bluuebunny/crossref_metadata_2025_split huggingface dataset:
The importance of the dorsal branch of the arcuate fasciculus in phonological working memory
Authors: Barbeau Elise B , Kousaie Shanna , Brass Kanontienentha , Descoteaux Maxime , Petrides Michael , Klein Denise 
Published: June 2023

Abstract
Phonological working memory (PWM) is important for language learning and processing. The most studied language brain regions are the classical Broca’s area on the inferior frontal gyrus and Wernicke’s area on the posterior temporal region and their anatomical connection via the classic arcuate fasciculus (AF) referred to here as the ventral AF (AFv). However, areas on the middle frontal gyrus (MFG) are essential for PWM processes. There is also a dorsal branch of the AF (AFd) that specifically links the posterior temporal region with the MFG. Furthermore, there is the temporo-frontal extreme capsule fasciculus (TFexcF) that courses ventrally and links intermediate temporal areas with the lateral prefrontal cortex. The AFv, AFd and TFexcF were dissected virtually in the same participants who performed a PWM task in a functional magnetic resonance imaging study. The results showed that good performance on the PWM task was exclusively related to the properties of the left AFd, which specifically links area 8A (known to be involved in attentional aspects of executive control) with the posterior temporal region. The TFexcF, consistent with its known anatomical connection, was related to brain activation in area 9/46v of the MFG that is critical for monitoring the information in memory.
Highly branched and complementary distributions of layer 5 and layer 6 auditory corticofugal axons in mouse
Authors: Issa Lina K , Sekaran Nathiya V C , Llano Daniel A 
Published: June 2023

Abstract
The auditory cortex exerts a powerful, yet heterogeneous, effect on subcortical targets. Auditory corticofugal projections emanate from layers 5 and 6 and have complementary physiological properties. While several studies suggested that layer 5 corticofugal projections branch widely, others suggested that multiple independent projections exist. Less is known about layer 6; no studies have examined whether the various layer 6 corticofugal projections are independent. Therefore, we examined branching patterns of layers 5 and 6 auditory corticofugal neurons, using the corticocollicular system as an index, using traditional and novel approaches. We confirmed that dual retrograde injections into the mouse inferior colliculus and auditory thalamus co-labeled subpopulations of layers 5 and 6 auditory cortex neurons. We then used an intersectional approach to relabel layer 5 or 6 corticocollicular somata and found that both layers sent extensive branches to multiple subcortical structures. Using a novel approach to separately label layers 5 and 6 axons in individual mice, we found that layers 5 and 6 terminal distributions partially spatially overlapped and that giant terminals were only found in layer 5-derived axons. Overall, the high degree of branching and complementarity in layers 5 and 6 axonal distributions suggest that corticofugal projections should be considered as 2 widespread systems, rather than collections of individual projections.
Restrictive Versus Permissive Use of Broad-spectrum Antibiotics in Patients Receiving Allogeneic Stem Cell Transplantation and With Early Fever Due to Cytokine Release Syndrome: Evidence for Beneficial Microbiota Protection Without Increase in Infectious Complications
Authors: Weber Daniela , Hiergeist Andreas , Weber Markus , Ghimire Sakhila , Salzberger Bernd , Wolff Daniel , Poeck Hendrik , Gessner André , Edinger Matthias , Herr Wolfgang , Meedt Elisabeth , Holler Ernst 
Published: June 2023

Abstract

Background
Intestinal microbiome contributes to the pathophysiology of acute gastrointestinal (GI) graft-versus-host disease (GvHD) and loss of microbiome diversity influences the outcome of patients after allogeneic stem cell transplantation (SCT). Systemic broad-spectrum antibiotics have been identified as a major cause of early intestinal dysbiosis.

Methods
In 2017, our transplant unit at the university hospital in Regensburg changed the antibiotic strategy from a permissive way with initiation of antibiotics in all patients with neutropenic fever independent of the underlying cause and risk to a restrictive use in cases with high likelihood of cytokine release syndrome (eg, after anti-thymocyte globulin [ATG] therapy). We analyzed clinical data and microbiome parameters obtained 7 days after allogeneic SCT from 188 patients with ATG therapy transplanted in 2015/2016 (permissive cohort, n = 101) and 2918/2019 (restrictive cohort, n = 87).

Results
Restrictive antibiotic treatment postponed the beginning of antibiotic administration from 1.4 ± 7.6 days prior to 1.7 ± 5.5 days after SCT (P = .01) and significantly reduced the duration of antibiotic administration by 5.8 days (P &lt; .001) without increase in infectious complications. Furthermore, we observed beneficial effects of the restrictive strategy compared with the permissive way on microbiome diversity (urinary 3-indoxylsulfate, P = .01; Shannon and Simpson indices, P &lt; .001) and species abundance 7 days post-transplant as well as a positive trend toward a reduced incidence of severe GI GvHD (P = .1).

Conclusions
Our data indicate that microbiota protection can be achieved by a more careful selection of neutropenic patients qualifying for antibiotic treatment during allogeneic SCT without increased risk of infectious complications.
Spontaneous coronary artery dissection in women with acute myocardial infarction: is there a new role for autoimmunity?
Authors: Civieri Giovanni , Vadori Marta , Masiero Giulia , Iop Laura , Tansella Donatella , Pergola Valeria , Cozzi Emanuele , Iliceto Sabino , Tona Francesco 
Published: June 2023

Abstract

Aims
Spontaneous coronary artery dissection (SCAD) is an uncommon cause of acute myocardial infarction in women and has an unclear pathophysiology. Autoantibodies (AAs) targeting angiotensin-II receptor type 1 (AT1R) and endothelin-1 receptor type A (ETAR) have known detrimental effects on endothelial function. We investigated the prevalence of these AAs in SCAD-affected female patients.

Methods and results
Female patients diagnosed at coronary angiography with myocardial infarction and SCAD were consecutively enrolled. Autoantibodies targeting angiotensin-II receptor type 1 and ETAR-AA titres and seropositivity prevalence were compared between SCAD patients, ST-elevation myocardial infarction (STEMI) patients, and healthy women. Ten women with SCAD and 20 age-matched controls (10 women with STEMI and 10 healthy women) were included. Six out of 10 (60%) women with myocardial infarction and SCAD were seropositive for AT1R-AAs and ETAR-AAs. In contrast, only one (10%) healthy woman and one (10%) STEMI patient were seropositive for AT1R-AAs (P = 0.03 and P = 0.03, respectively). One STEMI patient was seropositive for ETAR-AAs, while none of the healthy women was found to be seropositive (P = 0.03 and P = 0.01, respectively). The median AA titre was significantly higher in SCAD patients than in healthy women (P = 0.01 for AT1R-AAs; P = 0.02 for ETAR-AAs) and STEMI patients (P &lt; 0.001 for AT1R-AAs; P = 0.002 for ETAR-AAs).

Conclusion
Autoantibodies targeting angiotensin-II receptor type 1 and ETAR-AA seropositivity is significantly higher in SCAD women with myocardial infarction than in healthy women or female patients with STEMI. Our findings, corroborated by previous data in the literature and biological plausibility, suggest a possible role for AT1R-AAs and ETAR-AAs in the pathophysiology of SCAD in women with acute myocardial infarction and should warrant further studies with larger sample sizes.
Circulating Biomarkers, Fraction of Exhaled Nitric Oxide, and Lung Function in Patients With Human Immunodeficiency Virus and Tuberculosis
Authors: Maenetje Pholo , Baik Yeonsoo , Schramm Diana B , Vangu Mboyo Di-Tamba Willy , Wallis Robert S , Mlotshwa Mandla , Tiemessen Caroline T , Li Yun , Kornfeld Hardy , Churchyard Gavin , Auld Sara C , Bisson Gregory P 
Published: June 2023

Abstract

Background
Identification of proinflammatory factors responding to Mycobacterium tuberculosis is important to reduce long-term sequelae of pulmonary tuberculosis (TB).

Methods
We examined the association between plasma biomarkers, the fraction of exhaled nitric oxide (FeNO), and lung function among a prospective cohort of 105 adults newly diagnosed with TB/human immunodeficiency virus (HIV) in South Africa. Participants were followed for 48 weeks from antiretroviral therapy (ART) initiation with serial assessments of plasma biomarkers, FeNO, lung function, and respiratory symptoms. Linear regression and generalized estimating equations were used to examine the associations at baseline and over the course of TB treatment, respectively.

Results
At baseline, higher FeNO levels were associated with preserved lung function, whereas greater respiratory symptoms and higher interleukin (IL)-6 plasma levels were associated with worse lung function. After ART and TB treatment initiation, improvements in lung function were associated with increases in FeNO (rate ratio [RR] = 86 mL, 95% confidence interval [CI] = 34–139) and decreases in IL-6 (RR = −118 mL, 95% CI = −193 to −43) and vascular endothelial growth factor ([VEGF] RR = −178 mL, 95% CI = −314 to −43).

Conclusions
Circulating IL-6, VEGF, and FeNO are associated with lung function in adults being treated for TB/HIV. These biomarkers may help identify individuals at higher risk for post-TB lung disease and elucidate targetable pathways to modify the risk of chronic lung impairment among TB survivors.
Development of antisense peptide-peptide nucleic acids against fluoroquinolone-resistant Escherichia coli
Authors: Kim Se Kye , Lee Jun Bong , Lee Hyung Tae , Han Dalmuri , Yoon Jang Won 
Published: June 2023

Abstract

Background
Fluoroquinolones (FQs) are potent and broad-spectrum antibiotics commonly used to treat MDR bacterial infections, but bacterial resistance to FQs has emerged and spread rapidly around the world. The mechanisms for FQ resistance have been revealed, including one or more mutations in FQ target genes such as DNA gyrase (gyrA) and topoisomerase IV (parC). Because therapeutic treatments for FQ-resistant bacterial infections are limited, it is necessary to develop novel antibiotic alternatives to minimize or inhibit FQ-resistant bacteria.

Objectives
To examine the bactericidal effect of antisense peptide-peptide nucleic acids (P-PNAs) that can block the expression of DNA gyrase or topoisomerase IV in FQ-resistant Escherichia coli (FRE).

Methods
A set of antisense P-PNA conjugates with a bacterial penetration peptide were designed to inhibit the expression of gyrA and parC and were evaluated for their antibacterial activities.

Results
Antisense P-PNAs, ASP-gyrA1 and ASP-parC1, targeting the translational initiation sites of their respective target genes significantly inhibited the growth of the FRE isolates. In addition, ASP-gyrA3 and ASP-parC2, which bind to the FRE-specific coding sequence within the gyrA and parC structural genes, respectively, showed selective bactericidal effects against FRE isolates.

Conclusions
Our results demonstrate the potential of targeted antisense P-PNAs as antibiotic alternatives against FQ-resistance bacteria.
Analysis of thermostability for seven Phe to Ala and six Pro to Gly mutants in the Fab constant region of adalimumab
Authors: Yoshikawa Moeka , Nakamura Hitomi , Oda-Ueda Naoko , Ohkuri Takatoshi 
Published: June 2023

Abstract
To identify amino acids that play important roles in the structural stability of Fab, seven phenylalanine residues in the Fab constant region of the therapeutic antibody adalimumab were subjected to alanine mutagenesis. Six Fab mutants, H:F130A, H:F154A, H:F174A, L:F118A, L:F139A and L:F209A, showed decreased thermostability compared with wild-type Fab. In contrast, the Tm for the L:F116A mutant was 1.7°C higher than that of wild-type Fab, indicating that the F116 residue was unfavorable for Fab thermostability. Six proline mutants, H:P131G, H:P155G, H:P175G, L:P119G, L:P120G and L:P141G, were also prepared to investigate the effect of proline residues adjacent to mutated phenylalanine residues. The thermostability of the H:P155G and L:P141G mutants in particular was significantly reduced, with decreases in Tm of 5.0 and 3.0°C, respectively, compared with wild-type Fab. The H:P155 and L:P141 residues have a cis conformation, whereas the other mutated proline residues have a trans conformation. H:P155 and L:P141 had stacking interactions with the H:F154 and L:Y140, respectively, at the interface between the variable and constant regions. It is suggested that the interactions of the aromatic ring with a cis-form proline at the interface between the variable and constant regions is important for stability of Fab.
Evaluating relapse-free survival as an endpoint for overall survival in adjuvant immunotherapy trials
Authors: Li Yuanfang , Yuan Shuqiang , Chen Yingbo , Nie Man , Li Jibin , Chen Guoming , Chen Xiaojiang , Zhang Ruopeng , Zheng Ziqi , Wei Chengzhi , Zhou Zhiwei , Nie Runcong , Wang Yun 
Published: June 2023

Abstract

Background
Relapse-free survival (RFS) has been considered a primary endpoint to assess the effects of immunotherapy in the adjuvant setting among patients with early-stage disease. However, it is not clear whether RFS is a valid surrogate endpoint for overall survival (OS) in this clinical context.

Methods
Phase II or III clinical trials of adjuvant immunotherapy that reported hazard ratios on OS and RFS were identified. We used a weighted regression analysis at the arm and trial levels to assess the efficacy of RFS as a surrogate for OS, quantified by the weighted coefficient of determination (R2). Strong correlations (R2 ≥ 0.7) at the arm and trial levels indicated valid surrogacy. The surrogate threshold effect was also evaluated.

Results
Fifteen high-quality randomized clinical trials involving 13 715 patients were included. At the arm level, moderate and strong associations were observed between RFS2-year and OS3-year (R2 = 0.58, 95% confidence interval [CI] = 0.25 to 0.92) and RFS3-year and OS5-year (R2 = 0.72, 95% CI = 0.38 to 1.00), respectively. At the trial level, a moderate association was observed between effect of treatment on RFS and OS (R2 = 0.63, 95% CI = 0.33 to 0.94). The surrogate threshold effect for RFS was 0.86. Consistent results were confirmed in several sensitivity analyses based on different trial phases, experimental arms, cancer types, and treatment strategies.

Conclusions
Our meta-analysis failed to find a clinically strong association between RFS and OS in randomized clinical trials of adjuvant immunotherapy. Our findings challenge the use of RFS as the primary efficacy endpoint and suggest the use of OS in this clinical context.
The programmed death ligand 1 interactome demonstrates bidirectional signaling coordinating immune suppression and cancer progression in head and neck squamous cell carcinoma
Authors: Nieto Cera , Miller Bettina , Alzofon Nathaniel , Chimed Tugy , Himes Jack , Joshi Molishree , Gomez Karina , Chowdhury Farshad N , Le Phuong N , Weaver Alice , Somerset Hilary , Morton J Jason , Wang Jing H , Wang Xiao-Jing , Gao Dexiang , Hansen Kirk , Keysar Stephen B , Jimeno Antonio 
Published: June 2023

Abstract

Background
The programmed cell death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) are validated cancer targets; however, emerging mechanisms and impact of PD-L1 intracellular signaling on cancer behavior are poorly understood.

Methods
We investigated the cancer cell intrinsic role of PD-L1 in multiple patient-derived models in vitro and in vivo. PD-L1 overexpression, knockdown, and PD-L1 intracellular domain (PD-L1–ICD) deletion (Δ260-290PD-L1) models were assessed for key cancer properties: clonogenicity, motility, invasion, and immune evasion. To determine how PD-L1 transduces signals intracellularly, we used the BioID2 platform to identify the PD-L1 intracellular interactome. Both human papillomavirus-positive and negative patient-derived xenografts were implanted in NOD-scid-gamma and humanized mouse models to investigate the effects of recombinant PD-1, anti–PD-L1, and anti–signal transducer and activator of transcription 3 (STAT3) in vivo.

Results
PD-L1 intracellular signaling increased clonogenicity, motility, and invasiveness in multiple head and neck squamous cell carcinoma (HNSCC) models, and PD-1 binding enhanced these effects. Protein proximity labeling revealed the PD-L1 interactome, distinct for unbound and bound PD-1, which initiated cancer cell–intrinsic signaling. PD-L1 binding partners interleukin enhancer binding factors 2 and 3 (ILF2-ILF3) transduced their effect through STAT3. Δ260-290PD-L1 disrupted signaling and reversed pro-growth properties. In humanized HNSCC in vivo models bearing T-cells, PD-1 binding triggered PD-L1 signaling, and dual PD-L1 and STAT3 inhibition were required to achieve tumor control.

Conclusions
Upon PD-1 binding, the PD-L1 extracellular and intracellular domains exert a synchronized effect to promote immune evasion by inhibiting T-cell function while simultaneously enhancing cancer cell–invasive properties.
Exosome-like nanoparticles derived from Allium tuberosum prevent neuroinflammation in microglia-like cells
Authors: Ishida Tomoaki , Kawada Kei , Jobu Kohei , Morisawa Shumpei , Kawazoe Tetsushi , Nishimura Satomi , Akagaki Keita , Yoshioka Saburo , Miyamura Mitsuhiko 
Published: June 2023

Abstract

Objective
Exosome-like nanoparticles (ELNs), which are plant-derived extracellular membrane vesicles, can regulate mammalian gene expression. ELNs can cross the blood-brain barrier, making them potential therapeutic agents or drug-delivery carriers for neuroinflammation-related diseases. Here, we investigated the anti-neuroinflammatory potential of ELNs extracted from Allium tuberosum (A-ELNs).

Methods
A-ELNs were extracted, and their miRNA profile was characterized. A-ELNs were also applied to BV-2 microglial and MG-6 cells derived from C57/BL6 mice stimulated with lipopolysaccharide (LPS), followed by an examination of levels of inflammatory-related factors. To test their drug-carrying potential, A-ELNs were mixed with dexamethasone, an anti-inflammatory drug, to prepare dexamethasone-incorporated A-ELNs (Dex-A-ELNs).

Key findings
A-ELNs showed a particle size of 145 ± 2 nm and characteristic miRNAs. A-ELNs significantly decreased the LPS-induced nitric oxide (NO) and inflammatory cytokines levels in BV-2 and MG-6 cells. The mRNA expression of heme oxygenase-1 was significantly increased, and that of inducible NO synthase and inflammatory cytokines was significantly decreased by A-ELNs in BV-2 cells. Dex-A-ELNs inhibited NO production in BV-2 cells more potently than either A-ELNs or dexamethasone alone.

Conclusion
A-ELNs can alleviate microglial inflammation. Their effects can be potentiated by incorporating anti-inflammatory drugs, such as dexamethasone, making them potential therapeutic agents or drug-delivery carriers for neuroinflammation.
Excellent efficacy and beneficial safety during observational 5-year follow-up of rapid steroid withdrawal after renal transplantation (Harmony FU study)
Authors: Stumpf Julian , Thomusch Oliver , Opgenoorth Mirian , Wiesener Michael , Pascher Andreas , Woitas Rainer Peter , Suwelack Barbara , Rentsch Markus , Witzke Oliver , Rath Thomas , Banas Bernhard , Benck Urs , Sommerer Claudia , Kurschat Christine , Lopau Kai , Weinmann-Menke Julia , Jaenigen Bernd , Trips Evelyn , Hugo Christian 
Published: June 2023

ABSTRACT

Background
We previously reported excellent efficacy and improved safety aspects of rapid steroid withdrawal (RSWD) in the randomized controlled 1-year “Harmony” trial with 587 predominantly deceased-donor kidney transplant recipients randomized either to basiliximab or rabbit antithymocyte globulin induction therapy and compared with standard immunosuppressive therapy consisting of basiliximab, low tacrolimus once daily, mycophenolate mofetil and corticosteroids.

Methods
The 5-year post-trial follow-up (FU) data were obtained in an observational manner at a 3- and a 5-year visit only for those Harmony patients who consented to participate and covered clinical events that occurred from the second year onwards.

Results
Biopsy-proven acute rejection and death-censored graft loss rates remained low and independent of RSWD. Rapid steroid withdrawal was an independent positive factor for patient survival (adjusted hazard ratio 0.554, 95% confidence interval 0.314–0.976; P = .041).
The reduced incidence of post-transplantation diabetes mellitus in RSWD patients during the original 1-year study period was not compensated by later incidences during FU. Incidences of other important outcome parameters such as opportunistic infections, malignancies, cardiovascular morbidity/risk factors, donor-specific antibody formation or kidney function did not differ during FU period.

Conclusions
With all the limitations of a post-trial FU study, the Harmony FU data confirm excellent efficacy and beneficial safety aspects of RSWD under modern immunosuppressive therapy over the course of 5 years after kidney transplantation in an immunologically low-risk, elderly population of Caucasian kidney transplant recipients.
Trial registration: Clinical trial registration number: Investigator Initiated Trial (NCT 00724022, FU study DRKS00005786)
The mediating effect of social functioning on the relationship between catastrophizing and pain among patients with chronic low back pain
Authors: Papianou Lauren N , Wilson Jenna M , Edwards Robert R , Sieberg Christine B , Meints Samantha M 
Published: June 2023

Abstract

Objective
Pain catastrophizing can be characterized as an interpersonal form of coping used to elicit support or empathy from others. Despite intentions of increasing support, catastrophizing can impair social functioning. While considerable work has addressed the relationship between catastrophizing and pain, limited empirical work has examined this relationship within a social context. First, we examined the role of catastrophizing as a potential contributor to group differences (chronic low back pain [cLBP] vs pain-free controls) in social functioning. Then we conducted a follow-up, exploratory analysis to examine the relationships between catastrophizing, social functioning, and pain within the subgroup of participants with cLBP.

Methods
In this observational study, participants with cLBP (N = 62) and pain-free controls (N = 79) completed validated measures of pain, social functioning, and pain catastrophizing. A mediation analysis was conducted to examine whether catastrophizing mediated group differences (cLBP vs controls) in social functioning. A follow-up, exploratory mediation analysis then tested whether social functioning mediated the association between catastrophizing and pain within the subgroup of cLBP participants.

Results
Participants with cLBP reported higher levels of pain, impaired social functioning, and higher catastrophizing compared to pain-free controls. Catastrophizing partially mediated the group difference in impaired social functioning. Additionally, social functioning mediated the association between higher catastrophizing and greater pain within the subgroup of cLBP participants.

Conclusions
We showed that impaired social functioning was driving the relationship between higher pain catastrophizing and worse pain among participants with cLBP. Interventions, such as cognitive behavioral therapy, should address catastrophizing in individuals with cLBP, while simultaneously improving social functioning.