bluuebunny/crossref_metadata_2025 huggingface dataset:
A Visual Analog Scale for Self-Reported Quality of Life
Authors: Redford Elizabeth , Heuer Sabine
Published: September 2023

Purpose:

People with dementia (PWD) are one of the fastest-growing clinical populations for speech-language pathologists. Self-reported quality of life (QoL) assessments are critical patient-reported outcome measures that align with person-centered care principles. However, proxy-reporting is most often used due to assumptions that PWD cannot provide reliable self-report. Visual analog scales (VASs) have been successfully used with people with expressive and cognitive deficits to measure subjective constructs such as QoL, mood, and pain. The purpose of this project is to evaluate the feasibility and reliability of a VAS QoL assessment tool.

Methods:

Twenty older adults free of cognitive impairment were assessed using the quality of life in Alzheimer’s disease (QoL-AD) and the QoL-AD in combination with a VAS (VAS QoL-AD). The construct validity, internal consistency, and test-retest reliability of the VAS QoL-AD were assessed by performing both assessments twice, 4 weeks apart.

Results:

Significant correlations between the overall VAS QoL-AD and the QoL-AD scale ratings, between most of the QoL-AD and VAS QoL-AD subtests, and between the first and second assessment scores were observed.

Conclusions:

Results indicated strong construct validity, internal consistency, and test-retest reliability of the VAS QoL-AD in people without dementia. These results warrant further research into the development of a dementia-specific, self-reported VAS QoL scale for PWD.
Gender, Pain, and Function Associated With Physical Activity After Hospitalization in Persons Living With Dementia
Authors: Kuzmik Ashley , Boltz Marie , Resnick Barbara , Drazich Brittany F. , Galvin James E.
Published: September 2023

Background:

The purpose of this study was to identify factors that are associated with physical activity after hospitalization in persons living with dementia.

Methods:

Multiple linear regressions were conducted to test factors associated with objective activity levels (sedentary, low, moderate, and vigorous) among 244 patients living with dementia from a randomized controlled trial.

Results:

Within 48 hours of hospital discharge, time in sedentary behavior was associated with increased pain (β=0.164, P=0.015). Time in low activity was associated with less pain (β=−0.130, P=0.049) and higher physical function (β=0.300, P=<0.001). Time in moderate activity was associated with increased physical function (β=0.190, P=0.008) and male gender (β=0.155, P=0.016). No significant associations of potential factors were found with time in vigorous activity.

Conclusions:

Our findings suggest that managing or reducing pain, encouraging individual functional level, and gender could influence time spent in physical activity after acute hospitalization in persons living with dementia.
National Multi-Institutional Validation of a Surgical Transfusion Risk Prediction Model
Authors: Lou Sunny S , Liu Yaoming , Cohen Mark E , Ko Clifford Y , Hall Bruce L , Kannampallil Thomas
Published: September 2023

BACKGROUND:

Accurate estimation of surgical transfusion risk is important for many aspects of surgical planning, yet few methods for estimating are available for estimating such risk. There is a need for reliable validated methods for transfusion risk stratification to support effective perioperative planning and resource stewardship.

STUDY DESIGN:

This study was conducted using the American College of Surgeons NSQIP datafile from 2019. S-PATH performance was evaluated at each contributing hospital, with and without hospital-specific model tuning. Linear regression was used to assess the relationship between hospital characteristics and area under the receiver operating characteristic (AUROC) curve.

RESULTS:

A total of 1,000,927 surgical cases from 414 hospitals were evaluated. Aggregate AUROC was 0.910 (95% CI 0.904 to 0.916) without model tuning and 0.925 (95% CI 0.919 to 0.931) with model tuning. AUROC varied across individual hospitals (median 0.900, interquartile range 0.849 to 0.944), but no statistically significant relationships were found between hospital-level characteristics studied and model AUROC.

CONCLUSIONS:

S-PATH demonstrated excellent discriminative performance, although there was variation across hospitals that was not well-explained by hospital-level characteristics. These results highlight the S-PATH’s viability as a generalizable surgical transfusion risk prediction tool.
Claveliimonas bilis gen. nov., sp. nov., deoxycholic acid-producing bacteria isolated from human faeces, and reclassification of Sellimonas monacensis Zenner et al. 2021 as Claveliimonas monacensis comb. nov.
Authors: Hisatomi Atsushi , Kastawa Ni Wayan Eka Putri Gayatri , Song Isaiah , Ohkuma Moriya , Fukiya Satoru , Sakamoto Mitsuo
Published: September 2023

Obligately anaerobic, Gram-stain-positive, bacilli, strains 12BBH14T, 9CFEGH4 and 10CPCBH12, were isolated from faecal samples of healthy Japanese people. Strain 12BBH14T showed the highest 16S rRNA gene sequence similarity to

Sellimonas monacensis

Cla-CZ-80T (97.5 %) and ‘Lachnoclostridium phocaeense’ Marseille-P3177T (97.2 %). Strain 12BBH14T was also closely related to

Eubacterium

sp. c-25 with 99.7 % 16S rRNA gene sequence similarity. The 16S rRNA gene sequence analysis showed that strains 12BBH14T, 9CFEGH4 and 10CPCBH12 formed a monophyletic cluster with

Eubacterium

sp. c-25. Near this monophyletic cluster,

S. monacensis

Cla-CZ-80T and ‘L. phocaeense’ Marseille-P3177T formed a cluster and did not form a cluster with other

Sellimonas

species. The digital DNA–DNA hybridization (dDDH) and average nucleotide identity (ANI) values between strains 12BBH14T, 9CFEGH4, 10CPCBH12 and

Eubacterium

sp. c-25 were higher than the cut-off values of species demarcation (>88 % dDDH and >98 % ANI), indicating that these four strains are the same species. On the other hand, the dDDH and ANI values of these strains were lower than the cut-off values of species demarcation against other strains (<29 % dDDH and <76 % ANI). Moreover, the average amino acid identity values among these strains were higher than the genus boundary. These results indicate that the isolates should be considered to belong to a new genus of the family

Lachnospiraceae

. Based on the collected data, strains 12BBH14T, 9CFEGH4 and 10CPCBH12 represent a novel species of a novel genus, for which the name Claveliimonas bilis gen. nov., sp. nov. is proposed. The type strain of C. bilis is 12BBH14T (=JCM 35899T=DSM 115701T).

Eubacterium

sp. c-25 belongs to C. bilis. In addition,

S. monacensis

is transferred to the genus Claveliimonas as Claveliimonas monacensis comb. nov.
Pyruvate dehydrogenase kinase expression profile is a biomarker for cancer sensitivity to dichloroacetate-mediated growth inhibition
Authors: Gang Bevan P , Rooke Melissa , Sun Ramon C , Banskota Samagya , Mishra Sheenu , Dahlstrom Jane E , Blackburn Anneke C
Published: September 2023

Background

Cancer cells favour glycolysis and lactate production over mitochondrial metabolism despite the presence of oxygen (the Warburg effect). Increased pyruvate dehydrogenase kinase (PDK) activity contributes to this glycolytic phenotype. Dichloroacetate (DCA) is a PDK inhibitor with anti-cancer potential that inhibits all four isoforms of PDK but with differing potencies, thus expression of different isoforms may determine sensitivity to DCA.

Methods

The association of sensitivity to growth inhibition by DCA, on-target effects of DCA and expression of all four isoforms of PDKs in a range of epithelial cancer cell lines was investigatedin vitroandin vivo.

Results

DCA inhibited growth of cancer cellsin vivoandin vitro,reduced pyruvate dehydrogenase phosphorylation and reduced lactate production. The magnitude of the effect of DCA on growth was variable and correlated with the PDK expression profiles of the cells, with low expression of PDK3 (highest Kifor DCA) conferring the highest sensitivity towards DCA. PDK2 siRNA-knockdown inhibited growth to a similar extent to DCA, whilst PDK3 knockdown significantly increased sensitivity to DCA.

Conclusion

The PDK expression profile is a potential biomarker for sensitivity to DCA, and should be considered when translating PDK inhibitors into clinical use.
Testing Adaptive Therapy Protocols using Gemcitabine and Capecitabine on a Mouse Model of Endocrine-Resistant Breast Cancer
Authors: Seyedi Sareh , Teo Ruthanne , Foster Luke , Saha Daniel , Mina Lida , Northfelt Donald , Anderson Karen S. , Shibata Darryl , Gatenby Robert , Cisneros Luis , Troan Brigid , Anderson Alexander R. A. , Maley Carlo C.
Published: September 2023

Highly effective cancer therapies often face limitations due to acquired resistance and toxicity. Adaptive therapy, an ecologically inspired approach, seeks to control therapeutic resistance and minimize toxicity by leveraging competitive interactions between drug-sensitive and drug-resistant subclones, prioritizing patient survival and quality of life over maximum cell kill. In preparation for a clinical trial in breast cancer, we used large populations of MCF7 cells to rapidly generate endocrine-resistance breast cancer cell line. We then mimicked second line therapy in ER+ breast cancers by treating the endocrine-resistant MCF7 cells in a mouse xenograft model to test adaptive therapy with capecitabine, gemcitabine, or the combination of those two drugs. Dose-modulation adaptive therapy with capecitabine alone increased survival time relative to MTD, but not statistically significant (HR: 0.22, 95% CI 0.043-1.1 P = 0.065). However, when we alternated the drugs in both dose modulation (HR = 0.11, 95% CI: 0.024 - 0.55, P = 0.007) and intermittent adaptive therapies significantly increased survival time compared to high dose combination therapy (HR = 0.07, 95% CI: 0.013 - 0.42; P = 0.003). Overall, survival time increased with reduced dose for both single drugs (P < 0.01) and combined drugs (P < 0.001). Adaptive therapy protocols resulted in tumors with lower proportions of proliferating cells (P = 0.0026) and more apoptotic cells (P = 0.045). The results show that Adaptive therapy outperforms high-dose therapy in controlling endocrine-resistant breast cancer, favoring slower-growing tumors, and showing promise in two-drug alternating regimens.
Enhancing Luciferase Activity and Stability through Generative Modeling of Natural Enzyme Sequences
Authors: Xie Wen Jun , Liu Dangliang , Wang Xiaoya , Zhang Aoxuan , Wei Qijia , Nandi Ashim , Dong Suwei , Warshel Arieh
Published: September 2023

The availability of natural protein sequences synergized with generative artificial intelligence (AI) provides new paradigms to create enzymes. Although active enzyme variants with numerous mutations have been produced using generative models, their performance often falls short compared to their wild-type counterparts. Additionally, in practical applications, choosing fewer mutations that can rival the efficacy of extensive sequence alterations is usually more advantageous. Pinpointing beneficial single mutations continues to be a formidable task. In this study, using the generative maximum entropy model to analyzeRenillaluciferase homologs, and in conjunction with biochemistry experiments, we demonstrated that natural evolutionary information could be used to predictively improve enzyme activity and stability by engineering the active center and protein scaffold, respectively. The success rate of designed single mutants is ∼50% to improve either luciferase activity or stability. These finding highlights nature’s ingenious approach to evolving proficient enzymes, wherein diverse evolutionary pressures are preferentially applied to distinct regions of the enzyme, ultimately culminating in an overall high performance. We also reveal an evolutionary preference inRenillaluciferase towards emitting blue light that holds advantages in terms of water penetration compared to other light spectrum. Taken together, our approach facilitates navigation through enzyme sequence space and offers effective strategies for computer-aided rational enzyme engineering.
Neurorehabilitation of the upper extremity – Immersive virtual reality vs. robot-assisted training. A comparative study
Authors: Lülsdorff Kira , Junker Frederick Benjamin , Studer Bettina , Wittenberg Heike , Pickenbrock Heidrun , Schmidt-Wilcke Tobias
Published: September 2023

Background

Severe paresis of the contralesional upper extremity is one of the most common and debilitating post-stroke impairments. The need for cost-effective high-intensity training is driving the development of new technologies, which can complement and extent conventional therapies. Apart from established methods using robotic devices, immersive virtual reality (iVR) systems hold promise to provide cost-efficient high-intensity arm training.

Objective

We investigated whether iVR-based arm training yields at least equivalent effects on upper extremity function as compared to a robot-assisted training in stroke patients with severe arm paresis.

Methods

52 stroke patients with severe arm paresis received a total of ten daily group therapy sessions over a period of three weeks, which consisted of 20 minutes of conventional therapy and 20 minutes of either robot-assisted (ARMEOSpring®) or iVR-based (CUREO®) arm training. Changes in upper extremity function was assessed using the Action Research Arm Test (ARAT) and user acceptance was measured with the User Experience Questionnaire (UEQ).

Results

iVR-based training was not inferior to robot-assisted training. We found that 84% of patients treated with iVR and 50% of patients treated with robot-assisted arm training showed a clinically relevant improvement of upper extremity function. This difference could neither be attributed to differences between the groups regarding age, gender, duration after stroke, affected body side or ARAT scores at baseline, nor to differences in the total amount of therapy provided.

Conclusion

The present study results show that iVR-based arm training seems to be a promising addition to conventional therapy. Potential mechanisms by which iVR unfolds its effects are discussed.

Registry number

DRKS00032489
Comparison of Inter-Joint Coordination Strategies during Activities of Daily Living with Prosthetic and Anatomical Limbs
Authors: Lee Christina , Gates Deanna
Published: September 2023

While healthy individuals have redundant degrees of freedom of the joints, they coordinate their multi-joint movements such that the redundancy is effectively reduced. Achieving high inter-joint coordination may be difficult for upper limb prosthesis users due to the lack of proprioceptive feedback and limited motion of the terminal device. This study compared inter-joint coordination between prosthesis users and individuals without limb loss during different upper limb activities of daily living (ADLs). Nine unilateral prosthesis users (five males) and nine age- and sex-matched controls without limb loss completed three unilateral and three bilateral ADLs. Principal component analysis was applied to the three-dimensional motion trajectories of the trunk and arms to identify coordinative patterns. For each ADL, we quantified the cumulative variance accounted for (VAF) of the first five principal components (pcs), which was the lowest number of pcs that could achieve 90% VAF in control limb movements across all ADLs (5 < n < 9). The VAF was lower for movements involving a prosthesis compared to those completed by controls across all ADLs (p < 0.001). The pc waveforms were similar between movements involving a prosthesis and movements completed by control participants for pc1 (r > 0.78, p < 0.001). The magnitude of the relationship for pc2 and pc3 differed between ADLs, with the strongest correlation for symmetric bilateral ADLs (0.67 < r < 0.97, p < 0.001). Collectively, this study demonstrates that activities of daily living are less coordinated for prosthesis users compared to individuals without limb loss. Future work should explore how device features, such as the availability of sensory feedback or motorized wrist joints influence multi-joint coordination.
Development of a Neoadjuvant Treatment Pathway to Standardize Pancreatic Cancer Care and Improve Outcomes Across a Large Diverse Health System
Authors: Parakrama Ruwan , Sidiqi Baho U. , Demyan Lyudmyla , Standring Oliver , Cooper Dylan J. , Pasha Shamsher , Pinto Danielle M , Zavadsky Tiffany , Zou Xianghui , Patruni Sunita , Kapusta Adrianna , Nosrati Jason , Tchelebi Leila T. , Weiss Matthew J. , Herman Joseph M. , King Daniel A.
Published: September 2023

Background

Management of localized pancreatic cancer is variable. We describe the development of a neoadjuvant therapy pathway (NATP) to standardize care across a large healthcare system.

Methods

We conducted an IRB-approved retrospective analysis of NATP patients between June 2019 and March 2022. The primary endpoint was NATP completion, and secondary endpoints included overall survival (OS) and quality measures.

Results

Fifty-nine patients began NATP, median age 70, locally advanced 44.1%. Median time on NATP was 6.1 months. The initial chemotherapy was FOLFIRINOX (64.2%) and gemcitabine/nab-paclitaxel (GnP; (35.6%)) followed by radiation in 32 (54.2%) patients. Forty-four (74.6%) completed the NATP and 30 (50.8%) underwent surgical exploration with 86.7% undergoing successful resection (61.5% R0, 23.1% R1) while 14 remained unresectable. NATP completion was associated with increased likelihood of resection (p<0.001). At median follow-up of 13.4 months, median OS was 20.9 months (95% CI 13.3- 28.5) and 1- and 2-year OS was 82.5% and 49.7%. NATP completion resulted in improved OS with median OS not reached and 1- and 2-year OS of 89.7% and 59.4% (p=0.004). Median time to NATP start was 20 days after MDR and median time to surgery was 35 days. Age, ECOG, surgical stage, chemotherapy regimen and NATP completion were significant univariable predictors of OS with ECOG status remaining significant on multivariable analysis.

Conclusion

Our outcomes provide a baseline for future guidance in improving care across a large system. Efforts to complete NATP and improve patient ECOG may result in more patients undergoing surgery and improve survival.
Rare variation in noncoding regions with evolutionary signatures contributes to autism spectrum disorder risk
Authors: Shin Taehwan , Song Janet H.T. , Kosicki Michael , Kenny Connor , Beck Samantha G. , Kelley Lily , Qian Xuyu , Bonacina Julieta , Papandile Frances , Antony Irene , Gonzalez Dilenny , Scotellaro Julia , Bushinsky Evan M. , Andersen Rebecca E. , Maury Eduardo , Pennacchio Len A. , Doan Ryan N. , Walsh Christopher A.
Published: September 2023

Little is known about the role of noncoding regions in the etiology of autism spectrum disorder (ASD). We examined three classes of noncoding regions: Human Accelerated Regions (HARs), which show signatures of positive selection in humans; experimentally validated neural Vista Enhancers (VEs); and conserved regions predicted to act as neural enhancers (CNEs). Targeted and whole genome analysis of >16,600 samples and >4900 ASD probands revealed that likely recessive, rare, inherited variants in HARs, VEs, and CNEs substantially contribute to ASD risk in probands whose parents share ancestry, which enriches for recessive contributions, but modestly, if at all, in simplex family structures. We identified multiple patient variants in HARs nearIL1RAPL1and in a VE nearSIM1and showed that they change enhancer activity. Our results implicate both human-evolved and evolutionarily conserved noncoding regions in ASD risk and suggest potential mechanisms of how changes in regulatory regions can modulate social behavior.
Atypical heat shock transcription factor HSF5 is critical for male meiotic prophase under non-stress conditions
Authors: Yoshimura Saori , Shimada Ryuki , Kikuchi Koji , Kawagoe Soichiro , Abe Hironori , Iisaka Sakie , Fujimura Sayoko , Yasunaga Kei-ichiro , Usuki Shingo , Tani Naoki , Ohba Takashi , Kondoh Eiji , Saio Tomohide , Araki Kimi , Ishiguro Kei-ichiro
Published: September 2023

Meiotic prophase progression is differently regulated in males and females. In males, pachytene transition during meiotic prophase is accompanied by robust alteration in gene expression. However, how gene expression is regulated differently to ensure meiotic prophase completion in males remains elusive. Herein, we identified HSF5 as a male germ cell-specific heat shock transcription factor (HSF) for meiotic prophase progression. Genetic analyses and single-cell RNA-sequencing demonstrated that HSF5 is essential for progression beyond the pachytene stage under non-stress conditions rather than heat stress. Chromatin binding analysisin vivoand DNA-binding assaysin vitrosuggested that HSF5 binds to promoters in a subset of genes associated with chromatin organization. HSF5 recognizes a DNA motif different from typical heat shock elements recognized by other canonical HSFs. This study suggests that HSF5 is an atypical HSF that enforces the gene expression program for pachytene transition during meiotic prophase in males.
Complex structural variation is prevalent and highly pathogenic in pediatric solid tumors
Authors: van Belzen Ianthe A.E.M. , van Tuil Marc , Badloe Shashi , Janse Alex , Verwiel Eugène T.P. , Santoso Marcel , de Vos Sam , Baker-Hernandez John , Kerstens Hindrik H.D. , Solleveld-Westerink Nienke , Meister Michael T. , Drost Jarno , van den Heuvel-Eibrink Marry M. , Merks Johannes H. M. , Molenaar Jan J. , Peng Weng Chuan , Tops Bastiaan B.J. , Holstege Frank C.P. , Kemmeren Patrick , Hehir-Kwa Jayne Y.
Published: September 2023

Background

In pediatric cancer, structural variants (SVs) and copy number alterations can contribute to cancer initiation and progression, and hence aid diagnosis and treatment stratification. The few studies into complex rearrangements have found associations with tumor aggressiveness or poor outcome. Yet, their prevalence and biological relevance across pediatric solid tumors remains unknown.

Results

In a cohort of 120 primary tumors, we systematically characterized patterns of extrachromosomal DNA, chromoplexy and chromothripsis across five pediatric solid cancer types: neuroblastoma, Ewing sarcoma, Wilms tumor, hepatoblastoma and rhabdomyosarcoma. Complex SVs were identified in 56 tumors (47%) and different classes occurred across multiple cancer types. Recurrently mutated regions tend to be cancer-type specific and overlap with cancer genes, suggesting that selection contributes to shaping the SV landscape. In total, we identified potentially pathogenic complex SVs in 42 tumors that affect cancer driver genes or result in unfavorable chromosomal alterations. Half of which were known drivers, e.g.MYCNamplifications due to ecDNA andEWSR1::FLI1fusions due to chromoplexy. Recurrent novel candidate complex events include chromoplexy inWT1in Wilms tumors, focal chromothripsis with 1p loss in hepatoblastomas and complexMDM2amplifications in rhabdomyosarcomas.

Conclusions

Complex SVs are prevalent and pathogenic in pediatric solid tumors. They represent a type of genomic variation which currently remains unexplored. Moreover, carrying complex SVs seems to be associated with adverse clinical events. Our study highlights the potential for complex SVs to be incorporated in risk stratification or exploited for targeted treatments.
Hippocampal ripples linked to recognition memory judgments in children
Authors: Norman Yitzhak , Dorfmüller Georg , Taussig Delphine , Dorison Nathalie , Fohlen Martine , Chipaux Mathilde , Ferrand-Sorbets Sarah , Bulteau Christine , Harel Michal , Malach Rafael , Levy Mikael
Published: September 2023

Intracranial studies have demonstrated significant roles for hippocampal ripples in human declarative memory. Yet, the developmental trajectory and contribution of ripples to memory processes in children remain unknown. We studied hippocampal ripple activity using intracranial recordings in 14 children (age: 6-14) undergoing epilepsy monitoring. After watching a pink panther cartoon twice, participants engaged in an old/new recognition test, determining whether events portrayed in short (4s) videoclips stemmed from the cartoon they had just viewed. Our results reveal a significant rise in ripple rate during successful recognition of familiar events. An anticipatory decline in ripple rate preceded recognition errors. Interestingly, when participants viewed the cartoon passively during the initial full-length screenings, the overall temporal pattern of ripple activation remained consistent across repetitions, and significantly distinct from explicit recognition. We conclude that hippocampal ripples in children play a key role in declarative memory, supporting the explicit identification of previously encountered events.
Within-host rates of insertion and deletion in the HIV-1 surface envelope glycoprotein
Authors: Palmer John , Novitsky Vlad , Ferreira Roux-Cil , Poon Art F. Y.
Published: September 2023

Under selection by neutralizing antibodies, the HIV-1 envelope glycoprotein gp120 undergoes rapid evolution within hosts, particularly in regions encoding the five variable loops (V1-V5). Indel polymorphisms are abundant in these loops, where they can facilitate immune escape by modifying the length, composition and glycosylation profile of these structures. Here, we present a comparative analysis of within-host indel rates and characteristics within the variable regions of gp120. We analyzed a total of 3,437 HIV-1 gp120 sequences sampled longitudinally from 29 different individuals using coalescent models in BEAST. Next, we used Historian to reconstruct ancestral sequences from the resulting tree samples, and fit a Poisson generalized linear model to the distribution of indel events to estimate their rates in the five variable loops. Overall, the mean insertion and deletion rates were 1.6 × 10−3and 2.5 × 10−3/ nt / year, respectively, with significant variation among loops. Insertions and deletions also followed similar length distributions, except for significantly longer indels in V1 and V4 and shorter indels in V5. Insertions in V1, V2, and V4 tended to create new N-linked glycosylation sites significantly more often than expected by chance, which is consistent with positive selection to alter glycosylation patterns.
Human force control may trade-off force error with central tendency and recency biases
Authors: Ryu Hansol X. , Srinivasan Manoj
Published: September 2023

Understanding how humans control force is useful for understanding human movement behaviors and sensorimotor control. However, it is not well understood how the human nervous system handles different control criteria such as accuracy and energetic cost. We conducted force tracking experiments where participants applied force isometrically while receiving visual force feedback, tracking step changes in target forces. The experiments were designed to disambiguate different plausible objective function components. We found that force tracking error was largely explained by a trade-off between error-reducing tendency and force biases, but we did not need to include an effort-saving tendency. Central tendency bias, which is a shift towards the center of the task distribution, and recency bias, which is a shift towards recent action, were necessary to explain many of our observations. Surprisingly, we did not observe such biases when we removed force requirements for pointing to the target, suggesting that such biases may be task-specific. This study provides insights into the broader field of motor control and human perceptions where behavioral or perceptual biases are involved.
The larva and adult ofHelicoverpa armigerause differential gustatory receptors to sense sugars
Authors: Zhang Shuai-Shuai , Wang Pei-Chao , Ning Chao , Yang Ke , Li Guo-Cheng , Cao Lin-Lin , Huang Ling-Qiao , Wang Chen-Zhu
Published: September 2023

Almost all herbivorous insects feed on plants and use sucrose as a feeding stimulant, but the molecular basis of their sucrose reception remains unclear.Helicoverpa armigeraas a notorious crop pest worldwide mainly feeds on reproductive organs of many plant species in the larval stage, and its adult draws nectar. In this study, we determined that the sucrose sensory neurons located in the contact chemosensilla of larval maxillary galeae were 100–1000 times more sensitive to sucrose than those of adult antennae, tarsi and proboscis. Using theXenopusexpression system, we discovered that Gr10 highly expressed in the larval sensilla was specifically tuned to sucrose, while Gr6 highly expressed in the adult sensilla responded to fucose, sucrose and fructose. Moreover, using CRISPR/Cas9, we revealed that Gr10 was mainly used by larvae to detect lower sucrose, while Gr6 was primarily used by adults to detect higher sucrose and other saccharides, which results in differences in selectivity and sensitivity between larval and adult sugar sensory neurons. Our results demonstrate the sugar receptors in this moth are evolved to adapt towards the larval and adult foods with different types and amounts of sugar, and fill in a gap in sweet taste of animals.
Etifoxine inhibits NLRP3 inflammasome activity in human and murine myeloid cells
Authors: Osmond Jordan M. , Williams John B. , Matthews Paul M. , Owen David R. , Moore Craig S.
Published: September 2023

Background

Multiple sclerosis (MS) is a chronic neuroinflammatory disease that is characterized by immune-mediated demyelination within the central nervous system. NLRP3 inflammasome activation has been previously reported as a possible pathophysiological contributor to microglial activation and oligodendroglial loss in MS, particularly in progressive forms of the disease.

Methods

Using bothin vivoandin vitroapproaches, this report investigated the use of a previously described ligand of the 18kDa translocator protein (TSPO), etifoxine, as an immunomodulator that inhibits inflammasome activation in primary human and murine macrophages and microglia. To further elucidate pathologic relevance in the MS context, investigations were also performedex vivousing peripheral blood mononuclear cells and purified CD14+monocytes derived from secondary progressive MS patients.

Results

Herein, it is demonstrated that etifoxine attenuated clinical symptoms in a mouse model of MS and significantly inhibited NLRP3 inflammasome activation in human and murine myeloid-derived cellsin vitroby decreasing inflammasome-associated genes and inflammatory cytokine production. These anti-inflammatory effects of etifoxine were mediated independently of its previously described mechanisms related to engagement with TSPO and the GABAAreceptor. Furthermore, we observed a similar anti-inflammatory effect of etifoxine on MS patient-derived monocytes, which provides clinical relevance for the investigation of etifoxine as a potential therapeutic in progressive MS. Lastly, through the use of a gene array, we identified multiple signalling pathways in order to elucidate a novel mechanism whereby etifoxine may be inhibiting NLRP3 inflammasome activation.

Conclusions

Our results suggest that the anti-inflammatory effects of etifoxine were mediated independently of its previously described mechanisms related to engagement with TSPO and the GABAAreceptor. Furthermore, we observed an anti-inflammatory effect in murine- and human-derived myeloid cells, as well as in MS patient-derived monocytes, which provides clinically relevant evidence to support the exploration of etifoxine as a possible form of therapy for secondary progressive MS.
Inverted transflection spectroscopy of live cells using metallic grating on elevated nanopillars
Authors: Mahalanabish Aditya , Huang Steven H. , Shvets Gennady
Published: September 2023

Water absorption of mid-infrared (MIR) radiation severely limits the options for vibrational spectroscopy of the analytes – including live biological cells – that must be probed in aqueous environments. While internal reflection elements, such as attenuated total reflection prisms and metasurfaces, partially overcome this limitation, such devices have their own limitations: high cost, incompatibility with standard cell culture workflows, limited spectral range, and small penetration depth into the analyte. In this work, we introduce an alternative live cell biosensing platform based on metallic nanogratings fabricated atop elevated dielectric pillars. For the MIR wavelengths that are significantly longer than the grating period, reflection-based spectroscopy enables broadband sensing of the analytes inside the trenches separating the dielectric pillars. Because the depth of the analyte twice-traversed by the MIR light excludes the highly absorbing thick water layer above the grating, we refer to the technique as Inverted Transflection Spectroscopy (ITS). We demonstrate the analytic power of ITS by measuring protein concentrations in solution. The ability of ITS to interrogate live cells that naturally wrap themselves around the grating is also exploited to characterize their adhesion kinetics.
Crop improvement can accelerate agriculture adaptation to societal demands and climate change
Authors: Messina Carlos D , Borras Lucas , Tang Tom , Cooper Mark
Published: September 2023

A key question today is how to harmonize future crop improvement efforts for regenerative cropping systems that can mitigate further environmental degeneration and improve societal adaptation to climate change. Here we show that the US corn-belt based maize improvement system has been adapting to the changing climate. Analyses of the longest running field experiment (1990-2021) designed to quantify yield gains (37 hybrids sold from 1930 to 1990) demonstrate that rates of genetic gain were always positive and have increased over time (from 70 to 150 kg ha-1y-1in 1990 and 2021, respectively). Between 1930 and 2021 for the May through October period total rainfall for the U.S. corn belt increased 113 mm, and daily temperature amplitude decreased 1.3°C. At the same time, farmers modified their farming practices, helping modern hybrids to out-perform their older counterparts by a larger degree. In contrast to the conclusions reached by other observational studies, genetic gain estimates demonstrate that maize breeding and the production system are adapting to modern scenarios. Climate change is commonly linked to fears of food insecurity, but new cropping systems capable of providing food while regenerating resources such as water, the circularization of nutrients, and reduction of greenhouse gas emissions are possible.
PHYLOGENETIC ANALYSIS OF THErfbLOCUS GENES OF THE GENUSLeptospiraOF SEROGROUPS SERJOE, MINI AND HEBDOMADIS
Authors: Barros Setúbal Ruth Flávia , de Santana Souza Jorge Estefano , Venturim Cosate Maria Raquel , Sakamoto Tetsu
Published: September 2023

Leptospirosis is a zoonosis of great impact on public health since it is considered a notifiable disease occurring mainly in tropical regions with poor sanitation and vulnerable socioeconomic conditions. It is caused by bacteria of the genus Leptospira and phylum Spirochaetes and contamination occurs through direct or indirect contact with the contaminating agent. In addition to taxonomic classification, which is performed through sequencing and the analysis of some marker genes, such as 16S rRNA andsecY, they are usually classified based on their antigenic characteristics into serogroups and serovars. This kind of classification is largely applied in epidemiological studies and vaccine development. Despite its importance, few studies have been conducted to understand the evolutionary dynamics of the emergence or change of serology in this genus. In view of this, we applied phylogenetic methods in order to understand the evolutionary processes involving the serology of the genus. To this end, sequences of genes comprising therfblocus from samples of serogroups Sejroe, Mini, and Hebdomadis (34 samples) were extracted and submitted to the phylogenetic pipeline, resulting in the inference of 75 maximum likelihood trees. Topology tests showed that most of the gene trees are significantly different from the species tree. We could depict the occurrence of lateral gene transfer betweenL. borgpeterseniiandL. kirschneri; andL. interrogansandL. weilli. In this analysis, no evidence was found for the lateral gene transfer between samples of the Hardjo serovar ofL. interrogansandL. borgpetersenii. Thus, it is also suggested that the occurrence of horizontal transfer of genes from therfblocus between distinct species is less frequent than expected.
Consistent specificity and efficiency of tamoxifen-mediated cre induction across ages
Authors: Kellogg Collyn M. , Pham Kevin , Ko Sunghwan , Cox Jillian E. J. , Machalinski Adeline H. , Stout Michael B. , Sharpe Amanda L. , Beckstead Michael J. , Chucair-Elliott Ana J. , Ocañas Sarah R. , Freeman Willard M.
Published: September 2023

Temporally controlling cre recombination through tamoxifen (Tam) induction has many advantages for biomedical research. Most studies report Tam induction at early post-natal/juvenile (<2 m.o.) mouse ages, but age-related neurodegeneration and aging studies can require cre induction in older mice (>12 m.o.). While anecdotally reported as problematic, there are no published comparisons of Tam mediated cre induction at early and late ages. Here, microglial-specific Cx3cr1creERT2mice were crossed to a floxed NuTRAP reporter to compare cre induction at early (3-6 m.o.) and late (20 m.o.) ages. Specificity and efficiency of microglial labeling at 21-22 m.o. were identical in mice induced with Tam at 3-6 m.o. or 20 m.o. of age. Age-related microglial translatomic changes were also similar regardless of Tam induction age. Each cre and flox mouse line should be validated independently, however, these findings demonstrate that Tam-mediated cre induction can be performed even into older mouse ages.
Leukemic mutation FLT3-ITD is retained in dendritic cells and disrupts their homeostasis leading to expanded Th17 frequency
Authors: Flynn Patrick A , Long Mark D , Kosaka Yoko , Mulkey Jessica S , Coy Jesse L , Agarwal Anupriya , Lind Evan F
Published: September 2023

Dendritic cells (DC) are mediators of adaptive immune responses to pathogens and tumors. DC development is determined by signaling through the receptor tyrosine kinase Fms-like tyrosine kinase 3 (FLT3) in bone marrow myeloid progenitors. Recently the naming conventions for DC phenotypes have been updated to distinguish between “Conventional” DCs (cDCs) and plasmacytoid DCs (pDCs). Activating mutations of FLT3, including Internal Tandem Duplication (FLT3-ITD), are associated with poor prognosis for leukemia patients. To date, there is little information on the effects of FLT3-ITD in DC biology. We examined the cDC phenotype and frequency in bone marrow aspirates from patients with acute myeloid leukemia (AML) to understand the changes to cDCs associated with FLT3-ITD. When compared to healthy donor (HD) we found that a subset of FLT3-ITD+ AML patient samples have overrepresented populations of cDCs and disrupted phenotypes. Using a mouse model of FLT3-ITD+ AML, we found that cDCs were increased in percentage and number compared to control wild-type (WT) mice. Single cell RNA-seq identified FLT3-ITD+ cDCs as skewed towards a cDC2 T-bet-phenotype, previously shown to promote Th17 T cells. We assessed the phenotypes of CD4+ T cells in the AML mice and found significant enrichment of both Treg and Th17 CD4+ T cells. Furthermore, co-culture of AML mouse- derived DCs and naïve OT-II cells preferentially skewed T cells into a Th17 phenotype. Together, our data suggests that FLT3-ITD+ leukemia-associated cDCs polarize CD4+ T cells into Th17 subsets, a population that has been shown to be negatively associated with survival in solid tumor contexts. This illustrates the complex tumor microenvironment of AML and highlights the need for further investigation into the effects of FLT3-ITD mutations on DC phenotypes.
A fine-scale genetic map of the Japanese population
Authors: Takayama Jun , Makino Satoshi , Funayama Takamitsu , Ueki Masao , Narita Akira , Murakami Keiko , Orui Masatsugu , Ishikuro Mami , Obara Taku ,   the Tohoku Medical Megabank Project Study Group, Kuriyama Shinichi , Yamamoto Masayuki , Tamiya Gen
Published: September 2023

Genetic maps are fundamental resources for linkage and association studies. A fine-scale genetic map can be constructed by inferring historical recombination events from the genome-wide structure of linkage disequilibrium—a non-random association of alleles among loci—by using population-scale sequencing data. We constructed a fine-scale genetic map and identified recombination hotspots from 10,092,573 bi-allelic high-quality autosomal markers segregating among 150 unrelated Japanese individuals. These individuals’ genotypes were determined by high-coverage (30×) whole-genome sequencing, and the genotype quality was carefully controlled by using their parents’ and offspring’s genotypes. The pedigree information was also utilized for haplotype phasing. The resulting genome-wide recombination rate profiles were concordant with those of the HapMap worldwide population on a broad scale, and the resolution was much improved. We identified 9487 recombination hotspots and confirmed the enrichment of previously known motifs in the hotspots. Moreover, we demonstrated that the Japanese genetic map improved the haplotype phasing and genotype imputation accuracy for the Japanese population. The construction of a population-specific genetic map will help make genetics research more accurate.
Measuring Depression, and Its Association with Substance Use, during an Adherence Study of Patients Treated for Tuberculosis in Haitian Prisons
Authors: Ekwebelem Lovette C. , Bury Margarette R. , Prophete Edwin J. , Duverger Karine , Bircher Patrick M. , Spaulding Anne C.
Published: September 2023

Purpose

Diagnosed depression is prevalent in prisons of affluent countries; literature on depression screening in prisons of low-resource nations is sparse. Haiti has experienced multiple recent disasters, which could have both somatic and mental health consequences. To surveil its prisons for depression, ethnoculturally appropriate scales could be helpful.

Design/methodology/approach

We performed a cross-sectional analysis of symptoms of depression and its associations among participants in a 2019-2020 tuberculosis treatment adherence project across 6 Haitian prisons. To measure depression, we piloted the use of the Zanmi-Lasante Depression Symptom Inventory (ZLDSI) scale in a carceral setting. We calculated its Cronbach alpha in this setting and generated binary logistic models to study the associations of depression with basic demographic variables; use of cigarettes, marijuana, and alcohol; and incarceration history. We then performed a multivariate logistic regression to determine if substance use and education predicted depression, after adjusting for age.

Findings

Fifty subjects were recruited; age ranged from 18 to 59 years. Adherence to TB medication was recorded as above 99% in all subjects. The Cronbach alpha score for the ZLDSI scale in this population was 0.77, signifying the good fit of the scale for this population. A ZLDSI score ≥13.0 has been associated with depression; 66% of participants had scores of 13.0 or greater, mean 13.9 (S.D. 8.2). Multivariate analysis showed significant associations between depression, alcohol consumption, age, and income.

Originality/Conclusion

We believe this study represents the first measurement of depressive symptoms in a Haitian prison population; it found symptoms common.
Healthcare system barriers impacting the care of Canadians with myalgic encephalomyelitis: a scoping review
Authors: Hussein Said , Eiriksson Lauren , MacQuarrie Maureen , Merriam Scot , Dalton Maria , Stein Eleanor , Twomey Rosie
Published: September 2023

Background

Myalgic encephalomyelitis (ME, also known as chronic fatigue syndrome or ME/CFS) is a debilitating, complex, multi-system illness. Developing a comprehensive understanding of the multiple and interconnected barriers to optimal care will help advance strategies and care models to improve quality of life for people living with ME in Canada.

Objectives

To: (1) identify and systematically map the available evidence; (2) investigate the design and conduct of research; (3) identify and categorize key characteristics; and (4) identify and analyze knowledge gaps related to healthcare system barriers for people living with ME in Canada.

Methods

The protocol was preregistered in July 2022. Peer-reviewed and grey literature was searched, and patient partners retrieved additional records. Eligible records were Canadian, included people with ME/CFS and included data or synthesis relevant to healthcare system barriers.

Results

In total, 1821 records were identified, 406 were reviewed in full, and 21 were included. Healthcare system barriers arose from an underlying lack of consensus and research on ME and ME care; the impact of long-standing stigma, disbelief, and sexism; inadequate or inconsistent healthcare provider education and training on ME; and the heterogeneity of care coordinated by family physicians.

Conclusions

People living with ME in Canada face significant barriers to care, though this has received relatively limited attention. This synthesis, which points to several areas for future research, can be used as a starting point for researchers, healthcare providers and decision-makers who are new to the area or encountering ME more frequently due to the COVID-19 pandemic.

Funding

This study was funded by the University of Calgary (VPR Catalyst Grant) and the Interdisciplinary Canadian Collaborative ME (ICanCME) Research Network (New Frontier ME Discovery Grant).
Texture-based Probability Mapping in cardiac LGE Images: A novel automatic assessment of myocardial injury following revascularized STEMI
Authors: Frøysa Vidar , Berg Gøran J. , Singsaas Erlend , Eftestøl Trygve , Woie Leik , Ørn Stein
Published: September 2023

Background

Scar size is critical to left ventricular (LV) remodeling and adverse outcomes following myocardial infarction (MI). Late Gadolinium-enhancement (LGE) in cardiac magnetic resonance imaging is the gold standard for assessing MI size. Texture-based probability mapping (TPM) is a novel machine learning-based analysis of LGE images. This proof-of-concept study investigates the potential clinical implications of temporal changes in TPM during the first year following an acute revascularized MI.

Methods

41 patients with first-time acute ST-elevation MI were included in this study. All patients had a single-vessel disease and were successfully revascularized by primary percutaneous coronary intervention. LGE images were obtained two days, one week, two months, and one year post-MI. MI size by TPM was compared with manual LGE-based MI calculation, LV remodeling, and biomarkers.

Results

TPM showed a significant increase in infarct size from the second month through the first year (p<0.01). MI size estimated by TPM at all different time points demonstrated strong correlations with peak Troponin T levels. At one week, TPM assessment correlated positively with maximum C-reactive protein (r=0.54, p<0.01), and at two months, TPM positively correlated with N-Terminal Pro Brain Natriuretic Peptide.

Conclusion

This proof-of-concept study suggests that TPM may provide additional information to conventional LGE-based MI analysis of scar formation, LV remodeling, and biomarkers following an acute revascularized MI.

Highlights

Texture-based probability mapping (TPM) was used to analyze consecutive cardiac magnetic resonance images acquired during the first year after ST-elevation myocardial infarction (STEMI).

TPM size was related to biomarkers of inflammation, myocardial injury and stress.

TPM is a step toward automatic image processing.