bluuebunny/crossref_metadata_2025 huggingface dataset:
Interstitial Lung Disease Associated With Autoimmune Rheumatic Diseases: Checklists for Clinical Practice
Authors: Bosello Silvia Laura , Beretta Lorenzo , Del Papa Nicoletta , Harari Sergio , Palmucci Stefano , Pesci Alberto , Rechichi Gilda , Varone Francesco , Sebastiani Marco
Published: October 2021

Background: Interstitial lung diseases (ILDs) are often associated with rheumatic diseases. Their early diagnosis and management are not only difficult, but also crucial, because they are associated with major morbidity and mortality and can be the first cause of death in autoimmune rheumatic diseases (ARDs).

Objectives: By using methodologies, such as Nominal Group Technique (NGT) and Delphi Survey, the aims of this study were (1) to measure consensus between pulmonologists, radiologists, and rheumatologists experienced in the management of ARD-ILD; (2) to highlight the importance of a multidisciplinary approach; and (3) to provide clinicians with a practical tool aimed at improving the prompt recognition and follow-up of ILD associated with ARDs and of any possible rheumatic conditions underlying ILD.

Results: During the NGT round, the Steering Committee defined 57 statements to be used in the Delphi survey. A total of 78 experts participated in the Delphi survey, namely 28 pulmonologists, 33 rheumatologists, and 17 radiologists. During this round, consensus on agreement was reached in 47 statements, while disagreement was not reached in any statements. A secondary questionnaire was drafted by the Steering Committee to obtain clearer indications on ILD-ARD “red-flags” and follow-up. Delphi Panelists took part also in the second-questionnaire survey. Answers from both surveys were used to draft two checklists of “red flags” sign or symptom suggestive of ILD and ARD, respectively, and two checklists on identification and monitoring of rheumatoid arthritis (RA) and systemic sclerosis (SSc) ILD.

Limitations: This study is a consensus work, which cannot produce empiric data, and is limited to the Italian scenario.

Conclusions: This work showed a high level of agreement, but also shows some divergent opinions between different experts. This underlines the importance of a multidisciplinary approach. Eventually, we believe the drafted checklists can help clinicians in the diagnosis and follow-up of ILD-ARD.
Case Report: Cerebral Venous Sinus Thrombosis and COVID-19 Infection
Authors: Anipindi Manasa , Scott Amanda , Joyce Li , Wali Salman , Morginstin Mark
Published: October 2021

Coronavirus disease-2019 is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 virus). Coronavirus disease-2019 (COVID-19) was declared a pandemic in March 2020 and has changed our lives in many ways. This infection induces a hypercoagulable state leading to arterial and venous thrombosis, but the exact pathophysiology of thrombosis is unknown. However, various theories have been postulated including excessive cytokine release, endothelial activation, and disseminated intravascular coagulation (DIC). We present a patient diagnosed with cerebral venous sinus thrombosis (CVST) with COVID-19 infection. A 66-year-old man presented to a hospital for evaluation of persistent headaches. He tested positive for COVID-19, and MRI of the brain and CT venogram revealed CVST. He was started on heparin drip in the hospital and transitioned to oral anticoagulants at the time of discharge. His headaches improved with treatment. Even though headache is the most frequent and initial symptom of cerebral venous thrombosis, it is rarely the only symptom. A high index of suspicion is therefore required to diagnose CVST especially if the patient presents with a simple complaint like a headache. Common complaints can delay the diagnosis leading to disease progression. Considering the high mortality rates in patients diagnosed with CVST, we suggest the importance of knowing the association between COVID-19 infection and CVST, especially in susceptible patients.
Alterations in the Mineral Bone Metabolism of Living Kidney Donors After Uni-Nephrectomy: Prospective Observational Study
Authors: Lee Hanbi , Eum Sang Hun , Ko Eun Jeong , Cho Hyuck Jin , Yang Chul Woo , Chung Byung Ha
Published: October 2021

We investigated the dynamic change of mineral bone metabolism and explored factors associated with the alteration of mineral bone metabolism in the living kidney donors (LKDs) after uni-nephrectomy. One-hundred forty-four prospective LKDs who underwent kidney donation between May 2016 and September 2018 were enrolled. Laboratory evaluation regarding mineral bone metabolism including intact parathyroid hormone (iPTH), renal fractional excretion of phosphate (FEPi), and technetium-99m diethylenetriaminepentaacetate (99mTc-DTPA) scan was performed predonation and 6 months after donation. We divided donors into two groups, the low ΔFEPi and high ΔFEPi groups, according to the change of FEPi after donation, and investigated significant risk factors associated with high ΔFEPi. At 6 months after uni-nephrectomy, estimated glomerular filtration rate (eGFR) significantly declined by 30.95 ml/min/1.73 m2 (p < 0.001), but the measured GFR (mGFR) of the remaining kidney by 99mTc-DTPA scan showed significant increase. Serum phosphorus decreased (p < 0.001), whereas FEPi (13.34–20.23%, p < 0.001) and serum iPTH (38.70–52.20 pg/ml, p < 0.001) showed significant increase. In the high ΔFEPi group, the proportion of preexisting hypertension (HTN) was higher, the baseline FEPi was lower, and the percent decline in eGFR was greater. Moreover, all of these factors were independently associated with high ΔFEPi upon multivariable logistic regression analysis. LKDs showed a significant change in mineral bone metabolism after uni-nephrectomy, especially when the donors had preexisting HTN, lower baseline FEPi, and showed greater loss of kidney function. Hence, strict monitoring of the mineral bone metabolism parameters and bone health may be required for these donors.
Acute-On-Chronic Liver Failure Defined by Asian Pacific Association for the Study of the Liver Should Include Decompensated Cirrhosis
Authors: Xu Manman , Kong Ming , Yu Pengfei , Cao Yingying , Liu Fang , Zhu Bing , Zhang Yizhi , Lu Wang , Zou Huaibin , You Shaoli , Xin Shaojie , Duan Zhongping , Han Tao , Chen Yu
Published: October 2021

Background and Aims: Acute-on-chronic liver failure (ACLF) is an acute deterioration of chronic liver disease with high short-term mortality. The inclusion or exclusion of previously decompensated cirrhosis (DC) in the diagnostic criteria of ACLF defined by the Asian Pacific Association for the Study of the Liver (APASL-ACLF) has not been conclusive. We aimed to evaluate the prognostic impact of decompensated cirrhosis in ACLF.

Methods: We retrospectively collected a cohort of patients with a diagnosis of APASL-ACLF (with or without DC) hospitalized from 2012 to 2020 at three liver units in tertiary hospitals. Baseline characteristics and survival data at 28, 90, 180, 360, 540, and 720 days were collected.

Results: Of the patients assessed using APASL-ACLF criteria without the diagnostic indicator of chronic liver disease, 689 patients were diagnosed with ACLF, of whom 435 had no decompensated cirrhosis (non-DC-ACLF) and 254 had previously decompensated cirrhosis (DC-ACLF). The 28-, 90-, 180-, 360-, 540-, and 720-day mortality were 24.8, 42.9, 48.7, 57.3, 63.4, and 68.1%, respectively, in DC-ACLF patients, which were significantly higher than in non-DC-ACLF patients (p < 0.05). DC was independently associated with long-term (180/360/540/720 days) but not short-term (28/90 days) mortality in patients with ACLF. Age, total bilirubin, international normalized ratio, and hepatic encephalopathy were independent risk factors for short- and long-term mortality risk in ACLF patients (p < 0.05).

Conclusions: Patients with DC-ACLF have a higher mortality rate, especially long-term mortality, compared to non-DC-ACLF patients. Therefore, DC should be included in the diagnostic criteria of APASL-ACLF and treated according to the ACLF management process.
Psoriasis Is Associated With Myosteatosis but Not Sarcopenia: A Case-Control Study
Authors: Chen Xiaomei , Xiang Hongmei , Tan Lingling , Zhou Jie , Tang Jing , Hu Xiaoyi , Yang Ming
Published: October 2021

Background: The link between psoriasis and body fat (or obesity) has been well established. However, there are no reports detailing the possible relationship between psoriasis and fat infiltration in skeletal muscle, also known as myosteatosis. A recent study reported the possible association between psoriasis, arthritis, and sarcopenia (the loss of skeletal muscle mass or function). The present study aimed to explore the possible associations of chronic plaque psoriasis with myosteatosis and sarcopenia.

Methods: We conducted a case-control study. In-patients with chronic plaque psoriasis were retrospectively recruited. Healthy controls were prospectively and continuously recruited. Unenhanced cross-sectional chest computed tomography images at the 12th thoracic vertebral level were analyzed using Mimics software. Skeletal muscle area (SMA), skeletal muscle radiodensity (SMD), and intermuscular adiposity tissue (IMAT) were measured. The skeletal muscle index (SMI) was calculated as SMA/height2. The percentage of IMAT (IMAT%) was calculated as IMAT/SMA × 100%. Myosteatosis was defined by SMD or IMAT%, whereas sarcopenia was defined by SMI. Propensity score matching was performed to adjust for the main confounders. Logistic regression models were used to evaluate the associations of psoriasis with myosteatosis and sarcopenia.

Results: We included 155 psoriasis patients and 512 healthy controls. After propensity score matching, we retained 310 controls. The prevalence of sarcopenia was not significantly different between the psoriasis and control groups (men: 9.8% vs. 14.4%, p = 0.244; women: 7.0% vs. 11.7%, p = 0.548). Psoriasis patients were more prone to SMD-defined myosteatosis (men: 39.3% vs. 20.8%; women: 46.5% vs. 16.0%; both p < 0.001) and IMAT%-defined myosteatosis (men: 21.4% vs. 12.5%, p = 0.034; women: 46.5 vs. 28.7%, p = 0.042) than the control group. After adjustment for potential confounders, psoriasis was not significantly associated with sarcopenia (odds ratio [OR] 0.51, 95% confidence interval [CI] 0.25–1.19, p = 0.136). However, psoriasis was associated with SMD-defined myosteatosis (OR 3.16, 95% CI 1.86–5.37, p < 0.001) and IMAT%-defined myosteatosis (OR 1.76, 95% CI 1.04–3.00; p = 0.037).

Conclusions: Chronic plaque psoriasis is independently associated with myosteatosis but not sarcopenia. Since fat and muscle are considered endocrine organs and can drive the inflammatory process, further studies detailing the interaction between psoriasis, fat, and skeletal muscle are warranted.
Infection Kinetics and Transmissibility of a Reanimated Dengue Virus Serotype 4 Identified Originally in Wild Aedes aegypti From Florida
Authors: Ayers Jasmine B. , Xie Xuping , Coatsworth Heather , Stephenson Caroline J. , Waits Christy M. , Shi Pei-Yong , Dinglasan Rhoel R.
Published: October 2021

Dengue virus is the most prevalent mosquito-borne virus, causing approximately 390 million infections and 25,000 deaths per year. Aedes aegypti, the primary mosquito vector of dengue virus, is well-established throughout the state of Florida, United States. Autochthonous transmission of dengue virus to humans in Florida has been increasing since 2009, alongside consistent importation of dengue cases. However, most cases of first infection with dengue are asymptomatic and the virus can be maintained in mosquito populations, complicating surveillance and leading to an underestimation of disease risk. Metagenomic sequencing of A. aegypti mosquitoes in Manatee County, Florida revealed the presence of dengue virus serotype 4 (DENV-4) genomes in mosquitoes from multiple trapping sites over 2years, in the absence of a human DENV-4 index case, and even though a locally acquired case of DENV-4 has never been reported in Florida. This finding suggested that: (i) DENV-4 may circulate among humans undetected; (ii) the virus was being maintained in the mosquito population, or (iii) the detected complete genome sequence may not represent a viable virus. This study demonstrates that an infectious clone generated from the Manatee County DENV-4 (DENV-4M) sequence is capable of infecting mammalian and insect tissue culture systems, as well as adult female A. aegypti mosquitoes when fed in a blood meal. However, the virus is subject to a dose dependent infection barrier in mosquitoes, and has a kinetic delay compared to a phylogenetically related wild-type (WT) control virus from a symptomatic child, DENV-4H (strain Homo sapiens/Haiti-0075/2015, GenBank accession MK514144.1). DENV-4M disseminates from the midgut to the ovary and saliva at 14days post-infection. Viral RNA was also detectable in the adult female offspring of DENV-4M infected mosquitoes. These results demonstrate that the virus is capable of infecting vector mosquitoes, is transmissible by bite, and is vertically transmitted, indicating a mechanism for maintenance in the environment without human-mosquito transmission. These findings suggest undetected human-mosquito transmission and/or long-term maintenance of the virus in the mosquito population is occurring in Florida, and underscore the importance of proactive surveillance for viruses in mosquitoes.

GRAPHICAL ABSTRACT

In order to better assess the public health risk posed by a detection of DENV-4 RNA in Manatee County, FL Aedes aegypti, we produced an infectious clone using the sequence from the wild-caught mosquitoes and characterized it via laboratory infections of mosquitoes and mosquito tissues.
Single and Repeated Episodes of Candida Species Isolated From Cerebrospinal Fluid for Diagnosing Probable Candida meningitis
Authors: Xu Lijun , Zhao Handan , Zhou Minghan , Lang Guanjing , Lou Haiyan
Published: October 2021

Background: The clinical relevance of single or repeated episodes of Candida spp. in cerebrospinal fluid (CSF) in adult patients is debatable.

Methods: Forty-two patients with positive Candida episodes in CSF were enrolled in this retrospective study.

Results: A total of 42.9% (18/42) were determined to have probable Candida meningitis (PCM). Neurosurgery [odds ratio (OR) (95% confidence interval), OR: 14.4 (1.6–126.1), P = 0.004], lumbar drainage [OR: 5.8 (1.5–23.3), P = 0.009], VP shunt [(OR: 5.6 (1.2–25.8), P = 0.020)], external ventricular drainage [OR: 4.7 (1.3–17.7), P = 0.018], CRP ≥ 10.0 mg/L [OR: 4.9 (1.3–18.1), P = 0.034], and postsurgical broad-spectrum antibiotics [OR: 9.5 (1.8–50.5), P = 0.004] were risk factors associated with PCM. A single CSF Candida episode for the diagnosis of PCM had 7.7% (0.4–37.9%) sensitivity and 20.7% (8.7–40.3%) specificity, whereas repeated episodes of Candida had 66.7% (41.2–85.6%) sensitivity and 95.8% (76.9–99.8%) specificity. No significant difference was found in radiological imaging or CSF profiles between PCM and non-PCM patients. A total of 37.5% (9/24) of patients without PCM received empirical antifungal treatment, and 88.9% (16/18) of patients with PCM received preemptive antifungal treatment. PCM patients had hospitalized mortality rates of 50.0% (9/18). The odds ratio of mortality was 23.0 (2.5–208.6) for PCM patients compared with non-PCM patients (P = 0.001).

Conclusion: Both single and repeated positive CSF samples have low validity for the diagnosis of PCM, suggesting that novel strategies for diagnosis algorithms of PCM are urgently needed. Empirical antifungal treatment should be started immediately for suspicious patients with risk factors.
Wild Apple-Associated Fungi and Bacteria Compete to Colonize the Larval Gut of an Invasive Wood-Borer Agrilus mali in Tianshan Forests
Authors: Bozorov Tohir A. , Toshmatov Zokir O. , Kahar Gulnaz , Zhang Daoyuan , Shao Hua , Gafforov Yusufjon
Published: October 2021

The gut microflora of insects plays important roles throughout their lives. Different foods and geographic locations change gut bacterial communities. The invasive wood-borer Agrilus mali causes extensive mortality of wild apple, Malus sieversii, which is considered a progenitor of all cultivated apples, in Tianshan forests. Recent analysis showed that the gut microbiota of larvae collected from Tianshan forests showed rich bacterial diversity but the absence of fungal species. In this study, we explored the antagonistic ability of the gut bacteria to address this absence of fungi in the larval gut. The results demonstrated that the gut bacteria were able to selectively inhibit wild apple tree-associated fungi. Among them, Pseudomonas synxantha showed strong antagonistic ability, producing antifungal compounds. Using different analytical methods, such as column chromatography, mass spectrometry, HPLC, and NMR, an antifungal compound, phenazine-1-carboxylic acid (PCA), was identified. Activity of the compound was determined by the minimum inhibitory concentration method and electron microscopy. Moreover, our study showed that the gut bacteria could originate from noninfested apple microflora during infestation. Overall, the results showed that in newly invaded locations, A. mali larvae changed their gut microbiota and adopted new gut bacteria that prevented fungal colonization in the gut.
Differential Root Exudation and Architecture for Improved Growth of Wheat Mediated by Phosphate Solubilizing Bacteria
Authors: Yahya Mahreen , Islam Ejaz ul , Rasul Maria , Farooq Iqra , Mahreen Naima , Tawab Abdul , Irfan Muhammad , Rajput Lubna , Amin Imran , Yasmin Sumera
Published: October 2021

Phosphorous (P) deficiency is a major challenge faced by global agriculture. Phosphate-solubilizing bacteria (PSB) provide a sustainable approach to supply available phosphates to plants with improved crop productivity through synergistic interaction with plant roots. The present study demonstrates an insight into this synergistic P-solubilizing mechanism of PSB isolated from rhizosphere soils of major wheat-growing agro-ecological zones of Pakistan. Seven isolates were the efficient P solubilizers based on in vitro P-solubilizing activity (233-365 μg ml–1) with a concomitant decrease in pH (up to 3.5) by the production of organic acids, predominantly acetic acid (∼182 μg ml–1) and gluconic acid (∼117 μg ml–1). Amplification and phylogenetic analysis of gcd, pqqE, and phy genes of Enterobacter sp. ZW32, Ochrobactrum sp. SSR, and Pantoea sp. S1 showed the potential of these PSB to release orthophosphate from recalcitrant forms of phosphorus. Principal component analysis indicates the inoculation response of PSB consortia on the differential composition of root exudation (amino acids, sugars, and organic acids) with subsequently modified root architecture of three wheat varieties grown hydroponically. Rhizoscanning showed a significant increase in root parameters, i.e., root tips, diameter, and surface area of PSB-inoculated plants as compared to uninoculated controls. Efficiency of PSB consortia was validated by significant increase in plant P and oxidative stress management under P-deficient conditions. Reactive oxygen species (ROS)-induced oxidative damages mainly indicated by elevated levels of malondialdehyde (MDA) and H2O2 contents were significantly reduced in inoculated plants by the production of antioxidant enzymes, i.e., superoxide dismutase, catalase, and peroxidase. Furthermore, the inoculation response of these PSB on respective wheat varieties grown in native soils under greenhouse conditions was positively correlated with improved plant growth and soil P contents. Additionally, grain yield (8%) and seed P (14%) were significantly increased in inoculated wheat plants with 20% reduced application of diammonium phosphate (DAP) fertilizer under net house conditions. Thus, PSB capable of such synergistic strategies can confer P biofortification in wheat by modulating root morphophysiology and root exudation and can alleviate oxidative stress under P deficit conditions.
Cyclical Patterns Affect Microbial Dynamics in the Water Basin of a Nuclear Research Reactor
Authors: Van Eesbeeck Valérie , Props Ruben , Mysara Mohamed , Petit Pauline C. M. , Rivasseau Corinne , Armengaud Jean , Monsieurs Pieter , Mahillon Jacques , Leys Natalie
Published: October 2021

The BR2 nuclear research reactor in Mol, Belgium, runs in successive phases of operation (cycles) and shutdown, whereby a water basin surrounding the reactor vessel undergoes periodic changes in physico-chemical parameters such as flow rate, temperature, and radiation. The aim of this study was to explore the microbial community in this unique environment and to investigate its long-term dynamics using a 16S rRNA amplicon sequencing approach. Results from two sampling campaigns spanning several months showed a clear shift in community profiles: cycles were mostly dominated by two Operational Taxonomic Units (OTUs) assigned to unclassified Gammaproteobacterium and Pelomonas, whereas shutdowns were dominated by an OTU assigned to Methylobacterium. Although 1 year apart, both campaigns showed similar results, indicating that the system remained stable over this 2-year period. The community shifts were linked with changes in physico-chemical parameters by Non-metric Multidimensional Scaling (NMDS) and correlation analyses. In addition, radiation was hypothesized to cause a decrease in cell number, whereas temperature had the opposite effect. Chemoautotrophic use of H2 and dead cell recycling are proposed to be used as a strategies for nutrient retrieval in this extremely oligotrophic environment.
The Elusive Mitochondrial Genomes of Apicomplexa: Where Are We Now?
Authors: Berná Luisa , Rego Natalia , Francia María E.
Published: October 2021

Mitochondria are vital organelles of eukaryotic cells, participating in key metabolic pathways such as cellular respiration, thermogenesis, maintenance of cellular redox potential, calcium homeostasis, cell signaling, and cell death. The phylum Apicomplexa is entirely composed of obligate intracellular parasites, causing a plethora of severe diseases in humans, wild and domestic animals. These pathogens include the causative agents of malaria, cryptosporidiosis, neosporosis, East Coast fever and toxoplasmosis, among others. The mitochondria in Apicomplexa has been put forward as a promising source of undiscovered drug targets, and it has been validated as the target of atovaquone, a drug currently used in the clinic to counter malaria. Apicomplexans present a single tubular mitochondria that varies widely both in structure and in genomic content across the phylum. The organelle is characterized by massive gene migrations to the nucleus, sequence rearrangements and drastic functional reductions in some species. Recent third generation sequencing studies have reignited an interest for elucidating the extensive diversity displayed by the mitochondrial genomes of apicomplexans and their intriguing genomic features. The underlying mechanisms of gene transcription and translation are also ill-understood. In this review, we present the state of the art on mitochondrial genome structure, composition and organization in the apicomplexan phylum revisiting topological and biochemical information gathered through classical techniques. We contextualize this in light of the genomic insight gained by second and, more recently, third generation sequencing technologies. We discuss the mitochondrial genomic and mechanistic features found in evolutionarily related alveolates, and discuss the common and distinct origins of the apicomplexan mitochondria peculiarities.
AsnB Mediates Amidation of Meso-Diaminopimelic Acid Residues in the Peptidoglycan of Listeria monocytogenes and Affects Bacterial Surface Properties and Host Cell Invasion
Authors: Sun Lei , Rogiers Gil , Courtin Pascal , Chapot-Chartier Marie-Pierre , Bierne Hélène , Michiels Chris W.
Published: October 2021

A mutant of Listeria monocytogenes ScottA with a transposon in the 5' untranslated region of the asnB gene was identified to be hypersensitive to the antimicrobial t-cinnamaldehyde. Here, we report the functional characterization of AsnB in peptidoglycan (PG) modification and intracellular infection. While AsnB of Listeria is annotated as a glutamine-dependent asparagine synthase, sequence alignment showed that this protein is closely related to a subset of homologs that catalyze the amidation of meso-diaminopimelic acid (mDAP) residues in the peptidoglycan of other bacterial species. Structural analysis of peptidoglycan from an asnB mutant, compared to that of isogenic wild-type (WT) and complemented mutant strains, confirmed that AsnB mediates mDAP amidation in L. monocytogenes. Deficiency in mDAP amidation caused several peptidoglycan- and cell surface-related phenotypes in the asnB mutant, including formation of shorter but thicker cells, susceptibility to lysozyme, loss of flagellation and motility, and a strong reduction in biofilm formation. In addition, the mutant showed reduced invasion of human epithelial JEG-3 and Caco-2 cells. Analysis by immunofluorescence microscopy revealed that asnB inactivation abrogated the proper display at the listerial surface of the invasion protein InlA, which normally gets cross-linked to mDAP via its LPXTG motif. Together, this work shows that AsnB of L. monocytogenes, like several of its homologs in related Gram-positive bacteria, mediates the amidation of mDAP residues in the peptidoglycan and, in this way, affects several cell wall and cell surface-related properties. It also for the first time implicates the amidation of peptidoglycan mDAP residues in cell wall anchoring of InlA and in bacterial virulence.
Medial Temporal Lobe Subregional Atrophy in Aging and Alzheimer's Disease: A Longitudinal Study
Authors: Chauveau Léa , Kuhn Elizabeth , Palix Cassandre , Felisatti Francesca , Ourry Valentin , de La Sayette Vincent , Chételat Gaël , de Flores Robin
Published: October 2021

Medial temporal lobe (MTL) atrophy is a key feature of Alzheimer's disease (AD), however, it also occurs in typical aging. To enhance the clinical utility of this biomarker, we need to better understand the differential effects of age and AD by encompassing the full AD-continuum from cognitively unimpaired (CU) to dementia, including all MTL subregions with up-to-date approaches and using longitudinal designs to assess atrophy more sensitively. Age-related trajectories were estimated using the best-fitted polynomials in 209 CU adults (aged 19–85). Changes related to AD were investigated among amyloid-negative (Aβ−) (n = 46) and amyloid-positive (Aβ+) (n = 14) CU, Aβ+ patients with mild cognitive impairment (MCI) (n = 33) and AD (n = 31). Nineteen MCI-to-AD converters were also compared with 34 non-converters. Relationships with cognitive functioning were evaluated in 63 Aβ+ MCI and AD patients. All participants were followed up to 47 months. MTL subregions, namely, the anterior and posterior hippocampus (aHPC/pHPC), entorhinal cortex (ERC), Brodmann areas (BA) 35 and 36 [as perirhinal cortex (PRC) substructures], and parahippocampal cortex (PHC), were segmented from a T1-weighted MRI using a new longitudinal pipeline (LASHiS). Statistical analyses were performed using mixed models. Adult lifespan models highlighted both linear (PRC, BA35, BA36, PHC) and nonlinear (HPC, aHPC, pHPC, ERC) trajectories. Group comparisons showed reduced baseline volumes and steeper volume declines over time for most of the MTL subregions in Aβ+ MCI and AD patients compared to Aβ− CU, but no differences between Aβ− and Aβ+ CU or between Aβ+ MCI and AD patients (except in ERC). Over time, MCI-to-AD converters exhibited a greater volume decline than non-converters in HPC, aHPC, and pHPC. Most of the MTL subregions were related to episodic memory performances but not to executive functioning or speed processing. Overall, these results emphasize the benefits of studying MTL subregions to distinguish age-related changes from AD. Interestingly, MTL subregions are unequally vulnerable to aging, and those displaying non-linear age-trajectories, while not damaged in preclinical AD (Aβ+ CU), were particularly affected from the prodromal stage (Aβ+ MCI). This volume decline in hippocampal substructures might also provide information regarding the conversion from MCI to AD-dementia. All together, these findings provide new insights into MTL alterations, which are crucial for AD-biomarkers definition.
Curcumin Reduced H2O2- and G2385R-LRRK2-Induced Neurodegeneration
Authors: Zhang Jinru , Li Kai , Wang Xiaobo , Smith Amber M. , Ning Bo , Liu Zhaohui , Liu Chunfeng , Ross Christopher A. , Smith Wanli W.
Published: October 2021

Mutations in leucine-rich repeat kinase 2 gene (LRRK2) are the most frequent genetic factors contributing to Parkinson's disease (PD). G2385R-LRRK2 increases the risk for PD susceptibility in the Chinese population. However, the pathological role of G2385R-LRRK2 is not clear. In this study, we investigate the roles of G2385R-LRRK2 in neurodegeneration underlying PD pathogenesis using cell biology and pharmacology approaches. We demonstrated that expression of G2385R-LRRK2-induced neurotoxicity in human neuroblastoma SH-SY5Y and mouse primary neurons. G2385R-LRRK2 increased mitochondrial ROS, activates caspase-3/7, and increased PARP cleavage, resulting in neurotoxicity. Treatment with curcumin (an antioxidant) significantly protected against G2385R-LRRK2-induced neurodegeneration by reducing mitochondrial ROS, caspase-3/7 activation, and PARP cleavage. We also found that the cellular environmental stressor, H2O2 significantly promotes both WT-LRRK2- and G2385R-LRRK2-induced neurotoxicity by increasing mitochondrial ROS, caspase-3/7 activation, and PARP cleavage, while curcumin attenuated this combined neurotoxicity. These findings not only provide a novel understanding of G2385R roles in neurodegeneration and environment interaction but also provide a pharmacological approach for intervention for G2385R-LRRK2-linked PD.
Puerarin Alleviates Vascular Cognitive Impairment in Vascular Dementia Rats
Authors: Zhu Tiantian , Zhu Moli , Qiu Yue , Wu Zeqing , Huang Ning , Wan Guangrui , Xu Jian , Song Ping , Wang Shuangxi , Yin Yaling , Li Peng
Published: October 2021

Cerebral ischemia triggers vascular dementia (VD), which is characterized by memory loss, cognitive deficits, and vascular injury in the brain. Puerarin (Pur) represents the major isoflavone glycoside of Radix Puerariae, with verified neuroprotective activity and cardiovascular protective effects. However, whether Pur ameliorates cognitive impairment and vascular injury in rats with permanent occlusion of bilateral common carotid arteries (BCCAO) remains unknown. This work aimed to assess Pur’s effects on BCCAO-induced VD and to dissect the underlying mechanisms, especially examining the function of transient receptor potential melastatin-related 2 (TRPM2) in alleviating cognitive deficits and vascular injuries. Rats with BCCAO developed VD. Pur (50, 100, and 150 mg/kg) dose-dependently attenuated the pathological changes, increased synaptic structural plasticity in the dorsal CA1 hippocampal region and decreased oxidative stress, which eventually reduced cognitive impairment and vascular injury in BCCAO rats. Notably, Pur-improved neuronal cell loss, synaptic structural plasticity, and endothelial vasorelaxation function might be mediated by the reactive oxygen species (ROS)-dependent TRPM2/NMDAR pathway, evidenced by decreased levels of ROS, malondialdehyde (MDA), Bax, Bax/Bcl2, and TRPM2, and increased levels of superoxide dismutase (SOD), Bcl2, and NR2A. In conclusion, Pur has therapeutic potential for VD, alleviating neuronal cell apoptosis and vascular injury, which may be related to the ROS-dependent TRPM2/NMDAR pathway.
Differential Impact of Severity and Duration of Status Epilepticus, Medical Countermeasures, and a Disease-Modifier, Saracatinib, on Brain Regions in the Rat Diisopropylfluorophosphate Model
Authors: Gage Meghan , Putra Marson , Gomez-Estrada Crystal , Golden Madison , Wachter Logan , Gard Megan , Thippeswamy Thimmasettappa
Published: October 2021

Acute organophosphate (OP) toxicity poses a significant threat to both military and civilian personnel as it can lead to a variety of cholinergic symptoms including the development ofstatus epilepticus(SE). Depending on its severity, SE can lead to a spectrum of neurological changes including neuroinflammation and neurodegeneration. In this study, we determined the impact of SE severity and duration on disease promoting parameters such as gliosis and neurodegeneration and the efficacy of a disease modifier, saracatinib (AZD0530), a Src/Fyn tyrosine kinase inhibitor. Animals were exposed to 4 mg/kg diisopropylfluorophosphate (DFP, s.c.) followed by medical countermeasures. We had five experimental groups: controls (no DFP), animals with no continuous convulsive seizures (CS), animals with ∼20-min continuous CS, 31-60-min continuous CS, and > 60-min continuous CS. These groups were then assessed for astrogliosis, microgliosis, and neurodegeneration 8 days after DFP exposure. The 31-60-min and > 60-min groups, but not ∼20-min group, had significantly upregulated gliosis and neurodegeneration in the hippocampus compared to controls. In the piriform cortex and amygdala, however, all three continuous CS groups had significant upregulation in both gliosis and neurodegeneration. In a separate cohort of animals that had ∼20 and > 60-min of continuous CS, we administered saracatinib for 7 days beginning three hours after DFP. There was bodyweight loss and mortality irrespective of the initial SE severity and duration. However, in survived animals, saracatinib prevented spontaneous recurrent seizures (SRS) during the first week in both severity groups. In the ∼20-min CS group, compared to the vehicle, saracatinib significantly reduced neurodegeneration in the piriform cortex and amygdala. There were no significant differences in the measured parameters between the naïve control and saracatinib on its own (without DFP) groups. Overall, this study demonstrates the differential effects of the initial SE severity and duration on the localization of gliosis and neurodegeneration. We have also demonstrated the disease-modifying potential of saracatinib. However, its’ dosing regimen should be optimized based on initial severity and duration of CS during SE to maximize therapeutic effects and minimize toxicity in the DFP model as well as in other OP models such as soman.
Protocerebral Bridge Neurons That Regulate Sleep in Drosophila melanogaster
Authors: Tomita Jun , Ban Gosuke , Kato Yoshiaki S. , Kume Kazuhiko
Published: October 2021

The central complex is one of the major brain regions that control sleep in Drosophila. However, the circuitry details of sleep regulation have not been elucidated yet. Here, we show a novel sleep-regulating neuronal circuit in the protocerebral bridge (PB) of the central complex. Activation of the PB interneurons labeled by the R59E08-Gal4 and the PB columnar neurons with R52B10-Gal4 promoted sleep and wakefulness, respectively. A targeted GFP reconstitution across synaptic partners (t-GRASP) analysis demonstrated synaptic contact between these two groups of sleep-regulating PB neurons. Furthermore, we found that activation of a pair of dopaminergic (DA) neurons projecting to the PB (T1 DA neurons) decreased sleep. The wake-promoting T1 DA neurons and the sleep-promoting PB interneurons formed close associations. Dopamine 2-like receptor (Dop2R) knockdown in the sleep-promoting PB interneurons increased sleep. These results indicated that the neuronal circuit in the PB, regulated by dopamine signaling, mediates sleep-wakefulness.
Transcriptomic and Network Meta-Analysis of Frontotemporal Dementias
Authors: Bottero Virginie , Alrafati Fahed , Santiago Jose A. , Potashkin Judith A.
Published: October 2021

Frontotemporal lobar degeneration (FTLD), also known as frontotemporal dementia (FTD), results in a progressive decline in executive function, leading to behavioral changes, speech problems, and movement disorders. FTD is the second most common cause of young-onset dementia affecting approximately 50–60,000 Americans. FTD exists in familial and sporadic forms, with GRN progranulin and C9orf72 mutations being the most common causes. In this study, we compared the sporadic and familial transcriptome within the cerebellum, frontal cortex, hippocampus, and Brodmann’s area 8 of patients with FTD to determine genes and pathways involved in the disease process. Most dysregulated genes expression occurred in the frontal cortex and Brodmann’s area 8 for genetic and sporadic forms of FTD, respectively. A meta-analysis revealed 50 genes and 95 genes are dysregulated in at least three brain regions in patients with familial mutations and sporadic FTD patients, respectively. Familial FTD genes centered on the Wnt signaling pathway, whereas genes associated with the sporadic form of FTD centered on MAPK signaling. The results reveal the similarities and differences between sporadic and familial FTD. In addition, valproic acid and additional therapeutic agents may be beneficial in treating patients with FTD.
Molecular Characterization of AMPA-Receptor-Containing Vesicles
Authors: Peters John Jacob , Leitz Jeremy , Oses-Prieto Juan A. , Burlingame Alma L. , Brunger Axel T.
Published: October 2021

Regulated delivery of AMPA receptors (AMPARs) to the postsynaptic membrane is an essential step in synaptic strength modification, and in particular, long-term potentiation (LTP). While LTP has been extensively studied using electrophysiology and light microscopy, several questions regarding the molecular mechanisms of AMPAR delivery via trafficking vesicles remain outstanding, including the gross molecular make up of AMPAR trafficking organelles and identification and location of calcium sensors required for SNARE complex-dependent membrane fusion of such trafficking vesicles with the plasma membrane. Here, we isolated AMPA-containing vesicles (ACVs) from whole mouse brains via immunoisolation and characterized them using immunoelectron microscopy, immunoblotting, and liquid chromatography–tandem mass spectrometry (LC–MS/MS). We identified several proteins on ACVs that were previously found to play a role in AMPAR trafficking, including synaptobrevin-2, Rabs, the SM protein Munc18-1, the calcium-sensor synaptotagmin-1, as well as several new candidates, including synaptophysin and synaptogyrin on ACV membranes. Additionally, we identified two populations of ACVs based on size and molecular composition: small-diameter, synaptobrevin-2- and GluA1-containing ACVs, and larger transferrin- receptor-, GluA1-, GluA2-, and GluA3-containing ACVs. The small-diameter population of ACVs may represent a fusion-capable population of vesicles due to the presence of synaptobrevin-2. Because the fusion of ACVs may be a requisite of LTP, this population could represent trafficking vesicles related to LTP.
The Drivers of Environmentally Sustainable Hospital Foodservices
Authors: Carino Stefanie , Malekpour Shirin , Porter Judi , Collins Jorja
Published: October 2021

Background: Hospital foodservices have the potential to positively contribute to the local food system and planetary healthcare. Understanding the factors contributing to the success of “exemplar hospitals” with environmentally sustainable foodservices gives an opportunity to reimagine foodservices and guide strategic planning. The aim of this study was to identify the drivers of sustainable hospital foodservices.

Methods: For this qualitative multiple case study, purposive sampling was used to identify exemplar hospitals internationally. Semi-structured interviews were conducted with staff with extensive knowledge of their foodservices to explore the drivers of sustainable practices. Relevant documents provided background on the case. These documents and interview data were analyzed using the framework and thematic analysis.

Findings: There were 21 participants from 14 hospitals recruited across nine countries. Sustainable foodservice practices included local and organic food procurement, gardens onsite, vegetarian menus, re-serving unopened portion-controlled items, traditional foods, and food waste composting. Four themes were identified: initiating drivers, supporting enablers, challenges, and influence. Initiating drivers that “sparked” sustainable practices included the values of individuals or the hospital (e.g., community, environmental, or religious values), logical solutions to a problem, or government requirements. Enablers that facilitated success included motivated individuals, dedicated personnel, supportive leadership, internal protocols, and perceived benefits. External enablers included being part of member organizations, government requirements, and learning from other hospitals. Exemplar hospitals had broader influence, including educating the hospital community, supporting other hospitals, and influencing government policies/targets. Common challenges were staff resistance and inadequate policy directive.

Interpretation: These findings examine the successful international cases of sustainable hospital foodservices to provide a global overview to assist with strategic planning both within hospitals and within governing bodies.
Influence of Fruit and Vegetable Consumption on Antioxidant Status and Semen Quality: A Cross-Sectional Study in Adult Men
Authors: Madej Dawid , Granda Dominika , Sicinska Ewa , Kaluza Joanna
Published: October 2021

The influence of fruit and vegetable consumption on semen quality by reducing oxidative stress is inconsistent. Thus, the association between the consumption of these products, antioxidant status, and semen quality was investigated in 90 men aged 18–40. The consumption of fruit and vegetables was collected using the 3-day food record method. Antioxidant status: total antioxidant capacity in semen (TAC-s) and blood (TAC-b), blood superoxide dismutase (SOD-b), glutathione reductase (GR-b), glutathione peroxidase (GPx-b), catalase (CAT-b) activity, and malondialdehyde concentration in blood (MDA-b) were measured. Sperm concentration, leukocytes in the ejaculate, vitality, motility, and sperm morphology were examined using computer-aided semen analysis (CASA). The consumption of fruit and vegetables was positively correlated with sperm concentration, vitality, motility, TAC-s, TAC-b, and SOD-b activity. The TAC-s and TAC-b were positively related to motility, TAC-s was inversely correlated with sperm tail defects. The SOD-b activity was positively correlated with vitality, motility, sperm morphology, and inversely with sperm tail defects and leukocytes in the ejaculate. Compared to the men in the first quartile of fruit and vegetable consumption (<318 g/day), those in the highest quartile (>734 g/day) had the highest sperm concentration, vitality, motility, TAC-s, TAC-b, GPx-b activity, and the lowest MDA-b concentration (based on multivariate regression models). A high consumption of fruit and vegetables may positively influence selected sperm quality parameters by improving the antioxidant status of semen and blood.
Multiparameter MRI Model With DCE-MRI, DWI, and Synthetic MRI Improves the Diagnostic Performance of BI-RADS 4 Lesions
Authors: Sun Shi Yun , Ding Yingying , Li Zhuolin , Nie Lisha , Liao Chengde , Liu Yifan , Zhang Jia , Zhang Dongxue
Published: October 2021

Objectives

To evaluate the value of synthetic magnetic resonance imaging (syMRI), diffusion-weighted imaging (DWI), DCE-MRI, and clinical features in breast imaging–reporting and data system (BI-RADS) 4 lesions, and develop an efficient method to help patients avoid unnecessary biopsy.

Methods

A total of 75 patients with breast diseases classified as BI-RADS 4 (45 with malignant lesions and 30 with benign lesions) were prospectively enrolled in this study. T1-weighted imaging (T1WI), T2WI, DWI, and syMRI were performed at 3.0 T. Relaxation time (T1 and T2), apparent diffusion coefficient (ADC), conventional MRI features, and clinical features were assessed. “T” represents the relaxation time value of the region of interest pre-contrast scanning, and “T+” represents the value post-contrast scanning. The rate of change in the T value between pre- and post-contrast scanning was represented by ΔT%.

Results

ΔT1%, T2, ADC, age, body mass index (BMI), menopause, irregular margins, and heterogeneous internal enhancement pattern were significantly associated with a breast cancer diagnosis in the multivariable logistic regression analysis. Based on the above parameters, four models were established: model 1 (BI-RADS model, including all conventional MRI features recommended by BI-RADS lexicon), model 2 (relaxation time model, including ΔT1% and T2), model 3 [multi-parameter (mp)MRI model, including ΔT1%, T2, ADC, margin, and internal enhancement pattern], and model 4 (combined image and clinical model, including ΔT1%, T2, ADC, margin, internal enhancement pattern, age, BMI, and menopausal state). Among these, model 4 has the best diagnostic performance, followed by models 3, 2, and 1.

Conclusions

The mpMRI model with DCE-MRI, DWI, and syMRI is a robust tool for evaluating the malignancies in BI-RADS 4 lesions. The clinical features could further improve the diagnostic performance of the model.
Long-Term Effects of Pediatric Acute Lymphoblastic Leukemia Chemotherapy: Can Recent Findings Inform Old Strategies?
Authors: Al-Mahayri Zeina N. , AlAhmad Mohammad M. , Ali Bassam R.
Published: October 2021

During the last few decades, pediatric acute lymphoblastic leukemia (ALL) cure rates have improved significantly with rates exceeding 90%. Parallel to this remarkable improvement, there has been mounting interest in the long-term health of the survivors. Consequently, modified treatment protocols have been developed and resulted in the reduction of many adverse long-term consequences. Nevertheless, these are still substantial concerns that warrant further mitigation efforts. In the current review, pediatric-ALL survivors’ late adverse events, including secondary malignant neoplasms (SMNs), cardiac toxicity, neurotoxicity, bone toxicity, hepatic dysfunction, visual changes, obesity, impact on fertility, and neurocognitive effects have been evaluated. Throughout this review, we attempted to answer a fundamental question: can the recent molecular findings mitigate pediatric-ALL chemotherapy’s long-term sequelae on adult survivors? For SMNs, few genetic predisposition factors have been identified including TP53 and POT1 variants. Other treatment-related risk factors have been identified such as anthracyclines’ possible association with breast cancer in female survivors. Cardiotoxicity is another significant and common adverse event with some germline variants been found, albeit with conflicting evidence, to increase the risk of cardiac toxicity. For peripheral neurotoxicity, vincristine is the primary neurotoxic agent in ALL regimens. Some germline genetic variants were found to be associated with the vincristine neurotoxic effect’s vulnerability. However, these were mainly detected with acute neuropathy. Moreover, the high steroid doses and prolonged use increase bone toxicity and obesity risk with some pharmacogenetic biomarkers were associated with increased steroid sensitivity. Therefore, the role of these biomarkers in tailoring steroid choice and dose is a promising research area. Future directions in pediatric ALL treatment should consider the various opportunities provided by genomic medicine. Understanding the molecular bases underlying toxicities will classify patients into risk groups and implement a closer follow-up to those at higher risk. Pharmacogenetic-guided dosing and selecting between alternative agents have proven their efficacy in the short-term management of childhood ALL. It is the right time to think about a similar approach for the life-long consequences on survivors.