bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of non-β-Lactam covalent allosteric inhibitors targeting PBP2a in Methicillin-ResistantStaphylococcus aureus
Authors: Benin Bogdan M. , Kharel Rupak , Hillyer Trae , Sun Chuanqi , Cmolik Anna , Kuebler Taylor , Sham Yuk Yin , Bonomo Robert , Mighion Jeffrey D. , Shin Woo Shik 
Published: May 2024

AbstractMethicillin-resistantStaphylococcus aureus(MRSA), a Gram-positive bacterial pathogen, continues to pose a serious threat to the current public health system in our society. The high level of resistance to β-lactam antibiotics in MRSA is attributed to the expression of penicillin-binding protein 2a (PBP2a), which catalyzes cell wall cross-linking. According to numerous research reports, the activity of the PBP2a protein is known to be regulated by an allosteric site distinct from the active site where cell wall cross-linking occurs. Here, we conducted a screening of 113 compounds containing a 1,3,4-oxadiazole core to design new covalent inhibitors targeting the allosteric site of PBP2a and establish their structural-activity relationship. The stereochemically selective synthesis of sulfonyl oxadiazole compounds identified in the initial screening resulted in a maximum eightfold enhancement in cell inhibition activity. The sulfonyl oxadiazole-based compounds formulated as PEG-based ointments, with low toxicity test results on human cells (CC50: >78μM), demonstrated potent antimicrobial effects not only in a mouse skin wound infection model but also against oxacillin-resistant clinical isolate MRSA (IC50≈ 1μM), as evidenced by the results. Furthermore, additional studies utilizing LC-MS/MS and in-silico approaches clearly support the allosteric site covalent binding mechanism through the nucleophilic aromatic substitution (SNAr) reaction, as well as its association with the closure of the major active site of PBP2a.
CCR2 silencing in sensory neurons blocks bone cancer progression
Authors: Midavaine Élora , Côté Jérôme , Trépanier Alexandra , Kashem Sakeen W. , Dansereau Marc-André , Longpré Jean-Michel , Charbonneau Martine , Dubois Claire , Jacobi Ashley M. , Rose Scott D. , Belkhe Mark A. , Sarret Philippe 
Published: May 2024

AbstractThe peripheral nervous system has been shown to contribute to cancer growth by expanding the immunological niche. How the nervous system affects bone cancer progression and how neuroimmune pathways can be targeted for cancer treatment are not yet clear. Here, we demonstrate a profound influence of the peripheral nervous system on tumor progression, which can be targeted by silencing neuronal chemokine receptor signaling. We show that axotomy in animals with bone cancer inhibits tumor progression. Conversely, intrathecal injection of a known tumor-associated proinflammatory chemokine, CCL2, promotes tumor growth and allodynia. Silencing CCR2 in DRG neurons through a newly developed gene therapy successfully impedes tumor progression and bone remodeling and relieves bone cancer-associated pain. We demonstrate that the mechanism underlying CCR2-mediated tumor progression involves decreased neuropeptide secretion by peripheral nerves that promote expansion of the tumor-associated macrophage population. Silencing the CCR2 receptor in DRG neurons successfully normalizes the neuropeptide milieu and ameliorates altered bone remodeling. Thus, we have developed a novel therapeutic pathway for targeting a neuroimmune axis that contributes to cancer progression.HighlightsCancer progression activates sensory neurons, inducing pain hypersensitivity and neuropeptide release.Axotomy impedes tumor progression.CCL2 signaling in DRG neurons induces pain sensitivity and cancer growth.Silencing CCR2 in the DRG reduces pain sensitivity, tumor-associated macrophage numbers and cancer growth.
Epidemiology ofBurkholderia pseudomallei, Streptococcus suis, Salmonellaspp.,Shigellaspp. andVibriospp. infections in 111 hospitals in Thailand, 2022
Authors: Jitpeera Charuttaporn , Kripattanapong Somkid , Klaytong Preeyarach , Rangsiwutisak Chalida , Wannapinij Prapass , Doungngern Pawinee , Pinyopornpanish Papassorn , Chamawan Panida , Srisuphan Voranadda , Tuamsuwan Krittiya , Boonyarit Phairam , Sripichai Orapan , Hinjoy Soawapak , Stelling John , Turner Paul , Bhunyakitikorn Wichan , Iamsirithaworn Sopon , Limmathurotsakul Direk 
Published: May 2024

AbstractThe information on notifiable diseases in low- and middle-income countries is often incomplete, limiting our understanding of their epidemiology. Our study addresses this knowledge gap by analyzing microbiology laboratory and hospital admission data from 111 of 127 public referral hospitals in Thailand, excluding Bangkok, from January to December 2022. We evaluated factors associated with the incidence of notifiable bacterial diseases (NBDs) caused by 11 pathogens; includingBrucellaspp.,Burkholderia pseudomallei,Corynebacterium diphtheriae,Neisseria gonorrhoeae,Neisseria meningitidis, non-typhoidalSalmonellaspp. (NTS),Salmonella entericaserovar Paratyphi,Salmonella entericaserovar Typhi,Shigellaspp.,Streptococcus suis, andVibriospp.. We used multivariable Poisson random-effects regression models. Additionally, we compared their yearly incidence rates in 2022 with those from 2012-2015 in hospitals where paired data were available. In 2022, the NBD associated with the highest total number of deaths wasB. pseudomallei(4,407 patients; 1,219 deaths) infection, followed by NTS (4,501 patients; 461 deaths) andS. suis(867 patients, 134 deaths) infection. The incidence rate ofB. pseudomalleiandS. suisinfection was highest in the northeast and upper central, respectively. The incidence rate of NTS infection was not associated with geographical region. The yearly incidence rate ofB. pseudomalleiandS. suisinfection in 2022 were higher than those between 2012-2015, while those of fecal-oral transmitted NBDs including NTS infection, typhoid, shigellosis and vibriosis were lower. Overall,B. pseudomalleiandS. suisinfection are emerging and associated with a high number of deaths in Thailand. Specific public health interventions are warranted.
Deep Learning Model of Diastolic Dysfunction Risk Stratifies the Progression of Early-Stage Aortic Stenosis
Authors: Tokodi Márton , Shah Rohan , Jamthikar Ankush , Craig Neil , Hamirani Yasmin , Casaclang-Verzosa Grace , Hahn Rebecca T. , Dweck Marc R. , Pibarot Philippe , Yanamala Naveena , Sengupta Partho P. 
Published: May 2024

ABSTRACTBackgroundThe development and progression of aortic stenosis (AS) from aortic valve (AV) sclerosis is highly variable and difficult to predict.ObjectivesWe investigated whether a previously validated echocardiography-based deep learning (DL) model assessing diastolic dysfunction (DD) could identify the latent risk associated with the development and progression of AS.MethodsWe evaluated 898 participants with AV sclerosis from the Atherosclerosis Risk in Communities (ARIC) cohort study and associated the DL-predicted probability of DD with two endpoints: (1) the new diagnosis of AS and (2) the composite of subsequent mortality or AV interventions. We performed validation in two additional cohorts: 1) patients with mild-to-moderate AS undergoing cardiac magnetic resonance (CMR) imaging and serial echocardiographic assessments (n=50), and (2) patients with AV sclerosis undergoing18F-sodium fluoride (18F-NaF) and18F-fluorodeoxyglucose positron emission tomography (PET) combined with computed tomography (CT) to assess valvular inflammation and calcification (n=18).ResultsIn the ARIC cohort, a higher DL-predicted probability of DD was associated with the development of AS (adjusted HR: 3.482 [2.061 – 5.884], p<0.001) and subsequent mortality or AV interventions (adjusted HR: 7.033 [3.036 – 16.290], p<0.001). The multivariable Cox model (incorporating the DL-predicted probability of DD) derived from the ARIC cohort efficiently predicted the progression of AS (C-index: 0.798 [0.648 – 0.948]) in the CMR cohort. Moreover, the predictions of this multivariable Cox model correlated positively with valvular18F-NaF mean standardized uptake values in the PET/CT cohort (r=0.62, p=0.008).ConclusionsAssessment of DD using DL can stratify the latent risk associated with the progression of early-stage AS.CONDENSED ABSTRACTWe investigated whether DD assessed using DL can predict the progression of early-stage AS. In 898 patients with AV sclerosis, the DL-predicted probability of DD was associated with the development of AS. The multivariable Cox model derived from these patients also predicted the progression of AS in an external cohort of patients with mild-to-moderate AS (n=50). Moreover, the predictions of this model correlated positively with PET/CT-derived valvular18F-NaF uptake in an additional cohort of patients with AV sclerosis (n=18). These findings suggest that assessing DD using DL can stratify the latent risk associated with the progression of early-stage AS.
Running acceleration correlates with T2 magnetic resonance imaging values of the lumber intervertebral disc
Authors: Hakkaku Takayoshi , Kubo Yoshiaki , Koyama Koji , Nakazato Koichi , Okada Takashi , Hiranuma Kenji 
Published: May 2024

SummaryBackgroundRunning can contribute to both beneficial and detrimental responses in the intervertebral discs (IVDs). To better understand these effects, we investigated the relationship between loading directions during slow running and the rapid changes in T2 times occurring in the lumbar IVDs before and after running.MethodSixteen healthy male students were fitted with a triaxial accelerator and ran on a treadmill at 8 km/h for one minute. Three lumbar T2 times from the L3/L4 to L5/S1 levels were measured before, immediately after, and 30 minutes post-exercise via magnetic resonance imaging (MRI). The analysis focused on five regions of interest within each disc.ResultAcceleration was 0.23 ± 0.06 root mean square in the mediolateral (X-axis), 1.37 ± 0.08 in the vertical (Y-axis), and 0.30 ± 0.06 in the anteroposterior (Z-axis) direction. A strong correlation was observed between the T2 relaxation times and acceleration, particularly in the Z-axis. At L3/L4, a positive correlation was observed for the posterior nucleus (r = 0.72, p = 0.002, R2 = 0.59). At L4/L5, a positive correlation was observed for the central nucleus (r = 0.73, p = 0.003, R2 = 0.49). At L5/S1, a negative correlation was observed for the anterior annulus fibrosus (r = -0.73, p = 0.01, R2 = 0.48).ConclusionThese results suggest that anteroposterior loading may play a significant role in the response of the IVDs to running.
BRCA1 Interaction with Non-Canonical DNA Structures: Insights into Genome Maintenance and Disease Mechanisms
Authors: Lowran Kaitlin , Campbell Laura , Cismas Emma , Wu Colin G 
Published: May 2024

AbstractBreast Cancer Susceptibility Gene 1 (BRCA1) plays a crucial role in the homologous recombination (HR) pathway to repair double-stranded breaks (DSBs) in human cells. Interactions between BRCA1 protein and DNA have been mapped to the central region, which could be further divided as two DNA binding domains (DBDs); however, the relative substrate preferences of the DBDs and their functional role in HR remain poorly understood. We hypothesize that the DBDs have distinct binding preferences for DNA repair intermediates, and we have measured the DNA binding affinities of DBD1 (amino acids (aa) 330-554), DBD2 (aa894-1057), and the BRCA1 C-terminal repeats (BRCT) for single-stranded (ssDNA), double-stranded (dsDNA), and G-quadruplex (G4) DNA using biolayer interferometry. Our results indicate that DBD1 has the highest affinity for dsDNA, while DBD2 and BRCT bound tightest to G4 and ssDNA. Based on these findings, we propose a model in which DBD1 targets BRCA1 to DSBs for the promotion of DNA end resection, whereas DBD2 and BRCT target BRCA1 to telomeres to function in chromatin remodeling and telomere regulation.
The Mia40 substrate Mix17 exposes its N-terminus to the cytosolic side of the mitochondrial outer membrane
Authors: Resch Moritz , Frickel Johanna S. , Dischinger Korbinian , Wen Rachel Choo Shen , Hell Kai , Harner Max E. 
Published: May 2024

AbstractMitochondrial architecture and the contacts between the outer and the inner mitochondrial membrane depend on the mitochondrial contact site and cristae organizing system (MICOS) that is highly conserved from yeast to human. Mutations in the mammalian MICOS subunit Mic14/CHCHD10 have been linked to amyotrophic lateral sclerosis and frontotemporal dementia, indicating the importance of this protein. Mic14/CHCHD10 has a yeast ortholog, Mix17, a protein of unknown function, which has not been shown to interact with MICOS so far. As a first step to elucidate the function of Mix17 and its orthologs, we analyzed its interactions, biogenesis and mitochondrial sublocation.We report that Mix17 is no stable MICOS subunit in yeast. Our data suggest that Mix17 is the first Mia40 substrate in the mitochondrial outer membrane. Unlike all other Mia40 substrates, Mix17 spans the outer membrane and exposes its N-terminus to the cytosol. The insertion of Mix17 is likely to be mediated by its interaction with Tom40, the pore of the TOM complex. Moreover, we show that the exposure of Mix17 to the cytosolic side of the membrane depends on its N-terminus.
Unveiling Stimulus Transduction Artifacts in Auditory Steady-State Response Experiments: Characterization, Risks, and Mitigation Strategies
Authors: Strobl Jan , Viktorin Vojtech , Piorecky Marek , Griskova-Bulanova Inga , Hubeny Jan , Brunovsky Martin , Palenicek Tomas , Koudelka Vlastimil 
Published: May 2024

AbstractThis scientific paper addresses the potential risk of spurious responses in neuroscientific auditory steady-state response (ASSR) experiments attributed to transduction artifacts. The focus is particularly on click train stimuli, given their spectral content in the frequency range of interest (e.g., 40 Hz). Building upon a pilot experiment demonstrating the existence of the artifact in a phantom head, this study focuses on the characterization of stimulus artifacts in extended measurements with phantoms and the evaluation of associated risks in experiments involving human subjects. The investigation is divided into two parts: the first part scrutinizes stimulus artifact properties crucial for mitigation, while the second part assesses risks in ASSR experiments with human subjects based on the characterized artifact. The discussion covers stimulus characterization, experimental setups with phantoms, and experiments with human subjects, exploring potential sources of the artifact, its spatial properties, and the influence of re-referencing. The results reveal the role of headphone cables as a source of stimulus artifacts, along with the surprising impact of headphone transducers. The study emphasizes the need for careful experimental design and data analysis to avoid misinterpretations of stimulus artifacts as genuine brain responses in ASSR experiments.
Tissue Regeneration Requires Edema Fluid Clearance by Compensatory Lymphangiogenesis in Zebrafish
Authors: Olayinka Olamide , Ryu Hannah , Wang Xiaowei , Malik Asrar B. , Jung Hyun Min 
Published: May 2024

AbstractLymphangiogenesis is essential for tissue regeneration and edema clearance, and delayed or failed lymphangiogenesis is a critical cause of impaired healing. However, elucidating the dynamic changes in lymphangiogenesis during tissue regeneration in animal models in real-time has been challenging; thus, the mechanisms of compensatory lymphatic activation for edema clearance remain unclear. To address this, zebrafish were subjected to osmotic stress using a hypertonic solution (375 mOsm/L) and hypotonic solution (37.5 mOsm/L) to induce tissue damage followed by edema formation. Intravital imaging ofTg(mrc1a:egfp; kdrl:mcherry)larvae unveiled substantial lymphatic vessel remodeling during tissue regeneration. The increase of lymphatic endothelial progenitor cells accompanied by sustained expansion and remodeling of primary lymphatics during recovery suggested active lymphangiogenesis during tissue repair. We developed a novel method using translating ribosome affinity purification to scrutinize the translatome of lymphatic endothelial cellsin vivo. This analysis revealed the upregulation of key pro-lymphangiogenic genes, notably vegfr2 and vegfr3, during tissue regeneration. Pharmacological inhibition of these Vegfr2/Vegfr3 prevented compensatory lymphangiogenesis and impaired healing. Our findings provide a new model ofin vivolive imaging of regenerative lymphangiogenesis, presenting a novel approach to investigating lymphatic activation during tissue regeneration.
A qualitative analysis of student reflections on public health internships
Authors: Teng Cecilia Woon Chien , Lim Raymond Boon Tar , Tan Claire Gek Ling 
Published: May 2024

PurposeReflective practice (RP) is a key skill for developing one’s professional practice. It has, however, not been unanimously prioritised in public health (PH) competency and education frameworks. Reflection activities are often unstructured in higher education. There is also a dearth of literature on the RPs of undergraduate PH students. This study aims to explore in greater depth how RP helps undergraduate PH students explore their own learning in internships.Design/methodology/approachReflection prompts were designed using the DEAL model. 124 written reflection entries from 32 students were collected and analysed thematically using a deductive-inductive approach. The conceptual framework of internship learning goals by Ash and Clayton (2009) was used to guide the deductive analysis.FindingsThree themes were identified: initial engagement with reflective learning; gradual integration of reflective learning, and a transformative phase involving professional development, personal growth, civic learning, growth through struggle, being confronted with differences in expectations, and skill acquisition.Originality/valueThis study extends the limited evidence regarding RP in undergraduate non-medical PH education, and contributes toward informing the revision of undergraduate PH programmes, for example, by integrating structured reflection earlier in the curricula, and establishing/supporting mentorship programmes between institutions. The findings call for PH educators to be more intentional in creating opportunities to nurture RP among budding PH professionals.
Paradox of GPO size and a hospital’s relative power for purchasing efficiency and the moderating role of system membership
Authors: Kim Yoon Hee , Sharma Luv , Walker Daniel M. 
Published: May 2024

PurposeExtant research documents the cost benefits of group purchasing organizations (GPOs) to member hospitals, but understudies concerns about the market dominance of a few large GPOs and the relatively weakened buyer power of hospitals in the US healthcare product supply chain. To fill the gap in the literature, this study investigates whether GPO size and a hospital’s relative power to its GPO affect the hospital’s supply expenses, and whether and how system membership moderates the power–performance link.Design/methodology/approachFor this study, we collect the panel data from various secondary sources on GPO–hospital dyads, which include the seven largest GPOs and their 2,590 unique acute care hospital members in 51 states over the period of 2009–2017. To address the endogeneity issue associated with simultaneity, we establish a one-year time lag between dependent and independent variables and analyzed the 15,527 hospital-year observations using the time-series regression with fixed-effect.FindingsWe find that a hospital’s relative power to its GPO is the most critical factor to reduce its supply cost while GPO size has no effects. We also find that a nonsystem hospital achieves greater cost savings by leveraging its relative power to its GPO while a system hospital gains no benefits.Originality/valueTo the best of our knowledge, this study is the first to address the paradox of GPO size and a hospital’s relative power and the moderating role of system membership for the hospital’s purchasing efficiency using a large nation-wide dataset of US hospitals–GPO dyads.
A non‐antibiotic erythromycin derivative improves muscle endurance by regulating endogenous anti‐fatigue protein orosomucoid in mice
Authors: Feng Jiayi , Wan Jingjing , Guo Pengyue , Sun Yang , Chen Fei , Chen Yi , Sun Qingyan , Zhang Weidong , Liu Xia 
Published: May 2024

AbstractAt present, there are no official approved drugs for improving muscle endurance. Our previous research found acute phase protein orosomucoid (ORM) is an endogenous anti‐fatigue protein, and macrolides antibiotics erythromycin can elevate ORM level to increase muscle bioenergetics and endurance parameters. Here, we further designed, synthesized and screened a new erythromycin derivative named HMS‐01, which lost its antibacterial activity in vitro and in vivo. Data showed that HMS‐01 could time‐ and dose‐dependently prolong mice forced‐swimming time and running time, and improve fatigue index in isolated soleus muscle. Moreover, HMS‐01 treatment could increase the glycogen content, mitochondria number and function in liver and skeletal muscle, as well as ORM level in these tissues and sera. In Orm‐deficient mice, the anti‐fatigue and glycogen‐elevation activity of HMS‐01 disappeared. Therefore, HMS‐01 might act as a promising small molecule drug targeting ORM to enhance muscle endurance.
Determinants and outcomes of preterm births in Nigerian tertiary facilities
Authors: Fajolu Iretiola Bamikeolu , Dedeke Iyabode Olabisis Florence , Oluwasola Timothy A. , Oyeneyin Lawal , Imam Zainab , Ogundare Ezra , Campbell Ibijoke , Akinkunmi Bola , Ayegbusi Ekundayo O. , Agelebe Efeturi , Adefemi Ayodeji K. , Awonuga David , Jagun Olusoji , Salau Qasim , Kuti Bankole , Tongo Olukemi Oluwatoyin , Adebayo Tajudeen , Adebanjo‐Aina Damilola , Adenuga Emmanuel , Adewumi Idowu , Lavin Tina , Tukur Jamilu , Adesina Olubukola 
Published: May 2024

AbstractObjectiveTo describe the incidence, and sociodemographic and clinical factors associated with preterm birth and perinatal mortality in Nigeria.DesignSecondary analysis of data collected through the Maternal Perinatal Database for Quality, Equity and Dignity (MPD‐4‐QED) Programme.SettingData from births in 54 referral‐level hospitals across Nigeria between 1 September 2019 and 31 August 2020.PopulationA total of 69 698 births.MethodsMultilevel modelling was used to determine the factors associated with preterm birth and perinatal mortality.Outcome measuresPreterm birth and preterm perinatal mortality.ResultsOf 62 383 live births, 9547 were preterm (153 per 1000 live births). Maternal age (<20 years – adjusted odds ratio [aOR] 1.52, 95% CI 1.36–1.71; >35 years – aOR 1.23, 95% CI 1.16–1.30), no formal education (aOR 1.68, 95% CI 1.54–1.84), partner not gainfully employed (aOR 1.94, 95% CI 1.61–2.34) and no antenatal care (aOR 2.62, 95% CI 2.42–2.84) were associated with preterm births. Early neonatal mortality for preterm neonates was 47.2 per 1000 preterm live births (451/9547). Father's occupation (manual labour aOR 1.52, 95% CI 1.20–1.93), hypertensive disorders of pregnancy (aOR 1.37, 95% CI 1.02–1.83), no antenatal care (aOR 2.74, 95% CI 2.04–3.67), earlier gestation (28 to <32 weeks – aOR 2.94, 95% CI 2.15–4.10; 32 to <34 weeks – aOR 1.80, 95% CI 1.3–2.44) and birthweight <1000 g (aOR 21.35, 95% CI 12.54–36.33) were associated with preterm perinatal mortality.ConclusionsPreterm birth and perinatal mortality in Nigeria are high. Efforts should be made to enhance access to quality health care during pregnancy, delivery and the neonatal period, and improve the parental socio‐economic status.