Synthesis of Soluble High Molar Mass Poly(Phenylene Methylene)-Based Polymers.

Poly(phenylene methylene) (PPM) is a multifunctional polymer that is also active as an anticorrosion fluorescent coating material. Although this polymer was synthesized already more than 100 years ago, a versatile synthetic route to obtain soluble high molar mass polymers based on PPM has yet to be achieved. In this article, the influence of bifunctional bis-chloromethyl durene (BCMD) as a branching agent in the synthesis of PPM is reported. The progress of the reaction was followed by gel permeation chromatography (GPC) and NMR analysis. PPM-based copolymers with the highest molar mass reported so far for this class of materials (up to Mn of 205,300 g mol-1) were isolated. The versatile approach of using BCMD was confirmed by employing different catalysts. Interestingly, thermal and optical characterization established that the branching process does not affect the thermoplastic behavior and the fluorescence of the material, thus opening up PPM-based compounds with high molar mass for applications.

Use of semi-constrained total knee arthroplasty in gonarthrosis with collateral ligament insufficiency: Clinical and functional outcomes.

INTRODUCTION: Achieving stability in total knee arthroplasty (TKA) is crucial for long-term implant survival. In cases of severe deformity or ligament laxity, constrained implants may be required. Traditionally, increasing constraint involved intramedullary stems. However, there are intermediary alternatives, including employing a constrained polyethylene insert without stems, thereby avoiding complications related to them. The study aims to evaluate our experience with a non-modular constrained (NMC) implant in primary TKA. MATERIAL AND METHODS: We conducted a retrospective review of the clinical and radiographic outcomes of 108 non-stemmed primary TKAs performed at our institution between 2013 and 2021 in patients with at least 10° deformity or 10mm ligament laxity. Data included demographics, preoperative and postoperative deformities, clinical outcomes and revision rates. RESULTS: A total of 103 patients (108 knees) with a mean age of 74 were followed up for a minimum of 2 years. The mean postoperative range of motion was 105°/0°. The median Oxford Knee Score, Knee Society Score and Knee Society Function Score were 43.5, 92 and 90, respectively. 17 knees had varus deformity (mean tibiofemoral angle of 2.7°), and 87 knees had excessive valgus deformity (mean tibiofemoral angle of 15.1°). The remaining 4 knees had a neutral alignment. The mean postoperative tibiofemoral angle was 6.8°. The overall revision rate was 6.5% (7 patients): 3 deep periprosthetic infections, 2 patellar dislocations, 1 stiffness and 1 aseptic loosening. CONCLUSION: Our experience demonstrates favorable mid-term outcomes with the NMC implant, providing a safe alternative to stemmed implants in primary TKA, particularly in cases of severe deformity or ligament laxity.

Understanding limb necrotizing infections: A comprehensive approach.

INTRODUCTION: Necrotizing soft tissue infections (NSTI) are increasing, posing a significant risk of morbidity and mortality. Due to nonspecific symptoms, a high index of suspicion is crucial. Treatment involves a multidisciplinary approach, with broad-spectrum antibiotics, early surgical debridement, and life support. This study analyzes the characteristics, demographics, complications, and treatment of NSTI in a hospital in Madrid, Spain. METHODS: A retrospective observational study was conducted, including all surgically treated NSTI patients at our center from January 2016 to December 2022, examining epidemiological and clinical data. The Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) was prospectively calculated for all patients. RESULTS: Twenty-two patients (16 men, 6 women, mean age 54.8) were included. Median time from symptom onset to emergency room visit was 3.5 days. All reported severe treatment-resistant pain; sixteen had fever exceeding 37.8°C (72.7%). Skin lesions occurred in twelve (54.5%), and thirteen had hypotension and tachycardia (59.1%). Treatment involved resuscitative support, antibiotherapy, and radical debridement. Median time to surgery was 8.25h. Intraoperative cultures were positive in twenty patients: twelve Streptococcus pyogenes, four Staphylococcus aureus, one Escherichia coli, and four polymicrobial infection. In-hospital mortality rate was 22.73%. CONCLUSIONS: We examined the correlation between our results, amputation rates and mortality with LRINEC score and time to surgery. However, we found no significant relationship unlike some other studies. Nevertheless, a multidisciplinary approach with radical debridement and antibiotic therapy remains the treatment cornerstone. Our hospital stays, outcomes and mortality rates align with our literature review, confirming high morbimortality despite early and appropriate intervention.

Effect of Secukinumab Versus Adalimumab Biosimilar on Radiographic Progression in Patients With Radiographic Axial Spondyloarthritis: Results From a Head-to-Head Randomized Phase IIIb Study.

OBJECTIVE: Spinal radiographic progression is an important outcome in radiographic axial spondyloarthritis (SpA). The objective of the phase IIIb SURPASS study was to compare spinal radiographic progression in patients with radiographic axial SpA treated with secukinumab (interleukin-17A inhibitor) versus adalimumab biosimilar (Sandoz adalimumab [SDZ-ADL]; tumor necrosis factor inhibitor). METHODS: Biologic-naive patients with active radiographic axial SpA, at high risk of radiographic progression (high-sensitivity C-reactive protein [hsCRP] ≥5 mg/L and/or ≥1 syndesmophyte[s] on spinal radiographs), were randomized (1:1:1) to secukinumab (150/300 mg) or SDZ-ADL (40 mg). The proportion of patients with no radiographic progression (change from baseline [CFB] in modified Stoke Ankylosing Spondylitis Spinal Score [mSASSS] ≤0.5) on secukinumab versus SDZ-ADL at week 104 (primary endpoint), mean CFB-mSASSS, proportion of patients with ≥1 syndesmophyte(s) at baseline with no new syndesmophyte(s), and safety were evaluated. RESULTS: Overall, 859 patients (78.5% male, mSASSS 16.6, Bath Ankylosing Spondylitis Disease Activity Index 7.1, hsCRP 20.4 mg/L, and 73.0% with ≥1 syndesmophyte[s]) received secukinumab 150 mg (n = 287), secukinumab 300 mg (n = 286), or SDZ-ADL (n = 286). At week 104, the proportion of patients with no radiographic progression was 66.1%, 66.9%, and 65.6% (P = not significant, both secukinumab doses) and mean CFB-mSASSS was 0.54, 0.55, and 0.72 in secukinumab 150 mg, secukinumab 300 mg, and SDZ-ADL arms, respectively. Overall, 56.9%, 53.8%, and 53.3% of patients on secukinumab 150 mg, secukinumab 300 mg, and SDZ-ADL, respectively, with ≥1 syndesmophyte(s) at baseline did not develop new syndesmophyte(s) by week 104. There were no unexpected safety findings. CONCLUSION: Spinal radiographic progression over two years was low with no significant difference between secukinumab and SDZ-ADL arms. The safety of both treatments was consistent with previous reports.

Metal accumulation in female green sea turtles (Chelonia mydas) from Eastern Atlantic affects their egg quality with potential implications for embryonic development.

Sea turtles, with their global distribution and complex life cycle, often accumulate pollutants such as metals and metalloids due to their extended lifespan and feeding habits. However, there are limited studies exploring the impact of metal pollution on the reproductive health of female sea turtles, specifically focusing on the quality of their eggs, which has significant implications for the future generations of these charismatic animals. São Tomé Island, a crucial nesting and feeding habitat for green sea turtles, underscores the urgent need for comprehensive research in this ecologically significant area. This study aimed to investigate whether metals and metalloids in the blood of nesting female green sea turtles induce genotoxic effects in their erythrocytes and affect their egg morphometric characteristics and the composition of related compartments. Additionally, this study aimed to evaluate whether the quality of energetic reserves for embryo development (fatty acids in yolk's polar and neutral lipids) is influenced by the contamination status of their predecessors. Results revealed correlations between Cu and Hg levels and increased "lobed" erythrocytes, while As and Cu negatively influenced shell thickness. In terms of energy reserves, both polar and neutral lipid fractions contained primarily saturated and monounsaturated fatty acids, with prevalent 18:1n-9, 18:0, 16:0, 14:0, and 12:0 fatty acids in yolk samples. The yolk polar fraction was more susceptible to contaminant levels in female sea turtles, showing consistent negative correlations between pollution load index and essential n3 fatty acids, including linolenic, eicosatrienoic, eicosapentaenoic, and docosapentaenoic acids, crucial for embryonic development. These metals accumulation, coupled with the reduced availability of these key fatty acids, may disrupt the eicosanoid and other important pathways, affecting reproductive development. This study reveals a negative correlation between metal contamination in female sea turtles' blood and egg lipid reserves, raising concerns about embryonic development and the species' future generations.

Chronic rhinosinusitis with nasal polyposis and biological agents: the ARIA-ITALY Survey.

Summary: Background. Chronic rhinosinusitis (CRS) is an inflammatory disease that affects the nasal mucosa and the paranasal sinuses. CRS can be associated by nasal polyposis (CRSwNP phenotype) in up to 30% of patients and it is frequently associated with bronchial asthma. CRSwNP shows predominantly an underlying activation of type 2 inflammatory pathways with the involvement of eosinophils, IgE, interleukin (IL)-4, IL-5 and IL-13. Biological drugs that target these inflammatory cytokines are currently a therapeutic option recognized by guidelines for the treatment of uncontrolled form of the disease. Methods. As part of the activity of the "ARIA-Italy" working group, a panel of 255 Italian Ear, Nose and Throat (ENT) specialists, pneumologists and immuno-allergologists actively participated in this national survey and answered a series of questions geared toward understanding the main criteria for patient characterization and therapeutic decision, highlighting multidisciplinarity, and the implementation of the management of CRSwNP patients, as a part of the precision medicine concept and the appropriate use of the biologicals. Results. Two hundred and fifty-five experts and specialists participated in the survey. Conclusions. The results of this survey obtained from an extensive number of active specialists throughout Italy allow some important concluding remarks to be drawn. The main points of agreement were that multidisciplinary care teams provide many benefits but that, once the team is established, meetings and communication between members must be coordinated. Finally, the dissemination of national disease registries and the continuous updating of guidelines and position papers related to CRSwNP and comorbidities should be encouraged.

Mitochondrial targets in hyperammonemia: Addressing urea cycle function to improve drug therapies.

The urea cycle (UC) is a critically important metabolic process for the disposal of nitrogen (ammonia) produced by amino acids catabolism. The impairment of this liver-specific pathway induced either by primary genetic defects or by secondary causes, namely those associated with hepatic disease or drug administration, may result in serious clinical consequences. Urea cycle disorders (UCD) and certain organic acidurias are the major groups of inherited rare diseases manifested with hyperammonemia (HA) with UC dysregulation. Importantly, several commonly prescribed drugs, including antiepileptics in monotherapy or polytherapy from carbamazepine to valproic acid or specific antineoplastic agents such as asparaginase or 5-fluorouracil may be associated with HA by mechanisms not fully elucidated. HA, disclosing an imbalance between ammoniagenesis and ammonia disposal via the UC, can evolve to encephalopathy which may lead to significant morbidity and central nervous system damage. This review will focus on biochemical mechanisms related with HA emphasizing some poorly understood perspectives behind the disruption of the UC and mitochondrial energy metabolism, namely: i) changes in acetyl-CoA or NAD+ levels in subcellular compartments; ii) post-translational modifications of key UC-related enzymes, namely acetylation, potentially affecting their catalytic activity; iii) the mitochondrial sirtuins-mediated role in ureagenesis. Moreover, the main UCD associated with HA will be summarized to highlight the relevance of investigating possible genetic mutations to account for unexpected HA during certain pharmacological therapies. The ammonia-induced effects should be avoided or overcome as part of safer therapeutic strategies to protect patients under treatment with drugs that may be potentially associated with HA.

[Translated article] Efficacy of transplantation of lipoaspired mesenchymal stem cells in the treatment of chronic rotator cuff tears. Experimental model in rats.

BACKGROUND AND AIM: Rotator cuff tears emerge in approximately 30% of the population over 60 years of age. Arthroscopic surgical treatment of these lesions is the treatment of choice, however, despite the improved repair techniques, the rate of re-tears ranges between 11 and 94%. Therefore, researchers seek to improve the biological healing process through the use of different alternatives such as mesenchymal stem cells (MSCs). Our objective is to evaluate the efficacy of a cellular therapy drug made from allogeneic stem cells derived from adipose tissue in a rat model of chronic rotator cuff injury. MATERIAL AND METHODS: The supraspinatus lesion was created in 48 rats for subsequent suturing at 4 weeks. MSCs in suspension were added to 24 animals after suturing, and HypoThermosol-FRS® (HTS) to 24 animals as a control group. Histology (Åström and Rausing scale) and the maximum load, displacement and elastic constant of the supraspinatus tendon were analysed in both groups 4 months after the repair. RESULTS: No statistically significant differences were found in the histological score comparing the tendons treated with MSCs with respect to the tendons treated with HTS (P=0.811) nor in the results of maximum load (P=0.770), displacement (P=0.852) or elastic constant (P=0.669) of the tendon in both groups. CONCLUSIONS: The addition of adipose-derived cells in suspension to the repair of a chronic cuff injury does not improve the histology or biomechanics of the sutured tendon.

Efficacy of transplantation of lipoaspired mesenchymal stem cells in the treatment of chronic rotator cuff tears. Experimental model in rats. / Eficacia del trasplante de células madre mesenquimales de lipoaspirado en el tratamiento de lesiones crónicas del manguito rotador. Modelo experimental en ratas.

BACKGROUND AND AIM: Rotator cuff tears emerge in approximately 30% of the population over 60 years of age. Arthroscopic surgical treatment of these lesions is the treatment of choice, however, despite the improved repair techniques, the rate of re-tears ranges between 11 and 94%. Therefore, researchers seek to improve the biological healing process through the use of different alternatives such as mesenchymal stem cells (MSCs). Our objective is to evaluate the efficacy of a Cellular Therapy Drug made from allogeneic stem cells derived from adipose tissue in a rat model of chronic rotator cuff injury. MATERIAL AND METHODS: The supraspinatus lesion was created in 48 rats for subsequent suturing at 4 weeks. MSCs in suspension were added to 24 animals after suturing, and HypoThermosol-FRS® (HTS) to 24 animals as a control group. Histology (Åström and Rausing scale) and the maximum load, displacement and elastic constant of the supraspinatus tendon were analyzed in both groups 4 months after the repair. RESULTS: No statistically significant differences were found in the histological score comparing the tendons treated with MSCs with respect to the tendons treated with HTS (P=.811) nor in the results of maximum load (P=.770), displacement (P=.852) or elastic constant (P=.669) of the tendon in both groups. CONCLUSIONS: The addition of adipose-derived cells in suspension to the repair of a chronic cuff injury does not improve the histology or biomechanics of the sutured tendon.

Early life stage mechanisms of an active fish species to cope with ocean warming and hypoxia as interacting stressors.

Ocean's characteristics are rapidly changing, modifying environmental suitability for early life stages of fish. We assessed whether the chronic effects of warming (24 °C) and hypoxia (<2-2.5 mg L-1) will be amplified by the combination of these stressors on mortality, growth, behaviour, metabolism and oxidative stress of early stages of the white seabream Diplodus sargus. Combined warming and hypoxia synergistically increased larval mortality by >51%. Warming induced faster growth in length and slower gains in weight when compared to other treatments. Boldness and exploration were not directly affected, but swimming activity increased under all test treatments. Under the combination of warming and hypoxia, routine metabolic rate (RMR) significantly decreases when compared to other treatments and shows a negative thermal dependence. Superoxide dismutase and catalase activities increased under warming and were maintained similar to control levels under hypoxia or under combined stressors. Under hypoxia, the enzymatic activities were not enough to prevent oxidative damages as lipid peroxidation and DNA damage increased above control levels. Hypoxia reduced electron transport system activity (cellular respiration) and isocitrate dehydrogenase activity (aerobic metabolism) below control levels. However, lactate dehydrogenase activity (anaerobic metabolism) did not differ among treatments. A Redundancy Analysis showed that ∼99% of the variability in mortality, growth, behaviour and RMR among treatments can be explained by molecular responses. Mortality and growth are highly influenced by oxidative stress and energy metabolism, exhibiting a positive relationship with reactive oxygen species and a negative relationship with aerobic metabolism, regardless of treatment. Under hypoxic condition, RMR, boldness and swimming activity have a positive relationship with anaerobic metabolism regardless of temperature. Thus, seabreams may use anaerobic reliance to counterbalance the effects of the stressors on RMR, activity and growth. The outcomes suggests that early life stages of white seabream overcame the single and combined effects of hypoxia and warming.

Dosimetrically motivated beam-angle optimization for non-coplanar arc radiotherapy with and without dynamic collimator rotation.

BACKGROUND: Non-coplanar techniques have shown to improve the achievable dose distribution compared to standard coplanar techniques for multiple treatment sites but finding optimal beam directions is challenging. Dynamic collimator trajectory radiotherapy (colli-DTRT) is a new intensity modulated radiotherapy technique that uses non-coplanar partial arcs and dynamic collimator rotation. PURPOSE: To solve the beam angle optimization (BAO) problem for colli-DTRT and non-coplanar VMAT (NC-VMAT) by determining the table-angle and the gantry-angle ranges of the partial arcs through iterative 4π fluence map optimization (FMO) and beam direction elimination. METHODS: BAO considers all available beam directions sampled on a gantry-table map with the collimator angle aligned to the superior-inferior axis (colli-DTRT) or static (NC-VMAT). First, FMO is performed, and beam directions are scored based on their contributions to the objective function. The map is thresholded to remove the least contributing beam directions, and arc candidates are formed by adjacent beam directions with the same table angle. Next, FMO and arc candidate trimming, based on objective function penalty score, is performed iteratively until a desired total gantry angle range is reached. Direct aperture optimization on the final set of colli-DTRT or NC-VMAT arcs generates deliverable plans. colli-DTRT and NC-VMAT plans were created for seven clinically-motivated cases with targets in the head and neck (two cases), brain, esophagus, lung, breast, and prostate. colli-DTRT and NC-VMAT were compared to coplanar VMAT plans as well as to class-solution non-coplanar VMAT plans for the brain and head and neck cases. Dosimetric validation was performed for one colli-DTRT (head and neck) and one NC-VMAT (breast) plan using film measurements. RESULTS: Target coverage and conformity was similar for all techniques. colli-DTRT and NC-VMAT plans had improved dosimetric performance compared to coplanar VMAT for all treatment sites except prostate where all techniques were equivalent. For the head and neck and brain cases, mean dose reduction-in percentage of the prescription dose-to parallel organs was on average 0.7% (colli-DTRT), 0.8% (NC-VMAT) and 0.4% (class-solution) compared to VMAT. The reduction in D2% for the serial organs was on average 1.7% (colli-DTRT), 2.0% (NC-VMAT) and 0.9% (class-solution). For the esophagus, lung, and breast cases, mean dose reduction to parallel organs was on average 0.2% (colli-DTRT) and 0.3% (NC-VMAT) compared to VMAT. The reduction in D2% for the serial organs was on average 1.3% (colli-DTRT) and 0.9% (NC-VMAT). Estimated delivery times for colli-DTRT and NC-VMAT were below 4 min for a full gantry angle range of 720°, including transitions between arcs, except for the brain case where multiple arcs covered the whole table angle range. These times are in the same order as the class-solution for the head and neck and brain cases. Total optimization times were 25%-107% longer for colli-DTRT, including BAO, compared to VMAT. CONCLUSIONS: We successfully developed dosimetrically motivated BAO for colli-DTRT and NC-VMAT treatment planning. colli-DTRT and NC-VMAT are applicable to multiple treatment sites, including body sites, with beneficial or equivalent dosimetric performances compared to coplanar VMAT and reasonable delivery times.

Targeting Longevity Gene SLC13A5: A Novel Approach to Prevent Age-Related Bone Fragility and Osteoporosis.

Reduced expression of the plasma membrane citrate transporter SLC13A5, also known as INDY, has been linked to increased longevity and mitigated age-related cardiovascular and metabolic diseases. Citrate, a vital component of the tricarboxylic acid cycle, constitutes 1-5% of bone weight, binding to mineral apatite surfaces. Our previous research highlighted osteoblasts' specialized metabolic pathway facilitated by SLC13A5 regulating citrate uptake, production, and deposition within bones. Disrupting this pathway impairs bone mineralization in young mice. New Mendelian randomization analysis using UK Biobank data indicated that SNPs linked to reduced SLC13A5 function lowered osteoporosis risk. Comparative studies of young (10 weeks) and middle-aged (52 weeks) osteocalcin-cre-driven osteoblast-specific Slc13a5 knockout mice (Slc13a5cKO) showed a sexual dimorphism: while middle-aged females exhibited improved elasticity, middle-aged males demonstrated enhanced bone strength due to reduced SLC13A5 function. These findings suggest reduced SLC13A5 function could attenuate age-related bone fragility, advocating for SLC13A5 inhibition as a potential osteoporosis treatment.

Liver and Plasma Fatty Acid Characterization in Cultured Brown Trout at Distinct Reproductive Stages.

Fatty acids are energy sources, and their profiles are used as biomarkers of metabolic status and physiological changes in fish. Within this context, the main aim of this study was to identify the fatty acids that best discriminate the reproductive status of male and female farmed brown trout. The fatty acid composition in liver and plasma samples from the adults of both sexes was monitored along four distinct reproductive stages, namely the spawning capable (December), regressing (March), regenerating (July), and developing (November) stages. Irrespective of the sex and stage, the most representative fatty acids were palmitic acid (16:0), stearic acid (18:0), oleic acid (18:1 n-9), arachidonic acid (20:4 n-6), eicosapentaenoic acid (EPA, 20:5 n-3), and docosahexaenoic acid (DHA, 22:6 n-3). There were no significant sex differences in fatty acid classes in the liver and plasma. Despite this, there were several changes in individual fatty acid levels between the sexes. In the liver, both males and females showed high monounsaturated fatty acid and low polyunsaturated fatty acid (PUFA) levels during the regressing and regenerating stages. At spawning capable and developing stages, a reverse profile was noted. The plasma profiles were mainly influenced by changes in saturated fatty acids and PUFAs in males and by PUFA in females. Based on the most representative fatty acids, four patterns were established for female plasma samples, one for each reproductive stage. This scenario suggests that female plasma samples are promising for the discrimination of gonadal reproductive status, and this potential can be further explored in aquaculture and environmental monitoring studies.

Exploring disease-causing traits for drug repurposing in critically ill COVID-19 patients: A causal inference approach.

Despite recent development of vaccines to prevent SARS-CoV-2 infection, treatment of critically ill COVID-19 patients remains an important goal. In principle, genome-wide association studies (GWASs) provide a shortcut to the clinical evidence needed to repurpose existing drugs; however, genes identified frequently lack a causal disease link. We report an alternative method for finding drug repurposing targets, focusing on disease-causing traits beyond immediate disease genetics. Sixty blood cell types and biochemistries, and body mass index, were screened on a cohort of critically ill COVID-19 cases and controls that exhibited mild symptoms after infection, yielding high neutrophil cell count as a possible causal trait for critical illness. Our methodology identified CDK6 and janus kinase (JAK) inhibitors as treatment targets that were validated in an ex vivo neutrophil extracellular trap (NET) formation assay. Our methodology demonstrates the increased power for drug target identification by leveraging large disease-causing trait datasets.

Technical note: A collision prediction tool using Blender.

Non-coplanar radiotherapy treatment techniques on C-arm linear accelerators have the potential to reduce dose to organs-at-risk in comparison with coplanar treatment techniques. Accurately predicting possible collisions between gantry, table and patient during treatment planning is needed to ensure patient safety. We offer a freely available collision prediction tool using Blender, a free and open-source 3D computer graphics software toolset. A geometric model of a C-arm linear accelerator including a library of patient models is created inside Blender. Based on the model, collision predictions can be used both to calculate collision-free zones and to check treatment plans for collisions. The tool is validated for two setups, once with and once without a full body phantom with the same table position. For this, each gantry-table angle combination with a 2° resolution is manually checked for collision interlocks at a TrueBeam system and compared to simulated collision predictions. For the collision check of a treatment plan, the tool outputs the minimal distance between the gantry, table and patient model and a video of the movement of the gantry and table, which is demonstrated for one use case. A graphical user interface allows user-friendly input of the table and patient specification for the collision prediction tool. The validation resulted in a true positive rate of 100%, which is the rate between the number of correctly predicted collision gantry-table combinations and the number of all measured collision gantry-table combinations, and a true negative rate of 89%, which is the ratio between the number of correctly predicted collision-free combinations and the number of all measured collision-free combinations. A collision prediction tool is successfully created and able to produce maps of collision-free zones and to test treatment plans for collisions including visualisation of the gantry and table movement.

The Antiviral Potential of Algal Lectins.

Algae have emerged as fascinating subjects of study due to their vast potential as sources of valuable metabolites with diverse biotechnological applications, including their use as fertilizers, feed, food, and even pharmaceutical precursors. Among the numerous compounds found in algae, lectins have garnered special attention for their unique structures and carbohydrate specificities, distinguishing them from lectins derived from other sources. Here, a comprehensive overview of the latest scientific and technological advancements in the realm of algal lectins with a particular focus on their antiviral properties is provided. These lectins have displayed remarkable effectiveness against a wide range of viruses, thereby holding great promise for various antiviral applications. It is worth noting that several alga species have already been successfully commercialized for their antiviral potential. However, the discovery of a diverse array of lectins with potent antiviral capabilities suggests that the field holds immense untapped potential for further expansion. In conclusion, algae stand as a valuable and versatile resource, and their lectins offer an exciting avenue for developing novel antiviral agents, which may lead to the development of cutting-edge antiviral therapies.

FoxO3 Modulates Circadian Rhythms in Neural Stem Cells.

Both FoxO transcription factors and the circadian clock act on the interface of metabolism and cell cycle regulation and are important regulators of cellular stress and stem cell homeostasis. Importantly, FoxO3 preserves the adult neural stem cell population by regulating cell cycle and cellular metabolism and has been shown to regulate circadian rhythms in the liver. However, whether FoxO3 is a regulator of circadian rhythms in neural stem cells remains unknown. Here, we show that loss of FoxO3 disrupts circadian rhythmicity in cultures of neural stem cells, an effect that is mediated via regulation of Clock transcriptional levels. Using Rev-Erbα-VNP as a reporter, we then demonstrate that loss of FoxO3 does not disrupt circadian rhythmicity at the single cell level. A meta-analysis of published data revealed dynamic co-occupancy of multiple circadian clock components within FoxO3 regulatory regions, indicating that FoxO3 is a Clock-controlled gene. Finally, we examined proliferation in the hippocampus of FoxO3-deficient mice and found that loss of FoxO3 delayed the circadian phase of hippocampal proliferation, indicating that FoxO3 regulates correct timing of NSC proliferation. Taken together, our data suggest that FoxO3 is an integral part of circadian regulation of neural stem cell homeostasis.

Impact of the gradient in gantry-table rotation on dynamic trajectory radiotherapy plan quality.

BACKGROUND: To improve organ at risk (OAR) sparing, dynamic trajectory radiotherapy (DTRT) extends VMAT by dynamic table and collimator rotation during beam-on. However, comprehensive investigations regarding the impact of the gantry-table (GT) rotation gradient on the DTRT plan quality have not been conducted. PURPOSE: To investigate the impact of a user-defined GT rotation gradient on plan quality of DTRT plans in terms of dosimetric plan quality, dosimetric robustness, deliverability, and delivery time. METHODS: The dynamic trajectories of DTRT are described by GT and gantry-collimator paths. The GT path is determined by minimizing the overlap of OARs with planning target volume (PTV). This approach is extended to consider a GT rotation gradient by means of a maximum gradient of the path ( G m a x ${G}_{max}$ ) between two adjacent control points ( G = | Δ table angle / Δ gantry angle | $G = | \Delta {{\mathrm{table\ angle}}/\Delta {\mathrm{gantry\ angle}}} |$ ) and maximum absolute change of G ( Δ G m a x ${{\Delta}}{G}_{max}$ ). Four DTRT plans are created with different maximum G&∆G: G m a x ${G}_{max}$ & Δ G m a x ${{\Delta}}{G}_{max}$  = 0.5&0.125 (DTRT-1), 1&0.125 (DTRT-2), 3&0.125 (DTRT-3) and 3&1|(DTRT-4), including 3-4 dynamic trajectories, for three clinically motivated cases in the head and neck and brain region (A, B, and C). A reference VMAT plan for each case is created. For all plans, plan quality is assessed and compared. Dosimetric plan quality is evaluated by target coverage, conformity, and OAR sparing. Dosimetric robustness is evaluated against systematic and random patient-setup uncertainties between ± 3 mm $ \pm 3\ {\mathrm{mm}}$ in the lateral, longitudinal, and vertical directions, and machine uncertainties between ± 4 ∘ $ \pm 4^\circ \ $ in the dynamically rotating machine components (gantry, table, collimator rotation). Delivery time is recorded. Deliverability and delivery accuracy on a TrueBeam are assessed by logfile analysis for all plans and additionally verified by film measurements for one case. All dose calculations are Monte Carlo based. RESULTS: The extension of the DTRT planning process with user-defined G m a x & Δ G m a x ${G}_{max}\& {{\Delta}}{G}_{max}$ to investigate the impact of the GT rotation gradient on plan quality is successfully demonstrated. With increasing G m a x & Δ G m a x ${G}_{max}\& {{\Delta}}{G}_{max}$ , slight (case C, D m e a n , p a r o t i d l . ${D}_{mean,\ parotid\ l.}$ : up to|-1|Gy) and substantial (case A, D 0.03 c m 3 , o p t i c n e r v e r . ${D}_{0.03c{m}^3,\ optic\ nerve\ r.}$ : up to -9.3 Gy, case|B, D m e a n , b r a i n $\ {D}_{mean,\ brain}$ : up to -4.7|Gy) improvements in OAR sparing are observed compared to VMAT, while maintaining similar target coverage. All plans are delivered on the TrueBeam. Expected and actual machine position values recorded in the logfiles deviated by <0.2° for gantry, table and collimator rotation. The film measurements agreed by >96% (2%|global/2 mm Gamma passing rate) with the dose calculation. With increasing G m a x & Δ G m a x ${G}_{max}\& {{\Delta}}{G}_{max}$ , delivery time is prolonged by <2 min/trajectory (DTRT-4) compared to VMAT and DTRT-1. The DTRT plans for case A and B and the VMAT plan for case C plan reveal the best dosimetric robustness for the considered uncertainties. CONCLUSION: The impact of the GT rotation gradient on DTRT plan quality is comprehensively investigated for three cases in the head and neck and brain region. Increasing freedom in this gradient improves dosimetric plan quality at the cost of increased delivery time for the investigated cases. No clear dependency of GT rotation gradient on dosimetric robustness is observed.

Structural and functional impairments of skeletal muscle in patients with postacute sequelae of SARS-CoV-2 infection.

Following acute coronavirus disease 2019 (COVID-19), a substantial proportion of patients showed symptoms and sequelae for several months, namely the postacute sequelae of COVID-19 (PASC) syndrome. Major phenomena are exercise intolerance, muscle weakness, and fatigue. We aimed to investigate the physiopathology of exercise intolerance in patients with PASC syndrome by structural and functional analyses of skeletal muscle. At least 3 mo after infection, nonhospitalized patients with PASC (n = 11, age: 54 ± 11 yr; PASC) and patients without long-term symptoms (n = 12, age: 49 ± 9 yr; CTRL) visited the laboratory on four nonconsecutive days. Spirometry, lung diffusion capacity, and quality of life were assessed at rest. A cardiopulmonary incremental exercise test was performed. Oxygen consumption (V̇o2) kinetics were determined by moderate-intensity exercises. Muscle oxidative capacity (k) was assessed by near-infrared spectroscopy. Histochemical analysis, O2 flux (JO2) by high-resolution respirometry, and quantification of key molecular markers of mitochondrial biogenesis and dynamics were performed in vastus lateralis biopsies. Pulmonary and cardiac functions were within normal range in all patients. V̇o2peak was lower in PASC than CTRL (24.7 ± 5.0 vs. 32.9 ± 7.4 mL·min-1·kg-1, respectively, P < 0.05). V̇o2 kinetics was slower in PASC than CTRL (41 ± 12 vs. 30 ± 9 s-1, P < 0.05). k was lower in PASC than CTRL (1.54 ± 0.49 vs. 2.07 ± 0.51 min-1, P < 0.05). Citrate synthase, peroxisome proliferator-activated receptor-γ coactivator (PGC)1α, and JO2 for mitochondrial complex II were significantly lower in PASC vs. CTRL (all P values <0.05). In our cohort of patients with PASC, we showed limited exercise tolerance mainly due to "peripheral" determinants. Substantial reductions were observed for biomarkers of mitochondrial function, content, and biogenesis. PASC syndrome, therefore, appears to negatively impact skeletal muscle function, although the disease is a heterogeneous condition.NEW & NOTEWORTHY Several months after mild acute SARS-CoV-2 infection, a substantial proportion of patients present persisting, and often debilitating, symptoms and sequelae. These patients show reduced quality of life due to exercise intolerance, muscle weakness, and fatigue. The present study supports the hypothesis that "peripheral" impairments at skeletal muscle level, namely, reduced mitochondrial function and markers of mitochondrial biogenesis, are major determinants of exercise intolerance and fatigue, "central" phenomena at respiratory, and cardiac level being less relevant.