Search

Abstract Seqrutinator is an objective, flexible pipeline that removes sequences with sequencing and/or gene model errors and sequences from pseudogenes from complex, eukaryotic protein superfamilies. Testing Seqrutinator on major superfamilies BAHD, CYP, and UGT removes only 1.94% of SwissProt entries, 14% of entries from the model plant Arabidopsis thaliana, but 80% of entries from Pinus taeda’s recent complete proteome. Application of Seqrutinator on crude BAHDomes, CYPomes, and UGTomes obtained from 16 plant proteomes shows convergence of the numbers of paralogues. MSAs, phylogenies, and particularly functional clustering improve drastically upon Seqrutinator application, indicating good performance.

BackgroundExercise has been proposed as the “Universal Prescription for Parkinson’s Disease”; however, the specificity of exercise dose in terms of frequency, intensity, duration, and type to be prescribed remains to be elucidated. The 2018 US updated guidelines and WHO Guidelines on Physical Activity and Sedentary Behavior recommend older adults (> 65+ years) to achieve weekly minimal activity levels, indicating the intensity of aerobic exercise as the metabolic equivalent of task and duration as minutes/week (150–300 min/week at a moderate intensity of 3–5.9 MET- or 75–150 min/week of a vigorous intensity of ≥6 MET). Translating these recommendations to PD patients, the study aimed to assess the dose–response effects of standardized volume of structured exercise, measured as METs-minutes/week (weekly energy expenditure) of two different rehabilitation settings to quantify the change in neurotrophic factors. The exercise-induced benefits between the two rehabilitation settings will be evaluated based on motor and non-motor symptoms, kinematic parameters of gait, cognitive function, quality of life, and cortical activity and brain connectivity.MethodsMETEX-PD is a pilot, prospective, observational, cohort study. The study will enroll consecutively thirty (N = 30) participants with mild-to-moderate Parkinson’s disease diagnosis to be assigned to a non-intensive or intensive rehabilitation group. The non-intensive rehabilitation group will achieve a range of 180–270 METs-min/week (90 min/week of low-intensity aerobic exercise, 2–3 METs), while the intensive rehabilitation group will exercise at 1350–1980 METs-min/week (225 min/week of high-intensity aerobic exercise, 6–8.8 METs). The METEX-PD trial will last 12 weeks, including 4 weeks of aerobic training program and two follow-ups. Assessments will be performed at baseline (T0), at the end of the exercise program (T1—end of the program), and 4- and 8 weeks after the end of the training program (FU-1 and FU-2). The primary outcome is the change from baseline in peripheral blood BDNF levels. Secondary outcomes are differences in peripheral biomarkers, functional-motor assessments, clinical-functional evaluations, and brain imaging.ConclusionMETEX-PD trial will enable us to estimate the change in BDNF levels and other peripheral biomarkers under precise exercise-induced energy expenditure. The primary results of the METEX-PD study will allow the development of a larger multicenter randomized controlled trial to investigate the molecular pathways inducing the change in selected neurotrophic factors, such as BDNF, IGF-1, or irisin, and the downstream mechanisms of neuroplasticity in PD patients.

Levodopa is the gold standard for the symptomatic treatment of Parkinson's disease (PD). There are well documented motor and non-motor fluctuations, however, that occur almost inevitably once levodopa is started after a variable period in people with PD. Whilst brain neurodegenerative processes play a part in the pathogenesis of these fluctuations, a range of barriers across the gastrointestinal (GI) tract can alter levodopa pharmacokinetics, ultimately contributing to non-optimal levodopa response and symptoms fluctuations. GI barriers to levodopa transport and absorption include dysphagia, delayed gastric emptying, constipation, Helicobacter pylori infection, small intestinal bacterial overgrowth and gut dysbiosis. In addition, a protein-rich diet and concomitant medication intake can further alter levodopa pharmacokinetics. This can result in unpredictable or sub-optimal levodopa response, 'delayed on' or 'no on' phenomena. In this narrative review, we provided an overview on the plethora of GI obstacles to levodopa transport and absorption in PD and their implications on levodopa pharmacokinetics and development of motor fluctuations. In addition, management strategies to address GI dysfunction in PD are highlighted, including use of non-oral therapies to bypass the GI tract.

Abstract Black flounder (Paralichthys orbignyanus, Pleuronectiformes) is a commercially significant marine fish with promising aquaculture potential in Argentina. Despite extensive studies on Black flounder aquaculture, its limited genetic information available hampers the crucial role genetics plays in the development of this activity. In this study, we first employed Illumina sequencing technology to sequence the entire genome of Black flounder. Utilizing two independent libraries—one from a female and another from a male—with 150 bp paired-end reads, a mean insert length of 350 bp, and over 35 X-fold coverage, we achieved assemblies resulting in a genome size of ~ 538 Mbp. Analysis of the assemblies revealed that more than 98% of the core genes were present, with more than 78% of them having more than 50% coverage. This indicates a somehow complete and accurate genome at the coding sequence level. This genome contains 25,231 protein-coding genes, 445 tRNAs, 3 rRNAs, and more than 1,500 non-coding RNAs of other types. Black flounder, along with pufferfishes, seahorses, pipefishes, and anabantid fish, displays a smaller genome compared to most other teleost groups. In vertebrates, the number of transposable elements (TEs) is often correlated with genome size. However, it remains unclear whether the sizes of introns and exons also play a role in determining genome size. Hence, to elucidate the potential factors contributing to this reduced genome size, we conducted a comparative genomic analysis between Black flounder and other teleost orders to determine if the small genomic size could be explained by repetitive elements or gene features, including the whole genome genes and introns sizes. We show that the smaller genome size of flounders can be attributed to several factors, including changes in the number of repetitive elements, and decreased gene size, particularly due to lower amount of very large and small introns. Thus, these components appear to be involved in the genome reduction in Black flounder. Despite these insights, the full implications and potential benefits of genome reduction in Black flounder for reproduction and aquaculture remain incompletely understood, necessitating further research.

AbstractBackground Oral levodopa remains the mainstay of treatment for Parkinson’s disease (PD). However, as PD progresses, response to treatment may fluctuate. Managing fluctuations can be demanding for clinicians and patients. There is a paucity of real-world studies reporting on PD management in patients with fluctuations in treatment response, especially in patients with advanced stages of PD. The multicentre, observational Parkinson’s Disease Fluctuations treatment PAthway (PD-FPA) study describes the real-life management of response fluctuations in Italian patients with advanced PD.Patients and Methods PD-FPA had a retrospective and prospective phase; herein, retrospective results are presented. Ten Italian centres enrolled patients with a PD diagnosis from 10–15 years prior to study entry (T0) and who had ≥2-year history of fluctuations. Data on patient demographics, medical history, PD stage, fluctuation characteristics, symptoms, and prescribed treatments were collected at T0 and retrospectively (2 years prior to T0) via patient chart review/interview.Results Overall, 296 patients (60% male, mean age 68 years, 84% with Hoehn and Yahr scores 2–3) were enrolled. At T0, most patients (99.3%) were on oral levodopa therapy. All patients used dopaminergic medications; adjunctive medications included dopamine agonists (56%) and monoamine oxidase B (60%) and catechol-O-methyltransferase enzyme inhibitors (41%). At T0, 51% of patients had changed therapy, with response fluctuations being the most common reason (74%); wearing-off was the most common fluctuation (83%).Conclusion This interim analysis of PD-FPA suggests that adequate levodopa dosing and adjunctive medications can stabilize advanced PD and provide patients with a good quality of life.

Background/Objectives: This study is based on data collected from a medical health record review to assess whether multidisciplinary intensive rehabilitation treatment in Parkinson’s disease (PD) patients can improve global cognitive functioning and executive functions. Methods: The data related to PD patients were extrapolated from a clinical database called “NeuroRehab”. A total of 104 PD patients (51 males; 53 females) performed 6 weeks of multidisciplinary intensive rehabilitation treatment in clinical practice from January 2019 to May 2023. This training program was characterized by three daily sessions of 60 min of activities (muscle relaxation and stretching exercises, moderate physical aerobic exercise, and occupational therapy). The patients were classified and stratified according to disease severity (according to the Hoehn and Yahr scale), postural instability and gait difficulty (PIGD) or tremor-dominant (TD) subtypes, disease duration (DD), and the presence of dyskinesias. The effect of multidisciplinary intensive rehabilitation treatment on cognitive and executive functions was evaluated through the administration of cognitive tests, such as the Mini–Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Frontal Assessment Battery (FAB). All the parameters were evaluated at the baseline (T0) and at the end of the rehabilitation program (T1). Results: The multidisciplinary intensive rehabilitation treatment significantly improved cognitive performance. The MMSE, MoCA, and FAB test scores after the rehabilitation program (T1) were significantly higher compared to the scores obtained at the baseline (T0). Moreover, further analyses on subgroups of the patients who scored below the cut-off in the MMSE showed that at least 50% of patients overcame the cut-off score. Interestingly, the same analyses performed for the MoCA and FAB revealed a higher rate of improvement in cognitive functions, with normal scores in both tests after 6 weeks of multidisciplinary intensive rehabilitation treatment. Conclusions: This study revealed the potential effects of a 6-week multidisciplinary rehabilitation program in improving cognitive status in a PD inpatient cohort.

Abstract Relic coastal landforms (fossil corals, cemented intertidal deposits, or erosive features carved onto rock coasts) serve as sea‐level index points (SLIPs), that are widely used to reconstruct past sea‐level changes. Traditional SLIP‐based sea‐level reconstructions face challenges in capturing continuous sea‐level variability and dating erosional SLIPs, such as tidal notches. Here, we propose a novel approach to such challenges. We use a numerical model of cliff erosion embedded within a Monte Carlo simulation to investigate the most likely sea‐level scenarios responsible for shaping one of the best‐preserved tidal notches of Last Interglacial age in Sardinia, Italy. Results align with Glacial Isostatic Adjustment model predictions, indicating that synchronized or out‐of‐sync ice‐volume shifts in Antarctic and Greenland ice sheets can reproduce the notch morphology, with sea level confidently peaking at 6 m and only under a higher than present erosion regime. This new approach yields insight into sea‐level trends during the Last Interglacial.

Introduction The empty pelvis syndrome is a significant source of morbidity following pelvic exenteration surgery. It remains poorly defined with research in this field being heterogeneous and of low quality. Furthermore, there has been minimal engagement with patient representatives following pelvic exenteration with respect to the empty pelvic syndrome. ‘PelvEx—Beating the empty pelvis syndrome’ aims to engage both patient representatives and healthcare professionals to achieve an international consensus on a core outcome set, pathophysiology and mitigation of the empty pelvis syndrome.Methods and analysis A modified-Delphi approach will be followed with a three-stage study design. First, statements will be longlisted using a recent systematic review, healthcare professional event, patient and public engagement, and Delphi piloting. Second, statements will be shortlisted using up to three rounds of online modified Delphi. Third, statements will be confirmed and instruments for measurable statements selected using a virtual patient-representative consensus meeting, and finally a face-to-face healthcare professional consensus meeting.Ethics and dissemination The University of Southampton Faculty of Medicine ethics committee has approved this protocol, which is registered as a study with the Core Outcome Measures in Effectiveness Trials Initiative. Publication of this study will increase the potential for comparative research to further understanding and prevent the empty pelvis syndrome.Trial registration number NCT05683795.

The warmest peak of the Last Interglacial (ca. 128–116 ka) is considered a process analogue and is often studied to better understand the effects of a future warmer climate on the Earth's system. In particular, significant efforts have been made to better constrain ice sheet contributions to the peak Last Interglacial sea level through field observation of paleo relative sea level indicators. Along tropical coastal margins, these observations are predominantly based on fossil shallow coral reef sequences, which also provide the possibility of gathering reliable U-series chronological constraints. However, the preservation of many Pleistocene reef sequences is often limited to a series of discrete relative sea level positions within the interglacial, where corals suitable for dating were preserved. This, in turn, limits our ability to understand the continuous evolution of paleo relative sea level through an entire interglacial, also affecting the possibility of unraveling the existence and pattern of sub-stadial sea level oscillations. While the interpretation of lithostratigraphic and geomorphologic properties is often used to overcome this hurdle, geological interpretation may present issues related to subjectivity when dealing with missing facies or incomplete sequences. In this study, we try to step back from a conventional approach, generating a spectrum of synthetic Quaternary subtropical fringing reefs for a site in southwestern Madagascar (Indian Ocean). We use the Dionisos forward stratigraphic model (from Beicip-Franlab) to build a fossil reef at this location. In each model run, we use distinct Greenland and Antarctica ice sheet melt scenarios produced by a coupled ANICE–SELEN glacial isostatic adjustment model. The resulting synthetic reef sequences are then used test these melt scenarios against the stratigraphic record. We propose that this sort of stratigraphic modeling may provide further quantitative control when interpreting Last Interglacial reef sequences.

Tauroursodeoxycholic acid (TUDCA) increases the influx of primary bile acids into the gut. Results obtained on animal models suggested that Firmicutes and Proteobacteria phyla are more resistant to bile acids in rats. As part of a pilot study investigating the role of probiotics supplementation in elderly people with home enteral nutrition (HEN), a case of a 92-year-old woman with HEN is reported in the present study. She lives in a nursing home and suffers from Alzheimer’s disease (AD); the patient had been prescribed TUDCA for lithiasis cholangitis. The aim of this case report is therefore to investigate whether long-term TUDCA administration may play a role in altering the patient’s gut microbiota (GM) and the impact of an antibiotic therapy on the diversity of microbial species. Using next generation sequencing (NGS) analysis of the bacterial 16S ribosomal RNA (rRNA) gene a dominant shift toward Firmicutes and a remodeling in Proteobacteria abundance was observed in the woman’s gut microbiota. Considering the patient’s age, health status and type of diet, we would have expected to find a GM with a prevalence of Bacteroidetes phylum. This represents the first study investigating the possible TUDCA’s effect on human GM.

This paper presents an investigation into the design of ammonia tanks for long-duration and high-pressure blast loads. The focus is on cylindrical steel tanks that apply as outer pressure-tight containers for double-walled tanks storing refrigerated liquefied gases. Based on limited empirical data, it is known in the tank industry that these tanks can withstand an explosion pressure up to a peak overpressure of approximately 10 kPa and 100 ms positive load duration. However, there is a growing need to design tanks for higher peak overpressures in order to establish a higher safety standard and accommodate unforeseen future requirements. This paper explores the concept of adapting established steel tank designs to handle high-pressure and long-duration overpressure due to blast events. Numerical analysis is conducted on a representative steel tank geometry subjected to a triangular blast load of 30 kPa with a 300 ms positive load duration. Various load application and calculation options are analyzed numerically. Considering the challenging nature of analyzing tank structures under blast load, the paper addresses controversial aspects discussed in the literature and presents a suitable analysis concept for a deflagration blast scenario for cylindrical tanks. The results provide insights into the expected structural behavior of the tank under high-pressure and long-duration overpressure. The main finding is that the calculation method developed in this study demonstrates the feasibility of utilizing steel tanks in scenarios involving long-duration and high-pressure blast loads. Furthermore, the paper provides recommendations to guide future studies in this area. The findings have implications for the design and construction of tanks in critical infrastructure and offer valuable insights for engineers and researchers in this field, improving safety standards and ensuring adaptability to future utilization concepts.

Nowadays, modeling of tephra fallout hazard is coupled with probabilistic analysis that takes into account the natural variability of the volcanic phenomena in terms of eruption probability, eruption sizes, vent position, and meteorological conditions. In this framework, we present a prototypal methodology to carry out the long-term tephra fallout hazard assessment in southern Italy from the active Neapolitan volcanoes: Somma–Vesuvius, Campi Flegrei, and Ischia. The FALL3D model (v.8.0) has been used to run thousands of numerical simulations (1500 per eruption size class), considering the ECMWF ERA5 meteorological dataset over the last 30 years. The output in terms of tephra ground load has been processed within a new workflow for large-scale, high-resolution volcanic hazard assessment, relying on a Bayesian procedure, in order to provide the mean annual frequency with which the tephra load at the ground exceeds given critical thresholds at a target site within a 50-year exposure time. Our results are expressed in terms of absolute mean hazard maps considering different levels of aggregation, from the impact of each volcanic source and eruption size class to the quantification of the total hazard. This work provides, for the first time, a multi-volcano probabilistic hazard assessment posed by tephra fallout, comparable with those used for seismic phenomena and other natural disasters. This methodology can be applied to any other volcanic areas or over different exposure times, allowing researchers to account for the eruptive history of the target volcanoes that, when available, could include the occurrence of less frequent large eruptions, representing critical elements for risk evaluations.

ABSTRACTCampi Flegrei is one of the widest and most dangerous active volcanic complexes in the Mediterranean basin, known to be affected by continuous and sudden vertical ground movements (bradyseismic crisis) that have characterized the post-calderic volcanic activity since the Late Pleistocene and particularly during the Roman period. Despite the intense volcano-tectonic processes, the area has been densely inhabited since the Greek-Roman as testified by several submerged archaeological remains here used as high-precision relative sea-level markers. By using a complex multi-technique approach made of direct, indirect morpho-acoustic and optical surveys, and stratigraphic analysis, we present a detailed reconstruction of the coastal landscape of Campi Flegrei and its surroundings between the Roman Late Republican and Early Imperial ages. The coastal scenario aims to facilitate the comprehension of how volcano-tectonic events influenced the evolution of this singular coastal landscape, and how these interfered with human activity in terms of damages and adaptation.

Background: Dose optimization of sublingual apomorphine (SL-APO), a dopamine agonist for the treatment of OFF episodes in patients with Parkinson’s disease (PD), has been performed under clinical supervision in clinical trials. SL-APO may be a candidate for home dosing optimization which would be less burdensome for patients. Objectives: To evaluate the feasibility and safety of home optimization of SL-APO in patients with PD and OFF episodes. Design: A multicenter, randomized, crossover study comparing SL-APO with subcutaneous apomorphine was conducted, comprising an open-label dose-optimization phase and a treatment phase. This non-comparative analysis focuses on the outcomes of the dose-optimization phase with SL-APO only. Methods: Patients with PD and OFF episodes received SL-APO at an initial dose of 10 mg in the clinic (open-label). Further optimization could continue at home in 5 mg increments during subsequent OFF episodes (maximum dose of 30 mg). Optimization and tolerability were assessed daily by patient-reported feedback via telephone. Patients reporting a FULL ON returned to the clinic for a dose-confirmation visit (DCV). In patients with inadequate response as determined during the DCV, the dose could be further optimized at home. Results: Home optimization was continued by 81.4% (83/102) of patients. Of these, 80.7% identified an effective, tolerable dose. Mean time between initial clinic visit and DCV 1 was 6.8 days, and the final optimized dose of SL-APO was 30 mg (mode). In total, 62.7% of patients reported ⩾1 adverse event; the most common included nausea (31.4%), dizziness (9.8%), somnolence (8.8%), dyskinesia (7.8%), and fatigue (5.9%). The safety profile in this study in which most patients performed home dose optimization was consistent with the study utilizing clinic-based optimization. Conclusion: After the first clinic dose, home dose optimization of SL-APO appears feasible in patients with PD and OFF episodes, with most patients identifying their optimal SL-APO dose at home. Trial registration: This study is registered with EudraCT (2016-003456-7): Clinical Trials register – Search for eudract_number:2016-003456-70.

The purpose of this study is to assess the cardiometabolic responses of a lifestyle intervention (LI) conducted at home among breast cancer (BC) survivors during the two years of COVID-19 pandemic. A 3-month LI focused on diet and exercise was performed on thirty BC survivors (women; stages 0-II; non-metastatic; aged 53.6 ± 7.6 years; non-physically active) with a risk factor related to metabolic/endocrine diseases. Anthropometrics, cardiorespiratory fitness (V˙ O2max), physical activity level (PAL), adherence to the Mediterranean diet (MeDiet modified questionnaire), and several biomarkers (i.e., glycemia, insulin, insulin resistance [HOMA-IR] index, triglycerides, high- [HDL] and low- [LDL] density lipoproteins, total cholesterol, progesterone, testosterone, and hs-troponin) were evaluated before and 3-, 6-, 12-, and 24-month after the LI. Beneficial effects of the LI were observed on several variables (i.e., body mass index, waist circumference, MeDiet, PAL, V˙ O2max, glycemia, insulin, HOMA-IR index, LDL, total cholesterol, triglycerides, testosterone) after 3-month. The significant effect on Mediterranean diet adherence and V˙ O2max persisted up to the 24-month follow-up. Decreases in HOMA-IR index and triglycerides were observed up to 12-month, however did not persist afterward. This study provides evidence on the positive association between LI and cardiometabolic health in BC survivors.