bluuebunny/crossref_metadata_2025 huggingface dataset:
The Potential Utility of Single-Dose Long-Acting Intravenous Antibiotics for Acute Bacterial Skin and Skin-Structure Infections in the Emergency Department
Authors: Weant Kyle A. , Gregory Haili
Published: July 2023

Acute bacterial skin and skin-structure infections (ABSSSIs) are frequent clinical presentations to emergency departments (EDs) across the nation that can require substantial resources to treat due to several factors. These include an increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) as the causative organism, limited availability of oral antibiotics that treat ABSSSIs secondary to MRSA, absorption and pharmacodynamic concerns with oral therapy, and regimen adherence. In patients who are unable to tolerate oral therapy, or are unable to adhere to prescribed antibiotics, inpatient admission for intravenous (IV) antibiotics may be necessary. Although inpatient IV antibiotics used to treat MRSA, such as vancomycin, are relatively inexpensive, hospital admission itself incurs significant associated costs. The introduction of the long-acting lipoglycopeptides, dalbavancin and oritavancin, has many potential advantages for the treatment of ABSSSIs including one- or two-dose regimens, allowing patients to receive their dose in the ED or infusion center and avoid inpatient admission altogether. Existing data have borne out these results, demonstrating that these agents can significantly reduce the length of hospital stay and the overall treatment cost of ABSSSIs. However, as these agents have nontraditional therapeutic regimens compared with alternative IV and oral agents that require consistent dosing, it is imperative to have decision support tools in place to ensure that this therapy is utilized in appropriate patients with ABSSSIs and that its true benefits can be realized for both the patient and the health care system.
Atopic Dermatitis
Authors: Gooch Michael D. , Jordan Kathleen S.
Published: July 2023

Emergency nurse practitioners are expected to assess and manage a variety of patients. These patients may present with urgent care-type complaints to severe life-threatening illnesses or injuries. For some, dermatological problems can sometimes be just as challenging as a critically ill patient. Atopic dermatitis (AD) is one, if not, the most common chronic inflammatory disease. Its presentation can vary depending on the age of the patient, the patient's skin tone, and other comorbidities. Patients often seek emergency care related to the condition itself or associated complications. This article includes a review of the pathophysiology, clinical manifestations, and standard management of AD. Finally, the potential complications of AD are discussed. A better understanding of AD will allow emergency nurse practitioners to properly identify and treat this chronic condition, as well as its complications.
The Diagnostic Challenge of an Older Adult With Epigastric Pain in the Emergency Department
Authors: Hoyt Karen Sue , Jordan Kathleen S.
Published: July 2023

Epigastric pain is a common complaint in patients who present to the emergency department (ED); abdominal pain is the most common chief complaint in older adult patients who request treatment by a provider (A. B. Friedman et al., 2022). These patients may experience atypical presentations, which can result in delayed or missed diagnosis altogether, increasing morbidity, and mortality. This is the case of an older adult man who presented with chest and epigastric pain. The clinical presentation, atypical signs, and symptoms of gangrenous gallbladder are presented herein along with the differential diagnoses and diagnostics for this patient. The care for and the “what not to miss” in the management of this patent are also examined in this article. It is imperative that ED providers diagnose gangrenous gallbladder early on, especially in the older adult population, who may present with covert signs and symptoms to prevent complications and avoid poor outcomes including death in this age group.
Patient and Provider Gender and Kidney Transplant Referral in Canada: A Survey of Canadian Healthcare Providers
Authors: Thanamayooran Aran , Foster Bethany J. , Tennankore Karthik K. , Vinson Amanda J.
Published: July 2023

Background.

Referral for kidney transplant (KT) is variable, with women often disadvantaged. This study aimed to better characterize Canadian transplant referral practices and identify potential differences by respondent and/or patient gender using surveys targeted at healthcare practitioners (HCPs) involved in KT.

Methods.

Surveys consisting of 25 complex patient cases representing 7 themes were distributed to KT HCPs across Canada (March 3, 2022–April 27, 2022) using national nephrology/transplant society email registries. Respondents were asked whether they would refer the patient for transplant. Two identical surveys were created, differing only by gender/gender pronouns used in each case. Multivariable logistic regression was used to assess the association of respondent demographics and patient themes (including case gender) with the odds of transplant referral (overall and stratifying by respondent gender).

Results.

Overall, the referral rate was 58.0% among 97 survey respondents (46.4% male). Case themes associated with a lower likelihood of referral included adherence concerns (adjusted odds ratio [aOR] 0.65; 95% confidence interval [CI], 0.45-0.94), medical complexity (aOR 0.57; 95% CI, 0.38-0.85), and perceived frailty (aOR 0.63; 95% CI, 0.47-0.84). Respondent gender was not associated with differences in KT referral (aOR 0.91; 95% CI, 0.65-1.26 for male versus female respondents) but modified the association of frailty (less referral for male than female respondents, P = 0.005) and medical complexity (less referral for female than male respondents, P = 0.009) with referral. There were no differences in referral rate by case gender (P = 0.82).

Conclusions.

KT referral practices vary among Canadian HCPs. In this study, there were no differences in likelihood of transplant referral by candidate gender.
Adipose-derived stem cell exosomes ameliorate traumatic brain injury through the NLRP3 signaling pathway
Authors: Tang Linjun , Xu Yong , Wang Liangwei , Pan Jingjing
Published: July 2023

The exosomes of mesenchymal stem cells have immunoregulatory properties and can effectively mitigate secondary neuroinflammation due to traumatic brain injury (TBI). In this study, we found that adipose-derived stem cell exosomes (ADSCs-Exo) could reduce the inflammatory response after traumatic brain injury by reducing NLRP3 inflammasome secretion by microglial. ADSCs-Exo were monitored by Western blot and electron microscopy. An in-vitro lipopolysaccharide (LPS)-caused primary microglia model and a TBI rat model were constructed. Functional recovery was examined using the modified neurological severity score and foot fault tests. Inflammasome inactivation in LPS-stimulated microglial, ADSCs-Exo can reduce the secretion of interleukin (IL)-1β, IL-6 and tumor necrosis factor α. Compared with PBS-processed controls, the sensorimotor functional recovery was significantly improved by exosome treatment after injury at 14–35 days. Additionally, NLRP3 inflammasome was stimulated within 24 h after TBI. ADSCs-Exo application led to remarkable down-expression of NLRP3 and caspase-1. ADSCs-Exo can ameliorate LPS-induced inflammatory activation by reducing microglial pro-inflammatory cytokines. Moreover, the neuroprotective effect of ADSCs-Exo may be partially attributed to the inhibition thereof on the formation of NLRP3-mediated inflammasome. Such findings imply a potential function of ADSCs-Exo in treating TBI.
Defluviimonas sediminis sp. nov., isolated from mangrove sediment
Authors: Liu Lirui , Li Jiayi , Huang Yuhan , Pan Jie , Li Meng
Published: July 2023

A Gram-stain-negative, facultatively aerobic, motile and ovoid- to rod-shaped bacterium, designated as FT324T, was isolated from a surface mangrove sediment sample from Shenzhen, PR China. The taxonomic position of strain FT324T was determined by a combination of phylogenetic, physiological, biochemical and chemotaxonomic analyses. Strain FT324T grew at 20–40 °C (optimum, 30–37 °C), pH 5.0–9.0 (optimum, pH 8.0) and in the presence of 0–3 % (w/v) NaCl (optimum, 1 %). Its full-length 16S rRNA gene sequence was the most similar to

Frigidibacter oleivorans

XJ4T (97.4 %), followed by

Defluviimonas denitrificans

DSM 18921T (96.62 %),

Pseudothioclava arenosa

CAU 1312T (96.54 %) and

Defluviimonas nitratireducens

DL5-4T (96.47 %). The major fatty acids (>10 %) of FT324T were C19 : 0 cyclo ω8c (51.9 %) and summed feature 8(29.6 %). The predominant respiratory quinone was Q-10. Its polar lipid profile contained phosphatidylethanolamine, phosphatidylmethylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, one unidentified aminolipid, one unidentified lipid and two unidentified phospholipids. Its estimated genome size was 4 294 115 bp and the genomic DNA G+C content was 69.6 mol%. Based on its distinct phenotypic, chemotaxonomic and phylogenetic characteristics, strain FT324T should represent a novel species of the genus

Defluviimonas

, for which the name Defluviimonas sediminis sp. nov. is proposed (=MCCC 1K07685T=KCTC 92477T).
Mariniradius sediminis sp. nov., a multi-xenobiotics degrading genes harbouring bacterium isolated from sediment of river
Authors: Li Shucheng , Mu Weidong , Liu Haoran , Guo Bai , Mao Sidi , Su Changqing , Li Hui , Zhang Zhiqiang , Liu Aijv , Wei Shuzhen , Liu Hongliang
Published: July 2023

A Gram-stain-negative, strictly aerobic, non-motile, catalase- and oxidase-positive, pink and rod-shaped strain, designated RY-2T, was isolated from sediment of Fuyang River located in Wuqiang County, Hengshui City, Hebei Province, PR China. The strain grew at 25–45 °C (optimum, 37 °C), pH 7.0–8.0 (optimum, pH 7.0) and in the presence of 0–1.5 % (w/v) NaCl (optimum, 1 %). From the phylogenetic analysis of the 16S rRNA gene sequence, strain RY-2T was affiliated to the genus

Mariniradius

, and had the highest 16S rRNA gene sequence similarity to

Mariniradius saccharolyticus

JCM 17389T (98.3 %) and the similarity values between strain RY-2T and other type strains was all below 89.3 %. The genome size of strain RY-2T was 4.75 Mb and the DNA G+C content was 46.6 %. Values of digital DNA–DNA hybridization and average nucleotide identity between strain RY-2T and the reference strain were 63.2 and 95.5 %, respectively. The major fatty acids (≥5.0 %) were iso-C15 : 0 (37.9 %), summed feature 9 (8.4 %, iso-C17 : 1
ω9c and/or C16 : 010-methyl), anteiso-C15 : 0 (8.2 %), iso-C17 : 0 3-OH (7.6 %) and summed feature 4 (5.2 %, iso-C17 : 1 I and/or anteiso-C17 : 1 B) and its sole menaquinone was MK-7. The polar lipids consisted of phosphatidylethanolamine, an unknown phosphoglycolipid, an unidentified phospholipid, two unidentified aminolipids, three unidentified glycolipids and nine unidentified lipids. Based on the results of biochemical, physiological, phylogenomic and chemotaxonomic analyses, strain RY-2T is considered to represent a novel species of the genus

Mariniradius

within the family

Cyclobacteriaceae

, for which the name Mariniradius sediminis sp. nov. is proposed. The type strain is RY-2T (=GDMCC 1.2781T=JCM 35631T).
A mathematician’s guide to plasmids: an introduction to plasmid biology for modellers
Authors: Dewan Ian , Uecker Hildegard
Published: July 2023

Plasmids, extrachromosomal DNA molecules commonly found in bacterial and archaeal cells, play an important role in bacterial genetics and evolution. Our understanding of plasmid biology has been furthered greatly by the development of mathematical models, and there are many questions about plasmids that models would be useful in answering. In this review, we present an introductory, yet comprehensive, overview of the biology of plasmids suitable for modellers unfamiliar with plasmids who want to get up to speed and to begin working on plasmid-related models. In addition to reviewing the diversity of plasmids and the genes they carry, their key physiological functions, and interactions between plasmid and host, we also highlight selected plasmid topics that may be of particular interest to modellers and areas where there is a particular need for theoretical development. The world of plasmids holds a great variety of subjects that will interest mathematical biologists, and introducing new modellers to the subject will help to expand the existing body of plasmid theory.
Large-scale cortical networks are organized in structured cycles
Authors: van Es Mats W.J. , Higgins Cameron , Gohil Chetan , Quinn Andrew J. , Vidaurre Diego , Woolrich Mark W.
Published: July 2023

The brain needs to perform a diverse set of cognitive functions essential for survival, but it is unknown how it is organized to ensure that each of these functions is fulfilled within a reasonable period. One way in which this requirement can be met is if each of these cognitive functions occur as part of a repeated cycle. Here, we studied the temporal evolution of large-scale cortical networks, and show that while network dynamics are stochastic, the overall ordering of their activity forms a robust cyclical pattern. This cyclical structure groups states with similar function and spectral content at specific phases of the cycle and occurs at timescales of (300-1000 ms). These results are reproduced in five large magnetoencephalography (MEG) datasets. Moreover, we show that metrics that characterize the cycle strength and speed are heritable, and relate to age, cognition, and behavioural performance. These results suggest that cortical network activations are inherently cyclical, ensuring periodic activation of essential cognitive functions.
Decoding working memory information from persistent and activity-silent neurons in the primate prefrontal cortex
Authors: Thrower Lilianna , Dang Wenhao , Jaffe Rye G. , Sun Jasmine D. , Constantinidis Christos
Published: July 2023

Persistent activity of neurons in the prefrontal cortex has been thought to represent the information maintained in working memory, though alternative models have recently challenged this idea. Activity-silent theories posit that stimulus information may be maintained by the activity pattern of neurons that do not produce firing rate significantly elevated about their baseline during the delay period of working memory tasks. We thus tested the ability of neurons that do and do not generate persistent activity in the prefrontal cortex of monkeys to represent spatial and object information in working memory. Neurons that generated persistent activity represented more information about the stimuli in both spatial and object working memory tasks. The amount of information that could be decoded from neural activity depended on the choice of decoder and parameters used but neurons with persistent activity outperformed non-persistent neurons consistently. Although averaged across all neurons and stimuli, firing rate did not appear clearly elevated above baseline during the maintenance of neural activity particularly for object working memory, this grant average masked neurons that generated persistent activity selective for their preferred stimuli, which carried the majority of information about the stimulus identity. These results reveal that prefrontal neurons with generate persistent activity constitute the primary mechanism of working memory maintenance in the cortex.

NEW AND NOTEWORTHY

Competing theories suggest that neurons that generate persistent activity or do not are primarily responsible for the maintenance of information, particularly regarding object working memory. While the two models have been debated on theoretical terms, direct comparison of empirical results have been lacking. Analysis of neural activity in a large database of prefrontal recordings revealed that neurons that generate persistent activity were primarily responsible for the maintenance of both spatial and object working memory.
Taking time to compose thoughts with prefrontal schemata
Authors: Ryom Kwang Il , Basu Anindita , Stendardi Debora , Ciaramelli Elisa , Treves Alessandro
Published: July 2023

Under what conditions can prefrontal cortex direct the composition of brain states, to generate coherent streams of thoughts? Using a simplified Potts model of cortical dynamics, crudely differentiated into two halves, we show that once activity levels are regulated, so as to disambiguate a single temporal sequence, whether the contents of the sequence are mainly determined by the frontal or by the posterior half, or by neither, depends on statistical parameters that describe its microcircuits. The frontal cortex tends to lead if it has more local attractors, longer-lasting and stronger ones, in order of increasing importance. Its guidance is particularly effective to the extent that posterior cortices do not tend to transition from state to state on their own. The result may be related to prefrontal cortex enforcing its temporally-oriented schemata driving coherent sequences of brain states, unlike the atemporal “context” contributed by the hippocampus. Modelling a mild prefrontal (vs. posterior) lesion offers an account of mind-wandering and event construction deficits observed in prefrontal patients.
Vhl deletion inDmp1-expressing cells alters MEP metabolism and promotes stress erythropoiesis
Authors: Emery Janna M. , Chicana Betsabel , Taglinao Hanna , Ponce Citlaly , Donham Cristine , Padmore Hawa , Sebastian Aimy , Trasti Scott L. , Manilay Jennifer O.
Published: July 2023

In recent years, general hypoxia-inducible factor (HIF)-prolyl hydroxylase (PHD) enzyme inhibitors have been developed for the treatment of anemia due to renal disease and osteoporosis. However, it remains a challenge to target the HIF signaling pathway without dysregulating the skeletal and hematopoietic system. Here, we examined the effects ofVhldeletion in bone by performing longitudinal analyses ofVhlcKO mice at 3, 6, 10, and 24 weeks of age, where at 10 and 24 weeks of age, high bone mass and splenomegaly are present. Using flow cytometry, we observed increased frequency (%) of CD71loTER119hiFSCloorthochromatophilic erythroblasts and reticulocytes in 10- and 24-week-oldVhlcKO bone marrow (BM), which correlated with elevated erythropoietin levels in the BM and increased number of red blood cells in circulation. The absolute numbers of myeloerythroid progenitors (MEPs) in the BM were significantly reduced at 24 weeks. Bulk RNA-Seq of the MEPs showed upregulation ofEpas1(Hif1a)andEfnb2(Hif2a)inVhlcKO MEPs, consistent with a response to hypoxia, and genes involved in erythrocyte development, actin filament organization, and response to glucose. Additionally, histological analysis ofVhlcKO spleens revealed red pulp hyperplasia and the presence of megakaryocytes, both of which are features of extramedullary hematopoiesis (EMH). EMH in the spleen was correlated with the presence of mature stress erythroid progenitors, suggesting that stress erythropoiesis is occurring to compensate for the BM microenvironmental irregularities. Our studies implicate that HIF-driven alterations in skeletal homeostasis can accelerate erythropoiesis.

Key Points

• Dysregulation of HIF signaling in Dmp1+ bone cells induces stress erythropoiesis.

• Skeletal homeostasis modulates erythropoiesis.
Complementary cognitive roles for D2-MSNs and D1-MSNs during interval timing
Authors: Bruce R. Austin , Weber Matthew A. , Bova Alexandra S. , Volkman Rachael A. , Jacobs Casey E. , Sivakumar Kartik , Stutt Hannah R , Kim Young-cho , Curtu Rodica , Narayanan Nandakumar S.
Published: July 2023

The role of striatal pathways in cognitive processing is unclear. We studied dorsomedial striatal cognitive processing during interval timing, an elementary cognitive task that requires mice to estimate intervals of several seconds and involves working memory for temporal rules as well as attention to the passage of time. We harnessed optogenetic tagging to record from striatal D2- dopamine receptor-expressing medium spiny neurons (D2-MSNs) in the indirect pathway and from D1-dopamine receptor-expressing MSNs (D1-MSNs) in the direct pathway. We found that D2-MSNs and D1-MSNs exhibited distinct dynamics over temporal intervals as quantified by principal component analyses and trial-by-trial generalized linear models. MSN recordings helped construct and constrain a four-parameter drift-diffusion computational model in which MSN ensemble activity represented the accumulation of temporal evidence. This model predicted that disrupting either D2-MSNs or D1-MSNs would increase interval timing response times and alter MSN firing. In line with this prediction, we found that optogenetic inhibition or pharmacological disruption of either D2-MSNs or D1-MSNs increased interval timing response times. Pharmacologically disrupting D2-MSNs or D1-MSNs also changed MSN dynamics and degraded trial-by-trial temporal decoding. Together, our findings demonstrate that D2-MSNs and D1-MSNs had opposing dynamics yet played complementary cognitive roles, implying that striatal direct and indirect pathways work together to shape temporal control of action. These data provide novel insight into basal ganglia cognitive operations beyond movement and have implications for human striatal diseases and therapies targeting striatal pathways.
Progress Towards UNAIDS’s 95-95-95 Targets in Zimbabwe: Sociodemographic Constraints and Geospatial Heterogeneity
Authors: Chowdhury MD Tuhin , Bershteyn Anna , Milali Masabho , Citron Daniel , Nyimbili Sulani , Musuka Godfrey , Cuadros Diego F
Published: July 2023

The HIV/AIDS epidemic remains critical in sub-Saharan Africa, with UNAIDS establishing “95-95-95” targets to optimize HIV care. Using the Zimbabwe Population-based HIV Impact Assessment (ZIMPHIA) geospatial data, this study aimed to identify patterns in these targets and determinants impacting the HIV care continuum in underserved Zimbabwean communities. Analysis techniques, including Gaussian kernel interpolation, optimized hotspot, and multivariate geospatial k-means clustering, were utilized to establish spatial patterns and cluster regional HIV care continuum needs. Further, we investigated healthcare availability, access, and social determinants and scrutinized the association between socio-demographic and behavioral covariates with HIV care outcomes. Dispar-ities in progress toward the “95-95-95” targets were noted across different regions, with each target demonstrating unique geographic patterns, resulting in four distinct clusters with specific HIV care needs. Key factors associated with gaps in achieving targets included younger age, male sex, employment, and minority or no religious affiliation. Our study uncovers significant spatial heterogeneity in the HIV care continuum in Zimbabwe, with unique regional patterns in “95-95-95” targets. The spatial analysis of the UNAIDS targets presented here could prove instrumental in designing effective control strategies by identifying vulnerable communities that are falling short of these targets and require intensified efforts. Our result provides insights for designing region-specific interventions and enhancing community-level factors, emphasizing the need to address regional gaps and improve HIV care outcomes in vulnerable communities lagging behind.
The reach of reactivation: Effects of consciously-triggered versus unconsciously-triggered reactivation of associative memory
Authors: Tal Amir , Schechtman Eitan , Caughran Bruce , Paller Ken A , Davachi Lila
Published: July 2023

Newly formed memories are not passively stored for future retrieval; rather, they are reactivated offline and thereby strengthened and transformed. However, reactivation is not a uniform process: it occurs throughout different states of consciousness, including conscious rehearsal during wakefulness and unconscious processing during both wakefulness and sleep. In this study, we explore the consequences of reactivation during conscious and unconscious awake states. Forty-one participants learned associations consisting of adjective-object-position triads. Objects were clustered into distinct semantic groups (e.g., multiple fruits, vehicles, musical instruments) which allowed us to examine the consequences of reactivation on semantically-related memories. After an extensive learning phase, some triads were reactivated consciously, through cued retrieval, or unconsciously, through subliminal priming. In both conditions, the adjective was used as the cue. Reactivation impacted memory for the most distal association (i.e., the spatial position of associated objects) in a consciousness-dependent and memory-strength-dependent manner. First, conscious reactivation of a triad resulted in a weakening of other semantically related memories, but only those that were initially more accurate (i.e., memories with lower pre-reactivation spatial errors). This is similar to what has been previously demonstrated in studies employing retrieval-induced forgetting designs. Unconscious reactivation, on the other hand, benefited memory selectively for weak cued items. Semantically linked associations were not impaired, but rather integrated with the reactivated memory. Taken together, our results demonstrate that conscious and unconscious reactivation of memories during wakefulness have qualitatively different consequences on memory for distal associations. Effects are memory-strength-dependent, as has been shown for reactivation during sleep. Results support a consciousness-dependent inhibition account, according to which unconscious reactivation involves less inhibitory dynamics than conscious reactivation, thus allowing more liberal spread of activation. Our findings set the stage for additional exploration into the role of consciousness in memory structuring.
The relationships between genetic ancestry, somatic mutation frequency, and histologic subtypes in high-grade endometrial cancer
Authors: Bremseth-Vining Ryan , Borda Victor , Craig Douglas , Ruterbusch Julie J. , Boerner Julie , Fucinari Juliana , Ali-Fehmi Rouba , Elshaikh Mohamed , Abdallah Hassan , Maxwell G. Larry , Darcy Kathleen M. , Dyson Gregory , Conrads Thomas , Bateman Nicholas W. , Cote Michele L. , O’Connor Timothy D.
Published: July 2023

High-grade endometrial cancer, like numerous other cancer types, exhibits clear racial disparities in the United States for both the incidence and outcomes of the disease. While institutional factors are likely the primary contributor to these disparities, other underlying causes cannot be ignored (i.e., molecular, genetic, and histopathologic factors). This study seeks to interrogate the role that germline genetic influences, specifically genetic ancestry, may play in contributing to characteristics of high-grade endometrial cancer. This is mainly accomplished by examining the relationship between local ancestry inferences and somatic mutation frequency as well as histologic subtypes. An association between clinical characteristics and patient survival was also interrogated, and while global ancestry was seen to have no significant effect, tumor mutation burden (TMB) did impact patient survival. Here, we identify associations between local ancestry segments on chromosomes 1 and 14 and an increased TMB in self-described (SD) Black patients. We also highlight a complex relationship between heterozygous ancestry combinations within genomic regions (i.e., [European/African] vs. [African/African]) and an increase in local somatic mutation frequency.

Furthermore, we explore the relationship between local ancestry and histologic subtype. We identify one region (chr9q32) wherein the African/European local ancestry diplotype was associated with a higher incidence of serous carcinoma. We also underline a difference in somatic mutation frequency between endometrioid and serous carcinoma. While highly exploratory, these findings begin to characterize the complex relationship between genetic ancestry and characteristics of high-grade endometrial cancer, which may impact patient survival.
Shared GABA transmission pathology in dopamine agonist- and antagonist-induced dyskinesia
Authors: Abe Yoshifumi , Yagishita Sho , Sano Hiromi , Sugiura Yuki , Dantsuji Masanori , Suzuki Toru , Mochizuki Ayako , Yoshimaru Daisuke , Hata Junichi , Matsumoto Mami , Taira Shu , Takeuchi Hiroyoshi , Okano Hideyuki , Ohno Nobuhiko , Suematsu Makoto , Inoue Tomio , Nambu Atsushi , Watanabe Masahiko , Tanaka Kenji F
Published: July 2023

Dyskinesia is involuntary movement caused by long-term medication with dopamine-related agents: the dopamine agonist, L-DOPA, to treat Parkinson’s disease (L-DOPA-induced dyskinesia [LID]) or dopamine antagonists to treat schizophrenia (tardive dyskinesia [TD]). However, it remains unknown why distinct types of medications for distinct neuropsychiatric disorders induce similar involuntary movements. Here, we searched for a shared structural footprint using magnetic resonance imaging-based macroscopic screening and super-resolution microscopy-based microscopic identification. We identified the enlarged axon terminals of striatal medium spiny neurons in both LID and TD model mice. The striatal overexpression of vesicular gamma-aminobutyric acid transporter (VGAT) was necessary and sufficient for modeling these structural changes; VGAT levels gated the functional and behavioral alterations in dyskinesia models. Our findings indicate that lowered type 2 dopamine receptor signaling with repetitive dopamine fluctuations is a common cause of VGAT overexpression and late-onset dyskinesia formation, and that reducing dopamine fluctuation rescues dyskinesia pathology via VGAT downregulation.

Highlights

Enhancement of GABAergic transmission is a shared mechanism between LID and TD.

VGAT levels in MSNs govern the structure and function of MSN presynaptic terminals.

Gain and loss of VGAT function in MSNs exacerbates and ameliorates dyskinesia.

Lowered D2 signaling with repetitive DA fluctuations causes VGAT overexpression.

Graphical abstract
Artificial selection improves pollutant degradation by bacterial communities
Authors: Arias-Sánchez Flor I. , Vessman Björn , Haym Alice , Alberti Géraldine , Mitri Sara
Published: July 2023

Artificial selection is a promising way to improve microbial community functions, but previous experiments have only shown moderate success. Here, we experimentally evaluate a new method that was inspired by genetic algorithms to artificially select small bacterial communities of known species composition based on their degradation of an industrial pollutant. Starting from 29 randomly generated four-species communities, we repeatedly grew communities for four days, selected the 10 best-degrading communities, and rearranged them into 29 new communities composed of four species of equal ratios whose species compositions resembled those of the most successful communities from the previous round. The best community after 18 such rounds of selection degraded the pollutant better than the best community in the first round. It featured member species that degrade well, species that degrade badly alone but improve community degradation, and free-rider species that did not contribute to community degradation. Most species in the evolved communities did not differ significantly from their ancestors in their phenotype, suggesting that genetic evolution plays a small role at this time scale. These experiments show that artificial selection on microbial communities can work in principle, and inform on how to improve future experiments.
An active neural mechanism for relational learning and fast knowledge reassembly
Authors: Miconi Thomas , Kay Kenneth
Published: July 2023

How do we gain general insights from limited novel experiences? Humans and animals have a striking ability to learn relationships between experienced items, enabling efficient generalization and rapid assimilation of new information. One fundamental instance of such relational learning is transitive inference (learnA>BandB>C, inferA>C), which can be quickly and globally reorganized upon learning a new item (learnA>B>CandD>E>F, thenC>D, and inferB>E). Despite considerable study, neural mechanisms of transitive inference and fast reassembly of existing knowledge remain elusive. Here we adopt a meta-learning (“learning-to-learn”) approach. We train artificial neural networks, endowed with synaptic plasticity and neuromodulation, to be able to learn novel orderings of arbitrary stimuli from repeated presentation of stimulus pairs. We then obtain a complete mechanistic understanding of this discovered neural learning algorithm. Remarkably, this learning involves active cognition: items from previous trials are selectively reinstated in working memory, enabling delayed, self-generated learning and knowledge reassembly. These findings identify a new mechanism for relational learning and insight, suggest new interpretations of neural activity in cognitive tasks, and highlight a novel approach to discovering neural mechanisms capable of supporting cognitive behaviors.
CRISPR-Based Genome Editing inHarmonia Axyridis
Authors: Partosh Tamir , Davidovitz Michael , Firer Noa , Pines Gur
Published: July 2023

Harmonia axyridis(Pallas), commonly known as the Asian lady beetle, is a native insect species of Asia that has been intentionally introduced to various regions for biocontrol purposes. However, its widespread presence beyond its original release sites suggests a high degree of invasiveness. Previous studies have employed double-stranded RNA techniques to investigate the functional genomics of this species. In this study, we utilized the CRISPR-Cas9 approach to achieve precise genome editing inH. axyridis. Specifically, we targeted two distinct genes known to exhibit visible phenotypic effects. While the knockout of thelaccase2gene resulted in an early-detectable phenotype but also in lethality, we successfully established a viable and genetically stable mutant colony by disrupting thescarletgene. Our findings contribute to the expanding knowledge of genetic manipulation inH. axyridisand provide insights into its potential for future research and practical applications for biocontrol and invasive species management.
Chromatin-associated RNA Dictates the ecDNA Interactome in the Nucleus
Authors: Liang Zhengyu , Gilbreath Collin , Liu Wenyue , Wang Yan , Zhang Michael Q. , Zhang Dong-Er , Wu Sihan , Fu Xiang-Dong
Published: July 2023

Extrachromosomal DNA (ecDNA) promotes cancer by driving copy number heterogeneity and amplifying oncogenes along with functional enhancers. More recent studies suggest two additional mechanisms for further enhancing their oncogenic potential, one via forming ecDNA hubs to augment oncogene expression1and the other through acting as portable enhancers totrans-activate target genes2. However, it has remained entirely elusive about how ecDNA explores the three-dimensional space of the nucleus and whether different ecDNA have distinct interacting mechanisms. Here, by profiling the DNA-DNA and DNA-RNA interactomes in tumor cells harboring different types of ecDNAs in comparison with similarly amplified homogenously staining regions (HSRs) in the chromosome, we show that specific ecDNA interactome is dictated by ecDNA-borne nascent RNA. We demonstrate that the ecDNA co-amplifyingPVT1andMYCutilize nascent noncodingPVT1transcripts to mediate specifictrans-activation of both ecDNA and chromosomal genes. In contrast, the ecDNA amplifyingEGFRis weak in this property because of more efficient splicing to remove chromatin-associated nascent RNA. These findings reveal a noncoding RNA-orchestrated program hijacked by cancer cells to enhance the functional impact of amplified oncogenes and associated regulatory elements.
Whole Genome Assembly of a HybridTrypanosoma cruziStrain Assembled with Nanopore Sequencing Alone
Authors: Hakim Jill M.C. , Gutierrez Guarnizo Sneider A , Machaca Edith Málaga , Gilman Robert H. , Mugnier Monica R.
Published: July 2023

Trypanosoma cruziis the causative agent of Chagas disease, which causes 10,000 deaths per year. Despite the high mortality caused by the pathogen, relatively few parasite genomes have been assembled to date; even some commonly used laboratory strains do not have publicly available genome assemblies. This is at least partially due toT. cruzi’s highly complex and highly repetitive genome: while describing the variation in genome content and structure is critical to better understandingT. cruzibiology and the mechanisms that underlie Chagas disease, the complexity of the genome defies investigation using traditional short read sequencing methods. Here, we have generated a high-quality whole genome assembly of the hybrid Tulahuen strain, a commercially available Type VI strain, using long read Nanopore sequencing without short read scaffolding. Using automated tools and manual curation for annotation, we report a genome with 25% repeat regions, 17% variable multigene family members, and 27% transposable elements. Notably, we find that regions with transposable elements are significantly enriched for surface proteins, and that on average surface proteins are closer to transposable elements compared to other coding regions. This finding supports a possible mechanism for diversification of surface proteins in which mobile genetic elements such as transposons facilitate recombination within the gene family. This work demonstrates the feasibility of nanopore sequencing to resolve complex regions ofT. cruzigenomes, and with these resolved regions, provides support for a possible mechanism for genomic diversification.
Calcium-sensitive subthreshold oscillations and electrical coupling in principal cells of mouse dorsal cochlear nucleus
Authors: Hong H , Moore LA , Apostolides PF , Trussell LO
Published: July 2023

In higher sensory brain regions, slow oscillations (0.5-5 Hz) associated with quiet wakefulness and attention modulate multisensory integration, predictive coding, and perception. Although often assumed to originate via thalamocortical mechanisms, the extent to which sub-cortical sensory pathways are independently capable of slow oscillatory activity is unclear. We find that in the first station for auditory processing, the cochlear nucleus, fusiform cells from juvenile mice (of either sex) generate robust 1-2 Hz oscillations in membrane potential and exhibit electrical resonance. Such oscillations were absent prior to the onset of hearing, intrinsically generated by hyperpolarization-activated cyclic nucleotide-gated (HCN) and persistent Na+conductances (NaP) interacting with passive membrane properties, and reflected the intrinsic resonance properties of fusiform cells. Cx36-containing gap junctions facilitated oscillation strength and promoted pairwise synchrony of oscillations between neighboring neurons. The strength of oscillations were strikingly sensitive to external Ca2+, disappearing at concentrations > 1.7 mM, due in part to the shunting effect of small-conductance calcium-activated potassium (SK) channels. This effect explains their apparent absence in previousin vitrostudies of cochlear nucleus which routinely employed high-Ca2+extracellular solution. In contrast, oscillations were amplified in reduced Ca2+solutions, due to relief of suppression by Ca2+of Na+channel gating. Our results thus reveal mechanisms for synchronous oscillatory activity in auditory brainstem, suggesting that slow oscillations, and by extension their perceptual effects, may originate at the earliest stages of sensory processing.

SIGNIFICANCE STATEMENT (120 words max.)

Many studies show that electrical activity in higher brain regions is regulated by brain oscillations. Here we show that such oscillatory activity can arise even in the first levels of auditory processing in the cochlear nucleus of the brainstem (fusiform cells), and is generated not by neural networks but by the biophysical properties of individual neurons. Oscillations are highly sensitive to external Ca2+due to interplay of multiple ionic conductances. Gap junctions between cells allows for amplification and synchrony of such activity. Oscillations are absent in pre-hearing neurons, suggesting that sound activity might be important for their emergence. We propose that such early-level oscillations may serve to enhance signaling associated with particular environmental stimuli.
IF1 is a cold-regulated switch of ATP synthase to support thermogenesis in brown fat
Authors: Brunetta Henver S. , Jung Anna S. , Valdivieso-Rivera Fernando , Zani Stepheny C. C. , Guerra Joel , Furino Vanessa , Francisco Annelise , Berçot Marcelo , Moraes-Vieira Pedro M. M. , Keipert Susanne , Jastroch Martin , Martinez Laurent O. , Sponton Carlos H. , Castilho Roger F. , Mori Marcelo A. , Bartelt Alexander
Published: July 2023

While mechanisms controlling mitochondrial uncoupling protein-1 (UCP1) expression and function in thermogenic adipocytes play a pivotal role in non-shivering thermogenesis (NST), it remains unclear whether F1Fo-ATP synthase function is regulated during NST. Here, we show that Inhibitory Factor 1 (IF1, encoded byAtp5if1), an inhibitor of ATP synthase hydrolytic activity, is a critical negative regulator of brown adipocyte energy metabolism. In mice, IF1 protein content is markedly diminished in brown adipose tissue (BAT) after 5 days of cold exposure. Additionally, the capacity of ATP synthase to generate mitochondrial membrane potential through ATP hydrolysis (the so-called “reverse mode” of ATP synthase) is higher in mitochondria isolated from cold- adapted mice compared to mice housed at room temperature.In vitro, IF1 overexpression results in an inability of mitochondria to sustain mitochondrial membrane potential upon adrenergic stimulation and this occurs in a UCP1-dependent manner. In brown adipocytes, IF1 silencing is sufficient to increase mitochondrial lipid oxidation and the cellular dependency on glycolysis to produce ATP. Conversely, IF1 overexpression blunts mitochondrial respiration without causing cellular energetic stress, leading to a quiescent-like phenotype in brown adipocytes. In mice, adeno-associated virus- mediated IF1 overexpression in BAT suppresses adrenergic-stimulated thermogenesis and decreases mitochondrial respiration in this tissue. Taken together, our data shows that the downregulation of IF1 upon cold serves to facilitate the reverse mode of ATP synthase to enable energetic adaptation and effectively support NST in BAT.

Graphical abstract
Expression of a STING Gain-of-function Mutation in Endothelial Cells Initiates Lymphocytic Infiltration of the Lungs
Authors: Gao Kevin MingJie , Chiang Kristy , Korkmaz Filiz T , Janardhan Harish Palleti , Trivedi Chinmay M. , Quinton Lee J. , Gingras Sebastien , Fitzgerald Katherine A. , Marshak-Rothstein Ann
Published: July 2023

Patients afflicted with STING gain-of-function mutations frequently present with debilitating interstitial lung disease (ILD) that is recapitulated in mice expressing the STINGV154Mmutation (VM). Prior radiation chimera studies revealed an unexpected and critical role for non-hematopoietic cells in the initiation of ILD. To identify STING-expressing non-hematopoietic cell types relevant to ILD, we generated a conditional knock-in (CKI) model in which expression of the VM allele was directed to hematopoietic cells, fibroblasts, epithelial cells, or endothelial cells. Only endothelial cell-targeted expression of the mutant allele resulted in the recruitment of immune cells to the lung and the formation of bronchus-associated lymphoid tissue, as seen in the parental VM strain. These findings reveal the importance of endothelial cells as instigators of STING-driven lung disease and suggest that therapeutic targeting of STING inhibitors to endothelial cells could potentially mitigate inflammation in the lungs of SAVI patients or patients afflicted with other ILD-related disorders.

Patients with STING gain-of-function (GOF) mutations develop life-threatening lung autoinflammation. In this study, Gao et al. utilize a mouse model of conditional STING GOF to demonstrate a role for endothelial STING GOF in initiating immune cell recruitment into lung tissues of SAVI mice.
Perceived Timing of Postural Instability Onset With and Without Vision
Authors: McIlroy Robert E , Barnett-Cowan Michael
Published: July 2023

Background

Vision can significantly impact both the perception and behaviour related to postural control. This study examines the influence of vision on the perception of postural instability onset. Previous research employing Temporal Order Judgment (TOJ) tasks to investigate the perceived timing of postural perturbation onset has not incorporated visual cues.

Research question

Does the presence of visual feedback affect the point of subjective simultaneity (PSS) between postural perturbation onset and an auditory reference stimulus and does this additional sensory cue increase TOJ precision?

Methods

Using a lean-and-release paradigm, 10 participants were exposed to postural perturbations in both eyes closed (EC) and eyes open (EO) conditions using a TOJ task where they indicated whether they perceived postural instability onset or sound onset as occurring first for each trial. Separate paired t-tests between EC and EO PSS and just noticeable difference (JND) values were used. One-sample t-tests were also used on PSS values for both conditions, comparing them to 0ms (true simultaneity).

Results

The EC condition demonstrated a perceived delay of postural instability onset by 25.78 ms, while the EO condition showed a perceived delay of the auditory stimulus by 12.33 ms. However, no significant differences were found between the conditions or in comparison to true simultaneity. Mean JND values for EC (39.88 ms) and EO (46.48 ms) were not significantly different, suggesting visual information does not affect response precision for this task under these conditions.

Significance

These findings indicate that visual information does not significantly affect the perception of postural instability onset. This suggests that visual information may play a limited role in the early perceptual stages of postural instability.
Poly[[(μ-aqua)[μ4-4-(carboxylatomethyl)benzoato]cobalt(II)] hemi[1,4-bis(pyridin-4-ylmethyl)piperazine] hemihydrate]
Authors: Gaskin Gabrielle J. , LaDuca Robert L.
Published: July 2023

In the title compound, {[Co(C9H6O4)(H2O)]·0.5C16H20N4·0.5H2O}
n
, two-dimensional coordination polymer slabs are held together in the three-dimensional crystal structure by means of O—H...N hydrogen bonding between bound water molecules and pyridyl N atoms of cocrystallized 1,4-bis(pyridin-4-ylmethyl)piperazine molecules.
M-type Gd2[Si2O7]
Authors: Locke Ralf Jules Christian , Schleid Thomas
Published: July 2023

The title compound, digadolinium(III) oxidodisilicate, Gd2[Si2O7], was obtained in its M-type crystal structure after attempts to synthesize Gd5Br3[AsO3]4 as a by-product from fused silica ampoules. It crystallizes isotypically with M-type Eu2[Si2O7]. This structure consists of layers of ecliptically arranged oxidodisilicate [Si2O7]6− units separated from each other by bilayers consisting of GdIII cations.
Theatre arts in UK city of culture evaluation practices: the case for headphone verbatim
Authors: Ingram Charlie
Published: July 2023

Purpose

This article's purpose is to examine the case for the use of the theatre arts in the evaluation of UK City of Culture (UKCC) programmes, specifically headphone verbatim.

Design/methodology/approach

Through an analysis of secondary evidence, supported by some primary research, this article analyses past and present evaluation practices surrounding UKCC programmes and the case for headphone verbatim to be included as a method of gathering and distributing research data. The article also observes the challenges in how data may be disseminated through verbatim theatre performance practices, given the limited examples of its use in this context.

Findings

The author argues that the theatre arts can provide a different way of knowing and understanding the impacts of UKCC projects on the host city. Specifically, that headphone verbatim can bring an experiential perspective that is rarely if ever captured by existing UKCC evaluation methods and policymaking in general.

Originality/value

This article details an innovative method of evaluating social impacts associated with UKCC projects.