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α-synuclein aggregation is implicated in a variety of diseases including Parkinson’s disease, dementia with Lewy bodies, pure autonomic failure and multiple system atrophy. The association of protein aggregates made of a single protein with a variety of clinical phenotypes has been explained for prion diseases by the existence of different strains that propagate through the infection pathway. Here we structurally and functionally characterize two polymorphs of α-synuclein. We present evidence that the two forms indeed fulfil the molecular criteria to be identified as two strains of α-synuclein. Specifically, we show that the two strains have different structures, levels of toxicity, and in vitro and in vivo seeding and propagation properties. Such strain differences may account for differences in disease progression in different individuals/cell types and/or types of synucleinopathies. α-synuclein is implicated in neurodegenerative diseases. Bousset et al . generate two α-synuclein polymorphs and find differences in aggregation, function and toxicity, suggesting that these altered properties may be the cause for differences in disease progression.

Background: Fractional ablative and non-ablative lasers are useful treatments for skin rejuvenation. A procedure that provides the sequential application of fractional ablative followed by non-ablative laser treatment may reduce patients’ downtime and deliver better cosmetic results than with either laser alone. Objective: The purpose of the current study was to demonstrate the ameliorative and therapeutic effects in skin remodeling of the synergistic use of the two laser wavelengths (fractional ablative CO2 and non-ablative 1540 nm) with three different types of pulse shapes, S-Pulse (SP), D-Pulse (DP) and H-Pulse (HP), through which the CO2 laser can emit, performing an ex vivo histological evaluation. Methods: In this prospective study, ex vivo sheep inner thigh skin was chosen due to its similarity to human skin tissue, and a histological evaluation was performed. Three irradiation conditions, using all of the three CO2 pulse shapes (alone or averaged), were investigated: (1) 10.600 nm alone, the sequential irradiation of the two wavelengths in the same perfectly controlled energy pulses (DOT) for the entire scan area; ((2) 10.600 nm followed immediately by 1540 nm; and (3) 1540 nm followed immediately by 10.600 nm). Results: When comparing ablative to sequential irradiations, the synergy of the two wavelengths did not alter the typical ablative pulse shape of the 10.600 nm laser alone. With the same CO2 pulse shape, the lesion depth did not vary with the synergy of the two wavelengths, while thermal lesion width increased compared to CO2 alone. The ablation rate was achieved, while the total thermal lesion coverage in the scanning area of CO2 − 1540 lasers was greater than when using CO2 alone and then the other sequential irradiation. Conclusions: This study provides important preclinical data for new and early uses of the novel 10.600/1540 nm dual-wavelength non-ablative fractional laser. The synergy of the two wavelengths enhanced all the benefits already available when using CO2 laser systems both in terms of tone strengthening, thanks to a greater shrinking effect, and in terms of stimulation and collagen remodeling thanks to a greater volumetric thermal effect.

Background and Objectives: For many years, fully ablative laser treatments, particularly those performed with a carbon dioxide (CO2) laser, were regarded as the gold standard for resurfacing. This study’s goal is to assess the depth that can be reached by a new CO2 scanner system, through a skin model with greater dermal thickness, to use in the treatment of deep scarring. Materials and Methods: Male human skin tissue was laser-treated using a CO2 fractional laser and a new scanning system, and all samples were fixed in 10% neutral buffered formalin, dehydrated using a series of crescent alcohol, embedded in paraffin, sectioned in series (4–5 µm thick), stained with haematoxylin and eosin (H&E), and then analysed under an optical microscope. Results: From the epidermis through the underlying papillary and reticular dermis to various depths of the dermis, microablation columns of damage and coagulated microcolumns of collagen were observed. The reticular dermis was fully penetrated up to 6 mm at higher energy levels (210 mJ/DOT), resulting in deeper tissue injury. Although the laser might penetrate further, the skin stops there, leaving just the fat and muscular tissue. Conclusions: The deep layers of the dermis can be penetrated by the CO2 laser system throughout the entire dermal thickness when using the new scanning system, suggesting that this laser’s potential impact, at the selected settings, covers all skin targets required to perform superficial or deep treatments on any dermatological issue. Finally, patients who have problems, such as morbid scar-deep complications, which affect their quality of life, are more likely to profit from this innovative technique.

Protein aggregation in biotherapeutics can reduce their activity and effectiveness. It may also promote immune reactions responsible for severe adverse effects. The impact of plastic materials on protein destabilization is not totally understood. Here, we propose to deconvolve the effects of material surface, air/liquid interface, and agitation to decipher their respective role in protein destabilization and aggregation. We analyzed the effect of polypropylene, TEFLON, glass and LOBIND surfaces on the stability of purified proteins (bovine serum albumin, hemoglobin and α-synuclein) and on a cell extract composed of 6000 soluble proteins during agitation ( P = 0.1–1.2 W/kg). Proteomic analysis revealed that chaperonins, intrinsically disordered proteins and ribosomes were more sensitive to the combined effects of material surfaces and agitation while small metabolic oligomers could be protected in the same conditions. Protein loss observations coupled to Raman microscopy, dynamic light scattering and proteomic allowed us to propose a mechanistic model of protein destabilization by plastics. Our results suggest that protein loss is not primarily due to the nucleation of small aggregates in solution, but to the destabilization of proteins exposed to material surfaces and their subsequent aggregation at the sheared air/liquid interface, an effect that cannot be prevented by using LOBIND tubes. A guidance can be established on how to minimize these adverse effects. Remove one of the components of this combined stress - material, air (even partially), or agitation - and proteins will be preserved.

Birt-Hogg-Dubé syndrome (BHD) can cause benign skin lesions such as fibrofolliculomas, as well as systemic manifestations including pulmonary cysts, kidney tumors, and recurrent pneumothoraces. We report the successful treatment of fibrofolliculomas in a patient with BHDs using a combination of fractionated ablative CO2 laser and a flash lamp pulsed dye laser (FPDL). This combined method improves the CO2 healing process’s functional and cosmetic results; the first wavelength (ablative) has a greater capacity for excision and tissue regeneration, while the second (non-ablative) provides more control over the tissue healing process. The lesions were ablated up to the papillary dermis without enhancing the overall textural appearance. Therefore, deeper laser ablations may be able to stop dermal residual lesion relapses. In conclusion, fractionated CO2 laser and FPDL can be used safely and effectively to reduce the appearance of facial hamartomas related to BHDs.

Background: Dermal fillers for soft tissue for the treatment of face sagging, volume loss, and wrinkles have become popular among patients of all ages and ethnicities, and their use is becoming increasingly widespread. Aim: the goal of this study was to evaluate the effectiveness and safety of a micro-pulsed, 1444 nm Nd:YAG laser on dermal filler complications, in particular on granuloma management. Methods: A subcutaneous, 1444 nm Nd:YAG laser was used on five female patients (range age 52–68 years) with hyaluronic filler granulomas located on the face (two on the cheek area and three on the lips); three patients had self-injected the filler, buying it online. Before and after the therapy, the patients received a skin ultrasound to determine the form and location of the granulomas and to determine if there had been a full or partial resolution. During this study, all possible adverse effects at the treatment site were monitored. The 5-point Global Aesthetic Improvement Scale (GAIS) (0 point—no change; 1 point—25%, mild improvement; 2 points—50%, moderate improvement; 3 points—75%, good improvement; 4 points—100%, excellent improvement) was recorded at a 3-month follow-up. Results: good results were obtained in the treatment of filler granulomas with the intralesional 1444 nm laser, even if just a single treatment was performed (one intervention was effective for curing granulomas up to 5 mm in diameter). Three patients were satisfied with excellent improvement, and two patients experienced good improvement. The results are functional and aesthetically satisfying, as shown by photographic assessment. At the last follow-up, the granuloma had reduced or completely disappeared in all cases, and no infections, burns, scarring or fibrosis, episodes of severe bleeding, or other serious adverse effects had been reported. All subjects tolerated the post-treatment period well. Conclusions: Our findings showed that granuloma treatment with an intralesional 1444 nm Nd:YAG laser is a minimally invasive, easy, fast, efficient, and low-risk procedure.

Background: Classic Kaposi’s sarcoma (CKS) is distinguished by nodules and clustered papules over the extremities with persistent edema. Aim: This report examine the results of neodymium‐doped yttrium‐aluminum‐garnet (Nd:YAG) laser for the treatment of numerous nodular symptomatic nodules in CKS patients’ lower extremities that are ineligible for systemic therapy. Methods: Each lesion received two sessions Nd:YAG laser treatment performed at 1‐month intervals. Pretreatment and follow‐up visit (after 3 months) were accompanied by clinical photographs and improvement was assessed by a skilled medical professional by comparing before‐ and after‐treatment photos as well as by looking at patients directly. Videodermoscopy was performed on all lesions. Results : Just one session with long‐pulsed Nd:YAG laser proved to be successful, with the immediate coagulation of the lesions and the disappearance of most of them. Every single lesion healed in two to 4 weeks. Only one lesion, the largest one, presented a water blister after treatment, which resolved within a few days. At 2 months follow up, the patient reported total pain relief and full recovery after the symptomatic nodules vanished. Conclusion: Nd:YAG laser could represent a rapid and advantageous therapeutic approach for both early‐ and advanced‐stage CKS patients.

Background/Objectives: The role of α-synuclein (α-syn) in the pathogenesis of Parkinson’s disease (PD) or neurodegenerative diseases such as Lewy body dementia (LBD) and multiple system atrophy (MSA) is commonly accepted. Through different physiological dysfunctions, abnormal forms of α-syn are generated. These abnormal aggregates accumulate and alter pre- and postsynaptic transmission, in particular that of dopamine. Thus, the development of a diagnostic biomarker of synucleinopathies remains crucial and challenging. The development of an α-syn positron emission tomography (PET) radiopharmaceutical may be suitable to early diagnose and stratify patients, follow up disease progression, and evaluate future therapies. Methods: To develop a selective α-syn PET tracer, we synthesized an original series based on alkynyl(aza)indoles. Fifteen final ligands were synthesized bearing indoles or azaindoles from one side of the alkyne and a substituted phenyl ring for the opposite side of the alkyne. The final ligands were tested to determine Ki and/or Kd toward α-syn, tau, and Aβ. Results: The SAR showed that the indole series exhibited moderate to low affinity for α-syn and, moreover, lower Ki toward Aβ and tau (i.e., compound 39, Ki(αsyn) 21.7 nM, Ki(Aβ) 64.4 nM, Ki(Tau) 27.6 nM), highlighting the low potency of these series to afford an α-syn tracer. The introduction of a nitrogen on the different positions of the phenyl to obtain the corresponding azaindoles resulted for most of the compounds in better affinity for α-syn and selectivity towards Aβ compared to the indole analogs (i.e., compound 43, Ki(αsyn) 4.7 nM, Ki(Aβ) 24.4 nM, and Ki(Tau) 4.61 nM). A fluorinated azaindole derivative was prepared with a view to obtaining a 18F tracer and exhibited the highest affinity for α-syn but without selectivity against tau and Aβ. The radiosynthesis of [18F]45 was performed in a two-step procedure starting from the tosylated and protected precursor. [18F]45 was obtained in 85 ± 5 min with a radiochemical yield of 32 ± 3%. Molar activity, determined from a calibration with stable 45, was around 130 GBq/µmole. The dynamic PET imaging showed that [18F]45 was able to cross the blood–brain barrier, but non-specific uptake was observed, confirming the in vitro results. Conclusions: Although promising nanomolar affinity for the target, the new tracer showed mainly non-specific in vivo uptake in the rat brain, indicating that further pharmacomodulations on the azaindole series are required.

CD117 (or c‐kit) is expressed by the interstitial cells of Cajal (ICC), which are located within the gastrointestinal (GI) muscle coat and directly involved in its motility. CD34 is expressed by several cell types some of which have features and location resembling the ICC; however, a sure identification of these cells is still lacking. In order to establish whether the CD34‐positive cells of the human GI tract are to be considered as ICC subpopulation or a novel independent cell type, and to hypothesize their nature and role, we verified CD34 and CD117 receptor expression under light and fluorescence microscope and performed a routine and a CD34‐immuno‐electron microscopy. CD34‐positive cells were seen in the entire human GI tract. In the muscularis propria, shared morphologies similar to the c‐kit‐positive cells, in the submucosa, resembled fibroblasts. Their ultrastructure resembled that of the fibrocytes/fibroblasts and of the interstitial Cajal‐like cells (ICLC). Double labelling and immunoelectro‐microscopy demonstrated that they are unequivocally different to the ICC and, due to the similarities with the ICLC, we identified them as ICLC. The novelty of these results is that two types of interstitial cells are present in the GI muscle coat of humans: the ICC and the ICLC. We hypothesize a mechanical role for the septal ICLC, those at the myenteric plexus level and those bordering the muscle layers; a helping role in neurotransmission is proposed for the ICLC intercalated with the intramuscular ICC, possibly in spreading the slow waves generated by the ICC. Furthermore, the possibility that the ICLC represent the adult mesenchymal stromal cells able to guarantee the ICC renewal deserves to be considered.

Background/Objectives: Many lasers applied in skin rejuvenation protocols show emissions with wavelengths falling in the red or near-infrared (NIR) bands. To obtain further in vitro data on the potential therapeutic benefits regarding rejuvenation, we employed a 675 nm laser wavelength on cultured human dermal fibroblasts to understand the mechanisms involved in the skin rejuvenation process’s signaling pathways by analyzing cytoskeletal proteins, extracellular matrix (ECM) components, and membrane integrins. Methods: Normal human dermal fibroblasts (NHDFs) were irradiated with a 675 nm laser 24 h after seeding, and immunofluorescence microscopy and Western blotting were applied. Results: The results demonstrate that the laser treatment induces significant changes in human dermal fibroblasts, affecting cytoskeleton organization and the production and reorganization of ECM molecules. The cell response to the treatment appears to predominantly involve paxillin-mediated signaling pathways. Conclusions: These changes suggest that laser treatment can potentially improve the structure and function of skin tissue, with interesting implications for treating skin aging.