bluuebunny/crossref_metadata_2025 huggingface dataset:
Insanity in German Criminal Law
Authors: Rauxloh Regina E
Published: January 2023

This chapter discusses the conditions for the insanity plea in Germany and the consequences of a successful defence. While German criminal law does not recognize a defence of insanity as such, the question of mental illness of the defendant is linked to the concept of culpability (Schuld) which is an essential requirement for a criminal conviction. Surprisingly, this central term Schuld is not defined in the Criminal Code, but analysis of when it is excluded under section 20 provides insights into the German understanding of what it means to commit a crime. The culpability requirement consists of a two-step test, namely diagnosis of a mental disorder and its effects on the defendant’s cognitive ability at the time of the crime. Both steps pose difficulties and require legal and medical considerations. The first difficulty lies in the question of voluntary causation of a pathological mental disorder in the form of voluntary intoxication, as many crimes, especially violent crimes are committed under the influence of drugs or alcohol or a combination of both. The chapter discusses the difficult question of how to balance the principle of individual criminal responsibility with the voluntary act of disabling one’s own faculties. The second problem is the situation of patients placed in forensic psychiatric hospitals, both in terms of diagnosis and their living conditions in hospital. This leads to the problematic comparison between treatment of defendants who are convicted of a crime and then sanctioned through the prison system and those who are acquitted and interned in a forensic psychiatric hospital.
The Great Mystery
Authors: Le Poidevin Robin
Published: January 2023

This introductory chapter sets out the central challenge posed by the incarnation: to show that the idea of a single person being both human and divine is not an incoherent one. The constraints imposed by the early Ecumenical Councils of the Christian Church are presented, and the question discussed how far philosophical explorations of the incarnation should be conducted within the limits set by orthodoxy. Different strategies for dealing with the apparent paradoxical nature of this idea are outlined, and the four main models with which this book is concerned are introduced. Part I of the book (Chapters 2–4) explores those models in turn.
Classification
Authors: Schobert Harold
Published: January 2023

A classification system for coals provides a common vocabulary for describing, buying, selling, and using coals. Such a system is needed because of the great variability among the coals of the world. This chapter describes the ASTM system for classifying coals. The system is based on coal properties that are of key importance in the historical uses of coals: how they behave when heated, and how they behave when burned. These properties are determined in the proximate analysis and by measurement of the calorific value. In addition to the carboniferous or “coaly” material in a specimen of coal, coals as mined also contain some amounts of moisture and non-combustible substances that produce ash during combustion. Analytical data have to be corrected to account for the moisture and ash-forming constituents.
Coalification
Authors: Schobert Harold
Published: January 2023

Coals formed from plants that grew tens to hundreds of millions of years ago. The plants lived and grew because of photosynthesis, which uses the energy of sunlight to convert carbon dioxide to sugars. The sugars are used by the plants to synthesize all of the other components needed for the plants’ life cycles. Most plants decay when they die. Some are preserved; their constituents are converted with the aid of anaerobic bacteria into kerogen, which is the major intermediate material between plants and coals. Kerogen, buried inside the Earth, is converted into coals through the action of heat and pressure inside Earth’s crust. This process of coalification results in a steady increase of carbon content and decrease of oxygen content as the rank of coals increases. Conceptually, the end product is pure carbon—graphite—which can be thought of as the ultimate coal.
Minerals
Authors: Schobert Harold
Published: January 2023

All coals contain a variety of non-combustible inorganic constituents that form ash when a coal is burned. The inorganic constituents can be present as discrete minerals or as ions attached to the carbonaceous structure. Some inorganic constituents were part of the original plant material, others were carried into the coal during the process of coalification, and still others may have precipitated into the coal after it formed. Ash is not a constituent of coal. Ash forms from various chemical reactions experienced by the inorganic constituents originally in the coal. Because ash results from the use of coal, the properties and behavior of ash can have significant impacts on coal utilization processes. In addition to the major components of most coals—quartz, clays, pyrite, and carbonates—coals also contain many elements at trace levels. Some of the trace elements could be valuable byproducts of coal use.
Preparation
Authors: Schobert Harold
Published: January 2023

Most coals require one or more treatment operations to convert the coal as it came from the mine into a product of consistent quality that satisfies the specifications for its use. Coals can be prepared for use by one or more strategies. Size reduction of as-mined pieces produces material segregated into various size ranges. Coal cleaning reduces the amount of ash-forming inorganic constituents, decreasing the amount of ash to be handled when the coal is used. Removal of pyrite provides a way to reduce sulfur oxide emissions from combustion. Drying or dewatering reduces moisture content. None of the coal preparation operations destroys the unwanted components; they must be dealt with separately. Prepared coal often needs to be stored or stockpiled before it is used. For some coals, storage can lead to the problem of “spontaneous” combustion.
Competition
Authors: Schobert Harold
Published: January 2023

Coal is experiencing increasing competition from natural gas as well as from renewable energy—wind and solar. Increased supplies of natural gas are coming from the hydraulic fracturing (fracking) of shales. Natural gas has no ash and no appreciable nitrogen and sulfur. Its calorific value is about double that of coal. Carbon dioxide emissions per unit of heat are much lower than coal. Fracking requires very large volumes of water. Methane leaking into the atmosphere contributes to climate change. In some places fracking is considered to be associated with an increased number of earthquakes. Renewable energy resources perpetuate themselves and have little impact on the environment. Unlike one-off designs for large coal-fired power-plants, wind turbines and solar modules can be built on assembly lines, offering a cost advantage. Both wind and solar units require energy storage or back-up systems.
Chemicals
Authors: Schobert Harold
Published: January 2023

There are no technological barriers to an organic chemical industry based heavily on coal. The coal chemical industry dates from the late nineteenth century and was based on the byproduct of chemicals from coke ovens. These materials are totally inadequate in quantity to support a worldwide coal chemical industry. Alternative routes to chemicals from coal including solvent extraction, direct liquefaction, or Fischer-Tropsch technology are potentially suitable, but may produce very complex mixtures. Coal can be used to convert lime to calcium carbide, the raw material needed to make acetylene, another potential source of chemicals. Though not yet well-explored, the greatest potential could come from combining advances in molecular modeling with the principles of green chemistry to develop clean routes to specific, targeted products. Valuable trace elements, particularly the rare earth elements, could be extracted from coals or their ashes.
Carbons
Authors: Schobert Harold
Published: January 2023

Because of their high carbon content, coals are, in a sense, carbon materials. Coals can provide an array of carbon products used as materials rather than as not fuels, and having much greater value than the parent coal. Activated carbons have extensive applications in separating impurities from useful products. They can be made from coals or from unburned carbon in fly ash. Graphite has numerous applications, including anodes for the near-ubiquitous lithium-ion batteries. Batteries are crucial for energy storage in solar and wind systems. An alternative, carbon supercapacitors, can be made from coals. Graphene, a two-dimensional material that could replace silicon in some electronic applications, can be made from coals. Carbon fiber composites, which could be made from coal products, could be used for wind-turbine blades. Nanotubes and carbon dots can be made from coals. These possibilities offer the prospect of using carbon materials from coals to fabricate the infrastructure of the renewable energy industry.
Targeted Patrol and Problem-Solving in Hot Spots
Authors: Braga Anthony A. , Cook Philip J.
Published: January 2023

Gun violence is not evenly spread throughout cities. Specific public places can be persistent and very dangerous gun violence “hot spots.” Police can control recurring gun violence by concentrating patrol activities in specific places. One approach is to curtail illicit gun carrying by conducting stops and frisks in these locations. These kinds of enforcement strategies need to be very carefully implemented because they risk undermining police legitimacy in the communities they serve if stops are done excessively and unlawfully. Police stops need to be lawful, conducted in a procedurally just manner, and highly focused on risky people carry guns in relatively small violent places. Another approach involves analyzing violent situations in these hot spots, identifying ways to reduce risky situations, and implementing community problem-solving responses to improve public safety. These problem-oriented strategies economize on the use of costly enforcement actions that could produce unintended harms in minority communities.
There’s Much to Be Done
Authors: Braga Anthony A. , Cook Philip J.
Published: January 2023

Police can reduce gun violence if properly motivated, staffed, and guided. Given the multiple dimensions of gun violence problems, a portfolio of somewhat effective programs is recommended, developed through systematic analysis of local conditions. There are five key areas in which the police can better position themselves to control gun violence: (a) Address gun violence hot spots by reducing illegal gun carrying and modifying opportunities for gun crime in these locations; (b) deal with gangs, street crews, and other dangerous offenders through focused deterrence; (c) strengthen shooting investigations to hold violent gun offenders accountable; (d) reduce shootings by police by improving engagement protocols, organizational culture, and training; and (e) disrupt the underground gun markets that arm violent offenders. Police departments also need to embrace reform, redouble community policing efforts, and ensure lawful and procedurally just encounters with the public. Police are far from perfect but essential in gun violence prevention.
Shame at the Gates of Medicine: A Hermeneutic Exploration of Premedical Students’ Experiences of Shame
Authors: Bynum William E. , Jackson Joseph A. , Varpio Lara , Teunissen Pim W.
Published: January 2023

Purpose

Little is known about the nature of shame in students attempting to enter medical school, despite its potential to impact well-being and professional identity formation during training. In this study, the authors used hermeneutic phenomenology to ask: How do premedical students experience shame as they apply to medical school?

Method

From September 2020 to March 2021, the authors recruited 12 students from a U.S. Master of Biomedical Sciences program who intended to apply to medical school. Data collection consisted of each participant creating a “rich picture” depicting a shame experience during their premedical training, a semistructured interview that deeply explored this and other shame experiences, and a debriefing session. Data were analyzed using Ajjawi and Higgs’s 6 steps of hermeneutic analysis.

Results

Self-concept, composed of an individual’s identities and contingencies of self-esteem, was central to participants’ shame experiences. Through a confluence of past and future self-concepts and under the influence of external factors and the weight of expectations, shame often destabilized participants’ present self-concepts. This destabilization occurred because of events related to application processes (repeat Medical College Admission Test attempts), interpersonal interactions (prehealth advisor meetings), and objective performance measures (grades, test scores). Participants’ efforts to restabilize their self-concept catalyzed specific identity processes and self-concept formation.

Conclusions

Shame provided a window into the emotional experiences, identity processes, and ideologies that shape students’ attempts to enter medical school. The authors discuss the central role of contingencies of self-esteem, the potential origins of performance-based self-esteem in trainees, and the identity negotiation and identity work involved in shame reactions. They call for the adoption of contingencies of self-esteem within current conceptualizations of professional identity formation; training for faculty and prehealth advisors about the nature of shame in premedical learners; and consideration of the consequential validity of standardized tests, which may trigger damaging shame.
Research Trends and Hot Topics on Virtual Reality in Nursing
Authors: Turan Kavradim Selma , Yangöz Şefika Tuğba , Ozer Zeynep
Published: January 2023

This bibliometric analysis was conducted to provide a comprehensive overview of the development of virtual reality in nursing, and to identify the research trends and hot topics in this field. Data were collected from the Web of Science Core Collection database in May and June 2022, and analyses were performed using CiteSpace 6.1.R2. A total of 885 studies on virtual reality were included in the bibliometric analysis; 3570 authors from 1283 institutions and 60 countries contributed, and the studies were published in 356 different journals. It will be important for researchers and health professionals to determine the research trends, current issues, and research gaps on virtual reality in nursing.
Defining multimorbidity in people with HIV – what matters most?
Authors: Sukumaran Luxsena , Sabin Caroline A.
Published: January 2023

Purpose of review

Although multimorbidity (defined as the coexistence of multiple conditions) presents significant health challenges to people with HIV, there is currently no consensus on how it should be defined among this population. This review aimed to examine the definition of multimorbidity in existing studies among people with HIV (n = 22).

Recent findings

Variation in the definition of multimorbidity (in terms of the number and nature of conditions included) across studies among people with HIV was observed, with less than half (45%) reporting a selection criteria for conditions. The number of conditions considered ranged from 4 to 65. Certain conditions (e.g. stroke, myocardial infarction and chronic kidney disease) and risk factors (e.g. hypertension) were more frequently included, while other symptoms (e.g. joint pain, peripheral neuropathy and sleeping problems) and mental health conditions (e.g. anxiety and panic attacks) were rarely included in the definition of multimorbidity.

The definition of multimorbidity among people with HIV is highly variable, with certain conditions overlooked. We propose recommendations that researchers should consider when defining multimorbidity among this population to not only enable comparisons between studies/settings but also to ensure studies consider a person-centred approach that can accurately capture multimorbidity among people with HIV.
18F-FDG PET/CT features and management of primary cardiac lymphoma: a case report
Authors: Wang Ming , Zhang Shuyi , Han Wenzheng
Published: January 2023

An 81-year-old man presented with progressive symptoms of heart failure. Echocardiography showed a mass in the right atrium (approximately 31 × 55 mm) that extended to the tricuspid valves as well as the superior vena cava. Positron emission tomography-computed tomography (PET-CT) showed elevated 18F-fluorodeoxyglucose (18F-FDG) uptake throughout the space-occupying lesions. The patient received surgery based on a preliminary diagnosis of myxoma. Pathological examination of the resected specimen revealed large B-cell lymphoma. The patient received three cycles of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone regimen but no subsequent anti-tumor therapy. At the last follow-up 3.5 years later, he was still alive. In summary, primary cardiac lymphoma should be considered in differential diagnosis in isolated space-occupying lesions in the heart.
Chinese expert consensus on the risk assessment and management of panvascular disease inpatients with type 2 diabetes mellitus (2022 edition)
Authors: Chu Xi , Feng Bo , Ge Junbo , Guo Lixin , Huo Yong , Ji Linong , Jia Qian , Jiang Song , Li Yong , Liu Fang , Liu Xinfeng , Liu Yuping , Lu Bin , Lv Ankang , Wang Yongjun , Weng Jianping , Zeng Qiang , Zhang Yingmei , Zhou Jingmin ,   Chinese Physicians Association Cardiovascular Medicine Physicians Branch, Chinese Expert Consensus on the Risk Assessment and Management of Panvascular Disease in Patients with Type 2 Diabetes Mellitus Expert Panel
Published: January 2023

Panvascular disease is not only a common comorbidity of type 2 diabetes mellitus (T2DM) but also the leading cause of disability and death in T2DM patients. To promote multidisciplinary cooperation and integration for early detection of panvascular disease in patients with T2DM, a group of Chinese researchers in the fields of cardiovascular disease, endocrinology, nephrology, neurology, and health management led by the Chinese Society of Cardiology and Chinese Medical Association, formed a “Chinese Expert Consensus on Risk Assessment and Management of Panvascular Disease in Patients with Type 2 Diabetes” study group to review the latest evidence and major developments in relevant domestic and international disciplines to develop this consensus. The consensus covers the epidemiological characteristics, pathophysiological mechanisms, multidisciplinary collaborative treatments, and risk assessment and management of panvascular disease in patients with T2DM, with an emphasis on early-risk assessment of panvascular disease in patients with T2DM, including the assessment of risk factors, vascular structure and function, and target organ damage at least once a year. In addition, this consensus emphasized that managing panvascular disease in patients with T2DM requires the involvement of both patients and multidisciplinary physicians, and reinforces the importance of controlling blood glucose, blood pressure, and lipids and anti-platelet therapy in addition to lifestyle interventions. This consensus will help guide and assist clinicians regarding the standardized and comprehensive management of panvascular disease in patients with T2DM and improve patient prognosis.
Immediate stent fracture after everolimus-eluting stent implantation: a case report
Authors: Fu Mingqiang , Chang Shufu , Ma Jianying , Ge Junbo
Published: January 2023

A 60-year-old man presented with exertional chest pain and was hospitalized on a diagnosis of unstable angina. Coronary angiography revealed left main true bifurcation lesions and percutaneous coronary intervention (PCI) was conducted using the culotte-stenting technique. Post-dilatational angiography revealed an irregular protrusion of the stent strut in mid left anterior descending (LAD) coronary artery. Intravascular ultrasound (IVUS) showed a discontinuation of the middle stent strut with calcified nodules. An additional everolimus-eluting stent (EES) was placed across the discontinued lesions. Post-procedural IVUS revealed good expansion of the stents and final angiography showed optimal angiographic results with thromboly sis in myocardial infarction (TIMI) 3 flow. The patient was discharged the next day after the operation and maintained asymptomatic for chest pain at the 6-month follow-up point.
Exercise Training in Pulmonary Hypertension
Authors: Satyamurthy Akhila , Poojary Ganesha , Dibben Grace , Padmakumar Ramachandran , Taylor Rod S. , Babu Abraham Samuel
Published: January 2023

Purpose:

Given that previous reviews on exercise training in pulmonary hypertension (PH) were largely based on a small number of randomized controlled trials (RCT), their conclusions are subject to bias. This review sought to identify the impact of exercise training on functional capacity and health-related quality of life (HRQoL) in PH using advanced statistical approaches such as meta-analysis by stratification according to study design.

Review Methods:

Five databases were searched from January 2015 to April 2020 to update a previous review. Included articles had data extracted, risk of bias (ROB) assessed, and quality rating performed. Data were analyzed using meta-analysis with a random-effects model for 6-min walk test (6MWT) distance and HRQoL. Heterogeneity was explored using stratified meta-analysis, within patient correlation and meta-regression.

Results:

A total of 28 studies (11 RCT, 12 pre-/post-studies, 2 two-group non-RCT, and three case series) consisting of 1264 patients were included. Meta-analysis of six RCT demonstrated an improved 6MWT distance by 49.5 m (95% CI, 27.2-71.8: I
2 = 73%; 254 participants; low-moderate ROB) with a low correlation coefficient of 0.34, while the 12 pre-/post-non-RCT showed an improvement of 68.69 m (95% CI, 50.50-86.69: I
2 = 36%; 784 participants; high ROB) along with improvements in V˙ o
2peak (weighted mean difference [WMD] = 3.03 mL/kg/min, 95% CI, 2.17-3.90: I
2 = 0%, P = .82), and HRQoL (WMD = 2.74: 95% CI, −0.82 to 6.30). Metaregression showed that the benefit of exercise on 6MWT distance did not significantly vary across the trial study characteristics.

Conclusion:

This updated review identified an additional body of evidence supporting the efficacy of exercise training on 6MWT distance and HRQoL in stable PH patients. These benefits appeared to be consistent across models of delivery.
Hyperkalemia by eplerenone or esaxerenone in the presence or absence of clarithromycin in hypertensive patients: a retrospective observational cohort study
Authors: Hirai Toshinori , Ueda Shun , Ogura Toru , Katayama Kan , Dohi Kaoru , Hosohata Keiko , Aoyama Takahiko , Matsumoto Yoshiaki , Iwamoto Takuya
Published: January 2023

Objective:

Mineralocorticoid receptor antagonists (MRAs), eplerenone and esaxerenone, cause hyperkalemia dose-dependently. We investigated the cytochrome P450 3A4-mediated drug−drug interaction between the MRAs and clarithromycin.

Methods:

This retrospective observational study included adult hypertensive patients with MRA plus clarithromycin or MRA alone with a propensity score matching (1:1). The difference in serum potassium level (ΔK, maximum level – baseline level) between groups was compared using the Mann–Whitney U-test. Linear regression analysis was used to detect variables that correlated with ΔK in patients with MRA plus clarithromycin.

Results:

After propensity score matching (each nine patients), serum potassium level was elevated after treatment with MRA plus clarithromycin [4.3 (3.5 to 5.1) meq/l to 4.9 (4.0 to 5.5) meq/l, P = 0.0234] and MRA alone [4.3 (4.0 to 4.7) meq/l to 4.6 (4.4 to 5.2) meq/l, P = 0.0469]. Although there was no significant difference in ΔK between groups [MRA plus clarithromycin: 0.5 (0.1 to 1.1) meq/l vs. MRA alone: 0.3 (0.1 to 1.2) meq/l, P = 0.7231], ΔK was significantly higher in esaxerenone plus clarithromycin than in esaxerenone alone [0.6 (0.5 to 1.1) meq/l vs. 0.1 (0.1 to 0.2) meq/l, P = 0.0495]. Conversely, clarithromycin did not show a significant effect on ΔK in patients with eplerenone [0.4 (−0.2 to 1.2) meq/l vs. 0.8 (0.1 to 1.3) meq/l, P = 0.5745]. A positive correlation was found between ΔK and age in patients with MRA plus clarithromycin (y = 0.03 × x − 1.38, r = 0.71, P = 0.0336).

Conclusion:

The drug–drug interaction between MRAs and clarithromycin was evident, particularly in esaxerenone. Serum potassium levels should be closely monitored in older patients.
SUSTAINED-RELEASE LOW-DOSE FLUOCINOLONE ACETONIDE INTRAVITREAL IMPLANT FOR CHRONIC POSTOPERATIVE CYSTOID MACULAR EDEMA: TWO CASE REPORTS
Authors: Kiernan Daniel F.
Published: January 2023

Background/Purpose:

To describe two cases of patients diagnosed with chronic postoperative cystoid macular edema associated with noninfectious posterior uveitis who had limited treatment response to previous corticosteroid modalities and then received a single intravitreal fluocinolone 0.18-mg implant. Chronic postoperative cystoid macular edema (CME) may occur after intraocular surgery and is a common cause of postoperative visual loss. Sometimes called Irvine–Gass syndrome or persistent pseudophakic CME, chronic postoperative CME complicates roughly 0.1% to 2.0% of low-risk, small-incision phacoemulsification surgeries. There are a number of conventional approaches to chronic postoperative CME management, including topical corticosteroids with or without nonsteroidal anti-inflammatory drugs, intravitreal corticosteroid injections, and vascular endothelial growth factor (VEGF) inhibitor injections, but these options have several limitations. A major shortcoming of conventional formulations of anti-inflammatory therapies for chronic postoperative CME (i.e., topical drops, intraocular, and periocular injections) is the need for repeated dosing in chronic cases, which is expensive and burdensome to patients.

Methods:

Series of two case reports. Patient 1, a 75-year-old Latina woman, presented with a history of longstanding, recurrent inflammation after cataract extraction and subsequent vitreoretinal surgeries. Patient 2, an 85-year-old white woman, presented with acute blurred vision, swelling, and pain 5 years after cataract surgery and laser peripheral iridotomy. Both were diagnosed with chronic postoperative CME and ultimately treated with the 3-year sustained-release fluocinolone acetonide intravitreal implant (FAi) 0.18 mg.

Results:

Compared with baseline, both patients experienced resolution of their disease symptoms, >3 lines of visual acuity improvement, and macular edema reduction of 56.2% and 38.4% at 15 and 6 months, respectively, after the fluocinolone implant. No steroid related adverse events including any intraocular pressure measurement >25 mmHg were observed.

Conclusion:

A single intravitreal fluocinolone 0.18-mg implant can effectively and safely treat vision loss and increased central macular thickness because of chronic postoperative cystoid macular edema associated with noninfectious posterior uveitis. The FAi 0.18 mg provides a safe, long-acting, low-dose anti-inflammatory treatment in patients with noninfectious posterior-segment inflammation associated with chronic postoperative CME.
Targets of total glucosides of paeony in the treatment of Sjogren syndrome: A network pharmacology study
Authors: Xiao Lu , Xiao Wei , Zhan Feng
Published: January 2023

Background:

We aimed to explore the underlying mechanism of the total glucoside of peony (TGP) in treating Sjogren syndrome (SS) using the network pharmacology approach.

Methods:

The protein targets of TGP and SS were identified by database search. Then, the intersection of the two groups was studied. The drug–target network between TGP and the overlapping genes was constructed, visualized, and analyzed by Cytoscape software. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment were performed to analyze these genes. Finally, the predictions of potential targets were evaluated by docking study.

Results:

Forty-six overlapping genes were discovered. The results suggested that TGP used in the treatment of SS is associated with cellular tumor antigen p53, neurotrophic tyrosine kinase receptor type 1, and epidermal growth factor receptor, as well as their related 3372 protein networks, which regulate intrinsic apoptotic signaling pathway, cellular response to oxidative stress, rhythmic process, and other processes. Molecular docking analysis proved that hydrogen bonding is the main form of interaction.

Conclusion:

Our research provided the protein targets affected by TGP in SS treatment. The key targets (caspase 3, vascular endothelial growth factor A, glyceraldehyde-3-phosphate dehydrogenase, etc.), which involve 3372 proteins, are the multitarget mechanism of TGP in SS treatment.
A Back-Door Insights into the modulation of Src kinase activity by the polyamine spermidine
Authors: Rossini Sofia , Gargaro Marco , Scalisi Giulia , Bianconi Elisa , Ambrosino Sara , Panfili Eleonora , Volpi Claudia , Orabona Ciriana , Macchiarulo Antonio , Fallarino Francesca , Mondanelli Giada
Published: January 2023

Src is a protein tyrosine kinase commonly activated downstream of transmembrane receptors and plays key roles in cell growth, migration and survival signaling pathways. In conventional dendritic cells (cDCs), Src is involved in the activation of the non-enzymatic functions of indoleamine 2,3-dioxygenase 1 (IDO1), an immunoregulatory molecule endowed with both catalytic activity and signal transducing properties. Prompted by the discovery that the metabolite spermidine confers a tolerogenic phenotype on cDCs that is dependent on both the expression of IDO1 and the activity of Src kinase, we here investigated the spermidine mode of action. We found that spermidine directly binds Src in a previously unknown allosteric site located on the backside of the SH2 domain and thus acts as a positive allosteric modulator of the enzyme. Besides confirming that Src phosphorylates IDO1, here we showed that spermidine promotes the protein-protein interaction of Src with IDO1. Overall, this study may pave the way toward the design of allosteric modulators able to switch on/off the Src-mediated pathways, including those involving the immunoregulatory protein IDO1.
A recurrent network model of planning explains hippocampal replay and human behavior
Authors: Jensen Kristopher T. , Hennequin Guillaume , Mattar Marcelo G.
Published: January 2023

When faced with a novel situation, humans often spend substantial periods of time contemplating possible futures. For such planning to be rational, the benefits to behavior must compensate for the time spent thinking. Here we capture these features of human behavior by developing a neural network model where planning itself is controlled by prefrontal cortex. This model consists of a meta-reinforcement learning agent augmented with the ability to plan by sampling imagined action sequences from its own policy, which we call ‘rollouts’. The agent learns to plan when planning is beneficial, explaining empirical variability in human thinking times. Additionally, the patterns of policy rollouts employed by the artificial agent closely resemble patterns of rodent hippocampal replays recently recorded during spatial navigation. Our work provides a new theory of how the brain could implement planning through prefrontal-hippocampal interactions, where hippocampal replays are triggered by – and adaptively affect – prefrontal dynamics.
Preclinical Basis of the Efficacy and Pharmacodynamics of Finotonlimab, a Humanized Anti-PD-1 Monoclonal Antibody with Potent Implications for Clinical Benefit
Authors: Yang Xiaoning , Li Jing , Guo Erhong , Sun Chunyun , Zhang Xiao , Jia Jilei , Wang Rui , Ma Juan , Dai Yaqi , Deng Mingjing , Yu Chulin , Sun Lingling , Li Shuang , Xie Liangzhi
Published: January 2023

Background

The antibodies of programmed cell death protein 1 (PD-1) and its ligand (PD-L1) have dramatically changed the treatment landscapes for patients with cancer. Clinical uses of PD-1 antibodies have greatly improved the overall survival and durable responses in patients across selected tumor types.

Methods

We describe the preclinical characterization of Finotonlimab, a humanized anti-PD-1 antibody, by head to head comparison with Nivolumab or Pembrolizumab. Herein, we characterized the in vitro and in vivo efficacy, PK, PD and Fc mediated effector function of Finotonlimab. The single-agent anti-tumor activity of Finotonlimab was evaluated using humanized mouse models and a human PBMC reconstituted mouse model. Furthermore, in cynomolgus monkeys, comparative PK measurements confirmed better PK profiles of Finotonlimab than that of Pembrolizumab and Nivolumab.

Results

Our data showed Finotonlimab bind to human PD-1 with significantly high affinity and effectively inhibited its interaction with its ligands, PD-L1 and PD-L2, and thus could effectively stimulate the human T cell functionsin vitroand exhibited significant antitumor efficacyin vivo. In addition, Finotonlimab showed minimal impact on Fc receptor dependent effector cell activation, which may contribute to the killing of PD-1+T cells. In cynomolgus monkeys, Finotonlimab exhibited a non-linear pharmacokinetics (PK) profile in a dose-dependent manner, and approximately 90% of consistent receptor occupancy period was observed at 168 h after a single administration of 1 mg/kg. Following a 13-week successive administration of Finotonlimab, a pharmacodynamics study indicated a sustained mean receptor occupancy of ≥ 93% of PD-1 molecules on circulating T cells in cynomolgus monkeys up to 8 weeks even at 3 mg/kg.

Conclusions

Taken together, these preclinical data are encouraging and provide a basis for the efficacy and pharmacodynamics of Finotonlimab in clinical trials.
A macroevolutionary role for chromosomal fusion and fission inErebiabutterflies
Authors: Augustijnen Hannah , Bätscher Livio , Cesanek Martin , Chkhartishvili Tinatin , Dincă Vlad , Iankoshvili Giorgi , Ogawa Kota , Vila Roger , Klopfstein Seraina , de Vos Jurriaan M. , Lucek Kay
Published: January 2023

The impact of large-scale chromosomal rearrangements, such as fusions and fissions, on speciation is a long-standing conundrum. We assessed whether bursts of change in chromosome numbers resulting from chromosomal fusion and fission are related to increased speciation rates inErebia, one of the most species-rich and karyotypically variable butterfly groups. We established a genome-based phylogeny and employed state-dependent birth-death models to infer trajectories of karyotype evolution across this genus. We demonstrated that rates of anagenetic chromosomal changes (i.e. along phylogenetic branches) exceed cladogenetic changes (i. e. at speciation events), but when cladogenetic changes occur, they are mostly associated with chromosomal fissions rather than fusions. Moreover, we found that the relative importance of fusion and fission differs amongErebiaclades of different ages, where especially in younger, more karyotypically diverse clades, speciation is more frequently associated with chromosomal changes. Overall, our results imply that chromosomal fusions and fissions have contrasting macroevolutionary roles and that large-scale chromosomal rearrangements are associated with bursts of species diversification.
Functional specialization and structured representations for space and time in prefrontal cortex
Authors: Böhm Claudia , Lee Albert K.
Published: January 2023

Individual neurons in prefrontal cortex – a key brain area involved in cognitive functions – are selective for variables such as space or time, as well as more cognitive aspects of tasks, such as learned categories. Many neurons exhibit mixed selectivity, that is, they show selectivity for multiple variables. A fundamental question is whether neurons are functionally specialized for particular variables and how selectivity for different variables intersects across the population. Here, we analyzed neural correlates of space and time in rats performing a navigational task with two behaviorally important categories – starts and goals. Using simultaneous recordings of many medial prefrontal cortex (mPFC) neurons during behavior, we found that population codes for elapsed time were invariant to different locations within categories, and subsets of neurons had functional preferences for time or space across categories. Thus, mPFC exhibits structured selectivity, which may facilitate complex behaviors by efficiently generating informative representations of multiple variables.
All-optical interrogation of excitability during seizure propagation reveals high local inhibition amidst baseline excitability
Authors: Shah Prajay T. , Valiante Taufik A. , Packer Adam M.
Published: January 2023

Seizures are classically described as an epiphenomenon of hyperexcitability and hypersynchronicity across brain regions. However, this view is insufficient to explain the complex, dynamic evolution of focal-onset seizures in the brain. Recent studies have proposed mechanisms involving an evolution of excitability driven specifically by a spatiotemporally progressing seizure wavefront. These mechanisms attempt to align the abnormal propagation of neural activity with well-known neurobiological parameters, such as excitation-inhibition balance and neuronal connectivity patterns. We describe a direct test of these mechanisms by performing real-time,in vivoinvestigations of excitability in the acutely epileptic state and during seizure propagation. We used all-optical interrogation to test single-neuronal and local-circuit excitability in the epileptic brain. We demonstrate a surprising paradox during the acutely epileptic state, wherein the brain becomes susceptible to large synchronous inputs, yet single-cell excitability is largely maintained at baseline levels. At a finer scale, excitability of neurons at the single-cell level is related to their distance from the seizure wavefront. Local circuit excitability is increased in the distal penumbra but, crucially, we find inhibition in close proximity to the seizure wavefront. This is in contrast with previously suggested notions of widespread inhibition outside the direct area of action during a focal-onset seizure. These experimental results provide the first direct,in vivoevidence for the precise spatial scale over which single-cell excitability dynamics evolve during seizure propagation, providing support for local inhibitory restraint of seizure propagation.
Gaze patterns and brain activations in humans and marmosets in the Frith-Happé theory-of-mind animation task
Authors: Dureux Audrey , Zanini Alessandro , Selvanayagam Janahan , Menon Ravi S. , Everling Stefan
Published: January 2023

Theory of Mind (ToM) refers to the ability to ascribe mental states to other individuals. This process is so strong that it extends even to the attribution of mental states to animations depicting interacting simple geometric shapes, such as in the Frith-Happé animations in which two triangles move either purposelessly (Random condition), or as if one triangle is reacting to the other triangle’s mental state (ToM condition). Currently, there is no evidence that nonhuman primates attribute mental states to moving abstract shapes. Here we investigated whether highly social marmosets (Callithrix jacchus) process ToM and Random Frith-Happé animations differently. Our results show that marmosets and humans (1) follow more closely one of the triangles during the observation of ToM compared to Random animations, and (2) activate large and comparable brain networks when viewing ToM compared to Random animations. These findings indicate that marmosets, like humans, process ToM animations differently from Random animations.
FROM FOREST TO SAVANNA AND BACK TO FOREST: EVOLUTIONARY HISTORY OF THE GENUSDimorphandra(LEGUMINOSAE)
Authors: Rocha Vinicius Delgado da , Dal’Sasso Thaís Carolina da Silva , Williams Christina Cleo Vinson , Simon Marcelo Fragomeni , Bueno Marcelo Leandro , Oliveira Luiz Orlando de
Published: January 2023

The tree genusDimorphandracomprises 26 species, which are circumscribed into three subgenera. The subgenusDimorphandrais associated with both rainforests (Amazon and Atlantic Forest) and savanna-like vegetation (Cerrado); whereas the subgeneraPocillumandPhaneropsiaare restricted to the Amazon. We obtained DNA sequence data from six gene regions of the chloroplast genome (cpDNA) and the nuclear internal transcribed spacer (ITS) from 17 species ofDimorphandraand 12 closely related species. Bayesian phylogeny and haplotype network analyses together with both ancestral area reconstructions and ecological niche modeling allowed for exploring the late evolutionary history of the genusDimorphandra. Species within the subgenusPhaneropsiawere more closely related to species of the genusMorathan to the remaining congeners in the plastid tree (but not in the ITS tree), casting doubts on the monophyly ofDimorphandra. Such incongruence may be the result of incomplete lineage sorting of ancient polymorphisms. Amazonian lineages (subgeneraPocillumandPhaneropsia) were highly polymorphic and divergent; whereas lineages from either the Cerrado or the Atlantic Forest were genetically depauperate. The Amazon seems to be the likely source of the lineage that gave rise to the extant species ofDimorphandraof the Cerrado. In turn, a lineage that occupied the Cerrado likely gave rise to the extant species that occur in the Atlantic Forest. Habitat shifts may have been a key driving force that shaped the late evolutionary history ofDimorphandra.
Dichotomy in TCR V-domain dynamics binding the opposed inclined planes of pMHC-II and pMHC-I α-helices
Authors: Murray Joseph S.
Published: January 2023

Ligand recognition by the human α/β T-cell antigen receptor (TCR) heterodimer protein, unlike the surface immunoglobulin (sIg) B-cell receptor, is not governed by relative binding affinity. Its interaction with the peptide (p) plus major histocompatibility complex (MHC) protein (abbrev. pMHC) likely involves some different molecular mechanism linking pMHC binding to T-cell functions. Recent analytical geometry of TCR:pMHC-II solved crystallographic structures (n= 40) revealed that each variable (V)-domain is bound in similar, yet mathematically unique orientations to its target pMHC groove. The relative position of the central cysteine of each V-domain was examined by multivariable calculus in spherical coordinates, where a simple volume element (dV) was found to describe clonotypic geometry with pMHC-II. Here, the study was expanded to include TCR:pMHC-I structures, and to model a physical mechanism, specifically involving the two directionally opposedinclined planes(IP) manifest by the two major α-helices prominent in both MHC-I and MHC-II proteins. Calculations for rotational torque of each V-domain, together with acceleration up and down the slopes of both MHC α-helices were used to estimate the time a given V-domain spends sliding down its cognate MHC IP. This V-domain rotation/sliding mechanism appears to be quantitatively unique for each TCR:pMHC V-domain (n= 40). However, there is an apparent and common dichotomy between the mobility of each V-domain with respect to the two classes of MHC proteins. Evolutionary motifs in the MHC helices support that the V-domains negotiate the opposed inclined planes of pMHC ligands in clonotypic fashion. Thus, this model is useful in understanding how mechanical forces are linked to TCR function.
3D Chromatin Dynamics during Innate and Adaptive Immune Memory Acquisition
Authors: Santosa Endi K. , Lau Colleen M. , Sahin Merve , Leslie Christina S. , Sun Joseph C.
Published: January 2023

Immune cells responding to pathogens undergo molecular changes that are intimately linked to genome organization. Recent work has demonstrated that natural killer (NK) and CD8+T cells experience substantial transcriptomic and epigenetic rewiring during their differentiation from naïve to effector to memory cells. Whether these molecular adaptations are accompanied by changes in three-dimensional (3D) chromatin architecture is unknown. In this study, we combine histone profiling, ATAC-seq, RNA-seq and high-throughput chromatin capture (HiC) assay to investigate the dynamics of one-dimensional (1D) and 3D chromatin during the differentiation of innate and adaptive lymphocytes. To this end, we discovered a coordinated 1D and 3D epigenetic remodeling during innate immune memory differentiation, and demonstrate that effector CD8+T cells adopt an NK-like architectural program that is maintained in memory cells. Altogether, our study reveals the dynamic nature of the 1D and 3D genome during the formation of innate and adaptive immunological memory.
Efficiency enhancement of microparticles seeding density on the inner surface of polymer hollow microfibers using microfluidics
Authors: Aykar Saurabh S. , Hashemi Nicole N.
Published: January 2023

Lateral displacement of microparticles suspended in a viscoelastic fluid flowing through a microfluidic channel occurs due to an imbalance in the first (N1) and second (N2) normal stress differences. Here, we studied the lateral displacement of fluorescent microparticles suspended in a polyethylene glycol (PEG) solution in a two-phase flow with aqueous sodium alginate, flowing through a unique microfluidic device that manufactures microparticles seeded alginate-based hollow microfibers. Parameters such as concentration of the aqueous sodium alginate and flow rate ratios were optimized to enhance microparticle seeding density and minimize their loss to the collection bath. 4 % w/v aqueous sodium alginate was observed to confine the suspended microparticles within the hollow region of microfibers as compared to 2 % w/v. Moreover, the higher flow rate ratio of the core fluid, 250μL min−1resulted in about 192 % increase in the microparticle seeding density as compared to its lower flow rate of 100μL min−1. The shear thinning index (m) was measured to be 0.91 for 2 % w/v and 0.75 for 4 % w/v sodium alginate solutions. These results help gain insights into understanding the microparticle displacement within a viscoelastic polymer solution flowing through a microfluidic channel and motivate further studies to investigate the cellular response with the optimized parameters.
Active Gαi/o mutants accelerate breast tumor metastasis via the c-Src pathway
Authors: Lyu Cancan , Bhimani Aarzoo K , Draus William T , Weigel Ronald , Chen Songhai
Published: January 2023

Constitutively active mutations in the Gαi2and GαoAsubunits of heterotrimeric G proteins have been identified in several human cancers including breast cancer, but their functional significance in tumorigenesis and metastasis has not been well characterized. In this study, we show that expression of the constitutively active GαoAR243H and Gαi2R179C mutants alone was insufficient to induce mammary tumor formation in mice. However, in transgenic mouse models of breast cancer induced by Neu expression or PTEN loss, we found that the Gαi2R179C mutant enhanced spontaneous lung metastasis while having no effect on primary tumor initiation and growth. Additionally, we observed that ectopic expression of the GαoAR243H and Gαi2R179C mutants in tumor cells promote cell migrationin vitroas well as dissemination into multiple organsin vivoby activating c-Src signaling. Thus, our study uncovers a critical function of Gαi/osignaling in accelerating breast cancer metastasis via the c-Src pathway. This work is clinically significant, as it can potentially pave the way to personalized therapies for patients who present with active Gαi/omutations or elevated Gαi/osignaling by targeting c-Src to inhibit breast cancer metastasis.