bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparative genomics analysis of three conserved plasmid families in the Western Hemisphere soft tick-borne relapsing fever borreliae provides insight into variation in genome structure and antigenic variation systems
Authors: Kneubehl Alexander R. , Lopez Job E. 
Published: September 2023

ABSTRACT

Borrelia
spirochetes, causative agents of Lyme disease and relapsing fever (RF), have uniquely complex genomes, consisting of a linear chromosome and both circular and linear plasmids. The plasmids harbor genes important for the vector-host life cycle of these tick-borne bacteria. The role of plasmids from Lyme disease causing spirochetes is more refined compared to RF
Borrelia
because of limited plasmid-resolved genome assemblies for the latter. We recently addressed this limitation and found that three linear plasmid families (F6, F27, and F28) were syntenic across all the RF
Borrelia
species that we examined. Given this conservation, we further investigated the three plasmid families. The F6 family, also known as the megaplasmid, contained regions of repetitive DNA. The F27 was the smallest, encoding genes with unknown function. The F28 family encoded the putative expression locus for antigenic variation in all species except
Borrelia hermsii
and
Borrelia anserina
. Taken together, this work provides a foundation for future investigations to identify essential plasmid-localized genes that drive the vector-host life cycle of RF
Borrelia
.

IMPORTANCE

Borrelia
spp. spirochetes are arthropod-borne bacteria found globally that infect humans and other vertebrates. RF borreliae are understudied and misdiagnosed pathogens because of the vague clinical presentation of disease and the elusive feeding behavior of argasid ticks. Consequently, genomics resources for RF spirochetes have been limited. Analyses of
Borrelia
plasmids have been challenging because they are often highly fragmented and unassembled in most available genome assemblies. By utilizing Oxford Nanopore Technologies, we recently generated plasmid-resolved genome assemblies for seven
Borrelia
spp. found in the Western Hemisphere. This current study is an in-depth investigation into the linear plasmids that were conserved and syntenic across species. We identified differences in genome structure and, importantly, in antigenic variation systems between species. This work is an important step in identifying crucial plasmid-localized genetic elements essential for the life cycle of RF spirochetes.
In vitro
activity of new combinations of β-lactam and β-lactamase inhibitors against the
Mycobacterium tuberculosis
complex
Authors: Economou Lundeberg Elin , Andersson Viktoria , Wijkander Maria , Groenheit Ramona , Mansjö Mikael , Werngren Jim , Cortes Teresa , Barilar Ivan , Niemann Stefan , Merker Matthias , Köser Claudio U. , Davies Forsman Lina 
Published: September 2023

ABSTRACT

As meropenem-clavulanic acid is recommended for the treatment of drug-resistant tuberculosis, the repurposing of new carbapenem combinations may provide new treatment options, including oral alternatives. Therefore, we studied the
in vitro
activities of meropenem-vaborbactam, meropenem-clavulanic acid, and tebipenem-clavulanic acid. One hundred nine
Mycobacterium tuberculosis
complex (MTBC) clinical isolates were tested, of which 69 were pan-susceptible and the remaining pyrazinamide- or multidrug-resistant. Broth microdilution MICs were determined using the EUCAST reference method. Meropenem and tebipenem were tested individually and in combination with vaborbactam 8 mg/L and clavulanic-acid 2 and 4 mg/L, respectively. Whole-genome sequencing was performed to explore resistance mechanisms. Clavulanic acid lowered the modal tebipenem MIC approximately 16-fold (from 16 to 1 mg/L). The modal meropenem MIC was reduced twofold by vaborbactam compared with an approximately eightfold decrease by clavulanic acid. The only previously described high-confidence carbapenem resistance mutation,
crfA
T62A, was shared by a subgroup of lineage 4.3.4.1 isolates and did not correlate with elevated MICs. The presence of a β-lactamase inhibitor reduced the MTBC MICs of tebipenem and meropenem. The resulting MIC distribution was lowest for the orally available drugs tebipenem-clavulanic acid. Whether this
in vitro
activity translates to similar or greater clinical efficacy of tebipenem-clavulanic acid compared with the currently WHO-endorsed meropenem-clavulanic acid requires clinical studies.

IMPORTANCE

Repurposing of already approved antibiotics, such as β-lactams in combination with β-lactamase inhibitors, may provide new treatment alternatives for drug-resistant tuberculosis. Meropenem-clavulanic acid was more active
in vitro
compared to meropenem-vaborbactam. Notably, tebipenem-clavulanic acid showed even better activity, raising the potential of an all-oral treatment option. Clinical data are needed to investigate whether the better
in vitro
activity of tebipenem-clavulanic acid correlates with greater clinical efficacy compared with the currently WHO-endorsed meropenem-clavulanic acid.
Oral fosfomycin for treatment of acute bacterial prostatitis caused by multidrug-resistant Enterobacterales
Authors: Burgos Joaquin , Hoyos-Mallecot Yannick , Ferre-Losa Carles , Arando Maider , Monforte Arnau , Pumarola Tomas , Los-Arcos Ibai , Falcó Vicenç 
Published: September 2023

ABSTRACT

To assess the feasibility of oral fosfomycin-tromethamine (FT) for the management of acute bacterial prostatitis (ABP) caused by multidrug-resistant (MDR) Enterobacterales. An observational study of adult patients diagnosed with ABP from Vall d’Hebron University Hospital (Barcelona, Spain), treated with oral FT. The primary outcome was clinical cure defined as symptom relief at the control visit, 2–4 weeks post-end of treatment. Secondary outcomes included microbiological cure, relapse, and adverse events related to the treatment. Eighteen patients with ABP caused by Enterobacterales (15
Escherichia coli
and three
Klebsiella pneumoniae
) were included. Microorganisms were MDR bacteria [14 extended-spectrum beta-lactamase (ESBL) producers and two carbapenemase producing
K. pneumoniae
]. Patients received treatment with FT 3 g/48 hours during a median of 14 days (Q25–Q75, 12–17.75). Fifteen patients received a lead-in phase of intravenous suitable antimicrobial during a median of 7 days (Q25–Q75, 3.75–8). No patient had to stop treatment due to adverse events, and the only side effect reported in two patients was diarrhea. Clinical cure was achieved in all (18/18) patients and microbiological cure in 11/12 patients. After a median of follow-up of 5 months (Q25–Q75, 2–11), 2/18 patients relapsed with an orchitis and a new episode of ABP. FT is an attractive step-down therapy for ABP in patients with resistance or side effects to first-line drugs. The availability of oral treatment could reduce the use of the carbapenems, with a benefit in the quality of life of the patient, health costs, and an ecological impact.

IMPORTANCE
We present a brief but largest and interesting experience in which we use fosfomycin-tromethamine (FT) for the treatment of acute bacterial prostatitis (ABP) due to multiresistant bacteria. Our study provides new data that help to consider FT as a plausible alternative for treating ABP in patients with resistance or side effects to first-line drugs. The availability of an alternative oral treatment to avoid the use of the carbapenems could have important benefits in terms of quality of life of the patient, health costs, and an ecological impact.
Supplemental Material: Lateral and vertical characteristics of floodplain aggradation cycles in the lower Eocene Willwood Formation, Bighorn Basin, Wyoming, USA
Authors: Wang Youwei , et al.  
Published: September 2023

<p>Supplemental Text S1: More detailed workflow about the coefficient of variation (CV) calculation. Supplemental Text S2: More detailed workflow about the calculation and application of compensational stacking index. Table S1: Geostatistical features of thicknesses of different floodplain aggradation cycles. Figure S1: Example data distribution and schematic illustration of variogram components. Figure S2: An example showing how CV is calculated. </p>
Non-Immunoglobulin Synthetic Binding Proteins for Oncology
Authors: David Temitope I. , Pestov Nikolay B. , Korneenko Tatyana V. , Barlev Nikolai A. 
Published: September 2023

Abstract
Extensive application of technologies like phage display in screening peptide and protein combinatorial libraries has not only facilitated creation of new recombinant antibodies but has also significantly enriched repertoire of the protein binders that have polypeptide scaffolds without homology to immunoglobulins. These innovative synthetic binding protein (SBP) platforms have grown in number and now encompass monobodies/adnectins, DARPins, lipocalins/anticalins, and a variety of miniproteins such as affibodies and knottins, among others. They serve as versatile modules for developing complex affinity tools that hold promise in both diagnostic and therapeutic settings. An optimal scaffold typically has low molecular weight, minimal immunogenicity, and demonstrates resistance against various challenging conditions, including proteolysis – making it potentially suitable for peroral administration. Retaining functionality under reducing intracellular milieu is also advantageous. However, paramount to its functionality is the scaffold’s ability to tolerate mutations across numerous positions, allowing for the formation of a sufficiently large target binding region. This is achieved through the library construction, screening, and subsequent expression in an appropriate system. Scaffolds that exhibit high thermodynamic stability are especially coveted by the developers of new SBPs. These are steadily making their way into clinical settings, notably as antagonists of oncoproteins in signaling pathways. This review surveys the diverse landscape of SBPs, placing particular emphasis on the inhibitors targeting the oncoprotein KRAS, and highlights groundbreaking opportunities for SBPs in oncology.
Machine learning-based integration develops a metabolism-derived consensus model for improving immunotherapy in pancreatic cancer
Authors: Guo Yongdong , Wang Ronglin , Shi Jingjie , Yang Cheng , Ma Peixiang , Min Jie , Zhao Ting , Hua Lei , Song Yang , Li Junqiang , Su Haichuan 
Published: September 2023

BackgroundPancreatic cancer (PAC) is one of the most malignant cancer types and immunotherapy has emerged as a promising treatment option. PAC cells undergo metabolic reprogramming, which is thought to modulate the tumor microenvironment (TME) and affect immunotherapy outcomes. However, the metabolic landscape of PAC and its association with the TME remains largely unexplored.MethodsWe characterized the metabolic landscape of PAC based on 112 metabolic pathways and constructed a novel metabolism-related signature (MBS) using data from 1,188 patients with PAC. We evaluated the predictive performance of MBS for immunotherapy outcomes in 11 immunotherapy cohorts from both bulk-RNA and single-cell perspectives. We validated our results using immunohistochemistry, western blotting, colony-formation assays, and an in-house cohort.ResultsMBS was found to be negatively associated with antitumor immunity, while positively correlated with cancer stemness, intratumoral heterogeneity, and immune resistant pathways. Notably, MBS outperformed other acknowledged signatures for predicting immunotherapy response in multiple immunotherapy cohorts. Additionally, MBS was a powerful and robust biomarker for predicting prognosis compared with 66 published signatures. Further, we identified dasatinib and epothilone B as potential therapeutic options for MBS-high patients, which were validated through experiments.ConclusionsOur study provides insights into the mechanisms of immunotherapy resistance in PAC and introduces MBS as a robust metabolism-based indicator for predicting response to immunotherapy and prognosis in patients with PAC. These findings have significant implications for the development of personalized treatment strategies in patients with PAC and highlight the importance of considering metabolic pathways and immune infiltration in TME regulation.
Development of local density perturbation technique to identify cracking points in f(R, T) gravity
Authors: Malik Adnan , Shafaq Attiya , Koussour M. , Yousaf Z. 
Published: September 2023

AbstractThis paper investigate the impacts of local density perturbations on the stability of self-gravitating compact objects by utilizing cracking technique within the context of f(R, T) gravity, where R and T represent the Ricci scalar, and the trace of energy–momentum, respectively. To achieve this, we developed the hydrostatic equilibrium equation for spherically symmetric spacetime with anisotropic matter configuration and subsequently applied the Krori–Barua spacetime coefficient. Subsequently, the hydrostatic equilibrium equation of the configuration is perturbed by employing the local density perturbations to the system, while considering a barotropic equation of state. To ascertain the validity of the proposed technique, we applied it to several compact stars, including, Her X-1, SAX J1808.4-3658, 4U 1820-30, PSR J1614-2230, Vela X-1, Cen X-3, and RXJ1856-37 and found that all the considered stars exhibit cracking or overturning. This study conclusively highlights the significance of the cracking technique in providing valuable insights into the stability analysis of self-gravitating compact objects.
Geoheritage and geoconservation in the American Midwest: Silurian reefs of the Milwaukee–Chicago region
Authors: Mikulic Donald G. , Kluessendorf Joanne 
Published: September 2023

Abstract

Paleozoic reefs were first identified by James
Hall (1862)
in the Silurian rocks of the American Midwest. Scientifically, they were crucial in defining ancient reefs, documenting the early history of this marine ecosystem, and interpreting regional stratigraphy, palaeogeography and palaeoecology. Schoonmaker Reef in Wauwatosa, Wisconsin, is historically the most significant of these structures, as the first to be correctly identified as a ‘coral’ reef by exhibiting the transition between a reef mound and the surrounding seafloor. After nearly two hundred years of quarrying, Thornton Reef in Thornton, Illinois, is next in importance as it displays an unequalled three-dimensional exposure, demonstrating the impact of Silurian climate change on reef development. Silurian reefs were discovered and studied only through stone industry quarrying. Extensive nineteenth-century fossil collecting by local naturalists was also a key component in reef studies. These reefs are also an important part of the region's geoheritage, comprising elements of its economy, history, education and scenic landscape. Recognizing their scientific and historical importance, some reefs were part of geoconservation projects and are protected sites. However, other reefs and irreplaceable reef fossil collections need further initiatives to preserve the scientific value and historical legacy of these relatively small geological features.
Towards Safe Autonomy in Hybrid Traffic: Detecting Unpredictable Abnormal Behaviors of Human Drivers via Information Sharing
Authors: Wang Jiangwei , Su Lili , Han Songyang , Song Dongjin , Miao Fei 
Published: September 2023

Hybrid traffic which involves both autonomous and human-driven vehicles would be the norm of the autonomous vehicles’ practice for a while. On the one hand, unlike autonomous vehicles, human-driven vehicles could exhibit sudden abnormal behaviors such as unpredictably switching to dangerous driving modes—putting its neighboring vehicles under risks; such undesired mode switching could arise from numbers of human driver factors, including fatigue, drunkenness, distraction, aggressiveness, and so on. On the other hand, modern vehicle-to-vehicle (V2V) communication technologies enable the autonomous vehicles to efficiently and reliably share the scarce run-time information with each other [
1
]. In this article, we propose, to the best of our knowledge, the first efficient algorithm that can (1) significantly improve trajectory prediction by effectively fusing the run-time information shared by surrounding autonomous vehicles, and can (2) accurately and quickly detect abnormal human driving mode switches or abnormal driving behavior with formal assurance without hurting human drivers’ privacy.

To validate our proposed algorithm, we first evaluate our proposed trajectory predictor on NGSIM and Argoverse datasets and show that our proposed predictor outperforms the baseline methods. Then through extensive experiments on SUMO simulator, we show that our proposed algorithm has great detection performance in both highway and urban traffic. The best performance achieves detection rate of 97.3%, average detection delay of 1.2 s, and 0 false alarm.
Thinking Outside the Box about What it Means to Be a Citizen Centered Smart City
Authors: Kaczmarczyk Lisa 
Published: September 2023

"[We have] really finally started to look at why we build things the way we build them, which is very archaic. I mean, the way we built structures and roads is ancient, you know, we're finally questioning do we have to do it this way? Like we're doing it just because that's the way we did it before. But then how we run them. No one has asked that same question. The way that we influence the people within these cities still stems back to feudal and pre feudal systems. I am the magnificent Lord, and I know how you should behave. So do this, or I will punish you."
carry someone from A to B to make the right choices? What if we applied that at a civic level? What if we applied that in cities, because for the most part, [directing behavior takes place via] negative reinforcement. Do this, [you get a] fine, do this [you face] incarceration, but there's not a lot of positive design in civic or urban environments. I mean, there's very little, if any, at all. And so that's where I jumped in and really became fascinated in merging these ideas of art, entertainment and video games with this, behavioral activation, incentivizing the lay citizen to make good choices based on things they don't even know we're doing."
IoT program for parks and recreation for cities. Their slide deck was very focused on 'this is how much you could save as a city. This is how you could respond faster to vandalism or requisite services. This is how you can monitor if it's being used when it's not supposed to or without permits'. And it was so authoritarian. I mean, it was really genuinely like, you know, you're not using the way we told you to. And it took me about 30 seconds. I just said what if that exact same technology was just reused and reframed and said hey, the park is too busy considering COVID restrictions. You shouldn't go with your family. Here's a park less than half a mile down the street that's completely empty and probably safer for younger children. The exact same technology for a completely different purpose."
Autotaxin Secretion Is a Stromal Mechanism of Adaptive Resistance to TGFβ Inhibition in Pancreatic Ductal Adenocarcinoma
Authors: Pietrobono Silvia , Sabbadini Fabio , Bertolini Monica , Mangiameli Domenico , De Vita Veronica , Fazzini Federica , Lunardi Giulia , Casalino Simona , Scarlato Enza , Merz Valeria , Zecchetto Camilla , Quinzii Alberto , Di Conza Giusy , Lahn Michael , Melisi Davide 
Published: September 2023

Abstract

The TGFβ receptor inhibitor galunisertib demonstrated efficacy in patients with pancreatic ductal adenocarcinoma (PDAC) in the randomized phase II H9H-MC-JBAJ study, which compared galunisertib plus the chemotherapeutic agent gemcitabine with gemcitabine alone. However, additional stromal paracrine signals might confer adaptive resistance that limits the efficacy of this therapeutic strategy. Here, we found that autotaxin, a secreted enzyme that promotes inflammation and fibrosis by generating lysophosphatidic acid (LPA), mediates adaptive resistance to TGFβ receptor inhibition. Blocking TGFβ signaling prompted the skewing of cancer-associated fibroblasts (CAF) toward an inflammatory (iCAF) phenotype. iCAFs were responsible for a significant secretion of autotaxin. Paracrine autotaxin increased LPA-NFκB signaling in tumor cells that triggered treatment resistance. The autotaxin inhibitor IOA-289 suppressed NFκB activation in PDAC cells and overcame resistance to galunisertib and gemcitabine. In immunocompetent orthotopic murine models, IOA-289 synergized with galunisertib in restoring sensitivity to gemcitabine. Most importantly, treatment with galunisertib significantly increased plasma levels of autotaxin in patients enrolled in the H9H-MC-JBAJ study, and median progression-free survival was significantly longer in patients without an increase of autotaxin upon treatment with galunisertib compared with those with increased autotaxin. These results establish that autotaxin secretion by CAFs is increased by TGFβ inhibition and that circulating autotaxin levels predict response to the combination treatment approach of gemcitabine plus galunisertib.

Significance:
TGFβ inhibition skews cancer-associated fibroblasts toward an inflammatory phenotype that secretes autotaxin to drive adaptive resistance in PDAC, revealing autotaxin as a therapeutic target and biomarker of galunisertib response.
Survivin Dendritic Cell Vaccine Safely Induces Immune Responses and Is Associated with Durable Disease Control after Autologous Transplant in Patients with Myeloma
Authors: Freeman Ciara L. , Atkins Reginald , Varadarajan Indumathy , Menges Meghan , Edelman Jeffrey , Baz Rachid , Brayer Jason , Castaneda Puglianini Omar , Ochoa-Bayona Jose Leonel , Nishihori Taiga , Shain Kenneth H. , Shah Bijal , Chen Dung Tsa , Kelley Linda , Coppola Domenico , Alsina Melissa , Antonia Scott , Anasetti Claudio , Locke Frederick L. 
Published: September 2023

Abstract

Purpose:
We investigated whether a dendritic cell (DC) vaccine transduced with an adenoviral vector encoded with full-length survivin (Ad-S), with mutations neutralizing its antiapoptotic function, could safely generate an immune response and deepen clinical responses when administered before and after autologous stem cell transplant (ASCT) for multiple myeloma.

Patients and Methods:
This phase I first-in-human trial (NCT02851056) evaluated the safety of DC:Ad-S in newly diagnosed multiple myeloma not having achieved complete response with induction, given 7 to 30 days prior to stem cell collection and 20 to 34 days after ASCT. Anti-survivin antibodies and CD4+ and CD8+ specific T cells were quantified.

Results:
A total of 14 patients were treated and 13 included in the primary efficacy analysis. No serious adverse events were attributed to DC:Ad-S vaccine. Detectable anti-survivin antibodies increased from baseline in 9 of 13 (69%) patients, and 11 of 13 (85%) mounted either a cellular or humoral immune response to survivin. Seven patients had an improved clinical response at day +90, all of whom had mounted an immune response, and 6 of 7 patients remain event-free at a median follow-up of 4.2 years. Estimated progression-free survival at 4 years is 71% (95% confidence interval, 41–88).

Conclusions:
Two doses of DC:Ad-S, one given immediately before and another after ASCT, were feasible and safe. A high frequency of vaccine-specific immune responses was seen in combination with durable clinical outcomes, supporting ongoing investigation into the potential of this approach.
See related commentary by Dhodapkar, p. 4524