bluuebunny/crossref_metadata_2025_split huggingface dataset:
Retrospective Analysis of Mobile Colistin Resistance and Plasmid-Mediated Quinolone Resistance Genes inEscherichia coli: China, 1993-2019
Authors: Wang Yujin , Sun Dewei , Xu Zhengzhong , Jiao Xin’an , Chen Xiang 
Published: October 2023

ABSTRACTPlasmid-mediated quinolone resistance (PMQR) genes and mobile colistin resistance (MCR) genes inEscherichia coli(E. coli) have shown an increasing prevalence in recent years. This rise is particularly notable in China and several Southeast Asian countries, representing a significant threat to public health. In the present study, we conducted a retrospective analysis of MCR genes (mcr-1,mcr-2,mcr-3,mcr-4, andmcr-5) and PMQR genes (qnrA,qnrB,qnrC,qnrD,qnrE1,qnrVC,qnrS,aac(6’)-Ib-cr,qepA, andoqxAB). From the 3,663E. coliisolates examined, 1,613 (44.0%) tested positive for PMQR genes, either individually or in combination. Meanwhile, 262 isolates (7.0%) carried MCR genes. Minimum inhibitory concentration (MIC) analyses of 17 antibiotics for the MCR gene-carrying strains revealed universal multidrug resistance. Resistance to polymyxin varied between 4 μg/mL and 64 μg/mL, with MIC50 and MIC90 values at 8 μg/mL and 16 μg/mL, respectively. Additionally, fluctuations in the detection rates of these resistant genes correlated with the introduction of antibiotic policies, host origin, temporal trends, and geographical distribution.IMPORTANCEAntimicrobial resistance (AMR) has emerged as a threat to global health and development, andE. coliresistance remains an ongoing clinical challenge. However, the efficacy of colistin and quinolones has been compromised by the presence of various MCR and PMQR genes. To elucidate the prevalence and distribution of MCR and PMQR genes inE. coliisolates, we analyzed 3,663E. coliisolates from 29 provinces in China from 1993 to 2019. The results show that 1,613 (44.0%) tested positive for PMQR genes, 262 isolates (7.0%) carried MCR genes. And MICs analyses of 17 antibiotics for the MCR gene-carrying strains revealed universal multidrug resistance. These indicated prohibiting or strictly curtailing antimicrobial use in animal or human is urgently needed to reduce the growing threat from AMR.
Selenocysteine tRNA methylation promotes oxidative stress resistance in melanoma metastasis
Authors: Nease Leona A. , Church Kellsey P. , Delclaux Ines , Murakami Shino , Astorkia Maider , Zerhouni Marwa , Cascio Graciela , Hughes Riley O. , Aguirre Kelsey N. , Zumbo Paul , Dow Lukas E. , Jaffrey Samie , Betel Doron , Piskounova Elena 
Published: October 2023

AbstractSelenocysteine-containing proteins play a central role in redox homeostasis. Their translation is a highly regulated process, dependent upon two tRNASecisodecoders differing by a single 2’-O-ribose methylation, called Um34. We characterized FTSJ1 as the Um34 methyltransferase and show that its activity is required for efficient selenocysteine insertion at the UGA stop codon during translation. Specifically, Loss of Um34 leads to ribosomal stalling and decreased UGA recoding. FTSJ1-deficient cells are more sensitive to oxidative stress and have decreased metastatic colonization in xenograft models of melanoma metastasis. We found that FTSJ1 mediates efficient translation of selenoproteins essential for the cellular antioxidant response. Our findings uncover a role for tRNASecUm34 modification in oxidative stress resistance and highlight FTSJ1 as a potential therapeutic target specific for metastatic disease.
Sexually dimorphic mechanisms of VGLUT-mediated protection from dopaminergic neurodegeneration
Authors: Buck Silas A. , Rubin Sophie A. , Kunkhyen Tenzin , Treiber Christoph D. , Xue Xiangning , Fenno Lief E. , Mabry Samuel J. , Sundar Varun R. , Yang Zilu , Shah Divia , Ketchesin Kyle D. , Becker-Krail Darius D. , Vasylieva Iaroslavna , Smith Megan C. , Weisel Florian J. , Wang Wenjia , Erickson-Oberg M. Quincy , O’Leary Emma I. , Aravind Eshan , Ramakrishnan Charu , Kim Yoon Seok , Wu Yanying , Quick Matthias , Coleman Jonathan A. , MacDonald William A. , Elbakri Rania , De Miranda Briana R. , Palladino Michael J. , McCabe Brian D. , Fish Kenneth N. , Seney Marianne L. , Rayport Stephen , Mingote Susana , Deisseroth Karl , Hnasko Thomas S. , Awatramani Rajeshwar , Watson Alan M. , Waddell Scott , Cheetham Claire E. J. , Logan Ryan W. , Freyberg Zachary 
Published: October 2023

SummaryParkinson’s disease (PD) targets some dopamine (DA) neurons more than others. Sex differences offer insights, with females more protected from DA neurodegeneration. The mammalian vesicular glutamate transporter VGLUT2 andDrosophilaortholog dVGLUT have been implicated as modulators of DA neuron resilience. However, the mechanisms by which VGLUT2/dVGLUT protects DA neurons remain unknown. We discovered DA neuron dVGLUT knockdown increased mitochondrial reactive oxygen species in a sexually dimorphic manner in response to depolarization or paraquat-induced stress, males being especially affected. DA neuron dVGLUT also reduced ATP biosynthetic burden during depolarization. RNA sequencing of VGLUT+DA neurons in mice and flies identified candidate genes that we functionally screened to further dissect VGLUT-mediated DA neuron resilience across PD models. We discovered transcription factors modulating dVGLUT-dependent DA neuroprotection and identified dj-1β as a regulator of sex-specific DA neuron dVGLUT expression. Overall, VGLUT protects DA neurons from PD-associated degeneration by maintaining mitochondrial health.
Targeted inhibition of BET proteins in HPV-16 associated head and neck squamous cell carcinoma reveals heterogeneous transcription response
Authors: Rao Aakarsha , Ni Zijian , Suresh Dhruthi , Mohanty Chitrasen , Wang Albert R. , Lee Denis L , Nickel Kwangok P. , Varambally Sooryanarayana , Kimple Randall J. , Lambert Paul F. , Kendziorski Christina , Iyer Gopal 
Published: October 2023

AbstractIntegrated human papillomavirus (HPV-16) associated head and neck squamous cell carcinoma (HNSCC) tumors have worse survival outcomes compared to episomal HPV-16 HNSCC tumors. Therefore, there is a need to differentiate treatment for HPV-16 integrated HNSCC from other viral forms. We analyzed TCGA data and found that HPV+ HNSCC expressed higher transcript levels of the bromodomain and extra terminal domain (BET) family of transcriptional coregulators. However, the mechanism of BET protein-mediated transcription of viral-cellular genes in the integrated viral-HNSCC genomes needs to be better understood. We show that BET inhibition downregulates E6 significantly independent of the viral transcription factor, E2, and there was overall heterogeneity in the downregulation of viral transcription in response to the effects of BET inhibition across HPV-associated cell lines. Chemical BET inhibition was phenocopied with the knockdown of BRD4 and mirrored downregulation of viral E6 and E7 expression. Strikingly, there was heterogeneity in the reactivation of p53 levels despite E6 downregulation, while E7 downregulation did not alter Rb levels significantly. We identified that BET inhibition directly downregulated c-Myc and E2F expression and induced CDKN1A expression. Overall, our studies show that BET inhibition provokes a G1-cell cycle arrest with apoptotic activity and suggests that BET inhibition regulates both viral and cellular gene expression in HPV-associated HNSCC.
Uncovering the Roles ofMycobacterium tuberculosis melHin Redox and Bioenergetic Homeostasis: Implications for Antitubercular Therapy
Authors: Chen Yu-Ching , Yang Xinxin , Wang Nan , Sampson Nicole S. 
Published: October 2023

AbstractMycobacterium tuberculosis(Mtb), the pathogenic bacterium that causes tuberculosis, has evolved sophisticated defense mechanisms to counteract the cytotoxicity of reactive oxygen species (ROS) generated within host macrophages during infection. ThemelHgene inMtbandMycobacterium marinum(Mm) plays a crucial role in defense mechanisms against ROS generated during infection. We demonstrate thatmelHencodes an epoxide hydrolase and contributes to ROS detoxification. Deletion ofmelHinMmresulted in a mutant with increased sensitivity to oxidative stress, increased accumulation of aldehyde species, and decreased production of mycothiol and ergothioneine. This heightened vulnerability is attributed to the increased expression ofwhiB3, a universal stress sensor. The absence ofmelHalso resulted in reduced intracellular levels of NAD+, NADH, and ATP. Bacterial growth was impaired, even in the absence of external stressors, and the impairment was carbon-source-dependent. Initial MelH substrate specificity studies demonstrate a preference for epoxides with a single aromatic substituent. Taken together, these results highlight the role ofmelHin mycobacterial bioenergetic metabolism and provide new insights into the complex interplay between redox homeostasis and generation of reactive aldehyde species in mycobacteria.ImportanceThis study unveils the pivotal role played by themelHgene inMycobacterium tuberculosisandMycobacterium marinumin combatting the detrimental impact of oxidative conditions during infection. This investigation revealed notable alterations in the level of cytokinin-associated aldehyde,para-hydroxybenzaldehyde, as well as the redox buffer ergothioneine, upon deletion ofmelH. Moreover, changes in crucial cofactors responsible for electron transfer highlightedmelH’s crucial function in maintaining a delicate equilibrium of redox and bioenergetic processes. MelH prefers epoxide small substrates with a phenyl substituted substrate. These findings collectively emphasize the potential ofmelHas an attractive target for the development of novel antitubercular therapies that sensitize mycobacteria to host stress, offering new avenues for combating tuberculosis.
Single-cell signaling analysis reveals that Major Vault Protein facilitates RasG12C inhibitor resistance
Authors: Zhang Jason Z. , Ong Shao-En , Baker David , Maly Dustin J. 
Published: October 2023

AbstractRecently developed covalent inhibitors for RasG12C provide the first pharmacological tools to target mutant Ras-driven cancers. However, the rapid development of resistance to current clinical Ras G12C inhibitors is common. Presumably, a subpopulation of RasG12C-expressing cells adapt their signaling to evade these inhibitors and the mechanisms for this phenomenon are unclear due to the lack of tools that can measure signaling with single-cell resolution. Here, we utilized recently developed Ras sensors to profile the environment of active Ras and to measure the activity of endogenous Ras in order to pair structure (Ras signalosome) to function (Ras activity), respectively, at a single-cell level. With this approach, we identified a subpopulation of KRasG12C cells treated with RasG12C-GDP inhibitors underwent oncogenic signaling and metabolic changes driven by WT Ras at the golgi and mutant Ras at the mitochondria, respectively. Our Ras sensors identified Major Vault Protein (MVP) as a mediator of Ras activation at both compartments by scaffolding Ras signaling pathway components and metabolite channels. We found that recently developed RasG12C-GTP inhibitors also led to MVP-mediated WT Ras signaling at the golgi, demonstrating that this a general mechanism RasG12C inhibitor resistance. Overall, single-cell analysis of structure-function relationships enabled the discovery of a RasG12C inhibitor-resistant subpopulation driven by MVP, providing insight into the complex and heterogenous rewiring occurring during drug resistance in cancer.
Precise cortical contributions to feedback sensorimotor control during reactive balance
Authors: Boebinger Scott , Payne Aiden , Martino Giovanni , Kerr Kennedy , Mirdamadi Jasmine , McKay J. Lucas , Borich Michael , Ting Lena 
Published: October 2023

AbstractThe role of the cortex in shaping automatic whole-body motor behaviors such as walking and balance is poorly understood. Gait and balance are typically mediated through subcortical circuits, with the cortex becoming engaged as needed on an individual basis by task difficulty and complexity. However, we lack a mechanistic understanding of how increased cortical contribution to whole-body movements shapes motor output. Here we use reactive balance recovery as a paradigm to identify relationships between hierarchical control mechanisms and their engagement across balance tasks of increasing difficulty in young adults. We hypothesize that parallel sensorimotor feedback loops engaging subcortical and cortical circuits contribute to balance-correcting muscle activity, and that the involvement of cortical circuits increases with balance challenge. We decomposed balance-correcting muscle activity based on hypothesized subcortically- and cortically-mediated feedback components driven by similar sensory information, but with different loop delays. The initial balance-correcting muscle activity was engaged at all levels of balance difficulty. Its onset latency was consistent with subcortical sensorimotor loops observed in the lower limb. An even later, presumed, cortically-mediated burst of muscle activity became additionally engaged as balance task difficulty increased, at latencies consistent with longer transcortical sensorimotor loops. We further demonstrate that evoked cortical activity in central midline areas measured using electroencephalography (EEG) can be explained by a similar sensory transformation as muscle activity but at a delay consistent with its role in a transcortical loop driving later cortical contributions to balance-correcting muscle activity. These results demonstrate that a neuromechanical model of muscle activity can be used to infer cortical contributions to muscle activity without recording brain activity. Our model may provide a useful framework for evaluating changes in cortical contributions to balance that are associated with falls in older adults and in neurological disorders such as Parkinson’s disease.
The evolution of constitutively active humoral immune defenses inDrosophilapopulations under high parasite pressure
Authors: Zhou Shuyu Olivia , Arunkumar Ramesh , Ding Shuai Dominique , Leitão Alexandre B. , Jiggins Francis M. 
Published: October 2023

AbstractBoth constitutive and inducible immune mechanisms are employed by hosts for defense against infection. Constitutive immunity allows for a faster response, but it comes with an associated cost that is always present. This trade-off between speed and fitness costs leads to the theoretical prediction that constitutive immunity will be favored where parasite exposure is frequent. We selected populations ofDrosophila melanogasterunder high parasite pressure from the parasitoid waspLeptopilina boulardi.With RNA sequencing, we found the evolution of resistance in these populations was associated with them developing constitutively active humoral immunity, mediated by the larval fat body. Furthermore, these evolved populations were also able to induce gene expression in response to infection to a greater level, which indicates an overall more activated humoral immune response to parasitization. The anti-parasitoid immune response also relies on the JAK/STAT signaling pathway being activated in muscles following infection, and this induced response was only seen in populations that had evolved under high parasite pressure. We found that the cytokine Upd3, which induces this JAK/STAT response, is being expressed by immature lamellocytes. Furthermore, these immune cells became constitutively present when populations evolved resistance, potentially explaining why they gained the ability to activate JAK/STAT signaling. Thus, under intense parasitism, populations evolved resistance by increasing both constitutive and induced immune defenses, and there is likely an interplay between these two forms of immunity.Author SummaryImmune defenses can be induced after infection or they may be constitutively active, even in uninfected individuals. As constitutive immunity is a more rapid response, theory predicts that it will be favored when animals frequently encounter parasites. When we subjected populations ofDrosophila melanogasterto high rates of parasitization from its natural parasite,Leptopilina boulardiparasitoid wasps, we indeed observed that the immune response became constitutively active. Uninfected insects had an activated humoral immune response and produced cytokine-secreting immune cells that were normally induced after infection. However, we also found that these populations evolved a greater induced response. This included a greatly increased cytokine response after infection, suggesting that the constitutive activation of some aspects of the immune system may allow a greater induced response in other tissues.
Very high frequencies of Familial Breast Cancer, low BRCA1/2 mutations and high Luminal molecular subtypes in Eastern Saudi Arabia necessitate the hunt for novel breast cancer hub genes
Authors: Al-Qurashi Tahani , Balghonaim Sarah , Albunyan Haya , Alduhailan Hattan , Almqhawi Latiffah , Zafar Irtaza Fatima , Abubaker Rehab , Malik Anees R , Mustafa Hani , Alanazi Nawaf , Iqbal Zafar 
Published: October 2023

AbstractThis study was carried out to find out incidence of familial breast cancer, frequencies of different histological and molecular subtypes of breast cancer, and proportion of breast cancer patient with BRCA1/2 mutations, to plan for its implementation in early cancer screening and personalized treatment in Eastern Saudi Arabia. The breast cancer incidence increased from 2009-2016 and peaked in 2012. Ductal carcinoma (80%) was the most common histological type and Luminal A/B the most common (74%) molecular types among all patients. The familial and non-familial breast cancer groups were compared based on their demographic and clinical characteristics. The mean age at diagnosis was 51.6±13.5 and 53.5±12.7 for familial and non-familial breast cancer patients respectively. A total of 10 (24.3%) of familial breast cancer patients were tested for BRCA gene mutations, and 5 (12.2%) were abnormal, making it 4.3% of total patients. In the familial group, significant correlation (p 0.04) was found between patients with age less than 50 and with more than one family member affected with breast or ovarian cancer. Significance was found between unilateral familial breast cancer and bone metastasis (p 0.004). In both familial and non-familial groups, significant correlation was found between unilateral breast cancer and liver metastasis (0.005 and 0.017 respectively). There was a significant association between unilateral non-familial breast cancer and luminal A molecular type (p 0.012). Analysis of TNM staging showed that (61%) of familial breast cancer patients were diagnosed at stage II. In conclusion, familial breast cancer incidence is increasingly high in Al-Ahsa region as compared to western populations which could be due to consanguineous marriage and social behaviors. It warrants further studies to explore familial breast cancer hub genes in Eastern Saudi Arabia and its implementation in early diagnosis and patient-tailored treatment of breast cancer.
Some principles for using epidemiologic study results to parameterize transmission models
Authors: Joshi Keya , Kahn Rebecca , Boyer Christopher , Lipsitch Marc 
Published: October 2023

AbstractBackgroundInfectious disease models, including individual based models (IBMs), can be used to inform public health response. For these models to be effective, accurate estimates of key parameters describing the natural history of infection and disease are needed. However, obtaining these parameter estimates from epidemiological studies is not always straightforward. We aim to 1) outline challenges to parameter estimation that arise due to common biases found in epidemiologic studies and 2) describe the conditions under which careful consideration in the design and analysis of the study could allow us to obtain a causal estimate of the parameter of interest. In this discussion we do not focus on issues of generalizability and transportability.MethodsUsing examples from the COVID-19 pandemic, we first identify different ways of parameterizing IBMs and describe ideal study designs to estimate these parameters. Given real-world limitations, we describe challenges in parameter estimation due to confounding and conditioning on a post-exposure observation. We then describe ideal study designs that can lead to unbiased parameter estimates. We finally discuss additional challenges in estimating progression probabilities and the consequences of these challenges.ResultsCausal estimation can only occur if we are able to accurately measure and control for all confounding variables that create non-causal associations between the exposure and outcome of interest, which is sometimes challenging given the nature of the variables we need to measure. In the absence of perfect control, non-causal parameter estimates should still be used, as sometimes they are the best available information we have.ConclusionsIdentifying which estimates from epidemiologic studies correspond to the quantities needed to parameterize disease models, and determining whether these parameters have causal interpretations, can inform future study designs and improve inferences from infectious disease models. Understanding the way in which biases can arise in parameter estimation can inform sensitivity analyses or help with interpretation of results if the magnitude and direction of the bias is understood.