bluuebunny/crossref_metadata_2025_split huggingface dataset:
NetAn: A Python Toolbox Leveraging Network Topology for Comprehensive Gene Annotation Enrichments
Authors: Magnusson Rasmus 
Published: September 2023

AbstractSummaryGene annotation enrichment analysis is the gold standard for studying the biological context of a set of genes, but available tools often overlook important network properties of the underlying gene regulatory system. This paper introduces the NETwork ANnotation enrichment package, NetAn, which augments annotation analysis with approaches such as the inference of closely related genes to include local neighbors in the analysis, and the separation of over-representation analyses based on network clustering, cliques, and the extraction of separate components. By using NetAn, an example of how such approaches enhance the identification of pertinent annotations in human gene sets is demonstrated.Availability and ImplementationThe software is implemented in Python under a GNU GENERAL PUBLIC LICENSE V3, and can be downloaded fromhttps://github.com/rasma774/netan.Contactrasmus.magnusson@his.seSupplementary InformationThe code relevant to this article is available in the doc/article material folder of the NetAn repository.
CD45-antibody-drug conjugate clears tissue resident myeloid cells from their niches enabling therapeutic adoptive cell transfer
Authors: Gustafsson Karin , Rhee Catherine , Frodermann Vanessa , Scadden Elizabeth W. , Li Dan , Iwamoto Yoshiko , Palchaudhuri Rahul , Hyzy Sharon L. , Boitano Anthony E. , Nahrendorf Matthias , Scadden David T. 
Published: September 2023

AbstractTissue resident myeloid cells (TRM) in adults have highly variable lifespans and may be derived from early embryonic yolk sac, fetal liver or bone marrow. Some of these TRM are known pathogenic participants in congenital and acquired diseases. Myeloablative conditioning and hematopoietic stem cell transplant can replace long-lived brain TRM resulting in clinical improvements in metabolic storage diseases. With the advent of antibody-drug-conjugate (ADC) targeted cell killing as a cell selective means of transplant conditioning, we assessed the impact of anti-CD45-ADC on TRM in multiple tissues. Replacement of TRM ranged from 40 to 95 percent efficiencies in liver, lung, and skin tissues, after a single anti-CD45-ADC dose and bone marrow hematopoietic cell transfer. Of note, the population size of TRM in tissues returned to pre-treatment levels suggesting a regulated control of TRM abundance. As expected, brain, microglia were not affected, but brain monocytes and macrophages were 50% replaced. Anti-CD45-ADC and adoptive cell transfer were then tested in the chronic acquired condition, atherosclerosis exacerbated byTet2mutant clonal hematopoiesis. Plaque resident myeloid cells were efficiently replaced with anti-CD45-ADC and wild-type bone marrow cells. Notably, this reduced existent atherosclerotic plaque burden. Overall, these results indicate that anti-CD45-ADC clears both HSC and TRM niches enabling cell replacement to achieve disease modification in a resident myeloid cell driven disease.
Phagocytosis in macrophages is regulated by the ATP-binding cassette family gene ABCF1
Authors: Arora Hitesh , Choi Kyung Bok , Munro Lonna , Pfeifer Cheryl G. , Jefferies Wilfred A. 
Published: September 2023

AbstractPhagocytosis is a conserved biological mechanism that is integral to tissue remodeling, clearance of apoptotic cells, and immune defense in animals. Additionally, it serves as a pivotal means of sustenance for diverse unicellular eukaryotes. In the context of mammals, this crucial role is fulfilled by specific cell types such as macrophages, monocytes, dendritic cells, and neutrophils. It is orchestrated by an array of receptors, kinases, cytoskeletal elements, and enzymes, working collaboratively to enable the recognition, engulfment, and internalization of particles. Despite its profound significance, the intricate mechanisms underpinning the regulation of this phenomenon remains enigmatic. In this study, we present compelling evidence indicating the involvement of ABCF1, a member of the ATP-binding cassette family, in the FcγRIIA phagocytic pathway. ABCF1’s contribution lies in facilitating downstream signal activation through interactions with Src family members and SYK, pivotal players in this cascade. Additionally, our findings highlight ABCF1’s essentiality in the biosynthesis of various SFKs (Src family kinases) and MAPKs (mitogen-activated protein kinases). These molecules collectively oversee the orchestration of phagocytic cup formation, a pivotal step governing the engulfment process within macrophages. Consequently, the regulation of ABCF1 presents a potential avenue for modulating phagocytosis, allowing for the precise modulation of this fundamental process to either enhance or attenuate according to the specific physiological demands.
Dynamics and quantitative contribution of the aminoglycoside 6′-N-acetyltransferase type Ib [AAC(6′)-Ib] to amikacin resistance
Authors: d’Acoz Ophélie d’Udekem , Hue Fong , Ye Tianyi , Wang Louise , Leroux Maxime , Rajngewerc Lucila , Tran Tung , Phan Kimberly , Ramirez Maria S. , Reisner Walter , Tolmasky Marcelo E. , Reyes-Lamothe Rodrigo 
Published: September 2023

AbstractAminoglycosides are essential components in the available armamentarium to treat bacterial infections. The surge and rapid dissemination of resistance genes strongly reduce their efficiency, compromising public health. Among the multitude of modifying enzymes that confer resistance to aminoglycosides, the aminoglycoside acetyltransferase AAC(6′)-Ib is the most prevalent and relevant in the clinical setting as it can inactivate numerous aminoglycosides, such as amikacin. Although the mechanism of action, structure, and biochemical properties of the AAC(6′)-Ib protein have been extensively studied, the contribution of the intracellular milieu to its activity remains unclear. In this work, we used a fluorescent-based system to quantify the number of AAC(6′)-Ib per cell inEscherichia coli,and we modulated this copy number with the CRISPR interference method. These tools were then used to correlate enzyme concentrations with amikacin resistance levels. Our results show that resistance to amikacin increases linearly with a higher concentration of AAC(6′)-Ib until it reaches a plateau at a specific protein concentration.In vivoimaging of this protein shows that it diffuses freely within the cytoplasm of the cell, but it tends to form inclusion bodies at higher concentrations in rich culture media. Addition of a chelating agent completely dissolves these aggregates and partially prevents the plateau in the resistance level, suggesting that AAC(6′)-Ib aggregation lowers resistance to amikacin. These results provide the first step in understanding the cellular impact of each AAC(6′)-Ib molecule on aminoglycoside resistance. They also highlight the importance of studying its dynamic behavior within the cell.ImportanceAntibiotic resistance is a growing threat to human health. Understanding antibiotic resistance mechanisms can serve as foundation for developing innovative treatment strategies to counter this threat. While numerous studies clarified the genetics and dissemination of resistance genes and explored biochemical and structural features of resistance enzymes, their molecular dynamics and individual contribution to resistance within the cellular context remain unknown. Here, we examined this relationship modulating expression levels of AAC(6′)-Ib, an enzyme of clinical relevance. We show a linear correlation between copy number of the enzyme per cell and amikacin resistance levels up to a threshold where resistance plateaus. We propose that at concentrations below the threshold, the enzyme diffuses freely in the cytoplasm but aggregates at the cell poles at concentrations over the threshold. This research opens promising avenues for studying enzyme solubility’s impact on resistance, creating opportunities for future approaches to counter resistance.
PKA regulation of neuronal function requires the dissociation of catalytic subunits from regulatory subunits
Authors: Xiong Wei-Hong , Qin Maozhen , Zhong Haining 
Published: September 2023

AbstractProtein kinase A (PKA) plays essential roles in diverse cellular functions. However, the spatiotemporal dynamics of endogenous PKA upon activation remain debated. The classical model predicts that PKA catalytic subunits dissociate from regulatory subunits in the presence of cAMP, whereas a second model proposes that catalytic subunits remain associated with regulatory subunits following physiological activation. Here we report that different PKA subtypes, as defined by the regulatory subunit, exhibit distinct subcellular localization at rest in CA1 neurons of cultured hippocampal slices. Nevertheless, when all tested PKA subtypes are activated by norepinephrine, presumably via the β-adrenergic receptor, catalytic subunits translocate to dendritic spines but regulatory subunits remain unmoved. These differential spatial dynamics between the subunits indicate that at least a significant fraction of PKA dissociates. Furthermore, PKA-dependent regulation of synaptic plasticity and transmission can be supported only by wildtype, dissociable PKA, but not by inseparable PKA. These results indicate that endogenous PKA regulatory and catalytic subunits dissociate to achieve PKA function in neurons.
Early Morning Checkpoint Inhibitor Infusion and Overall Survival of Patients with Metastatic Cancer: an In-depth Chronotherapeutic Study
Authors: Catozzi Simona , Assaad Souad , Delrieu Lidia , Favier Bertrand , Dumas Elise , Hamy Anne-Sophie , Latouche Aurélien , Crochet Hugo , Blay Jean-Yves , Mullaert Jimmy , Ballesta Annabelle , Heudel Pierre 
Published: September 2023

AbstractIntroductionRecent retrospective studies suggest potential large patient’s benefit through proper timing of immune checkpoint inhibitors (ICI). The association between ICI treatment timing and patient survival, neoplastic response and toxicities was investigated, together with interactions with performance status (PS) and sex.MethodsA cohort of patients with metastatic or locally advanced solid tumors, who received pembrolizumab, nivolumab, atezolizumab, durvalumab, or avelumab, alone or with concomitant chemotherapy, between November 2015 and March 2021, at the Centre Leon Bérard (France), was retrospectively studied.Results361 patients were investigated (80% non-small cell lung cancer patients, mean [SD] age: 63 [11] years, 39% of women, 83% PS0-1 at first infusion, 19% received concomitant chemotherapy). ICI were administered from 07:25 to 17:21 and optimal morning/afternoon cut-off was 11:37. Morning infusions were associated with increased OS as compared to afternoon (median 30.3 vs 15.9 months, p=0.0024; HR 1.56 [1.17-2.1], p=0.003). A strong PS-timing interaction was found (PS0-1 patients, HR=1.53 [1.10-2.12], p=0.011; PS2-3 patients, HR=0.50 [0.25-0.97], p=0.042). Morning PS0-1 patients displayed increased OS (median 36.7 vs 21.3 months, p=0.023), partial/complete response rate (58% vs 41%, p=0.027), and grade1-3 toxicities (49% vs 34%, p=0.028). Mortality risk ratio between infusions at worst time-of-day, estimated at 13:36 [12:48-14:23], and in early morning was 5.5-fold ([2-20], p=0.008). Timing differences in toxicities resulted significant only in female patients (women vs men: p<0.001 vs 0.4).ConclusionsEarly morning ICI infusion was associated with increased OS, response, and toxicities in patients with PS0-1 as compared to later infusions within the day. Prospective randomized trials are needed to confirm this retrospective study.
What do men who have sex with men think of the use of antibiotics as pre- and post-exposure prophylaxis to prevent sexually transmitted infections?
Authors: Matser Amy , Hulstein Bas , de Vries Henry J.C. , Hoornenborg Elske , Prins Maria , Davidovich Udi , Schim van der Loeff Maarten 
Published: September 2023

ABSTRACTOBJECTIVEClinical trials have shown that doxycycline as post-exposure prophylaxis after sexual contact (doxy-PEP) prevents sexually transmitted bacterial infections (STI). We investigated current awareness about informal use of antibiotics as pre- and post-exposure prophylaxis to prevent STI (STI-PrEP/PEP) among men who have sex with men (MSM). In addition, we investigated psychosocial determinants of its use.METHODSData were collected in the Amsterdam Cohort Study among MSM, the Netherlands, between October 2021 and October 2022. In an online questionnaire, we assessed socio-demographics, sexual behavior, bacterial STI diagnoses, STI-PrEP/PEP awareness, perceived effectiveness of, and beliefs and attitudes towards STI-PrEP/PEP, and intention to use it. STI-PrEP/PEP users were described and (ordinal) logistic regression analysis was conducted to identify factors associated with STI-PrEP/PEP awareness (yes/no) and intention to use STI-PrEP/PEP (7-point Likert scale).RESULTSAmong 593 MSM with median age 46 years (IQR 36-53), 102 (17.2%) were aware of STI-PrEP/PEP and 15 (2.5%) had ever used it. STI-PrEP/PEP awareness was associated with living with HIV, HIV-PrEP use in the preceding 6 months, and sexualized drug use with casual partner(s). Median intention to use STI-PrEP-PEP was 3 (IQR 2-4). Higher intention to use STI-PrEP/PEP was associated with HIV-PrEP use, sexual contact with casual partners, being worried to get an STI, self-protection as reason to use it, the intention to reduce STI testing and sexual experimenting. Stigmatizing beliefs regarding STI-PrEP/PEP users were associated with lower use intentions.CONCLUSIONPreventive use of antibiotics for STI prevention is limited among MSM in the Netherlands in 2021/2022. Some men have a high intention for future use. Self-protection and a wish for sexual experimenting are amongst the intrinsic motivators for higher intention to use STI-PrEP/PEP. More studies on the safe use of STI-PrEP/PEP are required as well as a strategy to educate those who have already adopted STI-PrEP/PEP or have a high intention to do so, and their healthcare providers.
Release of fragmented host, cell-free, genomic DNA into the circulation of pigs during infection by virulent African swine fever virus
Authors: Olesen Ann Sofie , Lohse Louise , Johnston Camille Melissa , Rasmussen Thomas Bruun , Bøtner Anette , Belsham Graham J. 
Published: September 2023

AbstractAfrican swine fever virus (ASFV) causes a severe hemorrhagic disease in domestic pigs resulting in high case fatality rates. The virus replicates in circulating cells of the monocyte-macrophage lineage and within lymphoid tissues, e.g. tonsils, spleen and lymph nodes. The infection results in high fever and a variety of clinical signs from about 3 days post infection. In this study, it was observed that one of many changes resulting from ASFV- infection within pigs was a large (>1000-fold) increase in the level of circulating cell-free DNA (cfDNA), including the beta-actin gene, derived from the nuclei of host cells, in the serum. This change occurred in parallel with the increase in circulating ASFV DNA. In addition, elevated levels (about 30-fold higher) of host mitochondrial DNA (mtDNA) were detected in serum from ASFV-infected pigs, but with a much higher baseline level of mtDNA in sera from uninfected pigs. The host derived cfDNA is derived from dead cells which may, or may not, have been infected. For comparison, the release of the cellular enzyme, lactate dehydrogenase (LDH), a commonly used marker of cellular damage, was also found to be elevated during the infection. The cfDNA is readily detected in serum and is a more sensitive host marker of ASFV infection than the release of mtDNA or LDH. In addition, sera from pigs infected by classical swine fever virus (CSFV), which causes a clinically similar disease as ASFV, were also tested but this infection did not result in the release of cfDNA, mtDNA or LDH.Author summaryAfrican swine fever virus causes a severe hemorrhagic disease in domestic pigs and wild boar, which often leads to death within a week. The infection results in a spectrum of different clinical signs and other changes within infected animals. In this study, we have shown, for the first time, that one consequence of infection by a highly virulent strain of this virus is the release into the blood of host genomic DNA, in a highly fragmented form. We found an increase of >1000-fold in the level of this cell-free DNA within the serum of infected animals. Furthermore, we also showed that the level of the small circular DNA from the cell mitochondria is also elevated in serum from infected animals as is the cellular enzyme lactate dehydrogenase but these changes were less marked and occurred later. The increase in the level of the cell-free host DNA is coincident with the increase in level of the viral DNA within blood and may act as a marker for infection by a highly virulent form of the virus. Remarkably, pigs infected by classical swine fever virus, which produces similar clinical signs, did not have elevated levels of these markers in their serum.
Intragroup sociality drives individual participation in intergroup competition in an urban-dwelling nonhuman primate
Authors: Chakraborty Bidisha , Kaburu Stefano S.K. , Balasubramaniam Krishna N. , Marty Pascal R. , Beisner Brianne , Bliss-Moreau Eliza , Mohan Lalit , Rattan Sandeep K. , McCowan Brenda 
Published: September 2023

ABSTRACTThere is significant variability in the extent to which individuals from group-living species participate in intergroup competition (IGC) over resources. Such variability may be particularly robust in human-impacted environments, wherein anthropogenic resources may strongly impact intergroup overlap and competition. Examining the socio-ecological causal factors driving these differences can shed new lights on animals’ costs-benefits trade-offs driving engagement in such interactions. Here we use (peri)urban-dwelling rhesus macaques (Macaca mulatta) as model-systems to examine how individual differences in socio-ecological characteristics (i.e., animals’ sex, rank, and affiliative connections) may influence propensities to participate in IGC in anthropogenic environments. We found that participation was strongly influenced by individuals’ affiliative connections. Interestingly, monkeys with more coalitionary support partners had higher IGC participation, but this was more pronounced for individuals that are more peripheral in their proximity and multilayer affiliative networks, compared to more socially central individuals. Moreover, males and low-ranking individuals were more likely to participate in IGC. Our findings suggest that differential access to socio-ecological resources likely drives IGC participation. The evaluation of such inter-individual differences in socio-ecological flexibility and decision-making in dynamic environments is critical for future research related to the links between behavioural ecology, health outcomes, and human-wildlife co-existence in anthropogenic landscapes.
Targeting tumor-stromal interactions in triple-negative breast cancer using a human vascularized micro-tumor model
Authors: Hachey Stephanie J. , Hatch Christopher J. , Gaebler Daniela , Mocherla Aneela , Nee Kevin , Kessenbrock Kai , Hughes Christopher C.W. 
Published: September 2023

AbstractTriple-negative breast cancer (TNBC) is highly aggressive with limited available treatments. Stromal cells in the tumor microenvironment (TME) are crucial in TNBC progression; however, understanding the molecular basis of stromal cell activation and tumor-stromal crosstalk in TNBC is limited. To investigate therapeutic targets in the TNBC stromal niche, we used an advanced humanin vitromicrophysiological system called the vascularized micro-tumor (VMT). Using single-cell RNA sequencing (scRNA-seq), we revealed that normal breast-tissue stromal cells activate neoplastic signaling pathways in the TNBC TME. By comparing interactions in VMTs with clinical data, we identified therapeutic targets at the tumor-stromal interface with potential clinical significance. Combining treatments targeting Tie2 signaling with paclitaxel resulted in vessel normalization and increased efficacy of paclitaxel in the TNBC VMT. Dual inhibition of Her3 and Akt also demonstrated efficacy against TNBC. These data demonstrate the potential of inducing a favorable TME as a targeted therapeutic approach in TNBC.
Sumaira Latif at P&G: pioneering inclusive design and accessibility to all
Authors: Prasad V. Namratha 
Published: September 2023

Social implications
This case talks about the role that can be expected to be played by a disabled woman in an organization and shows how a disabled woman can assume a leadership position and be a role model.

Learning outcomes
This case identifies the qualities that help a person from a minority group succeed in the corporate environment; examines the contribution that a disabled person, especially a woman can make to an organization; analyzes transformational leadership; assesses the importance of inclusive design in today’s products; and recognizes the corporate role in ensuring an inclusive culture that encouraged disabled people.

Case overview/synopsis
The case “Sumaira Latif at P&G: pioneering inclusive design and accessibility to all” provides an in-depth look at the efforts of Sumaira “Sam” Latif (she), Accessibility Leader at P&G, to incorporate inclusive design in the company’s product packaging. Sam – a blind woman and mother of three – had always struggled to use various everyday products. Her personal struggles drove her to find ways to fix such problems for people with disabilities. So, after a decade of experience at P&G, when she got an opportunity to interact with the top management, she convinced them that catering to the disabled was not charity, but a smart business move. Sam also put forth the role she could play in helping P&G make products with an inclusive design. Impressed with her, P&G made her Special Consultant for Inclusive Design, a position specifically created for her. Sam created the widely lauded tactile indicators which helped the blind differentiate between shampoo and conditioner bottles. P&G then promoted her to the position of Company Accessibility Leader, wherein she played a pivotal role in bringing inclusive design to more of P&G’s products. Sam also played a critical role in making P&G adopt certain technologies to help the blind shop for the company’s products independently, apart from ensuring that all P&G ads were audio-described. However, Sam had an ambitious vision to infuse inclusive design into all products, which required her to bring about a culture change in the CPG industry. She was also faced with the predicament of how to ensure that audio-described ads became a media buying standard, considering the wide-scale resistance to it. How can Sam succeed in making the CPG industry develop inclusive design, the way she convinced P&G to do it?.

Complexity academic level
Graduate and post-graduate programs.

Supplementary materials
Supplementary materials Teaching Notes are available for educators only.