bluuebunny/crossref_metadata_2025 huggingface dataset:
Brain Atrophy and White Matter Damage Linked to Peripheral Bioenergetic Deficits in the Neurodegenerative Disease FXTAS
Authors: Wang Jun , Napoli Eleonora , Kim Kyoungmi , McLennan Yingratana , Hagerman Randi , Giulivi Cecilia
Published: August 2021

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder affecting subjects (premutation carriers) with a 55-200 CGG-trinucleotide expansion in the 5′UTR of the fragile X mental retardation 1 gene (FMR1) typically after age 50. As both the presence of white matter hyperintensities (WMHs) and atrophied gray matter on magnetic resonance imaging (MRI) are linked to age-dependent decline in cognition, here we tested whether MRI outcomes (WMH volume (WMHV) and brain volume) were correlated with mitochondrial bioenergetics from peripheral blood monocytic cells in 87 carriers with and without FXTAS. As a parameter assessing cumulative damage, WMHV was correlated to both FXTAS stages and age, and brain volume discriminated between carriers and non-carriers. Similarly, mitochondrial mass and ATP production showed an age-dependent decline across all participants, but in contrast to WMHV, only FADH2-linked ATP production was significantly reduced in carriers vs. non-carriers. In carriers, WMHV negatively correlated with ATP production sustained by glucose-glutamine and FADH2-linked substrates, whereas brain volume was positively associated with the latter and mitochondrial mass. The observed correlations between peripheral mitochondrial bioenergetics and MRI findings—and the lack of correlations with FXTAS diagnosis/stages—may stem from early brain bioenergetic deficits even before overt FXTAS symptoms and/or imaging findings.
Directional Persistence of Cell Migration in Schizophrenia Patient-Derived Olfactory Cells
Authors: Tee Jing Yang , Mackay-Sim Alan
Published: August 2021

Cell migration is critical for brain development and linked to several neurodevelopmental disorders, including schizophrenia. We have shown previously that cell migration is dysregulated in olfactory neural stem cells from people with schizophrenia. Although they moved faster than control cells on plastic substrates, patient cells were insensitive to regulation by extracellular matrix proteins, which increase the speeds of control cells. As well as speed, cell migration is also described by directional persistence, the straightness of movement. The aim of this study was to determine whether directional persistence is dysregulated in schizophrenia patient cells and whether it is modified on extracellular matrix proteins. Directional persistence in patient-derived and control-derived olfactory cells was quantified from automated live-cell imaging of migrating cells. On plastic substrates, patient cells were more persistent than control cells, with straighter trajectories and smaller turn angles. On most extracellular matrix proteins, persistence increased in patient and control cells in a concentration-dependent manner, but patient cells remained more persistent. Patient cells therefore have a subtle but complex phenotype in migration speed and persistence on most extracellular matrix protein substrates compared to control cells. If present in the developing brain, this could lead to altered brain development in schizophrenia.
Injectable Thixotropic β–Cyclodextrin–Functionalized Hydrogels Based on Guanosine Quartet Assembly
Authors: Sardaru Monica-Cornelia , Rosca Irina , Morariu Simona , Ursu Elena-Laura , Ghiarasim Razvan , Rotaru Alexandru
Published: August 2021

Facile method for the preparation of β–cyclodextrin–functionalized hydrogels based on guanosine quartet assembly was described. A series of seven hydrogels were prepared by linking β–cyclodextrin molecules with guanosine moieties in different ratios through benzene–1,4–diboronic acid linker in the presence of potassium hydroxide. The potassium ions acted as a reticulation agent by forming guanosine quartets, leading to the formation of self–sustained transparent hydrogels. The ratios of the β–cyclodextrin and guanosine components have a significant effect on the internal structuration of the components and, correspondingly, on the mechanical properties of the final gels, offering a tunablity of the system by varying the components ratio. The insights into the hydrogels’ structuration were achieved by circular dichroism, scanning electron microscopy, atomic force microscopy, and X–ray diffraction. Rheological measurements revealed self–healing and thixotropic properties of all the investigated samples, which, in combination with available cyclodextrin cavities for active components loading, make them remarkable candidates for specific applications in biomedical and pharmaceutical fields. Moreover, all the prepared samples displayed selective antimicrobial properties against S. aureus in planktonic and biofilm phase, the activity also depending on the guanosine and cyclodextrin ratio within the hydrogel structure.
Immunoelectron Microscopic Characterization of Vasopressin-Producing Neurons in the Hypothalamo-Pituitary Axis of Non-Human Primates by Use of Formaldehyde-Fixed Tissues Stored at −25 °C for Several Years
Authors: Otubo Akito , Maejima Sho , Oti Takumi , Satoh Keita , Ueda Yasumasa , Morris John F. , Sakamoto Tatsuya , Sakamoto Hirotaka
Published: August 2021

Translational research often requires the testing of experimental therapies in primates, but research in non-human primates is now stringently controlled by law around the world. Tissues fixed in formaldehyde without glutaraldehyde have been thought to be inappropriate for use in electron microscopic analysis, particularly those of the brain. Here we report the immunoelectron microscopic characterization of arginine vasopressin (AVP)-producing neurons in macaque hypothalamo-pituitary axis tissues fixed by perfusion with 4% formaldehyde and stored at −25 °C for several years (4–6 years). The size difference of dense-cored vesicles between magnocellular and parvocellular AVP neurons was detectable in their cell bodies and perivascular nerve endings located, respectively, in the posterior pituitary and median eminence. Furthermore, glutamate and the vesicular glutamate transporter 2 could be colocalized with AVP in perivascular nerve endings of both the posterior pituitary and the external layer of the median eminence, suggesting that both magnocellular and parvocellular AVP neurons are glutamatergic in primates. Both ultrastructure and immunoreactivity can therefore be sufficiently preserved in macaque brain tissues stored long-term, initially for light microscopy. Taken together, these results suggest that this methodology could be applied to the human post-mortem brain and be very useful in translational research.
CRKL, AIFM3, AIF, BCL2, and UBASH3A during Human Kidney Development
Authors: Lozic Mirela , Minarik Luka , Racetin Anita , Filipovic Natalija , Saraga Babic Mirna , Vukojevic Katarina
Published: August 2021

We aimed to investigate the spatio-temporal expression of possible CAKUT candidate genes CRKL, AIFM3, and UBASH3A, as well as AIF and BCL2 during human kidney development. Human fetal kidney tissue was stained with antibodies and analyzed by fluorescence microscopy and RT-PCR. Quantification of positive cells was assessed by calculation of area percentage and counting cells in nephron structures. Results showed statistically significant differences in the temporal expression patterns of the examined markers, depending on the investigated developmental stage. Limited but strong expression of CRKL was seen in developing kidneys, with increasing expression up to the period where the majority of nephrons are formed. Results also lead us to conclude that AIFM3 and AIF are important for promoting cell survival, but only AIFM3 is considered a CAKUT candidate gene due to the lack of AIF in nephron developmental structures. Our findings imply great importance of AIFM3 in energy production in nephrogenesis and tubular maturation. UBASH3A raw scores showed greater immunoreactivity in developing structures than mature ones which would point to a meaningful role in nephrogenesis. The fact that mRNA and proteins of CRKL, UBASH3A, and AIFM3 were detected in all phases of kidney development implies their role as renal development control genes.
Troponin Variants in Congenital Myopathies: How They Affect Skeletal Muscle Mechanics
Authors: van de Locht Martijn , Borsboom Tamara C. , Winter Josine M. , Ottenheijm Coen A. C.
Published: August 2021

The troponin complex is a key regulator of muscle contraction. Multiple variants in skeletal troponin encoding genes result in congenital myopathies. TNNC2 has been implicated in a novel congenital myopathy, TNNI2 and TNNT3 in distal arthrogryposis (DA), and TNNT1 and TNNT3 in nemaline myopathy (NEM). Variants in skeletal troponin encoding genes compromise sarcomere function, e.g., by altering the Ca2+ sensitivity of force or by inducing atrophy. Several potential therapeutic strategies are available to counter the effects of variants, such as troponin activators, introduction of wild-type protein through AAV gene therapy, and myosin modulation to improve muscle contraction. The mechanisms underlying the pathophysiological effects of the variants in skeletal troponin encoding genes are incompletely understood. Furthermore, limited knowledge is available on the structure of skeletal troponin. This review focusses on the physiology of slow and fast skeletal troponin and the pathophysiology of reported variants in skeletal troponin encoding genes. A better understanding of the pathophysiological effects of these variants, together with enhanced knowledge regarding the structure of slow and fast skeletal troponin, will direct the development of treatment strategies.
Silver Nanoparticles Modulate the Epithelial-to-Mesenchymal Transition in Estrogen-Dependent Breast Cancer Cells In Vitro
Authors: Rakowski Michał , Porębski Szymon , Grzelak Agnieszka
Published: August 2021

Silver nanoparticles (AgNPs) are frequently detected in many convenience goods, such as cosmetics, that are applied directly to the skin. AgNPs accumulated in cells can modulate a wide range of molecular pathways, causing direct changes in cells. The aim of this study is to assess the capability of AgNPs to modulate the metastasis of breast cancer cells through the induction of epithelial-to-mesenchymal transition (EMT). The effect of the AgNPs on MCF-7 cells was investigated via the sulforhodamine B method, the wound healing test, generation of reactive oxygen species (ROS), the standard cytofluorimetric method of measuring the cell cycle, and the expression of EMT marker proteins and the MTA3 protein via Western blot. To fulfill the results, calcium flux and HDAC activity were measured. Additionally, mitochondrial membrane potential was measured to assess the direct impact of AgNPs on mitochondria. The results indicated that the MCF-7 cells are resistant to the cytotoxic effect of AgNPs and have higher mobility than the control cells. Treatment with AgNPs induced a generation of ROS; however, it did not affect the cell cycle but modulated the expression of EMT marker proteins and the MTA3 protein. Mitochondrial membrane potential and calcium flux were not altered; however, the AgNPs did modulate the total HDAC activity. The presented data support our hypothesis that AgNPs modulate the metastasis of MCF-7 cells through the EMT pathway. These results suggest that AgNPs, by inducing reactive oxygen species generation, alter the metabolism of breast cancer cells and trigger several pathways related to metastasis.
Recent Advances in Gene Therapy for Cardiac Tissue Regeneration
Authors: Kim Yevgeniy , Zharkinbekov Zharylkasyn , Sarsenova Madina , Yeltay Gaziza , Saparov Arman
Published: August 2021

Cardiovascular diseases (CVDs) are responsible for enormous socio-economic impact and the highest mortality globally. The standard of care for CVDs, which includes medications and surgical interventions, in most cases, can delay but not prevent the progression of disease. Gene therapy has been considered as a potential therapy to improve the outcomes of CVDs as it targets the molecular mechanisms implicated in heart failure. Cardiac reprogramming, therapeutic angiogenesis using growth factors, antioxidant, and anti-apoptotic therapies are the modalities of cardiac gene therapy that have led to promising results in preclinical studies. Despite the benefits observed in animal studies, the attempts to translate them to humans have been inconsistent so far. Low concentration of the gene product at the target site, incomplete understanding of the molecular pathways of the disease, selected gene delivery method, difference between animal models and humans among others are probable causes of the inconsistent results in clinics. In this review, we discuss the most recent applications of the aforementioned gene therapy strategies to improve cardiac tissue regeneration in preclinical and clinical studies as well as the challenges associated with them. In addition, we consider ongoing gene therapy clinical trials focused on cardiac regeneration in CVDs.
Multiple Leptin Signalling Pathways in the Control of Metabolism and Fertility: A Means to Different Ends?
Authors: Evans Maggie C. , Lord Rebecca A. , Anderson Greg M.
Published: August 2021

The adipocyte-derived ‘satiety promoting’ hormone, leptin, has been identified as a key central regulator of body weight and fertility, such that its absence leads to obesity and infertility. Plasma leptin levels reflect body adiposity, and therefore act as an ‘adipostat’, whereby low leptin levels reflect a state of low body adiposity (under-nutrition/starvation) and elevated leptin levels reflect a state of high body adiposity (over-nutrition/obesity). While genetic leptin deficiency is rare, obesity-related leptin resistance is becoming increasingly common. In the absence of adequate leptin sensitivity, leptin is unable to exert its ‘anti-obesity’ effects, thereby exacerbating obesity. Furthermore, extreme leptin resistance and consequent low or absent leptin signalling resembles a state of starvation and can thus lead to infertility. However, leptin resistance occurs on a spectrum, and it is possible to be resistant to leptin’s metabolic effects while retaining leptin’s permissive effects on fertility. This may be because leptin exerts its modulatory effects on energy homeostasis and reproductive function through discrete intracellular signalling pathways, and these pathways are differentially affected by the molecules that promote leptin resistance. This review discusses the potential mechanisms that enable leptin to exert differential control over metabolic and reproductive function in the contexts of healthy leptin signalling and of diet-induced leptin resistance.
Measuring and Interpreting Nuclear Transport in Neurodegenerative Disease—The Example of C9orf72 ALS
Authors: Semmelink Marije F. W. , Steen Anton , Veenhoff Liesbeth M.
Published: August 2021

Transport from and into the nucleus is essential to all eukaryotic life and occurs through the nuclear pore complex (NPC). There are a multitude of data supporting a role for nuclear transport in neurodegenerative diseases, but actual transport assays in disease models have provided diverse outcomes. In this review, we summarize how nuclear transport works, which transport assays are available, and what matters complicate the interpretation of their results. Taking a specific type of ALS caused by mutations in C9orf72 as an example, we illustrate these complications, and discuss how the current data do not firmly answer whether the kinetics of nucleocytoplasmic transport are altered. Answering this open question has far-reaching implications, because a positive answer would imply that widespread mislocalization of proteins occurs, far beyond the reported mislocalization of transport reporters, and specific proteins such as FUS, or TDP43, and thus presents a challenge for future research.
Sodium Iodate-Induced Degeneration Results in Local Complement Changes and Inflammatory Processes in Murine Retina
Authors: Enzbrenner Anne , Zulliger Rahel , Biber Josef , Pousa Ana Maria Quintela , Schäfer Nicole , Stucki Corinne , Giroud Nicolas , Berrera Marco , Kortvely Elod , Schmucki Roland , Badi Laura , Grosche Antje , Pauly Diana , Enzmann Volker
Published: August 2021

Age-related macular degeneration (AMD), one of the leading causes of blindness worldwide, causes personal suffering and high socioeconomic costs. While there has been progress in the treatments for the neovascular form of AMD, no therapy is yet available for the more common dry form, also known as geographic atrophy. We analysed the retinal tissue in a mouse model of retinal degeneration caused by sodium iodate (NaIO3)-induced retinal pigment epithelium (RPE) atrophy to understand the underlying pathology. RNA sequencing (RNA-seq), qRT-PCR, Western blot, immunohistochemistry of the retinas and multiplex ELISA of the mouse serum were applied to find the pathways involved in the degeneration. NaIO3 caused patchy RPE loss and thinning of the photoreceptor layer. This was accompanied by the increased retinal expression of complement components c1s, c3, c4, cfb and cfh. C1s, C3, CFH and CFB were complement proteins, with enhanced deposition at day 3. C4 was upregulated in retinal degeneration at day 10. Consistently, the transcript levels of proinflammatory ccl-2, -3, -5, il-1β, il-33 and tgf-β were increased in the retinas of NaIO3 mice, but vegf-a mRNA was reduced. Macrophages, microglia and gliotic Müller cells could be a cellular source for local retinal inflammatory changes in the NaIO3 retina. Systemic complement and cytokines/chemokines remained unaltered in this model of NaIO3-dependent retinal degeneration. In conclusion, systemically administered NaIO3 promotes degenerative and inflammatory processes in the retina, which can mimic the hallmarks of geographic atrophy.
Phosphorylation of SARS-CoV-2 Orf9b Regulates Its Targeting to Two Binding Sites in TOM70 and Recruitment of Hsp90
Authors: Brandherm Lukas , Kobaš Antonio Mario , Klöhn Mara , Brüggemann Yannick , Pfaender Stephanie , Rassow Joachim , Kreimendahl Sebastian
Published: August 2021

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the causative agent of the COVID19 pandemic. The SARS-CoV-2 genome encodes for a small accessory protein termed Orf9b, which targets the mitochondrial outer membrane protein TOM70 in infected cells. TOM70 is involved in a signaling cascade that ultimately leads to the induction of type I interferons (IFN-I). This cascade depends on the recruitment of Hsp90-bound proteins to the N-terminal domain of TOM70. Binding of Orf9b to TOM70 decreases the expression of IFN-I; however, the underlying mechanism remains elusive. We show that the binding of Orf9b to TOM70 inhibits the recruitment of Hsp90 and chaperone-associated proteins. We characterized the binding site of Orf9b within the C-terminal domain of TOM70 and found that a serine in position 53 of Orf9b and a glutamate in position 477 of TOM70 are crucial for the association of both proteins. A phosphomimetic variant Orf9bS53E showed drastically reduced binding to TOM70 and did not inhibit Hsp90 recruitment, suggesting that Orf9b–TOM70 complex formation is regulated by phosphorylation. Eventually, we identified the N-terminal TPR domain of TOM70 as a second binding site for Orf9b, which indicates a so far unobserved contribution of chaperones in the mitochondrial targeting of the viral protein.
Application of Machine Learning Methods on Patient Reported Outcome Measurements for Predicting Outcomes: A Literature Review
Authors: Verma Deepika , Bach Kerstin , Mork Paul Jarle
Published: August 2021

The field of patient-centred healthcare has, during recent years, adopted machine learning and data science techniques to support clinical decision making and improve patient outcomes. We conduct a literature review with the aim of summarising the existing methodologies that apply machine learning methods on patient-reported outcome measures datasets for predicting clinical outcomes to support further research and development within the field. We identify 15 articles published within the last decade that employ machine learning methods at various stages of exploiting datasets consisting of patient-reported outcome measures for predicting clinical outcomes, presenting promising research and demonstrating the utility of patient-reported outcome measures data for developmental research, personalised treatment and precision medicine with the help of machine learning-based decision-support systems. Furthermore, we identify and discuss the gaps and challenges, such as inconsistency in reporting the results across different articles, use of different evaluation metrics, legal aspects of using the data, and data unavailability, among others, which can potentially be addressed in future studies.
Mild Traumatic Brain Injury in Older Adults: Are Routine Second cCT Scans Necessary?
Authors: Hofmann Valeska , Deininger Christian , Döbele Stefan , Konrads Christian , Wichlas Florian
Published: August 2021

Fall-related hospitalizations among older adults have been increasing in recent decades. One of the most common reasons for this is minimal or mild traumatic brain injury (mTBI) in older individuals taking anticoagulant medication. In this study, we analyzed all inpatient stays from January 2017 to December 2019 of patients aged > 75 years with a mTBI on anticoagulant therapy who received at least two cranial computer tomography (cCT) scans. Of 1477 inpatient stays, 39 had primary cranial bleeding, and in 1438 the results of initial scans were negative for cranial bleeding. Of these 1438 cases, 6 suffered secondary bleeding from the control cCT scan. There was no significance for bleeding related to the type of anticoagulation. We conclude that geriatric patients under anticoagulant medication don’t need a second cCT scan if the primary cCT was negative for intracranial bleeding and the patient shows no clinical signs of bleeding. These patients can be dismissed but require an evaluation for need of home care or protective measures to prevent recurrent falls. The type of anticoagulant medication does not affect the risk of bleeding.
Topo-Pachimetric Accelerated Epi-On Cross-Linking Compared to the Dresden Protocol Using Riboflavin with Vitamin E TPGS: Results of a 2-Year Randomized Study
Authors: Caruso Ciro , Epstein Robert Leonard , Troiano Pasquale , Napolitano Francesco , Scarinci Fabio , Costagliola Ciro
Published: August 2021

In the present study (clinical trial registration number: NCT05019768), we compared the clinical outcome of corneal cross-linking with either the standard Dresden (sCXL) or the accelerated custom-fast (aCFXL) ultraviolet A irradiation protocol using riboflavin–D-α-tocopheryl poly(ethylene glycol)-1000 succinate for progressive keratoconus. Fifty-four eyes of forty-one patients were randomized to either of the two CXL protocols and checked before treatment and at the 2-year follow-up. The sCXL group was subjected to CXL with 30 min of pre-soaking and 3 mW/cm2 UVA irradiation for 30 min. The aCFXL group was subjected to CXL with 10 min of pre-soaking and UVA irradiation of 1.8 ± 0.9 mW/cm2 for 10 min ± 1.5 min. In both groups, a solution of riboflavin–vitamin E TPGS was used. Uncorrected distance visual acuity, corrected distance visual acuity, pachymetry, Scheimpflug tomography, and corneal hysteresis were performed at baseline and after 24 months. Both groups showed a statistically significant improvement in corrected distance visual acuity, and keratometric and corneal hysteresis compared to baseline conditions; no statistically significant differences in outcomes between the two groups were observed. Improvement in refractive, topographic, and biomechanical parameters were observed after sCXL and aCFXL, making the riboflavin–VE-TPGS solution an effective option as a permeation enhancer in CXL procedures. Deeper stromal penetration of riboflavin could be complemented by photo-protection against UVA and free radicals formed during photoinduced processes.
Association between Pneumonia, Fracture, Stroke, Heart Attack and Other Hospitalizations with Changes in Mobility Disability and Gait Speed in Older Adults
Authors: Brown Joshua D. , Sato Reiko , Morley John E.
Published: August 2021

Pathophysiological changes after acute hospitalizations may influence physical functioning in older adults, which can lead to disability and loss of independence. This study evaluated the association between pneumonia, fracture, heart attack, stroke, and other hospitalizations with major mobility disability (MMD) and gait speed. This was a secondary analysis of the Lifestyle Interventions and Independence for Elders (LIFE) Study, which was conducted across eight sites during 2010–2013 with longitudinal follow-up for 1635 individuals over an average of 2.6 years. Participants included adults ≥70 years old with pre-existing mobility limitations randomized to a physical activity intervention or a health education control arm. Hospitalizations were recorded via self-report and adjudicated by medical reviewers. MMD was measured by the inability to complete a 400 m walk test, or other proxies, as a binary outcome. Gait speed was recorded during the walk test in meters per second (m/s) and measured on a linear scale. Mixed-effects repeated measures regression adjusted for baseline demographics, comorbid conditions, and frailty. Among the 1635 participants, there were 1458 hospitalizations, which included 80 (5.5% of all hospitalizations) cases of pneumonia, 92 (6.3%) hospitalized fractures, 87 (6.0%) heart attacks, and 61 (4.2%) strokes. In the short-term measurement period immediately following hospitalization (1 day to 6 months), stroke (OR = 3.98 (3.41–4.54)) had the strongest association with MMD followed by fracture (OR = 3.03 (2.54–3.52)), pneumonia (OR = 2.76 (2.23–3.30)), and heart attack (OR = 2.03 (1.52–2.53)). Associations with long-term (6–12 months after) MMD were decreased or not significant for all causes. Pneumonia, fracture, stroke, and other hospitalizations were associated with short-term relative gait speed changes between −4.8% up to −19.5%, and only fracture was associated with long-term changes. Hospitalizations for pneumonia, heart attack, stroke, and fractures were associated with short-term decreases in mobility in older adults. Older adults may be at risk for decreased mobility and disability following acute hospitalizations, with the magnitude determined by the cause of the precipitating event.
The Effectiveness of Physical Therapy in Patients with Generalized Joint Hypermobility and Concurrent Temporomandibular Disorders—A Cross-Sectional Study
Authors: Kulesa-Mrowiecka Małgorzata , Piech Joanna , Gaździk Tadeusz S.
Published: August 2021

Temporomandibular disorders (TMD) consist of a group of symptoms such as: pain of temporomandibular joints, masticatory muscles or surrounding tissues, dysfunctions of TMJs’ mobility, and crepitation. The Hypermobility Joint Syndrome (HJS) manifests in the flaccidity of joint structures, an increase in the range of joint motion, and occurs more often in the young and women. The aim of this study was to present the occurrence of HJS among patients with myogenic TMD and disc displacement with reduction. The secondary goal was to assess the effectiveness of physiotherapy directed to TMD with coexisting HJS. The study involved 322 patients with symptoms of TMD. HJS was diagnosed using the Beighton Scale, which confirmed its occurrence in 26 cases. 79 subjects (7 males and 72 females; mean age, 33.9 ± 10.4 years) were selected and divided into two groups: HJS + TMD (n = 26; 2 males and 24 females; mean age, 27.1 ± 9.4 years) and TMD (n = 53; 5 males and 48 females; mean age, 37.4 ± 9.2 years). These patients completed 3-week physiotherapy management. Before and after physiotherapy, the myofascial pain severity on Numeric Pain Rating Scale, linear measurement of maximum mouth opening, and opening pattern, were assessed. To demonstrate differences between the results, the level of significance for statistical analysis was set at α = 0.05. A statistically significant improvement was obtained in decreasing myofascial pain in both groups. Coordination of mandibular movements was achieved in both groups. Generalized joint hypermobility occurred among patients with TMD. Physiotherapy directed to TMD was effective in reducing myofascial pain and restoring TMJ’s coordination also in patients with HJS.
The Extent and Diverse Trajectories of Longitudinal Changes in Rheumatoid Arthritis Interstitial Lung Diseases Using Quantitative HRCT Scores
Authors: Lee Jeong Seok , Kim Grace-Hyun J. , Ha You-Jung , Kang Eun Ha , Lee Yun Jong , Goldin Jonathan G. , Lee Eun Young
Published: August 2021

We aimed to validate quantitative high-resolution computed tomography (HRCT) imaging analyses of interstitial lung disease (ILD) in rheumatoid arthritis (RA) patients, and to delineate a broad spectrum of annual longitudinal changes of ILD severity in the RA-ILD cohorts. Retrospective cohort 1 (n = 26) had matched PFT results and prospective cohort 2 (n = 34) were followed for over two years with baseline serum specimen. Automated quantitative analysis of HRCT was expressed as the extent of ground-glass opacity, lung fibrosis, honeycombing, and their summation—the total extent of quantitative ILD (QILD). Higher QILD score was associated with lower pulmonary function especially for DLCO% (ρ = −0.433, p = 0.027). Higher serum level of Krebs von den Lungen 6 were significantly associated with high QILD scores (ρ = 0.400, p = 0.026). Regarding QILD score changes in whole lung, even a single point increase was significantly associated with interval progression detected by the radiologist. Four distinct patterns (improvement, worsening, convex-like, and concave-like) during the 24 months were described by QILD scores. Prolonged disease duration of ILD at baseline was significantly associated with worsening of QILD scores. QILD has the potential to reliably evaluate the dynamic severity changes in patients with RA-ILD.
Surviving to Acute Myocardial Infarction: The Role of Psychological Factors and Alexithymia in Delayed Time to Searching Care: A Systematic Review
Authors: Sancassiani Federica , Montisci Roberta , Preti Antonio , Paribello Pasquale , Meloni Luigi , Romano Ferdinando , Nardi Antonio E. , Carta Mauro Giovanni
Published: August 2021

The time from symptom onset to reperfusion is a critical determinant of myocardial salvage and clinical outcomes in patients with acute myocardial infarction (AMI). This time period could be delayed if people do not seek help promptly and/or if the health system is not efficient in responding quickly and attending to these individuals. The aim of this study was to identify psychological factors associated with pre-hospital delay (PHD) or patients’ decisional delay (PDD) in people with an ongoing AMI. A search in PubMed/Medline from 1990 to 2021 with the keywords “pre-hospital delay” OR “prehospital delay” OR “patient delay” OR “decisional delay” OR “care seeking behavior” AND “psychological factors” OR “alexithymia” AND “myocardial infarction” was performed. Thirty-six studies were included, involving 10.389 patients. Wrong appraisal, interpretation and causal beliefs about symptoms, denial of the severity of the symptoms and high levels of alexithymia were found related to longer PHD or PDD. Alexithymia may be an overarching construct that explains the disparate findings of the studies exploring the role of psychological factors in PHD or PDD. Further studies are needed in order to analyse the role of alexithymia in patients with risk factors for AMI to prevent delay.
Skin-Resident Memory T Cells: Pathogenesis and Implication for the Treatment of Psoriasis
Authors: Vu Trung T. , Koguchi-Yoshioka Hanako , Watanabe Rei
Published: August 2021

Tissue-resident memory T cells (TRM) stay in the peripheral tissues for long periods of time, do not recirculate, and provide the first line of adaptive immune response in the residing tissues. Although TRM originate from circulating T cells, TRM are physiologically distinct from circulating T cells with the expression of tissue-residency markers, such as CD69 and CD103, and the characteristic profile of transcription factors. Besides defense against pathogens, the functional skew of skin TRM is indicated in chronic skin inflammatory diseases. In psoriasis, IL-17A-producing CD8+ TRM are regarded as one of the pathogenic populations in skin. Although no licensed drugs that directly and specifically inhibit the activity of skin TRM are available to date, psoriatic skin TRM are affected in the current treatments of psoriasis. Targeting skin TRM or using TRM as a potential index for disease severity can be an attractive strategy in psoriasis.
Predicting Duration of Mechanical Ventilation in Acute Respiratory Distress Syndrome Using Supervised Machine Learning
Authors: Sayed Mohammed , Riaño David , Villar Jesús
Published: August 2021

Background: Acute respiratory distress syndrome (ARDS) is an intense inflammatory process of the lungs. Most ARDS patients require mechanical ventilation (MV). Few studies have investigated the prediction of MV duration over time. We aimed at characterizing the best early scenario during the first two days in the intensive care unit (ICU) to predict MV duration after ARDS onset using supervised machine learning (ML) approaches. Methods: For model description, we extracted data from the first 3 ICU days after ARDS diagnosis from patients included in the publicly available MIMIC-III database. Disease progression was tracked along those 3 ICU days to assess lung severity according to Berlin criteria. Three robust supervised ML techniques were implemented using Python 3.7 (Light Gradient Boosting Machine (LightGBM); Random Forest (RF); and eXtreme Gradient Boosting (XGBoost)) for predicting MV duration. For external validation, we used the publicly available multicenter database eICU. Results: A total of 2466 and 5153 patients in MIMIC-III and eICU databases, respectively, received MV for >48 h. Median MV duration of extracted patients was 6.5 days (IQR 4.4–9.8 days) in MIMIC-III and 5.0 days (IQR 3.0–9.0 days) in eICU. LightGBM was the best model in predicting MV duration after ARDS onset in MIMIC-III with a root mean square error (RMSE) of 6.10–6.41 days, and it was externally validated in eICU with RMSE of 5.87–6.08 days. The best early prediction model was obtained with data captured in the 2nd day. Conclusions: Supervised ML can make early and accurate predictions of MV duration in ARDS after onset over time across ICUs. Supervised ML models might have important implications for optimizing ICU resource utilization and high acute cost reduction of MV.
Vascular Resection for Intrahepatic Cholangiocarcinoma: Current Considerations
Authors: Alikhanov Ruslan , Dudareva Anna , Trigo Miguel Ángel , Serrablo Alejandro
Published: August 2021

Intrahepatic cholangiocarcinoma (iCCA) accounts for approximately 10% of all primary liver cancers. Surgery is the only potentially curative treatment, even in cases of macrovascular invasion. Since resection offers the only curative chance, even extended liver resection combined with complex vascular or biliary reconstruction of the surrounding organs seems justified to achieve complete tumour removal. In selected cases, the major vascular resection is the only change to try getting the cure. The best results are achieved by the referral centre with a wide experience in complex liver surgery, such as ALPPS procedure, IVC resection, and ante-situ and ex-situ resections. However, despite aggressive surgery, tumour recurrence occurs frequently and long-term oncological results are very poor. This suggests that significant progress in prognosis cannot be expected by surgery alone. Instead, multimodal treatment including neoadjuvant chemotherapy, radiotherapy, and subsequent adjuvant treatment for iCCA seem to be necessary to improve results.
Method of Studying Modulation Effects of Wind and Swell Waves on Tidal and Seiche Oscillations
Authors: Dolgikh Grigory Ivanovich , Budrin Sergey Sergeevich
Published: August 2021

This paper describes a method for identifying modulation effects caused by the interaction of waves with different frequencies based on regression analysis. We present examples of its application on experimental data obtained using high-precision laser interference instruments. Using this method, we illustrate and describe the nonlinearity of the change in the period of wind waves that are associated with wave processes of lower frequencies—12- and 24-h tides and seiches. Based on data analysis, we present several basic types of modulation that are characteristic of the interaction of wind and swell waves on seiche oscillations, with the help of which we can explain some peculiarities of change in the process spectrum of these waves.
The Emergence of Echinocandin-Resistant Candida glabrata Exhibiting High MICs and Related FKS Mutations in Turkey
Authors: Sig Ali Korhan , Sonmezer Meliha Cagla , Gülmez Dolunay , Duyan Serhat , Uzun Ömrüm , Arikan-Akdagli Sevtap
Published: August 2021

The frequency of invasive fungal infections shows a rising trend as well as a high morbidity and mortality. Among the causative agents, a shift toward the non-albicans Candida species including Candida glabrata species complex is being observed in several centers. Echinocandin resistance is increasingly published; however, isolates presenting with an in vitro resistance have not yet been reported from Turkey. We, herein, report the first FKS mutant and phenotypically echinocandin-resistant C. glabrata clinical strains from a single center in Turkey. In a 43-year-old female patient, several enterocutaneous fistulae developed after a long term hospitalization period and several complicated surgeries. She eventually required parenteral nutrition via a tunneled central venous catheter (CVC). Following a number of bacteremic and fungemic episodes as well as intensive antimicrobial interventions (including fluconazole, caspofungin and anidulafungin), a CVC-related candidemia caused by C. glabrata was detected. The isolated strain yielded high minimum inhibitory concentration (MIC) values for echinocandins and was categorized as resistant. A resistance-related mutation was detected in FKS2 HS1 (D666V). Blood cultures remained negative after the removal of the CVC and treatment with caspofungin and high-dose fluconazole. Following this first case, two additional C. glabrata strains with high echinocandin MICs were isolated from the urine cultures of two unrelated patients from different wards with different mutations in FKS2 HS1 (S663P and delF659). Our findings indicate that routine antifungal susceptibility testing is crucial and underlines the need for attention for the increasing trend of acquired echinocandin resistance in C. glabrata.
Safety Evaluation of Fungal Pigments for Food Applications
Authors: Poorniammal Rajendran , Prabhu Somasundaram , Dufossé Laurent , Kannan Jegatheesh
Published: August 2021

Pigments play a major role in many industries. Natural colors are usually much safer when compared to synthetic colors and may even possess some medicinal benefits. Synthetic colors are economical and can easily be produced compared to natural colors. In addition, raw plant materials for natural colors are limited and season dependent. Microorganisms provide an alternative source for natural colors and, among them, fungi provide a wide range of natural colorants that could easily be produced cheaply and with high yield. Along with pigment, some microbial strains are also capable of producing a number of mycotoxins. The commercial use of microbial pigments relies on the safety of colorants. This review provides a toxicity evaluation of pigments from fungal origins for food application.
Molecular Prognostic Factors for Distant Metastases in Premenopausal Patients with HR+/HER2− Early Breast Cancer
Authors: Ni Hua , Kumbrink Jörg , Mayr Doris , Seiler Alina , Hagemann Friederike , Degenhardt Tom , Sagebiel Sabine , Würstlein Rachel , Kates Ronald , Harbeck Nadia , Eggersmann Tanja K.
Published: August 2021

Molecular factors that drive metastasis in premenopausal patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2−), early breast cancer (EBC) are largely unknown. To identify markers/signatures contributing to metastasis, we analyzed molecular changes in tumors from premenopausal patients who developed metastasis (M1) and who did not (M0). Ninety-seven premenopausal patients with HR+/HER2− EBC were included (M1, n = 48, median distant metastasis-free survival (DMFS): 54 (7–184) months; M0, n = 49, median follow-up: 149 (121–191) months). Gene expression profiling on tumor RNA (Breast Cancer 360TM panel, Nanostring) was performed, followed by comprehensive bioinformatic and statistical analyses. Significantly enhanced ROR (risk of recurrence) scores and reduced signature scores of PGR (progesterone receptor), claudin-low, and mammary stemness were determined in M1. These differences were significantly associated with shorter DMFS in univariate survival analyses. Gene set enrichment analysis showed an enriched mTORC1 pathway in M1. Moreover, a metastasis signature of 19 differentially expressed genes (DEGs) that were DMFS-related was defined. Multivariate analysis including the four signatures, 19 DEGs, pN, and pT status, identified LRP2, IBSP, and SCUBE2 as independent prognostic factors. We identified prognostic gene signatures and single-gene markers for distant metastasis in premenopausal HR+/HER2− EBC potentially applicable in future clinical practice.
Metabolomic Biomarker Candidates for Skeletal Muscle Loss in the Collagen-Induced Arthritis (CIA) Model
Authors: Alabarse Paulo V. G. , Silva Jordana M. S. , Santo Rafaela C. E. , Oliveira Marianne S. , Almeida Andrelise S. , de Oliveira Mayara S. , Immig Mônica L. , Freitas Eduarda C. , Teixeira Vivian O. N. , Bathurst Camilla L. , Brenol Claiton V. , Filippin Lidiane I. , Young Stephen P. , Lora Priscila S. , Xavier Ricardo M.
Published: August 2021

There is no consensus for diagnosis or treatment of RA muscle loss. We aimed to investigate metabolites in arthritic mice urine as biomarkers of muscle loss. DBA1/J mice comprised collagen-induced arthritis (CIA) and control (CO) groups. Urine samples were collected at 0, 18, 35, 45, 55, and 65 days of disease and subjected to nuclear magnetic resonance spectroscopy. Metabolites were identified using Chenomx and Birmingham Metabolite libraries. The statistical model used principal component analysis, partial least-squares discriminant analysis, and partial least-squares regression analysis. Linear regression and Fisher’s exact test via the MetaboAnalyst website were performed (VIP-score). Nearly 100 identified metabolites had CIA vs. CO and disease time-dependent differences (p < 0.05). Twenty-eight metabolites were muscle-associated: carnosine (VIPs 2.8 × 102) and succinyl acetone (VIPs 1.0 × 10) showed high importance in CIA vs. CO models at day 65; CIA pair analysis showed histidine (VIPs 1.2 × 102) days 55 vs. 65, histamine (VIPs 1.1 × 102) days 55 vs. 65, and L-methionine (VIPs 1.1 × 102) days 0 vs. 18. Carnosine was fatigue- (0.039) related, creatine was food intake- (−0.177) and body weight- (−0.039) related, and both metabolites were clinical score- (0.093; 0.050) and paw edema- (0.125; 0.026) related. Therefore, muscle metabolic alterations were detected in arthritic mice urine, enabling further validation in RA patient’s urine, targeting prognosis, diagnosis, and monitoring of RA-mediated muscle loss.
Habitat Restoration: An Applicative Approach to “Biodiversity Heritage Relicts” in Social-Ecological Systems
Authors: Semeraro Teodoro , Turco Alessio , Arzeni Stefano , La Gioia Giuseppe , D’Armento Roberta , Taurino Riccardo , Medagli Pietro
Published: August 2021

Many landscapes are the result of interactions between ecological processes, economic activities, and the administrative and political organisation of society. Therefore, as a consequence of human transformations over time, some landscapes may contain residual damaged habitats hosting testimony of past biodiversity that can be called “biodiversity heritage relicts”. From this perspective, the aim of the paper is to describe an applicative approach to habitat restoration in social-ecological landscapes. The approach entails the restoration of vegetation using GIS analysis integrated with field activities and a phytosociological method. The methodology includes expert and stakeholder involvement in order to increase the resilience of the measures over time, thereby consolidating landscape value. The approach was applied in the municipality of Campi Salentina, Province of Lecce, Italy, and the result was the restoration of an important riparian habitat classified under Directive 92/43/EEC as “Salix alba and Populus alba galleries” (code 92A0), which had not previously been recorded in the Province of Lecce. In this case, the project re-established a natural habitat that represented a “biodiversity heritage relict” in the landscape. The paper shows that direct knowledge of the landscape and the ability to identify “biodiversity heritage relicts”, in combination with a phytosociological approach, can enhance the effectiveness of ecological restoration projects. Moreover, social and institutional integration in projects helps ensure the management of the measures over time.
Dynamin Inhibitors Prevent the Establishment of the Cytomegalovirus Assembly Compartment in the Early Phase of Infection
Authors: Štimac Igor , Jug Vučko Natalia , Blagojević Zagorac Gordana , Marcelić Marina , Mahmutefendić Lučin Hana , Lučin Pero
Published: August 2021

Cytomegalovirus (CMV) infection initiates massive rearrangement of cytoplasmic organelles to generate assembly compartment (AC). The earliest events, the establishment of the preAC, are initiated in the early phase as an extensive reorganization of early endosomes (EEs), endosomal recycling compartment (ERC), trans-Golgi network (TGN), and the Golgi. Here, we demonstrate that dynamin inhibitors (Dynasore, Dyngo-4a, MiTMAB, and Dynole-34-2) block the establishment of the preAC in murine CMV (MCMV) infected cells. In this study, we extensively analyzed the effect of Dynasore on the Golgi reorganization sequence into the outer preAC. We also monitored the development of the inner preAC using a set of markers that define EEs (Rab5, Vps34, EEA1, and Hrs), the EE-ERC interface (Rab10), the ERC (Rab11, Arf6), three layers of the Golgi (GRASP65, GM130, Golgin97), and late endosomes (Lamp1). Dynasore inhibited the pericentriolar accumulation of all markers that display EE-ERC-TGN interface in the inner preAC and prevented Golgi unlinking and dislocation to the outer preAC. Furthermore, in pulse-chase experiments, we demonstrated that the presence of dynasore only during the early phase of MCMV infection (4–14 hpi) is sufficient to prevent not only AC formation but also the synthesis of late-phase proteins and virion production. Therefore, our results indicate that dynamin-2 acts as a part of the machinery required for AC generation and rearrangement of EE/ERC/Golgi membranes in the early phase of CMV infection.