bluuebunny/crossref_metadata_2025 huggingface dataset:
A molecular phylogeny of Boronia (Rutaceae): placement of enigmatic taxa and a revised infrageneric classification
Authors: Duretto Marco F. , Heslewood Margaret M. , Bayly Michael J.
Published: April 2023

A phylogeny of Boronia (Rutaceae) is presented on the basis of maximum parsimony and Bayesian analyses of plastid (psbA–trnH, trnL–trnF, rbcL) and nuclear (ITS, ETS) markers. Analyses of either plastid or nuclear sequences recovered the same major clades, although with conflicts in resolution among them. The existing classification of Boronia is largely confirmed; sections Boronella, Pedunculatae and Valvatae are supported, and the monotypic sections Alatae and Imbricatae are isolated. Boronia corynophylla Paul G.Wilson is removed from section Algidae to the new section Corynophyllae. Boronia coriacea Paul G.Wilson is removed from section Boronia and placed, with B. inornata Turcz., in the new section Inornatae. Boronia humifusa Paul G.Wilson, B. ovata Lindl. and B. scabra Lindl. are placed in the new section Ovatae. Boronia koniambiensis is retained in section Boronella but placed in a new monotypic series. Section Boronia resolves into two clades that are confined to either south-eastern or south-western Australia, the latter containing three strongly to robustly supported subclades. An identified problem within section Boronia is the lack of morphological apomorphies to assist with formal classification. Despite this, a classification of four series, justified on the basis of the results of the molecular analysis, is proposed. Relationships among the 10 sections of Boronia remain poorly resolved apart from the sister relationships of sections Imbricatae with Pedunculatae, and, Alatae with Corynophyllae.
The cyclic nature of negation: From implicit to explicit
Authors: Bardenstein Ruti
Published: April 2023

The Hebrew negation adverbialbilti‘not’ seems to function very differently in Biblical Hebrew than it does in Contemporary Hebrew. This paper addresses this difference and discusses its evolution. The main question addressed in this paper is: How has Hebrewbilti, originally an exceptive marker (with sentential scoping), ended up functioning solely as a privative in contemporary Hebrew? First, this paper argues that the biblical usage ofbiltiwas expanded and turned into a polyfunctional (or ‘polysemous’) item. This happened via a constructionalization process which led to grammatical changes (‘grammaticalization’): The initially implicated negation (via a generalized implicature) turned explicit (semantic). In addition, in Hebrew’s later periods, the usage ofbiltiwas narrowed and it became a privative. Thus, firstly, a pragmatically motivated path of constructionalization ofbiltiin Biblical Hebrew is suggested. That is, the “pragmatic negation” that arose via a generalized implicature shifted to the semantic level (performing semantic negation, explicit negation). Secondly,bilti’s functions in post-biblical Hebrew periods are outlined, tracing its narrowing functions until its fixation in Contemporary Hebrew as a privative.
Analytical assessment of stay cable vibration mitigation using shape memory alloy wire
Authors: Rajoriya Sourabh , Mishra Shambhu Sharan
Published: April 2023

The stay cables are axial load-carrying members in cable-stayed bridges and are subjected to the problems of large amplitude oscillations mainly due to wind. The investigations presented in this paper attempt to tackle the problem by the application of a shape memory alloy wire, which are understood to have excellent recovery property under large deformation. The aim is to determine how the dynamic behavior of a taut steel cable changes when a Ni-Ti SMA wire is connected to the cable and which location of SMA at the taut cable may provide the best results in terms of vibration dissipation of the cable. Before the analytical study on the taut cable, the behavior of Ni-Ti SMA wire in hysteresis was studied under different strain as well as in tension and compression loadings. The responses of the cable with and without SMA wire were determined in free as well as in forced vibrations. The SMA wire was used at different locations of the cable to determine its most effective location and the damping introduced to the cable. The variation of the amplitude response is investigated at varying excitation frequencies. It is found that the SMA wire can be effectively used as a damping element in dissipating the cable oscillation. It is also found that the mid-length of the cable where maximum amplitude dissipation occurs is the best location, although not a practical one, to attach the SMA wire.
BMI Trajectories in Late Middle Age, Genetic Risk, and Incident Diabetes in Older Adults: Evidence From a 26-Year Longitudinal Study
Authors: Luo Yaxin , Liu Zheran , Luo Jiawei , Li Ruidan , Wei Zhigong , Yang Lianlian , Li Juejin , He Ling , Su Yonglin , Peng Xingchen , Hu Xiaolin
Published: April 2023

This study investigated the association between body mass index (BMI) trajectories in late middle age and incident diabetes in later years. A total of 11,441 participants aged 50–60 years from the Health and Retirement Study with at least 2 self-reported BMI records were included. Individual BMI trajectories representing average BMI changes per year were generated using multilevel modeling. Adjusted risk ratios (ARRs) and 95% confidence intervals (95% CIs) were calculated. Associations between BMI trajectories and diabetes risk in participants with different genetic risks were estimated for 5,720 participants of European ancestry. BMI trajectories were significantly associated with diabetes risk in older age (slowly increasing vs. stable: ARR = 1.31, 95% CI: 1.12, 1.54; rapidly increasing vs. stable: ARR = 1.5, 95% CI: 1.25, 1.79). This association was strongest for normal-initial-BMI participants (slowly increasing: ARR = 1.34, 95% CI: 0.96, 1.88; rapidly increasing: ARR = 2.06, 95% CI: 1.37, 3.11). Participants with a higher genetic liability to diabetes and a rapidly increasing BMI trajectory had the highest risk for diabetes (ARR = 2.15, 95% CI: 1.67, 2.76). These findings confirmed that BMI is the leading risk factor for diabetes and that although the normal BMI group has the lowest incidence rate for diabetes, people with normal BMI are most sensitive to changes in BMI.
Spike propagation mapping reveals effective connectivity and predicts surgical outcome in epilepsy
Authors: Matarrese Margherita A G , Loppini Alessandro , Fabbri Lorenzo , Tamilia Eleonora , Perry M Scott , Madsen Joseph R , Bolton Jeffrey , Stone Scellig S D , Pearl Phillip L , Filippi Simonetta , Papadelis Christos
Published: April 2023

Neurosurgical intervention is the best available treatment for selected patients with drug resistant epilepsy. For these patients, surgical planning requires biomarkers that delineate the epileptogenic zone, the brain area that is indispensable for the generation of seizures. Interictal spikes recorded with electrophysiological techniques are considered key biomarkers of epilepsy. Yet, they lack specificity, mostly because they propagate across brain areas forming networks. Understanding the relationship between interictal spike propagation and functional connections among the involved brain areas may help develop novel biomarkers that can delineate the epileptogenic zone with high precision. Here, we reveal the relationship between spike propagation and effective connectivity among onset and areas of spread and assess the prognostic value of resecting these areas.

We analysed intracranial EEG data from 43 children with drug resistant epilepsy who underwent invasive monitoring for neurosurgical planning. Using electric source imaging, we mapped spike propagation in the source domain and identified three zones: onset, early-spread and late-spread. For each zone, we calculated the overlap and distance from surgical resection. We then estimated a virtual sensor for each zone and the direction of information flow among them via Granger causality. Finally, we compared the prognostic value of resecting these zones, the clinically-defined seizure onset zone and the spike onset on intracranial EEG channels by estimating their overlap with resection.

We observed a spike propagation in source space for 37 patients with a median duration of 95 ms (interquartile range: 34–206), a spatial displacement of 14 cm (7.5–22 cm) and a velocity of 0.5 m/s (0.3–0.8 m/s). In patients with good surgical outcome (25 patients, Engel I), the onset had higher overlap with resection [96% (40–100%)] than early-spread [86% (34–100%), P = 0.01] and late-spread [59% (12–100%), P = 0.002], and it was also closer to resection than late-spread [5 mm versus 9 mm, P = 0.007]. We found an information flow from onset to early-spread in 66% of patients with good outcomes, and from early-spread to onset in 50% of patients with poor outcome. Finally, resection of spike onset, but not area of spike spread or the seizure onset zone, predicted outcome with positive predictive value of 79% and negative predictive value of 56% (P = 0.04).

Spatiotemporal mapping of spike propagation reveals information flow from onset to areas of spread in epilepsy brain. Surgical resection of the spike onset disrupts the epileptogenic network and may render patients with drug resistant epilepsy seizure-free without having to wait for a seizure to occur during intracranial monitoring.
The microbiology of arabica and robusta coffee cherries: a comparative study of indigenous bacteria with presumptive impact on coffee quality
Authors: Mahatmanto Tunjung , Sunarharum Wenny B , Putri Fanny A , Susanto Caroline A , Davian Aga O , Murdiyatmo Untung
Published: April 2023

Arabica and robusta are the two major coffee beans being sold worldwide. It is well recognized that coffee quality is influenced by their origin and the microbiological activities that drive their fermentation. However, in many coffee plantations, information about the natural diversity of bacteria that inhabit the arabica and robusta coffee cherries is limited. Here, we sampled arabica and robusta coffee cherries from Malang, East Java, Indonesia, then sequenced and analysed their bacterial composition. We found that: (a) arabica cherries contained bacteria with less diversity and abundance compared with robusta; (b) both coffee cherries were heavily populated by extremophiles, presumably dispersed from volcanic activities; (c) groups known to be involved in coffee fermentation such as lactic acid bacteria, acetic acid bacteria, Enterobacteria, and soil-associated bacteria were present in both arabica and robusta coffee cherries, and (d) arabica cherries were dominated by Leuconostoc pseudomesenteroides. These findings highlight that coffee cherry bacteria are highly diverse, the majority of which might come from the environment, with some potentially beneficial or detrimental to coffee quality. Knowledge of the natural microbial diversity of coffee cherries may be useful for the development of coffee fermentation technologies to yield coffee beans with consistent quality.
Treatment of coking wastewater by a novel full-scale microaerobic-anoxic-oxic (M/A/O) system: performance and microbial community analysis
Authors: Yuan Ke , Dong Jing , Li Ruipeng
Published: April 2023

The aim of this study was to investigate the relationship between system removal performance and microbial community structure in a novel full-scale microaerobic-anoxic-oxic (M/A/O) system for coking wastewater (CWW) treatment. The results showed that 93% of chemical oxygen demand (COD) and 99% of NH4+-N removal efficiency were achieved via the M/A/O process, meanwhile, main organic pollutants in CWW, including phenolic compounds, heterocyclic compounds and polycyclic aromatic hydrocarbons were basically removed. Four dominant phyla of Proteobacteria, Firmicutes, Bacteroidetes and Nitrospirae were demonstrated to be distributed in the system and played significant roles in the M/A/O biological treatment process. The major function of the M process was to partly remove the biodegradable substances such as phenols and hydrolyze the refractory contaminants such as N-heterocyclic compounds to improve the biological oxygen demand/COD (BOD5) ratio and release ammonia. This work illustrated the structure and function of the microbial community in the M/A/O system and provided a new choice for high-strength CWW treatment.
The efficacy of thoracoscopic surgery for descending necrotizing mediastinitis
Authors: Tanaka Yugo , Maniwa Yoshimasa , Sugio Kenji , Okamoto Tatsuro , Nibu Ken-Ichi , Omori Takashi , Endo Shunsuke , Kuwano Hiroyuki , Chida Masayuki , Toh Yasushi , Okada Morihito , Shiotani Akihiro , Yoshino Ichiro
Published: April 2023

OBJECTIVES

Thoracotomy is a reliable approach for descending necrotizing mediastinitis (DNM), and the use of video-assisted thoracic surgery (VATS), a minimally invasive procedure, has been increasing. However, which approach is more effective for DNM treatment is controversial.

METHODS

We analysed patients who underwent mediastinal drainage via VATS or thoracotomy, using a database with DNM from 2012 to 2016 in Japan, which was constructed by the Japanese Association for Chest Surgery and the Japan Broncho-esophagological Society. The primary outcome was 90-day mortality, and the adjusted risk difference between the VATS and thoracotomy groups using a regression model, which incorporated the propensity score, was estimated.

RESULTS

VATS was performed on 83 patients and thoracotomy on 58 patients. Patients with a poor performance status commonly underwent VATS. Meanwhile, patients with infection extending to both the anterior and posterior lower mediastinum frequently underwent thoracotomy. Although the postoperative 90-day mortality was different between the VATS and thoracotomy groups (4.8% vs 8.6%), the adjusted risk difference was almost the same, −0.0077 with 95% confidence interval of −0.0959 to 0.0805 (P = 0.8649). Moreover, we could not find any clinical and statistical differences between the 2 groups in terms of postoperative 30-day and 1-year mortality. Although patients who underwent VATS had higher postoperative complication (53.0% vs 24.1%) and reoperation (37.9% vs 15.5%) rates than those who underwent thoracotomy, the complications were not serious and most could be treated with reoperation and intensive care.

CONCLUSIONS

The outcome of DNM treatment does not depend on thoracotomy or VATS.
Selling Gāyatrī: Questioning cultural appropriation of a Mantra
Authors: Dalal Neil
Published: April 2023

This essay employs the Gāyatrī mantra as a case study to parse out cultural appropriation’s complex entanglements with modern yoga in North America. Public debates on appropriation in North America are largely based on premises of ownership, authenticity, purity, and corruption; however, theoretical arguments of non-essentialisms implicitly undermine accusations of harmful appropriation. Non-essentialisms potentially decompose fixed cultural essences so that intangible cultural artefacts or cultural groups are not subject to properties of authenticity, purity, and ownership. This position a priori blocks the possibility of appropriation (as conceived in popular discourse) because it deconstructs the premises that frame appropriation. This essay considers non-essentialist arguments, as well as several others that conflict with the possibility of harmful appropriation, such as those based on Indigenous agency and contested identity politics within Hindu-American communities. I argue that even though such arguments are substantially important, they are near sighted if weaponised to wholly dismiss the potential harmful effects of cultural appropriation. They overlook many other problems, such as exclusion, neo-colonial extraction, epistemic violence, and lack of representation of marginalised communities. These further issues are entangled with the Orientalist roots of Spiritual but not Religious ideologies.
Diagnosis
Authors: Graham Kennedy Ashley
Published: April 2023

The process of clinical diagnosis—from establishing the patient–physician relationship to gathering evidence, to performing, evaluating, interpreting, and allocating diagnostic tests, to settling upon a working explanation for the patient’s condition and pursuing a treatment plan, all the while avoiding the pitfalls of both overdiagnosis and underdiagnosis—is, arguably, the cornerstone of all of modern medicine. Via the discussion of actual case studies, this book shows that the process of clinical diagnosis, even in what might be considered to be ordinary or routine cases, is complex, fascinating, multifaceted, and involves considerations of logic, evidence, ethics, probability, and economics. Thus, the process of clinical diagnosis is about far more than just basic science. Here, as in all areas of medical practice, ethics is inextricably intertwined with evidence: Becoming a good diagnostician requires not only an understanding of probability theory and statistical analysis but also learning to listen to your patients, learning how to interpret the results of diagnostic tests by taking into account clinical considerations, learning how to manage and communicate diagnostic uncertainty in the clinical setting, understanding the potential reasons to conduct diagnostic tests or not, and being concerned with issues of diagnostic justice, while keeping in mind the concerns of the actual patient who is in front of you.
Direct Lineage Reprogramming for Induced Keratinocyte Stem Cells: A Potential Approach for Skin Repair
Authors: Lin Haohui , Pan Yu , Cai Sa
Published: April 2023

Severe trauma or chronic wounds can deplete the keratinocyte stem cells (KSCs) present in the epidermal basal layer or inhibit their migration leading to compromised wound healing. Supplementing KSCs is the key to solution while lineage reprogramming provides a new approach to acquiring KSCs. Through direct lineage reprogramming, induced KSCs (iKSCs) can be produced from somatic cells, which exhibit great application potential. Two strategies are currently being used to directly generate iKSCs, lineage transcription factor (TF)-mediated and pluripotency factors-mediated. This review focuses on lineage TF-mediated direct reprogramming and describes the conversion process along with the underlying epigenetic mechanisms. It also discusses other potential induction strategies to generate iKSCs and challenges associated with in situ reprogramming for skin repair.
Current management of inherited arrhythmia syndromes associated with the cardiac ryanodine receptor
Authors: Przybylski Robert , Abrams Dominic J.
Published: April 2023

Purpose of review

Gain-of-function variants in the gene encoding the cardiac ryanodine receptor (RYR2) are associated with catecholaminergic polymorphic ventricular tachycardia (CPVT). The exercise stress test (EST) has long been fundamental in diagnosis and management, but recent work has further explored its role. A new entity termed calcium release deficiency syndrome (CRDS) has been associated with loss-of-function RYR2 variants and a different arrhythmic phenotype.

Recent findings

Standard EST is not perfectly reproducible with regards to provocation of arrhythmia in CPVT. A newly described burst EST protocol may be more sensitive in this regard. Nadolol is the most effective beta blocker in CPVT, though arrhythmic events remain frequent and dual therapy with flecainide and/or left cardiac sympathetic denervation may add protection. A recent report renews debate regarding the use of implantable defibrillator therapy in CPVT. CRDS is characterized by later age of presentation, normal/near normal EST, and ventricular arrhythmia induced by a novel ventricular stimulation protocol.

Burst EST may aid in the diagnosis and management of CPVT. Nadolol is the preferred beta blocker in CPVT, and consideration should be given to early dual therapy. CRDS should be suspected in patients with arrhythmic events, rare RYR2 variants, and a phenotype inconsistent with CPVT.
Cost-effectiveness of MRE versus VCTE in staging fibrosis for nonalcoholic fatty liver disease (NAFLD) patients with advanced fibrosis
Authors: Sangha Kinpritma , Chang Stephanie T. , Cheung Ramsey , Deshpande Vibhas S.
Published: April 2023

Introduction:

NAFLD is a common cause of liver disease. To determine the optimal testing strategy for NAFLD patients with advanced fibrosis, several factors such as diagnostic accuracy, failure rates, costs of examinations, and potential treatment options need to be considered. The purpose of this study was to determine the cost-effectiveness of combination testing involving vibration-controlled transient elastography (VCTE) versus magnetic resonance elastography (MRE) as a frontline imaging strategy for NAFLD patients with advanced fibrosis.

Methods:

A Markov model was developed from the US perspective. The base-case scenario in this model included patients aged 50 years with a Fibrosis-4 score of ≥2.67 and suspected advanced fibrosis. The model included a decision tree and a Markov state-transition model including 5 health states: fibrosis stage 1–2, advanced fibrosis, compensated cirrhosis, decompensated cirrhosis, and death. Both deterministic and probabilistic sensitivity analyses were performed.

Results:

Staging fibrosis with MRE cost $8388 more than VCTE but led to an additional 1.19 Quality-adjusted life years (QALYs) with the incremental cost-effectiveness ratio of $7048/QALY. The cost-effectiveness analysis of the 5 strategies revealed that MRE+biopsy and VCTE+MRE+biopsy were the most cost-effective with the incremental cost-effectiveness ratios of $8054/QALY and $8241/QALY, respectively. Furthermore, sensitivity analyses indicated that MRE remained cost-effective with a sensitivity of ≥0.77, whereas VCTE became cost-effective with a sensitivity of ≥0.82.

Conclusions:

MRE was not only cost-effective than VCTE as the frontline modality for staging NAFLD patients with Fibrosis-4 ≥2.67 with incremental cost-effectiveness ratio of $7048/QALY but also remained cost-effective when used as a follow-up in instances of VCTE failure to diagnose.
Deficiency of neutrophil high-mobility group box-1 in liver transplant recipients exacerbates early allograft injury in mice
Authors: Song Zhuolun , Han Hui , Ge Xiaodong , Das Sukanta , Desert Romain , Athavale Dipti , Chen Wei , Komakula Sai Santosh Babu , Lantvit Daniel , Nieto Natalia
Published: April 2023

Background and Aims:

Early allograft dysfunction (EAD) is a severe event leading to graft failure after liver transplant (LT). Extracellular high-mobility group box-1 (HMGB1) is a damage-associated molecular pattern that contributes to hepatic ischemia-reperfusion injury (IRI). However, the contribution of intracellular HMGB1 to LT graft injury remains elusive. We hypothesized that intracellular neutrophil-derived HMGB1 from recipients protects from post-LT EAD.

Approach and Results:

We generated mice with conditional ablation or overexpression of Hmgb1 in hepatocytes, myeloid cells, or both. We performed LTs and injected lipopolysaccharide (LPS) to evaluate the effect of intracellular HMGB1 in EAD. Ablation of Hmgb1 in hepatocytes and myeloid cells of donors and recipients exacerbated early allograft injury after LT. Ablation of Hmgb1 from liver grafts did not affect graft injury; however, lack of Hmgb1 from recipient myeloid cells increased reactive oxygen species (ROS) and inflammation in liver grafts and exacerbated injury. Neutrophils lacking HMGB1 were more activated, showed enhanced pro-oxidant and pro-inflammatory signatures, and reduced biosynthesis and metabolism of inositol polyphosphates (InsPs). On LT reperfusion or LPS treatment, there was significant neutrophil mobilization and infiltration into the liver and enhanced production of ROS and pro-inflammatory cytokines when intracellular Hmgb1 was absent. Depletion of neutrophils using anti-Ly6G antibody attenuated graft injury in recipients with myeloid cell Hmgb1 ablation.

Conclusions:

Neutrophil HMGB1 derived from recipients is central to regulate their activation, limits the production of ROS and pro-inflammatory cytokines, and protects from early liver allograft injury.
Kir4.1 deletion prevents salt-sensitive hypertension in early streptozotocin-induced diabetic mice via Na+–Cl− cotransporter in the distal convoluted tubule
Authors: Gao Zhong-Xiuzi , Wei Qi-Chao , Shu Ting-Ting , Li Shu-Ting , Zhou Rui , Li Ming-Yan , Mao Zi-Hui , Liu Dong-Wei , Liu Zhang-Suo , Wu Peng
Published: April 2023

Objectives:

Functional impairment of renal sodium handling and blood pressure (BP) homeostasis is an early characteristic manifestation of type 1 diabetes. However, the underlying mechanisms remain unclear.

Methods:

Metabolic cages, radio-telemetry, immunoblotting, and electrophysiology were utilized to examine effects of high salt (8% NaCl, HS) intake on Na+/K+ balance, BP, Na+–Cl− cotransporter (NCC) function, and basolateral K+ channel activity in the distal convoluted tubule (DCT) under diabetic conditions.

Results:

Improper Na+ balance, hypernatremia, and a mild but significant increase in BP were found in streptozotocin (STZ)-induced diabetic mice in response to HS intake for 7 days. Compared to the vehicle, STZ mice showed increased Kir4.1 expression and activity in the DCT, a more negative membrane potential, higher NCC abundance, and enhanced hydrochlorothiazide-induced natriuretic effect. However, HS had no significant effect on basolateral Kir4.1 expression/activity and DCT membrane potential, or NCC activity under diabetic conditions, despite a downregulation in phosphorylated NCC abundance. In contrast, HS significantly downregulated the expression of Na+–H+ exchanger 3 (NHE3) and cleaved epithelial sodium channel-γ in STZ mice, despite an increase in NHE3 abundance after STZ treatment. Kir4.1 deletion largely abolished STZ-induced upregulation of NCC expression and prevented BP elevation during HS intake. Interestingly, HS causes severe hypokalemia in STZ-treated kidney-specific Kir4.1 knockout (Ks-Kir4.1 KO) mice and lead to death within a few days, which could be attributed to a higher circulating aldosterone level.

Conclusions:

We concluded that Kir4.1 is required for upregulating NCC activity and may be essential for developing salt-sensitive hypertension in early STZ-induced diabetes.
Inferring transcriptional bursting kinetics from single-cell snapshot data using a generalized telegraph model
Authors: Luo Songhao , Zhang Zhenquan , Wang Zihao , Yang Xiyan , Chen Xiaoxuan , Zhou Tianshou , Zhang Jiajun
Published: April 2023

Gene expression has inherent stochasticity resulting from transcription's burst manners. Single-cell snapshot data can be exploited to rigorously infer transcriptional burst kinetics, using mathematical models as blueprints. The classical telegraph model (CTM) has been widely used to explain transcriptional bursting with Markovian assumptions. However, growing evidence suggests that the gene-state dwell times are generally non-exponential, as gene-state switching is a multi-step process in organisms. Therefore, interpretable non-Markovian mathematical models and efficient statistical inference methods are urgently required in investigating transcriptional burst kinetics. We develop an interpretable and tractable model, the generalized telegraph model (GTM), to characterize transcriptional bursting that allows arbitrary dwell-time distributions, rather than exponential distributions, to be incorporated into the ON and OFF switching process. Based on the GTM, we propose an inference method for transcriptional bursting kinetics using an approximate Bayesian computation framework. This method demonstrates an efficient and scalable estimation of burst frequency and burst size on synthetic data. Further, the application of inference to genome-wide data from mouse embryonic fibroblasts reveals that GTM would estimate lower burst frequency and higher burst size than those estimated by CTM. In conclusion, the GTM and the corresponding inference method are effective tools to infer dynamic transcriptional bursting from static single-cell snapshot data.
Helpers or halos: examining the evaluative mechanisms underlying selective prosociality
Authors: Dunfield Kristen A. , Isler Laina , Chang Xiao Min , Terrizzi Brandon , Beier Jonathan
Published: April 2023

This research examines the proximate evaluative mechanisms underlying prosocial partner choice-based reciprocity. Across four studies we presented 855 university undergraduates (online for course credit) and 76 4- to 6-year-olds (offline at a university laboratory) with vignettes describing prosocial, social and non-social characters, and asked participants about their person preferences in prosocial, social and general contexts. Adults demonstrated sophisticated appraisals, coordinating between relevant trait and contextual cues to make selections. Adults were particularly attentive to prosocial cues in costly conditions, suggesting that they were using dispositional attributions to make their selections. By contrast, children were largely unable to integrate trait and contextual cues in determining their partner preferences, instead displaying valenced preferences for non-social cues, suggesting the use of affective tagging. Together, these studies demonstrate that the mechanisms underlying prosocial, partner choice-based reciprocity are not early emerging and stable but show considerable development over the lifespan.
Reproductive success of jack and full-size males in a wild coho salmon population
Authors: King Erika M. , Tallmon David A. , Vulstek Scott C. , Russell Joshua R. , McPhee Megan V.
Published: April 2023

Despite the wealth of research on Pacific salmon
Oncorhynchus
spp. life histories there is limited understanding of the lifetime reproductive success of males that spend less time at sea and mature at a smaller size (jacks) than full-size males. Over half of returning male spawners can be jacks in some populations, so it is crucial to understand their contribution to population productivity. We quantified adult-to-adult reproductive success (RS) of jacks and their relative reproductive success (RRS) compared to full-size males in a wild population of coho salmon in the Auke Creek watershed, Juneau, Alaska. We used genetic data from nearly all individuals (approx. 8000) returning to spawn over a decade (2009–2019) to conduct parentage analysis and calculate individual RS. The average adult-to-adult RS of jacks (mean = 0.7 and s.e. = 0.1) was less than that of full-size males (mean = 1.1 and s.e. = 0.1). Jack RRS was consistently below 1.0 but ranged widely (0.23 to 0.96). Despite their lower average success, jacks contributed substantially to the population by siring 23% of the total returning adult offspring (1033 of 4456) produced between 2009 and 2015. Our results imply that jacks can affect evolutionary and population dynamics, and are relevant to the conservation and management of Pacific salmon.
Pests or prey? Micromammal species within an ancient anthropic environment at the Norse settlement site of Tuquoy (Westray, Orkney)
Authors: Romaniuk Andrzej A. , Troalen Lore G. , Bendrey Robin , Herman Jeremy S. , Owen Olwyn , Smith Catherine
Published: April 2023

Micromammals, like rodents and shrews, adapt rapidly to take advantage of new food sources, habitats and ecological niches, frequently thriving in anthropogenic environments. Their remains, often retrieved during archaeological investigations, can be a valuable source of information about the past environmental conditions as well as interspecies interactions and human activity. However, the research on such finds rarely covers multiple approaches, often relying on single species or data type (e.g. identification/information for proxy studies). Here we investigate micromammal remains from the Norse and medieval (AD tenth–fourteenth centuries) archaeological site at Tuquoy, Orkney, to elucidate the relationships between micromammals, humans and other species present using a variety of data. Four micromammal species were identified, and their species dynamics as well as relationships with humans could be inferred by tracking changes in spatial and temporal location of remains, from their taphonomic history and by age estimation for individual animals. A larger, predatory assemblage was also identified, with species composition differing from that in the rest of the archaeological assemblage, and possibly therefore representing small mammal species composition in the wild. The assemblage was probably deposited by a diurnal raptor, though identification to species is not certain due to post-depositional processes.
N
-Arylacetamide derivatives of methyl 1,2-benzothiazine-3-carboxylate as potential drug candidates for urease inhibition
Authors: Hina Sajila , Zaib Sumera , Uroos Maliha , Zia-ur-Rehman Muhammad , Munir Rubina , Riaz Huma , Syed Quratulain , Abidi Syed Hussain Imam
Published: April 2023

Urease enzyme is an infectious factor that provokes the growth and colonization of virulence pathogenic bacteria in humans. To overcome the deleterious effects of bacterial infections, inhibition of urease enzyme is one of the promising approaches. The current study is designed to synthesize new 1,2-benzothiazine-
N
-arylacetamide derivatives
5
(
a-n
) that can effectively provide a new drug candidate to avoid bacterial infections by urease inhibition. After structural elucidation by FT-IR, proton and carbon-13 NMR and mass spectroscopy, the synthesized compounds
5
(
a-n
) were investigated to evaluate their inhibitory potential against urease enzyme.
In vitro
analysis against positive control of thiourea indicated that all the synthesized compounds have strong inhibitory strengths as compared to the reference drug. Compound
5k
, being the most potent inhibitor, strongly inhibited the urease enzymes and revealed an IC
50
value of 9.8 ± 0.023 µM when compared with the IC
50
of thiourea (22.3 ± 0.031 µM)—a far more robust inhibitory potential. Docking studies of
5k
within the urease active site revealed various significant interactions such as H-bond, π-alkyl with amino acid residues like Val744, Lys716, Ala16, Glu7452, Ala37 and Asp730.
Beyond Scenarios - Optimization of breeding program design (MoBPSopti)
Authors: Hassanpour Azadeh , Geibel Johannes , Simianer Henner , Pook Torsten
Published: April 2023

In recent years, breeding programs have become increasingly larger and more structurally complex, with various highly interdependent parameters and contrasting breeding goals. Therefore, resource allocation in a breeding program has become more complex, and the derivation of an optimal breeding strategy has become more and more challenging. As a result, it is a common practice to reduce the optimization problem to a set of scenarios that are only changed in a few parameters and, in turn, can be deeply analyzed in detail. This paper aims to provide a framework for the numerical optimization of breeding programs beyond just comparing scenarios. For this, we first determine the space of potential breeding programs that is only limited by basic constraints like the budget and housing capacities. Subsequently, the goal is to identify the optimal breeding program by finding the parametrization that maximizes the target function, as a combination of the different breeding goals. To assess the value of the target function for a parametrization, we propose the use of stochastic simulations and the subsequent use of a kernel regression method to cope with the stochasticity of simulation outcomes. This procedure is performed iteratively to narrow down the most promising areas of the search space and perform more and more simulations in these areas of interest. The developed concept was applied to a dairy cattle program with a target function aiming at genetic gain and genetic diversity conservation limited by budget constraints.
Structure and Interactions of the Endogenous Human Commander Complex
Authors: Laulumaa Saara , Kumpula Esa-Pekka , Huiskonen Juha T , Varjosalo Markku
Published: April 2023

The Commander complex, a 16-protein subunit assembly, plays multiple roles in various intracellular events, including regulation of cell homeostasis, cell cycle, and immune response. The complex is composed of COMMD1-10, CCDC22, CCDC93, DENND10, VPS26C, VPS29, and VPS35L. These proteins are expressed ubiquitously in the human body and have been linked to diseases including Wilson’s disease, atherosclerosis, and several cancers. Despite its importance, the structure and molecular functions of the Commander complex are poorly understood. Here, we report the structure and key interactions of the endogenous human Commander complex by cryogenic electron microscopy (cryo-EM) and mass spectrometry-based proteomics. Our results show that the complex is asymmetric, consisting of a stable core of a pseudo-symmetric ring of COMMD proteins 1–10 and a mobile effector consisting of DENND10 and the Retriever sub-complex, constituted by VPS35L, VPS29 and VPS26C. The two halves are scaffolded together by CCDC22 and CCDC93. This study directly confirms the cellular composition of Commander and identifies major interaction interfaces, defining the structure and interaction landscape of the complex. These findings offer new insights into its known roles in endosomal processes and intracellular transport, and uncovers a strong association with cilium assembly, and centrosome and centriole functions.

Highlights

High-resolution structure of the Commander complex determined by cryo-EM shows a rigid COMMD1–10 core decorated by mobile effectors DENND10 and the Retriever sub-complex.

Comprehensive interactome analysis uncovers a plethora of novel interactions, implicating the Commander complex in previously unidentified processes, such as cilium assembly, cell cycle, and organelle biogenesis.

Structural organization and identified interaction partners of the Commander complex provide a basis for further research into its molecular functions, related diseases, and potential therapeutic targets.

eTOC blurb

We provide a comprehensive structural analysis of the endogenous human Commander complex, revealing its functional organization and novel interactions involved in diverse cellular processes. These findings uncover new interaction surfaces and pave the way for further research into the molecular mechanisms of the Commander complex.
Robust analysis of allele-specific copy number alterations from scRNA-seq data with XClone
Authors: Huang Rongting , Huang Xianjie , Tong Yin , Yan Helen Y.N. , Leung Suet Yi , Stegle Oliver , Huang Yuanhua
Published: April 2023

Somatic copy number alterations (CNAs) are major mutations that contribute to the development and progression of various cancers. Despite a few computational methods proposed to detect CNAs from single-cell transcriptomic data, the technical sparsity of such data makes it challenging to identify allele-specific CNAs, particularly in complex clonal structures. In this study, we present a statistical method, XClone, that strengthens the signals of read depth and allelic imbalance by effective smoothing on cell neighborhood and gene coordinate graphs to detect haplotype-aware CNAs from scRNA-seq data. By applying XClone to multiple datasets with challenging compositions, we demonstrated its ability to robustly detect different types of allele-specific CNAs and potentially indicate whole genome duplication, therefore enabling the discovery of corresponding subclones and the dissection of their phenotypic impacts.
The role of microglial LRRK2 in manganese-induced inflammatory neurotoxicity via NLRP3 inflammasome and RAB10-mediated autophagy dysfunction
Authors: Pajarillo Edward , Kim Sang Hoon , Digman Alexis , Dutton Matthew , Son Deok-Soo , Aschner Michael , Lee Eunsook
Published: April 2023

Chronic exposure to manganese (Mn) can lead to manganism, a neurological disorder sharing common symptoms with Parkinson’s disease (PD). Studies have shown that Mn can increase the expression and activity of leucine-rich repeat kinase 2 (LRRK2), leading to inflammation and toxicity in microglia. LRRK2 G2019S mutation also elevates LRRK2 kinase activity. Thus, we tested if Mn-increased microglial LRRK2 kinase is responsible for Mn-induced toxicity, and exacerbated by G2019S mutation, using WT and LRRK2 G2019S knock-in mice, and BV2 microglia. Mn (30 mg/kg, nostril instillation, daily for 3 weeks) caused motor deficits, cognitive impairments, and dopaminergic dysfunction in WT mice, which were exacerbated in G2019S mice. Mn induced proapoptotic Bax, NLRP3 inflammasome, IL-1β and TNF-α in the striatum and midbrain of WT mice, and these effects were exacerbated in G2019S mice. BV2 microglia were transfected with human LRRK2 WT or G2019S, followed by Mn (250 μM) exposure to better characterize its mechanistic action. Mn increased TNF-α, IL-1β, and NLRP3 inflammasome activation in BV2 cells expressing WT LRRK2, which was exacerbated in G2019S-expressing cells, while pharmacological inhibition of LRRK2 mitigated these effects in both genotypes. Moreover, the media from Mn-treated BV2 microglia expressing G2019S caused greater toxicity to cath.a-differentiated (CAD) neuronal cells compared to media from microglia expressing WT. Mn-LRRK2 activated RAB10, which was exacerbated in G2019S. RAB10 played a critical role in LRRK2-mediated Mn toxicity by dysregulating the autophagy-lysosome pathway, and NLRP3 inflammasome in microglia. Our novel findings suggest that microglial LRRK2 via RAB10 plays a critical role in Mn-induced neuroinflammation.
The Functional RNA Identification (FRID) Pipeline: Identification of Potential Pseudoknot-Containing RNA Elements as Therapeutic Targets for SARS-CoV-2
Authors: Forstmeier Peter C. , Meyer McCauley O. , Bevilacqua Philip C.
Published: April 2023

The COVID-19 pandemic persists despite the development of effective vaccines. As such, it remains crucial to identify new targets for antiviral therapies. The causative virus of COVID-19, SARS-CoV-2, is a positive-sense RNA virus with RNA structures that could serve as therapeutic targets. One such RNA with established function is the frameshift stimulatory element (FSE), which promotes programmed ribosomal frameshifting. To accelerate identification of additional functional RNA elements, we introduce a novel computational approach termed the Functional RNA Identification (FRID) pipeline. The guiding principle of our pipeline, which uses established component programs as well as customized component programs, is that functional RNA elements have conserved secondary and pseudoknot structures that facilitate function. To assess the presence and conservation of putative functional RNA elements in SARS-CoV-2, we compared over 6,000 SARS-CoV-2 genomic isolates. We identified 22 functional RNA elements from the SARS-CoV-2 genome, 14 of which have conserved pseudoknots and serve as potential targets for small molecule or antisense oligonucleotide therapeutics. The FRID pipeline is general and can be applied to identify pseudoknotted RNAs for targeted therapeutics in genomes or transcriptomes from any virus or organism.
Coronary Artery Disease Risk GenePRDM16is Preferentially Expressed in Vascular Smooth Muscle Cells and a Potential Novel Regulator of Smooth Muscle Homeostasis
Authors: Dong Kunzhe , He Xiangqin , Hu Guoqing , Yao Yali , Zhou Jiliang
Published: April 2023

Objective

Vascular smooth muscle cells (VSMCs) are the primary contractile component of blood vessels and can undergo phenotypic switching from a contractile to a synthetic phenotype in vascular diseases such as coronary artery disease (CAD). This process leads to decreased expression of SMC lineage genes and increased proliferative, migratory and secretory abilities that drive disease progression. Super-enhancers (SE) and occupied transcription factors are believed to drive expression of genes that maintain cell identify and homeostasis. The goal of this study is to identify novel regulator of VSMC homeostasis by screening for SE-regulated transcription factors in arterial tissues.

Approach and Results

We characterized human artery SEs by analyzing the enhancer histone mark H3K27ac ChIP-seq data of multiple arterial tissues. We unexpectedly discovered the transcription factor PRDM16, a GWAS identified CAD risk gene with previously well-documented roles in brown adipocytes but with an unknown function in vascular disease progression, is enriched with artery-specific SEs. Further analysis of public bulk RNA-seq and scRNA-seq datasets, as well as qRT-PCR and Western blotting analysis, demonstrated that PRDM16 is preferentially expressed in arterial tissues and in contractile VSMCs but not in visceral SMCs, and down-regulated in phenotypically modulated VSMCs. To explore the function ofPrdm16in vivo, we generatedPrdm16SMC-specific knockout mice and performed histological and bulk RNA-Seq analysis of aortic tissues. SMC-deficiency ofPrdm16does not affect the aortic morphology but significantly alters expression of many CAD risk genes and genes involved in VSMC phenotypic modulation. Specifically,Prdm16negatively regulates the expression ofTgfb2that encodes for an upstream ligand of TGF-β signaling pathway, potentially through binding to the promoter region ofTgfb2. These transcriptomic changes likely disrupt VSMC homeostasis and predispose VSMCs to a disease state.

Conclusions

Our results suggest that the CAD risk genePRDM16is preferentially expressed in VSMCs and is a novel regulator of VSMC homeostasis. Future studies are warranted to investigate its role in VSMCs under pathological conditions such as atherosclerosis.
Objective assessment of visual attention in toddlerhood
Authors: Braithwaite E. , Kyriakopoulou V. , Mason L. , Davidson A. , Tusor N. , Harper N. , Earl M. , Datoo-Partridge S. , Young A. , Chew A. , Falconer S. , Hajnal Joseph V , Johnson M.H. , Nosarti C. , Edwards A.D. , Jones E.J.H.
Published: April 2023

Visual attention is an important mechanism through which children learn about their environment, and individual differences could substantially shape later development. Eyetracking provides a sensitive and scalable tool for assessing visual attention that has potential for objective assessment of child development, but to date the majority of studies are small and replication attempts are rare. This study investigates the feasibility of a comprehensive eye-tracking assessment of visual attention and introduces a shared data resource for the scientific community. Data from eight eyetracking tasks were collected from 350 term-born (166 females) 18-month-olds recruited as neonateshttp://www.developingconnectome.org/). Analyses showed expected condition effects for seven of eight tasks (p-values from <.001 to .04), an important indication of replicability. Consistent with some theoretical models of visual attention, structural equation modelling indicated participants’ performance could be explained by two factors representing social and non-social attention. Comprehensive eye-tracking batteries can objectively measure individual differences in core components of visual attention in large-scale toddlerhood studies. This is the first large-scale comprehensive study to present high-quality normative eye-tracking data from a large task battery in toddlers and make them freely available to the scientific community.