Pharmacological inhibition of α-synuclein aggregation within liquid condensates.

Aggregated forms of α-synuclein constitute the major component of Lewy bodies, the proteinaceous aggregates characteristic of Parkinson's disease. Emerging evidence suggests that α-synuclein aggregation may occur within liquid condensates formed through phase separation. This mechanism of aggregation creates new challenges and opportunities for drug discovery for Parkinson's disease, which is otherwise still incurable. Here we show that the condensation-driven aggregation pathway of α-synuclein can be inhibited using small molecules. We report that the aminosterol claramine stabilizes α-synuclein condensates and inhibits α-synuclein aggregation within the condensates both in vitro and in a Caenorhabditis elegans model of Parkinson's disease. By using a chemical kinetics approach, we show that the mechanism of action of claramine is to inhibit primary nucleation within the condensates. These results illustrate a possible therapeutic route based on the inhibition of protein aggregation within condensates, a phenomenon likely to be relevant in other neurodegenerative disorders.

Intrinsically disordered proteins: modes of binding with emphasis on disordered domains.

Our notions of protein function have long been determined by the protein structure-function paradigm. However, the idea that protein function is dictated by a prerequisite complementarity of shapes at the binding interface is becoming increasingly challenged. Interactions involving intrinsically disordered proteins (IDPs) have indicated a significant degree of disorder present in the bound state, ranging from static disorder to complete disorder, termed 'random fuzziness'. This review assesses the anatomy of an IDP and relates how its intrinsic properties permit promiscuity and allow for the various modes of interaction. Furthermore, a mechanistic overview of the types of disordered domains is detailed, while also relating to a recent example and the kinetic and thermodynamic principles governing its formation.

Natural Carbon By-Products for Transparent Heaters: The Case of Steam-Cracker Tar.

Steam-cracker tar (SCT) is a by-product of ethylene production that is in massive quantities globally (>150 × 106 tons per year). With few useful applications, the production of unwanted SCT leads to the need for its costly disposal or burning at the boiler plant. The discovery of new uses for SCT would therefore bring both economic and environmental benefits, although, to date, efforts toward employing SCT in diverse applications have been limited, and progress is further hampered by a lack of understanding of the material itself. Although complex and highly heterogeneous in nature, the molecular composition of SCT has the potential to serve as a diverse and tunable feedstock for wide-ranging applications. Here, a simple solution-processing method for SCT that allows its conductivity and optical properties to be controlled over orders of magnitude is reported. Here, by way of example, the focus is on the production of transparent conductive thin films, which exhibit a wide range of transparencies (23-93%) and sheet resistances (2.5 Ω â–¡-1 to 1.2 kΩ â–¡-1 ) that are tuned by a combination of solution concentration and thermal annealing. As transparent Joule heaters, even without optimization, these SCT devices show competitive performance compared to established technologies such as those based on reduced graphene oxide, and surpass the temperature stability limit of other materials. Furthermore, it is demonstrated that laser annealing can be used to process the SCT films and directly pattern transparent heaters on an arbitrary substrate. These results highlight the potential of SCT as a feedstock material for electronic applications and suggest that broader classes of either naturally occurring carbon or produced carbonaceous by-products could prove useful in a range of applications.

Origins of the Stokes Shift in PbS Quantum Dots: Impact of Polydispersity, Ligands, and Defects.

Understanding the origins of the excessive Stokes shift in the lead chalcogenides family of colloidal quantum dots (CQDs) is of great importance at both the fundamental and applied levels; however, our current understanding is far from satisfactory. Here, utilizing a combination of ab initio computations and UV-vis and photoluminescence measurements, we investigated the contributions to the Stokes shift from polydispersity, ligands, and defects in PbS CQDs. The key results are as follows: (1) The size and energetic disorder of a polydisperse CQD film increase the Stokes shift by 20 to 50 meV compared to that of an isolated CQD; (2) Franck-Condon (FC) shifts increase as the electronegativities of the ligands increase, but the variations are small (<15 meV). (3) Unlike the aforementioned two minor factors, the presence of certain intrinsic defects such as VCl+ (in Cl-passivated CQDs) can cause substantial electron density localization of the band edge states and consequent large FC shifts (100s of meV). This effect arising from defects can explain the excessive Stokes shifts in PbS CQDs and improve our understanding of the optical properties of PbS CQDs.

Intra-operative ultrasound versus wire-guided localization in the surgical management of non-palpable breast cancer.

BACKGROUND: Non-palpable breast lesions require some method of localization when performing breast conserving surgery (BCS). Despite the advent of newer techniques, ultrasound (US) and wire-guided localization (WGL) remain the most popular approaches. OBJECTIVE: We aim to compare the positive margin rate of US versus WGL in the excision of breast lesions. METHODS: Data were collected from the Clinical Access Portal. All patients who underwent US or WGL BCS were identified and consecutive data collected. Positive margins were evaluated using histopathology reports. Baseline demographics and specimen size data were also collected. RESULTS: A total of 198 patients were included in total over a three-year period. There was some evidence of an association of type of surgery with positive margin (OR=2.11, p=0.075) where a 2.11 fold increase in the odds of a positive margin was estimated for the US method relative to WGL, but this was not statistically significant at the 5% level. This effect decreased after adjusting for potential confounders (OR=1.81, p=0.34). CONCLUSIONS: This retrospective study of US versus WGL in BCS demonstrated no significant difference in the positive margin rate, although a trend was observed in favor of the WGL group. We have provided further evidence for the debate on the accuracy of US and WGL for non-palpable breast lesions. Available data remains sparse, and our results contradict the findings of other comparative studies.

Sham feeding with chewing gum after elective colorectal resectional surgery: a randomized clinical trial.

OBJECTIVE: To determine whether sham feeding with chewing gum improved gastrointestinal recovery after colorectal resection surgery, in the presence of routine postoperative feeding. BACKGROUND: Sham feeding with chewing gum has been shown to accelerate the return of gut function after colorectal surgery. This study sought to determine whether sham feeding with gum, after colorectal resection, accelerates return of gastrointestinal function in patients on a rapid feeding enhanced recovery program. METHODS: A randomized "two armed" controlled clinical trial was performed. Equal groups of open and laparoscopic colorectal resection surgical patients were recruited. Patients in the intervention arm received chewing gum 4 times a day postoperatively. All patients in the trial were placed on an established, standardized Enhanced Recovery After Surgery program. The primary outcome was time to return of gut function, assessed by time to flatus and first bowel motion. Secondary outcomes were time to tolerate diet, symptoms of ileus in the form of nausea, vomiting and distension, pain as assessed by analgesic consumption and visual analogue scales, complications, and length of hospital stay. RESULTS: A total of 161 patients were recruited. Postoperative morbidity was equivalent between groups, with no complications related to gum chewing. There was no difference between groups with respect to the primary outcomes of time to flatus and bowel motion. There was less perception of pain in the intervention group on days 2 to 5, and no difference with respect to all other secondary outcomes. CONCLUSIONS: Sham feeding with gum, after open and laparoscopic colorectal resectional surgery is safe, but does not hasten the return of gastrointestinal function in patients who receive accelerated postoperative feeding. (ACTRN12607000538448).

Reactions to tetanus toxoid.

In a factory population the occurrence of reactions to tetanus toxoid was recorded after 6740 injections. The incidence of general reactions was 0.3% and of local reactions 2.6%. The local reaction rate to the first injection of the basic immunization course was 0.9%, to the second injection 2.7%, and to the third injection 7.4%. To booster injections the rate was 1.6%. The local reaction rate was appreciably higher in women than in men - 14.4% and 5.7% respectively in the case of the third injection - and the incidence among women increased with age.Tetanus vaccine containing 10 Lf of toxoid caused fewer reactions than one containing 20 Lf, but a reduction in the content of aluminium adjuvant did not affect the reaction rate.Almost all reactors were found to have a satisfactory serum antitoxin concentration at the time of the reaction or developed a satisfactory immunity within 1-6 months.Skin tests were made in 32 hypersensitive patients. Neither the diluent, thiomersal preservative, nor the culture medium appeared to be responsible for hypersensitivity. The degree of hypersensitivity elicited by a special highly purified toxoid was only very slightly less than that elicited by the commercially pure toxoid. It is suggested that reactions are largely due to the toxoid antigen itself rather than to impurities or other components of the vaccine.