bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting autophagy reverses de novo resistance in homologous recombination repair proficient breast cancers to PARP inhibition
Authors: Pai Bellare Ganesh , Saha Bhaskar , Patro Birija Sankar 
Published: January 2021

Abstract
Background
Poly(ADP-ribose) polymerase inhibitors (PARPi) target tumours defective in homologous recombination (HR). Most BRCA-wild-type (WT) HR-proficient breast cancers are intrinsically resistant to PARP inhibitors, e.g., talazoparib. We evaluated the role of autophagy in this de novo resistance and determined the underlying mechanism to overcome this.

Methods
Autophagosome formation and autophagic flux were assessed by evaluating endogenous LC3-II levels and ectopic expression of EGFP-LC3 and mRFP-EGFP-LC3 in breast cancer cells. Autophagy-defective cells were generated by genetic depletion of BECN1, ATG5, p62/SQSTM1 and LAMP1 by using CRISPR-Cas9 double nickase system. The response of PARPi was evaluated in autophagy-proficient and -defective breast cancer cells and in xenograft SCID-mice model.

Results
Pro-survival autophagy was significantly enhanced upon talazoparib treatment in BRCA-WT breast cancer cell lines. Autophagy-deficient cells were hypersensitive to talazoparib. Targeting autophagy synergistically enhanced the therapeutic efficacy of talazoparib in BRCA1-WT breast cancer cells in vitro and in vivo xenograft tumour mouse model. Mechanistically, autophagy inhibition by chloroquine promoted deleterious NHEJ mediated DSB-repair, leading to extensive genomic instability and mitotic catastrophe.

Conclusions
Autophagy confers de novo resistance to PARP inhibitor, talazoparib. Autophagy inhibition improves the therapeutic outcome of PARPi treatment in preclinical mice model, bearing HR-proficient breast tumours, warranting its usage in the clinical settings.
Systemic inflammation scores correlate with survival prognosis in patients with newly diagnosed brain metastases
Authors: Starzer Angelika M. , Steindl Ariane , Mair Maximilian J. , Deischinger Carola , Simonovska Anika , Widhalm Georg , Gatterbauer Brigitte , Dieckmann Karin , Heller Gerwin , Preusser Matthias , Berghoff Anna S. 
Published: January 2021

Abstract
Background
Systemic inflammation measured by the neutrophil-to-lymphocyte ratio (NLR), leucocyte-to-lymphocyte ratio (LLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR) and CRP/albumin ratio (CRP/Alb) was shown to impact the survival prognosis in patients with extracranial solid cancer.

Methods
One thousand two hundred and fifty patients with newly diagnosed brain metastases (BM) were identified from the Vienna Brain Metastasis Registry.

Results
PLR and CRP/Alb were higher in patients with progressive extracranial disease and lower in patients with no evidence of extracranial disease. Lower NLR (cut-off = 5.07; 9.3 vs. 5.0 months), LLR (cut-off = 5.76; 10.0 vs. 5.3 months), PLR (cut-off = 335; 8.0 vs. 3.8 months), MLR (cut-off = 0.53; 6.0 vs. 3.5 months) and CRP/Alb (cut-off = 2.93; 8.5 vs. 3.7 months; padj < 0.05) were associated with longer overall survival (OS). In multivariate analysis with graded prognostic assessment (hazard ratio (HR) 1.45; 95% confidence interval (CI): 1.32–1.59; padj = 1.62e − 13), NLR (HR 1.55; 95% CI: 1.38–1.75; padj = 1.92e − 11), LLR (HR 1.57; 95% CI: 1.39–1.77; padj = 1.96e − 11), PLR (HR 1.60; 95% CI: 1.39–1.85; padj = 2.87955e − 9), MLR (HR 1.41; 95% CI: 1.14–1.75; padj = 0.027) and CRP/Alb (HR 1.83; 95% CI: 1.54–2.18; padj = 2.73e − 10) remained independent factors associated with OS at BM diagnosis.

Conclusions
Systemic inflammation, measured by NLR, LLR, PLR, MLR and CRP/Alb, was associated with OS in patients with BM. Further exploration of immune modulating therapies is warranted in the setting of BM.
Tubular Mas receptor mediates lipid-induced kidney injury
Authors: Kong Yonglun , Zhao Xiaoduo , Qiu Miaojuan , Lin Yu , Feng Pinning , Li Suchun , Liang Baien , Zhu Qing , Huang Hui , Li Chunling , Wang Weidong 
Published: January 2021

AbstractObesity-related kidney diseases are becoming serious health problems worldwide, yet the mechanism by which obesity causes kidney injury is not fully understood. The purpose of current study was to investigate the role of Mas receptor in lipid-induced kidney injury. In mice fed with high-fat diet (HFD), the protein abundance of markers of autophagy, endoplasmic reticulum stress (ER stress) and apoptosis was dramatically increased in the kidney cortex, which was markedly prevented by Mas deletion (Mas−/−) or Mas receptor antagonist A779. Palmitic acid (PA) induced persistently increased autophagy, ER stress, and apoptosis as well as mitochondrial injuries in primary cultured proximal tubular cells from wild type, but not from Mas−/− mice. In human proximal tubular HK2 cells, PA-induced autophagy and ER stress was aggravated by Mas agonists Ang (1–7) or AVE0991, but attenuated by A779 or Mas knockdown. Stimulation of Mas resulted in elevated intracellular calcium levels [Ca2+]i in HK2 cells treated with PA, whereas inhibition or knockdown of Mas decreased [Ca2+]i. Mitochondrial outer membrane located voltage-dependent anion channel (VDAC1) was markedly upregulated in HK2 cells treated with PA, which was associated with impaired mitochondrial morphology and depolarization. These were enhanced by AVE0991 and suppressed by A779 or Mas knockdown. Mas knockdown in HK2 cells prevented impaired interactions among VDAC1, autophagy adaptor P62, and ubiquitin, induced by PA, leading to a potential ubiquitination of VDAC1. In conclusion, Mas receptor-mediated lipid-induced impaired autophagy and ER stress in the kidney, likely contributing to tubular injuries in obesity-related kidney diseases.
3D high-density microelectrode array with optical stimulation and drug delivery for investigating neural circuit dynamics
Authors: Shin Hyogeun , Jeong Sohyeon , Lee Ju-Hyun , Sun Woong , Choi Nakwon , Cho Il-Joo 
Published: January 2021

AbstractInvestigation of neural circuit dynamics is crucial for deciphering the functional connections among regions of the brain and understanding the mechanism of brain dysfunction. Despite the advancements of neural circuit models in vitro, technologies for both precisely monitoring and modulating neural activities within three-dimensional (3D) neural circuit models have yet to be developed. Specifically, no existing 3D microelectrode arrays (MEAs) have integrated capabilities to stimulate surrounding neurons and to monitor the temporal evolution of the formation of a neural network in real time. Herein, we present a 3D high-density multifunctional MEA with optical stimulation and drug delivery for investigating neural circuit dynamics within engineered 3D neural tissues. We demonstrate precise measurements of synaptic latencies in 3D neural networks. We expect our 3D multifunctional MEA to open up opportunities for studies of neural circuits through precise, in vitro investigations of neural circuit dynamics with 3D brain models.
Adenosine modulators and calcium channel blockers as add-on treatment for schizophrenia
Authors: Lintunen Jonne , Lähteenvuo Markku , Tiihonen Jari , Tanskanen Antti , Taipale Heidi 
Published: January 2021

AbstractRelapses remain common among individuals with schizophrenia indicating a need for improved treatments. Creating a completely new drug molecule is expensive and time consuming, and therefore drug repurposing should be considered. Aim of this study was to investigate the risk of psychiatric rehospitalization associated with use of adenosine modulators (AMs) and calcium channel blockers (CCBs) in schizophrenia. Individuals diagnosed with schizophrenia (N = 61,889) in inpatient care between 1972–2014 in Finland were included. The follow-up lasted from 1996 to 2017. Main exposures were use of AMs (allopurinol and dipyridamole) and CCBs (dihydropyridines, diltiazem, and verapamil). Thiazide diuretics were used as a negative control. Within-individual models in stratified Cox regression were used and adjusted hazard ratios (HR) with 95% confidence intervals (CIs) are reported. Use of AMs was associated with a reduced risk of psychiatric rehospitalization on drug class level (HR 0.74, 95% CI 0.65–0.84, P < 0.0001), as well as on the level of individual drugs (allopurinol HR 0.82, 95% CI 0.70–0.97, P = 0.02; dipyridamole HR 0.65, 95% CI 0.55–0.77, P < 0.0001). Use of CCBs was associated with a reduced risk of psychiatric rehospitalization on drug class level (HR 0.81, 95% CI 0.77–0.86, P < 0.0001). From the different CCBs, only exposure to dihydropyridines was associated with a reduced risk (HR 0.79, 95% CI 0.74–0.84, P < 0.0001). No effect was observed for the negative control, thiazide diuretics (HR 0.96, 0.90–1.02, P = 0.20). The effects of dipyridamole and dihydropyridines were more pronounced among younger persons and combination of AMs, and CCBs was associated with a lower risk than either drug class as monotherapy. These results indicate a need for randomized controlled trials of these drugs.
Gene co-expression in the interactome: moving from correlation toward causation via an integrated approach to disease module discovery
Authors: Paci Paola , Fiscon Giulia , Conte Federica , Wang Rui-Sheng , Farina Lorenzo , Loscalzo Joseph 
Published: January 2021

AbstractIn this study, we integrate the outcomes of co-expression network analysis with the human interactome network to predict novel putative disease genes and modules. We first apply the SWItch Miner (SWIM) methodology, which predicts important (switch) genes within the co-expression network that regulate disease state transitions, then map them to the human protein–protein interaction network (PPI, or interactome) to predict novel disease–disease relationships (i.e., a SWIM-informed diseasome). Although the relevance of switch genes to an observed phenotype has been recently assessed, their performance at the system or network level constitutes a new, potentially fascinating territory yet to be explored. Quantifying the interplay between switch genes and human diseases in the interactome network, we found that switch genes associated with specific disorders are closer to each other than to other nodes in the network, and tend to form localized connected subnetworks. These subnetworks overlap between similar diseases and are situated in different neighborhoods for pathologically distinct phenotypes, consistent with the well-known topological proximity property of disease genes. These findings allow us to demonstrate how SWIM-based correlation network analysis can serve as a useful tool for efficient screening of potentially new disease gene associations. When integrated with an interactome-based network analysis, it not only identifies novel candidate disease genes, but also may offer testable hypotheses by which to elucidate the molecular underpinnings of human disease and reveal commonalities between seemingly unrelated diseases.
An epitope-based malaria vaccine targeting the junctional region of circumsporozoite protein
Authors: Jelínková Lucie , Jhun Hugo , Eaton Allison , Petrovsky Nikolai , Zavala Fidel , Chackerian Bryce 
Published: January 2021

AbstractA malaria vaccine that elicits long-lasting protection and is suitable for use in endemic areas remains urgently needed. Here, we assessed the immunogenicity and prophylactic efficacy of a vaccine targeting a recently described epitope on the major surface antigen on Plasmodium falciparum sporozoites, circumsporozoite protein (CSP). Using a virus-like particle (VLP)-based vaccine platform technology, we developed a vaccine that targets the junctional region between the N-terminal and central repeat regions of CSP. This region is recognized by monoclonal antibodies, including mAb CIS43, that have been shown to potently prevent liver invasion in animal models. We show that CIS43 VLPs elicit high-titer and long-lived anti-CSP antibody responses in mice and is immunogenic in non-human primates. In mice, vaccine immunogenicity was enhanced by using mixed adjuvant formulations. Immunization with CIS43 VLPs conferred partial protection from malaria infection in a mouse model, and passive transfer of serum from immunized macaques also inhibited parasite liver invasion in the mouse infection model. Our findings demonstrate that a Qβ VLP-based vaccine targeting the CIS43 epitope combined with various adjuvants is highly immunogenic in mice and macaques, elicits long-lasting anti-CSP antibodies, and inhibits parasite infection in a mouse model. Thus, the CIS43 VLP vaccine is a promising pre-erythrocytic malaria vaccine candidate.
Synthesis of nano-fibers containing nano-curcumin in zein corn protein and its physicochemical and biological characteristics
Authors: Fereydouni Narges , Movaffagh Jebrail , Amiri Nafise , Darroudi Susan , Gholoobi Aida , Goodarzi Arash , Hashemzadeh Alireza , Darroudi Majid 
Published: January 2021

AbstractCurcumin contains many biological activities as a natural bioactive substance, however, its low solubility stands as a huge bioavailability disadvantage. Recently, different methods have been developed for utilizing the tremendous medicinal properties of this material. In this study, an Oil/Water nano-emulsion of curcumin (Nano-CUR) has been woven in zein polymer at three percentages of 5%, 10%, and 15% (v/v). We have investigated the physicochemical properties of nanofibers (NFs) including FESEM, FTIR, tensile strength, encapsulation efficiency, and release profile, as well as biological properties. According to the data, the NFs have been observed to become significantly thinner and more uniformed as the involved percentage of Nano-CUR had been increased from 5 to 15%. It is considerable that the tensile strength can be increased by heightening the existing Nano-CUR from 5% towards 15%. The resultant NFs of zein/Nano-CUR 15% have exhibited higher in vitro release and lower encapsulation efficiency than the other evaluated zein/Nano-CUR NFs. It has been confirmed through the performed viability and antioxidant studies that zein/Nano-CUR 10% NFs are capable of providing the best conditions for cell proliferation. Considering the mentioned facts, this work has suggested that Nano-CUR can be successfully woven in zein NFs and maintain their biological properties.
The 20-million-year old lair of an ambush-predatory worm preserved in northeast Taiwan
Authors: Pan Yu-Yen , Nara Masakazu , Löwemark Ludvig , Miguez-Salas Olmo , Gunnarson Björn , Iizuka Yoshiyuki , Chen Tzu-Tung , Dashtgard Shahin E. 
Published: January 2021

AbstractThe feeding behavior of the giant ambush-predator “Bobbit worm” (Eunice aphroditois) is spectacular. They hide in their burrows until they explode upwards grabbing unsuspecting prey with a snap of their powerful jaws. The still living prey are then pulled into the sediment for consumption. Although predatory polychaetes have existed since the early Paleozoic, their bodies comprise mainly soft tissue, resulting in a very incomplete fossil record, and virtually nothing is known about their burrows and behavior beneath the seafloor. Here we use morphological, sedimentological, and geochemical data from Miocene strata in northeast Taiwan to erect a new ichnogenus,Pennichnus. This trace fossil consists of an up to 2 m long, 2–3 cm in diameter, L-shaped burrow with distinct feather-like structures around the upper shaft. A comparison ofPennichnusto biological analogs strongly suggests that this new ichnogenus is associated with ambush-predatory worms that lived about 20 million years ago.
Study of the effect of band gap and photoluminescence on biological properties of polyaniline/CdS QD nanocomposites based on natural polymer
Authors: Alipour Azita , Mansour Lakouraj Moslem , Tashakkorian Hamed 
Published: January 2021

AbstractIn this work, band gap, photoluminescence and biological properties of new bionanocomposites based on polyaniline (PANi)/hydrolyzed pectin (HPEc)/cadmium sulfide (CdS) QD nanoparticles (NPs) were studied. In order to improve the morphology and properties, CdS NPs were modified with epichlorohydrin to obtain the modified CdS (mCdS). The CdS@HPEc-g-PANi and mCdS@HPEc-g-PANi samples were synthesized via heterogeneous chemical polymerization and characterized by FTIR, 1HNMR, SEM/XRD, EDX/TEM/EDX-mapping and TGA analyses. The objective of this work is the study of physical, optical and cytotoxicity properties of the nanocomposites and comparison between them. The SEM, XRD and TGA images showed that the modification of NPs resulted in homogeneous morphology, increase of crystalline structure and high thermal stability which influenced on physical and biological property. According to UV-DRS analysis, the mCdS@HPEc-g-PANi indicated lower energy gap compared to the CdS@HPEc-g-PANi nancomposite. The presence of conductive polymer and synergy effect between the PANi and CdS caused higher PL intensity in the CdS@HPEc-g-PANi nanocomposite compared to pure CdS. The emission intensity in the mCdS@HPEc-g-PANi nanocomposite was reduced since the organic modifying agent cause reducing emission intensity. The mCdS@HPEc-g-PANi nanocomposite, due to more compatibility of organic agent with cellular walls of biological cells that help to the diffusion of metal CdS NPs into cell tissue indicated more toxicity effect on cell growth.
Dehydration of d-fructose to 5-hydroxymethyl-2-furfural in DMSO using a hydrophilic sulfonated silica catalyst in a process promoted by microwave irradiation
Authors: Barbosa Sandro L. , de S. Freitas Milton , dos Santos Wallans T. P. , Nelson David Lee , Klein Stanlei I. , Clososki Giuliano Cesar , Caires Franco J. , Baroni Adriano C. M. , Wentz Alexandre P. 
Published: January 2021

AbstractSiO2-SO3H, with a surface area of 115 m2/g, pore volumes of 0.38 cm3g−1 and 1.32 mmol H+/g, was used as a 10% w/w catalyst for the preparation of 5-hydroxymethyl-2-furfural (HMF) from fructose. A conversion of 100% was achieved in a microwave reactor during 10 min at 150 °C in DMSO, with 100% selectivity for HMF, at a molar ratio of fructose: DMSO equal to 1:56. The catalyst could be re-used three times.
Altered structural balance of resting-state networks in autism
Authors: Moradimanesh Z. , Khosrowabadi R. , Eshaghi Gordji M. , Jafari G. R. 
Published: January 2021

AbstractWhat makes a network complex, in addition to its size, is the interconnected interactions between elements, disruption of which inevitably results in dysfunction. Likewise, the brain networks’ complexity arises from interactions beyond pair connections, as it is simplistic to assume that in complex networks state of a link is independently determined only according to its two constituting nodes. This is particularly of note in genetically complex brain impairments, such as the autism spectrum disorder (ASD), which has a surprising heterogeneity in manifestations with no clear-cut neuropathology. Accordingly, structural balance theory (SBT) affirms that in real-world signed networks, a link is remarkably influenced by each of its two nodes’ interactions with the third node within a triadic interrelationship. Thus, it is plausible to ask whether ASD is associated with altered structural balance resulting from atypical triadic interactions. In other words, it is the abnormal interplay of positive and negative interactions that matters in ASD, besides and beyond hypo (hyper) pair connectivity. To address this question, we explore triadic interactions based on SBT in the weighted signed resting-state functional magnetic resonance imaging networks of participants with ASD relative to healthy controls (CON). We demonstrate that balanced triads are overrepresented in the ASD and CON networks while unbalanced triads are underrepresented, providing first-time empirical evidence for the strong notion of structural balance on the brain networks. We further analyze the frequency and energy distributions of different triads and suggest an alternative description for the reduced functional integration and segregation in the ASD brain networks. Moreover, results reveal that the scale of change in the whole-brain networks’ energy is more narrow in the ASD networks during development. Last but not least, we observe that energy of the salience network and the default mode network are lower in ASD, which may be a reflection of the difficulty in dynamic switching and flexible behaviors. Altogether, these results provide insight into the atypical structural balance of the ASD brain (sub) networks. It also highlights the potential value of SBT as a new perspective in functional connectivity studies, especially in the case of neurodevelopmental disorders.
Further evidence supporting a potential role for ADH1B in obesity
Authors: Morales Liza D. , Cromack Douglas T. , Tripathy Devjit , Fourcaudot Marcel , Kumar Satish , Curran Joanne E. , Carless Melanie , Göring Harald H. H. , Hu Shirley L. , Lopez-Alvarenga Juan Carlos , Garske Kristina M. , Pajukanta Päivi , Small Kerrin S. , Glastonbury Craig A. , Das Swapan K. , Langefeld Carl , Hanson Robert L. , Hsueh Wen-Chi , Norton Luke , Arya Rector , Mummidi Srinivas , Blangero John , DeFronzo Ralph A. , Duggirala Ravindranath , Jenkinson Christopher P. 
Published: January 2021

AbstractInsulin is an essential hormone that regulates glucose homeostasis and metabolism. Insulin resistance (IR) arises when tissues fail to respond to insulin, and it leads to serious health problems including Type 2 Diabetes (T2D). Obesity is a major contributor to the development of IR and T2D. We previously showed that gene expression of alcohol dehydrogenase 1B (ADH1B) was inversely correlated with obesity and IR in subcutaneous adipose tissue of Mexican Americans. In the current study, a meta-analysis of the relationship between ADH1B expression and BMI in Mexican Americans, African Americans, Europeans, and Pima Indians verified that BMI was increased with decreased ADH1B expression. Using established human subcutaneous pre-adipocyte cell lines derived from lean (BMI < 30 kg m−2) or obese (BMI ≥ 30 kg m−2) donors, we found that ADH1B protein expression increased substantially during differentiation, and overexpression of ADH1B inhibited fatty acid binding protein expression. Mature adipocytes from lean donors expressed ADH1B at higher levels than obese donors. Insulin further induced ADH1B protein expression as well as enzyme activity. Knockdown of ADH1B expression decreased insulin-stimulated glucose uptake. Our findings suggest that ADH1B is involved in the proper development and metabolic activity of adipose tissues and this function is suppressed by obesity.
Whole genomic sequencing based genotyping reveals a specific X3 sublineage restricted to Mexico and related with multidrug resistance
Authors: Jiménez-Ruano Ana Cristina , Madrazo-Moya Carlos Francisco , Cancino-Muñoz Irving , Mejía-Ponce Paulina M. , Licona-Cassani Cuauhtémoc , Comas Iñaki , Muñiz-Salazar Raquel , Zenteno-Cuevas Roberto 
Published: January 2021

AbstractWhole genome sequencing (WGS) has been shown to be superior to traditional procedures of genotyping in tuberculosis (TB), nevertheless, reports of its use in drug resistant TB (DR-TB) isolates circulating in Mexico, are practically unknown. Considering the above the main of this work was to identify and characterize the lineages and genomic transmission clusters present in 67 DR-TB isolates circulating in southeastern Mexico. The results show the presence of three major lineages: L1 (3%), L2 (3%) and L4 (94%), the last one included 16 sublineages. Sublineage 4.1.1.3 (X3) was predominant in 18 (27%) of the isolates, including one genomic cluster, formed by eleven multidrug resistant isolates and sharing the SIT 3278, which seems to be restricted to Mexico. By the use of WGS, it was possible to identify the high prevalence of L4 and a high number of sublineages circulating in the region, also was recognized the presence of a novel X3 sublineage, formed exclusively by multidrug resistant isolates and with restrictive circulation in Mexico for at least the past 17 years.