (IPA) of the transcriptomic data revealed several upregulated and downregulated gene expressions along with novel core canonical pathways including Sirtuin signaling, Oxidative Phosphorylation and Mitochondrial dysfunction events involved in EMT changes of the TNBC cells.