bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combining renin-angiotensin system blockade and sodium-glucose cotransporter-2 inhibition in experimental diabetes results in synergistic beneficial effects
Authors: Cruz-López Edwyn O. , Ye Dien , Stolk Daniel G. , Clahsen-van Groningen Marian C. , van Veghel Richard , Garrelds Ingrid M. , Poglitsch Marko , Domenig Oliver , Alipour Symakani Rahi S. , Merkus Daphne , Verdonk Koen , Jan Danser A.H. 
Published: December 2023

Background:
Sodium-glucose cotransporter-2 (SGLT2) inhibition exerts cardioprotective and renoprotective effects, often on top of renin-angiotensin system (RAS) blockade. We investigated this in diabetic hypertensive (mREN2)27 rats.

Methods:
Rats were made diabetic with streptozotocin and treated with vehicle, the angiotensin receptor blocker valsartan, the SGLT2 inhibitor empagliflozin, or their combination. Blood pressure (BP) was measured by telemetry.

Results:
Diabetes resulted in albuminuria, accompanied by glomerulosclerosis, without a change in glomerular filtration rate. Empagliflozin did not lower BP, while valsartan did, and when combined the BP drop was largest. Only dual blockade reduced cardiac hypertrophy and prevented left ventricular dilatation. Valsartan, but not empagliflozin, increased renin, and the largest renin rise occurred during dual blockade, resulting in plasma angiotensin II [but not angiotensin-(1–7)] upregulation. In contrast, in the kidney, valsartan lowered angiotensin II and angiotensin-(1–7), and empagliflozin did not alter this. Although both valsartan and empagliflozin alone tended to diminish albuminuria, the reduction was significant only when both drugs were combined. This was accompanied by reduced glomerulosclerosis, no change in glomerular filtration rate, and a favorable expression pattern of fibrosis and inflammatory markers (including SGLT2) in the kidney.

Conclusion:
RAS blockade and SGLT2 inhibition display synergistic beneficial effects on BP, kidney injury and cardiac hypertrophy in a rat with hypertension and diabetes. The synergy does not involve upregulation of angiotensin-(1–7), but may relate to direct RAS-independent effects of empagliflozin in the heart and kidney.
A Comparative Study of Medium-sized Macular Hole Surgery with Inverted Internal Limiting Membrane Flap Technique versus Conventional Peeling
Authors: Iwasaki Masanori , Nakashizuka Hiroyuki , Tanaka Koji , Wakatsuki Yu , Onoe Hajime , Sakakibara Takuya , Nakagawa Naoya , Fujimiya Taishi , Koutari Sawako , Kitagawa Yorihisa , Takayuki Hattori , Mori Ryusaburo , Shimada Hiroyuki 
Published: December 2023

Purpose:
To investigate surgical results for medium-sized (251–400 µm) macular holes (MHs).

Methods:
This retrospective observational study involved 266 eyes of 262 consecutive patients who underwent internal limiting membrane (ILM) peeling (147 eyes in the ILM peeling group) or inverted ILM flap cover technique (119 eyes in the inverted flap group) for primary medium-sized full-thickness MHs. MH associated with retinal detachment, recurrent MH, and traumatic MH were excluded.

Results:
The primary closure rate for overall medium-sized MHs was 100% (119/119 eyes) in the inverted flap group, which was significantly higher than that (94.6% [139/147 eyes]; p = 0.010) in the ILM peeling group. Notably, even after adjusting for the minimum MH diameter, presence of high myopia, or pre-existing posterior vitreous detachment, the primary closure rate was significantly better in the inverted flap group than in the ILM peeling group (Cochran–Mantel–Haenszel Test, overall adjusted p = 0.006, 0.009, 0.005, respectively). The pre- and postoperative restoration of the outer retinal layers and visual acuity were comparable between the inverted ILM flap and ILM peeling techniques.

Conclusion:
Primary closure for medium-sized MHs was significantly superior in the inverted flap group than in the ILM peeling group.
Pulmonary hypertension in chronic obstructive pulmonary disease: current understanding, knowledge gaps and future directions
Authors: Atchley William T. , Kakkera Teja Krishna 
Published: December 2023

Purpose of review
Despite the advent of effective and mechanistically diverse treatments for pulmonary arterial hypertension (PAH) and their positive impacts on the functional capacities and outcomes for PAH patients, the much larger population of patients with pulmonary hypertension (PH) in chronic lung diseases like chronic obstructive pulmonary disease (PH-COPD) remain without effective therapies.

Recent findings
In this review, we will highlight advances in the understanding of PH-COPD pathobiology, the clinical impact comorbid PH has on COPD outcomes, and detail the spectrum of disease and clinical phenotypes that encompass the heterogenous disease manifestations of PH-COPD. Finally, we will examine recent studies exploring the effects of potential treatments for PH-COPD and highlight sub-populations and treatment options that warrant further study.

Summary
As the PAH population-base ages and comorbid diseases become more frequently diagnosed in PAH patients, the need to clearly delineate subpopulations for clinical applications of PH therapies and research becomes even more urgent. Through an improved understanding of the clinical phenotypes of PH-COPD and the overlap with certain subpopulations of PAH, a framework for future research and potential for therapeutic impact is highlighted.
Advances in desensitization for human leukocyte antigen incompatible kidney transplantation
Authors: Vo Ashley , Ammerman Noriko , Jordan Stanley C. 
Published: December 2023

Purpose of review
Human leukocyte antigen (HLA) sensitization is a major barrier to kidney transplantation induced by exposure to alloantigens through pregnancy, blood product exposure and previous transplantations. Desensitization strategies are undertaken to improve the chances of finding compatible organ offers. Standard approaches to desensitization include the use of plasmapheresis/low dose intravenous immunoglobulin (IVIG) or high dose IVIG plus anti-CD20. However, current methods to reduce HLA antibodies are not always successful, especially in those with calculated panel reactive antibody 99–100%.

Recent findings
Newer desensitization strategies such as imlifidase [immunoglobulin G (IgG) endopeptidase] rapidly inactivates IgG molecules and creates an “antibody-free zone”, representing an important advancement in desensitization. However, pathogenic antibodies rebound, increasing allograft injury that is not addressed by imlifidase. Here, use of anti-IL-6R (tocilizumab) or anti-interleukin-6 (clazakizumab) could offer long-term control of B-memory and plasma cell DSA responses to limit graft injury. Agents aimed at long-lived plasma cells (anti-CD38 and anti-BCMAxCD3) could reduce or eliminate HLA-producing plasma cells from marrow niches. Other agents such as complement inhibitors and novel agents inhibiting the Fc neonatal receptor (FcRn) mediated IgG recycling will likely find important roles in desensitization.

Summary
Use of these agents alone or in combination will likely improve the efficacy and durability of desensitization therapies, improving access to kidney transplantation for immunologically disadvantaged patients.
Slower intravenous tramadol administration can prevent nausea and vomiting and predict postoperative nausea and vomiting: a randomized controlled trial
Authors: Gan Wanxia , Zheng Xiaozhu , Chen Yuanjing , Shu Bin , Dan Ling , Duan Guangyou , Chen Jie 
Published: December 2023

Objective:
Nausea and vomiting are the most common complications in patients who use tramadol for analgesia. This study evaluated the risk of nausea and vomiting related to intravenous tramadol administration.

Methods:
In this study, 315 patients who received pre-analgesia before elective surgery were selected, and participants were divided into groups based on the Apfel risk assessment of nausea and vomiting, as follows: high risk (Apfel=4), medium risk (Apfel=2–3), and low-risk (Apfel=1). Tramadol (1.5 mg/kg) was administered intravenously over a duration of 1 min, 2 min, or 3 min before anaesthesia induction to observe preoperative nausea and vomiting reactions within 10 min.

Results:
In the low-risk group, the numeric rating scale for postoperative nausea scores and the incidence of nausea and vomiting were significantly lower in the 3-min group than those in the 1-min group, and the incidence of preoperative nausea and vomiting after intravenous administration of tramadol in the 1-min and 3-min groups were significantly related to the incidence of postoperative nausea and vomiting. The incidence of nausea and vomiting during pre-administration in the 1-min and 3-min groups was identified as an independent risk factor for postoperative nausea and vomiting.

Conclusions:
In the clinical treatment of pain with tramadol, the slow intravenous application of tramadol within 3 min is worthy of being adopted and promoted by clinicians in their daily work.
A computational study to assess the pathogenicity of single or combinations of missense variants on respiratory Complex I
Authors: Rigobello Laura , Lugli Francesca , Caporali Leonardo , Bartocci Alessio , Fadanni Jacopo , Zerbetto Francesco , Iommarini Luisa , Carelli Valerio , Ghelli Anna Maria , Musiani Francesco 
Published: December 2023

AbstractVariants found in the respiratory complex I (CI) subunit genes encoded by mitochondrial DNA can cause severe genetic diseases. However, it is difficult to establisha prioriwhether a single or a combination of CI variants may impact oxidative phosphorylation. Here we propose a computational approach based on coarse-grained molecular dynamics simulations. One of the primary CI variants (m.14484T>C/MT-ND6) associated with the Leber hereditary optic neuropathy was used as a test case. This variant was investigated alone or in combination with two additional rare CI variants whose role remains uncertain. We found that the primary variant stiffens CI dynamics in the crucial E-channel region and that one of the other variants, located in the vicinity of the primary one, further worsens the stiffening. This approach may be extended to other variants candidate to exert a pathogenic impact on CI function, or to investigate the interaction of multiple variants.TeaserMolecular dynamics is able to predict the functional impact of variants hitting respiratory complex I mitochondrial genes.
Identifying drug sensitivity of multifocal primary prostate cancer
Authors: Kang Juening , Chouvardas Panagiotis , Ovchinnikova Katja , Thalmann George N. , Karkampouna Sofia , Kruithof-de Julio Marianna 
Published: December 2023

AbstractThe pronounced intra-patient variability in multifocal primary prostate cancer (PCa) has curtailed the efficacy of current treatment options. Patient-derived organoids (PDOs) have emerged as a pivotal model for functional testing due to their capability to retain the histopathological and molecular characteristics of parental tissues, allowing timely acquisition of drug response outcomes. In our study, employing twin biopsies from multiple lesions with matched PDO modelsin vitro, we investigated the molecular heterogeneity of PCa, and how it is linked to in vitro PDO pharmacological heterogeneity. Our functional testing approach leverages PDOs to screen standard-of-care treatment and FDA-approved compounds for other malignancies, aiming to repurpose their use in PCa and explore alternatives to androgen deprivation therapy. By integrating gene expression data from parental tissue with drug response results from PDOs, we have established a transcriptomics-based drug prediction models. The machine learning-based prediction model can predict the experimental PDO response to a specific drug, for the majority of screened drugs. This study offers a preclinical approach to potentially procure drug prediction outcomes and validate them in PDO models, as a prior step to clinical trial investigations or for selection of targeted therapeutic options.
A cyclic dipeptide for salinity stress alleviation and the trophic flexibility of an endophyte reveal niches in salt marsh plant-microbe interactions
Authors: Hung Shih-Hsun Walter , Yeh Pin-Hsien , Huang Tsai-Ching , Huang Shao-Yu , Wu I-Chen , Liu Chia-Ho , Lin Yu-Hsi , Chien Pei-Ru , Huang Fan-Chen , Ho Ying-Ning , Kuo Chih-Horng , Hwang Hau-Hsuan , Chiang En-Pei Isabel , Huang Chieh-Chen 
Published: December 2023

AbstractIn response to climate change, the nature of endophytes and their applications in sustainable agriculture has attracted the attention of academia and agro-industries. We focused on the endophytic halophiles of the endangered Taiwanese salt marsh plant,Bolboschoenus planiculmis, and evaluated the functions of the isolates throughin plantasalinity stress alleviation assay usingArabidopsis. An endophytic strainPriestia megateriumBP01R2 that could promote plant growth and salinity tolerance was further characterised through multi-omics approaches. The transcriptomics results suggested that BP01R2 could function by tuning hormone signal transduction, energy-producing metabolism, multiple stress responses, etc. In addition, a cyclodipeptide, cyclo(L-Ala-Gly), identified by metabolomics analysis was later confirmed to contribute to salinity stress alleviation in stressed plants by exogenous supplementation. Here we provide a new perspective on host-microbe interactions in the wetland biome based on the multi-omics investigation and mixotrophic character of BP01R2. This study revealed a biostimulant-based plant-endophyte symbiosis with potential application in sustainable agriculture and facilitated our understanding of those enigmatic cross-kingdom relationships.
Cryptic proteins translated from deletion-containing viral genomes dramatically expand the influenza virus proteome
Authors: Ranum Jordan N , Ledwith Mitchell P , Alnaji Fadi G , Diefenbacher Meghan , Orton Richard , Sloan Elisabeth , Guereca Melissa , Feltman Elizabeth M , Smollett Katherine , da Silva Filipe Ana , Conley Michaela , Russell Alistair B , Brooke Christopher B , Hutchinson Edward , Mehle Andrew 
Published: December 2023

AbstractProductive infections by RNA viruses require faithful replication of the entire genome. Yet many RNA viruses also produce deletion-containing viral genomes (DelVGs), aberrant replication products with large internal deletions. DelVGs interfere with the replication of wild-type virus and their presence in patients is associated with better clinical outcomes as they. The DelVG RNA itself is hypothesized to confer this interfering activity. DelVGs antagonize replication by out-competing the full-length genome and triggering innate immune responses. Here, we identify an additionally inhibitory mechanism mediated by a new class of viral proteins encoded by DelVGs. We identified hundreds of cryptic viral proteins translated from DelVGs. TheseDelVG-encodedproteins (DPRs) include canonical viral proteins with large internal deletions, as well as proteins with novel C-termini translated from alternative reading frames. Many DPRs retain functional domains shared with their full-length counterparts, suggesting they may have activity during infection. Mechanistic studies of DPRs derived from the influenza virus protein PB2 showed that they poison replication of wild-type virus by acting as dominant-negative inhibitors of the viral polymerase. These findings reveal that DelVGs have a dual inhibitory mechanism, acting at both the RNA and protein level. They further show that DPRs have the potential to dramatically expand the functional proteomes of diverse RNA viruses.
Ku-binding motifs in RAG2, XLF, PAXX and MRI support functional redundancy during V(D)J recombination
Authors: Tadi Satish K. , Gesnik Armelle , Frit Philippe , Iehl Florence , Ropars Virginie , Dingli Florent , Loew Damarys , Calsou Patrick , Callebaut Isabelle , Charbonnier Jean-Baptiste , de Villartay Jean-Pierre 
Published: December 2023

AbstractThe interaction of several partners with Ku through Ku-binding motifs (KBMs) in their sequences governs their enrolment in NHEJ repair complexes. Here, we first established more specifically the function of KBMs in V(D)J recombination as the molecular basis of functional redundancy between XLF and the NHEJ proteins MRI and PAXX. Then, given the functional redundancy between RAG2 and XLF, we explored the hypothesis of a KBM-mediated interaction between RAG2 and Ku. Through sequence alignment and biophysical methods, we identified a KBM at the C-terminus of RAG2 (R2CT) that mediates its interaction with Ku bothin vitroandin cellulo. Notably, we showed that R2CT/Ku interaction is independent of the RAG nuclease activity. Finally, we demonstrated that the respective KBMs of RAG2 and XLF support their functional redundancy for V(D)J recombination.
Involvement of FKBP5, but not of stress, in alcohol memory reconsolidation
Authors: Rahamim Nofar , Aronovici Coral , Liran Mirit , Goltseker Koral , Levin-Greenwald Matar , Heymann Tim , Hausch Felix , Barak Segev 
Published: December 2023

AbstractRelapse is a fundamental challenge in drug addiction, often evoked by exposure to drug-associated cues. Upon retrieval, memories become temporarily labile before re-stabilizing in a process termed reconsolidation. Therefore, targeting the reconsolidation process offers a therapeutic approach for relapse prevention via the disruption of the drug-cue memories. We recently demonstrated that retrieval of contextual alcohol memories increased the expression of the mRNA encoding for FK506 binding protein 51 (FKBP51), a regulator of the hypothalamic-pituitary-adrenal (HPA) axis. Here, we explored the role of the HPA axis, and FKBP5/FKBP51 in particular, in the reconsolidation of alcohol memories. We found that the FKBP51 inhibitor SAFit2 given before alcohol-memory retrieval using contextual cues prevented the extinction of alcohol place preference behavior in female mice, suggesting that this protein may play a role in cognitive flexibility in a sex-dependent manner. Conversely, the retrieval of alcohol memories using an odor-taste cue did not affectFkbp5expression in rats with a history of chronic alcohol consumption, suggesting that FKBP5 may play a differential role in different alcohol-associated memories. In addition, we provide evidence for HPA axis activation following alcohol memory retrieval, by showing that exposure to an alcohol-associated context led to elevated corticosterone secretion. However, we found that the reconsolidation process was unaffected by HPA axis-related manipulations, namely stress exposure, and administration of corticosterone or the glucocorticoid receptors inhibitor, mifepristone. Our results suggest that although FKBP5 can affect cognitive flexibility, and thereby impact the reconsolidation of alcohol memories, this effect is not likely mediated by HPA axis-related mechanisms.
Exosome derived multi-gene biomarker panel identifies the risk of liver metastasis in lung cancer patients
Authors: Shah Kanisha A , Rawal Rakesh M 
Published: December 2023

AbstractBackgroundThe lack of non-invasive methods for detection of early metastasis is a crucial reason for the poor prognosis of lung cancer (LC) liver metastasis (LM) patients. In this study, the goal was to identify circulating biomarkers based on a biomarker model for the early diagnosis and monitoring of patients with LCLM.MethodsAn 8-gene panel identified in our previous study was validated in CTC, cfRNA and exosomes isolated from primary lung cancer with & without metastasis. Further multivariate analysis including PCA & ROC was performed to determine the sensitivity and specificity of the biomarker panel. Model validation cohort (n= 79) was used to verify the stability of the constructed predictive model. Further, clinic-pathological factors, survival analysis and immune infiltration correlations were also performed.ResultsIn comparison to our previous tissue data, exosomes demonstrated a good discriminative value with an AUC of 0.7247, specificity (72.48 %) and sensitivity (96.87%) for the 8-gene panel. Further individual gene patterns led us to a 5-gene panel that showed an AUC of 0.9488 (p = <0.001) and 0.9924 (p = <0.001) respectively for tissue and exosomes. Additionally, on validating the model in a larger cohort a risk score was obtained (RS >0.2) for prediction of liver metastasis with an accuracy of 95%. Survival analysis and immune filtration markers suggested that four exosomal markers were independently associated with poor overall survival.ConclusionWe report a novel blood-based exosomal biomarker panel for early diagnosis, monitoring of therapeutic response, and prognostic evaluation of patients with LCLM.
Can calmodulin bind to lipids of the cytosolic leaflet of plasma membranes?
Authors: Scollo Federica , Tempra Carmelo , Evci Hüseyin , Riopedre-Fernandez Miguel , Olżyńska Agnieszka , Javanainen Matti , Uday Arunima , Cebecauer Marek , Cwiklik Lukasz , Martinez-Seara Hector , Jungwirth Pavel , Jurkiewicz Piotr , Hof Martin 
Published: December 2023

ABSTRACTCalmodulin (CaM) is a ubiquitous calcium-sensitive messenger in eukaryotic cells. It was previously shown that CaM possesses an affinity for diverse lipid moieties, including those found on CaM-binding proteins. These facts together with our observation that CaM accumulates in membrane-rich protrusions of HeLa cells upon increased cytosolic calcium, motivated us to perform a systematic search for unmediated CaM interactions with model lipid membranes mimicking the cytosolic leaflet of plasma membranes. A range of experimental techniques and Molecular Dynamics simulations proves unambiguously that CaM interacts with lipid bilayers in the presence of calcium ions. Lipids phosphatidylserine (PS) and phosphatidylethanolamine (PE) hold the key to CaM-membrane interactions. Calcium induces an essential conformational rearrangement of CaM, but its binding to the headgroup of PS also neutralizes the membrane negative surface charge. More intriguingly, PE plays a dual role - it forms hydrogen bonds with CaM, but also destabilizes the lipid bilayer to increase exposure of hydrophobic acyl chains to the interacting proteins. Our findings suggest that upon increased intracellular calcium concentration, CaM and the cytosolic leaflet of cellular membranes can be functionally connected.