•Biological specimens introduce wavefront aberrations and deteriorate the image quality of optical microscopy.•Adaptive optics is used in optical microscopy to recover ideal imaging ...performance.•Adaptive optical imaging improves structural imaging of neurons, allowing for synaptic-level resolution at depth.•Adaptive optical imaging leads to a more accurate characterization of the functional properties of neurons.
With the ability to correct for the aberrations introduced by biological specimens, adaptive optics—a method originally developed for astronomical telescopes—has been applied to optical microscopy to recover diffraction-limited imaging performance deep within living tissue. In particular, this technology has been used to improve image quality and provide a more accurate characterization of both structure and function of neurons in a variety of living organisms. Among its many highlights, adaptive optical microscopy has made it possible to image large volumes with diffraction-limited resolution in zebrafish larval brains, to resolve dendritic spines over 600μm deep in the mouse brain, and to more accurately characterize the orientation tuning properties of thalamic boutons in the primary visual cortex of awake mice.
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► Survey creative pathways to improve metal-binding agents according to the multifunctional concept. ► Tuning a basic scaffold with binding properties to coordinate metal ions and ...comprises other functionalities. ► Classification according to common molecular structures.
Metal-ion homeostasis in the brain is critical for many physiological functions, particularly in the central nervous system where metals are essential in complex signaling pathways. Most common neurological diseases such as Alzheimer's (AD), Parkinson's (PD) and prion diseases, despite having distinct etiological bases, share similarities associated with metalloprotein misfolding and aggregation. In the last few years, several studies have provided evidence that abnormal concentrations of Cu(II), Zn(II) and/or Fe(III) specifically impair protein deposition and/or cause oxidative damage. This apparently critical role played by metal imbalance makes chelation therapy an attractive and challenging strategy to alleviate the development and progression of neurological disorders. Due to the multiple factors closely involved in the pathogenesis of these diseases, the classic drug discovery paradigm of “one molecule, one target” is limited in its ability to combat such complex diseases. Therefore, significant effort has been devoted to designing multifunctional metal-chelators aiming at multiple targets that must be addressed in these neurodegenerative diseases. In this review, the state-of-the-art in this latest strategy for designing metal-ion chelators as potential therapeutic agents in neurodegenerative diseases will be discussed, with special emphasis on AD and additional coverage of PD and prion diseases.
Targeted alpha‐therapy (TAT) has great potential for treating a broad range of late‐stage cancers by delivering a focused and lethal radiation dose to tumors. Actinium‐225 (225Ac) is an emerging ...alpha emitter suitable for TAT; however, the availability of chelators for Ac remains limited to a small number of examples (DOTA and macropa). Herein, we report a new Ac macrocyclic chelator named ‘crown’, which binds quantitatively and rapidly (<10 min) to Ac at ambient temperature. We synthesized 225Ac‐crown‐αMSH, a peptide targeting the melanocortin 1 receptor (MC1R), specifically expressed in primary and metastatic melanoma. Biodistribution of 225Ac‐crown‐αMSH showed favorable tumor‐to‐background ratios at 2 h post injection in a preclinical model. In addition, we demonstrated dramatically different biodistrubution patterns of 225Ac‐crown‐αMSH when subjected to different latency times before injection. A combined quality control methodology involving HPLC, gamma spectroscopy and radioTLC is recommended.
225Ac is an emerging and powerful radioisotope for late‐stage cancer therapy. Herein, we report a new actinium‐225 chelator, ‘crown’ and the synthesis and in vivo evaluation of a melanoma targeting peptide 225Ac‐crown‐αMSH. Expanded quality control requirements are also discussed (see figure).
The accountable bureaucrat Bernstein, Anya; Rodríguez, Cristina
The Yale law journal,
04/2023, Letnik:
132, Številka:
6
Journal Article
Common wisdom has it that bureaucrats are unaccountable to the people they regulate and must therefore be closely supervised by elected officials or (perhaps ironically) the federal courts. For many ...detractors of the administrative state, as well as many proponents, agency accountability hangs on the concentrated power of the President in particular. This article presents a different vision. Drawing on in-depth interviews with officials from numerous agencies, we show that everyday administrative practices and relationships themselves support accountability of a kind that neither elections nor judicial review alone can achieve. Our interviews reveal that agency officials work within structures that promote the very values accountability is supposed to serve: deliberation, inclusivity, and responsiveness. Three primary features of the administrative state support this vision of accountability. First, political appointees and career civil servants, often presented as adversaries, actually represent complementary decision- making modalities. Appointees do not impose direct presidential control but imbue agencies with a diffuse, differentiated sense of abstract political values and policy priorities tied to the electoral and civil-society coalitions that support the administration in power. Civil servants use expertise and experience to set the parameters within which decisions can be made. Combining these different but interdependent approaches to policy-making promotes deliberation informed by public opinion and the public interest. Second, agencies work through what we refer to as a decision-making web, which facilitates continual justification and negotiation among officials with different roles inside the state. This claim stands in stark contrast to the strict hierarchy often attributed to government bureaucracy. We show how the principal-agent model gives way, more often than not, to the dispersion of decision-making power, which promotes the pluralistic inclusivity of views in a way hierarchical decision-making does not. Finally, numerous practices connect agencies directly and pervasively to the people and situations they regulate. Those required by law, like notice-and-comment rulemaking, are supplemented by varied other means by which agencies respond and adapt to the views of affected publics and the realities of the regulated world. Our research provides crucial empirical evidence of how the everyday work of government gets done and gives the often-invoked notion of accountability some real content. It leads us to reject formalistic claims about what constitutes accountability in the abstract and to focus instead on the relationships, structures, and practices that actually promote accountability - features of the administrative state that help head off arbitrariness, incorporate multiple perspectives, and encourage negotiated, provisional outcomes. These resources for promoting republican democracy within the bureaucracy, however, are neither inherent nor eternal: they must be actively nourished. This article thus should change how we think about government accountability and inform how we structure our institutions to achieve it.
Progesterone use in assisted reproductive technology Labarta, Elena; Rodríguez, Cristina
Best practice & research. Clinical obstetrics & gynaecology,
November 2020, 2020-11-00, 20201101, Letnik:
69
Journal Article
Recenzirano
Progesterone is the main hormone in the luteal phase. It plays a key role in preparing the uterus for a possible pregnancy, and in maintaining it after it has occurred. In assisted reproduction ...treatments, there is usually a luteal phase deficiency, so it is necessary to supplement this critical phase to obtain the best results, not only of implantation but also of ongoing pregnancy. Among all the available options, exogenously administered progestogens are the most used, as they have proven their efficacy and safety. This review will address the most relevant aspects of luteal phase support with progesterone in the different scenarios an embryo transfer can be performed, such as the stimulated cycle, the artificial cycle, or the natural cycle. Although there is no evidence of the perfect protocol for all patients, recent studies point to the need of individualizing luteal phase support according to the needs of each patient.
•Progesterone treatment is recommended in ART cycles to enhance embryo implantation and decrease the risk of miscarriage.•In stimulated cycles, exogenous P is highly recommended and should be initiated the day after oocyte retrieval.•In artificial cycles, exogenous P is absolutely needed as no endogenous production of P is present.•In natural cycles, exogenous P might improve pregnancy outcomes.•Serum P levels in the mid-luteal phase relate to the chances of pregnancy. Thus, monitoring P levels and individualizing LPS is recommended.
Local as well as systemic therapy is often used to treat bacterial lung infections. Delivery of antibiotics to the vascular side of infected lung tissue using lung-targeting microspheres (MS) is a ...good alternative to conventional administration routes, allowing for localized high levels of antibiotics. This delivery route can also complement inhaled antibiotic therapy, especially in the case of compromised lung function. We prepared and characterized monodisperse poly(lactic-co-glycolic acid) (PLGA) MS loaded with levofloxacin using a flow-focusing glass microfluidic chip. In vitro characterization showed that the encapsulated LVX displayed a biphasic controlled release during 5 days and preserved its antibacterial activity. The MS degradation was investigated in vitro by cross-sectioning the MS using a focused ion beam scanning electron microscope and in vivo by histological examination of lung tissue from mice intravenously administered with the MS. The MS showed changes in the surface morphology and internal matrix, whereas the degradation in vivo was 3 times faster than that in vitro. No effect on the viability of endothelial and lung epithelial cells or hemolytic activity was observed. To evaluate the pharmacokinetics and biodistribution of the MS, complete quantitative imaging of the 111indium-labeled PLGA MS was performed in vivo with single-photon emission computed tomography imaging over 10 days. The PLGA MS distributed homogeneously in the lung capillaries. Overall, intravenous administration of 12 μm PLGA MS is suitable for passive lung targeting and pulmonary therapy.
Summary Background A subset of patients with metastatic renal-cell carcinoma show indolent growth of metastases. Because of the toxicity and non-curative nature of systemic therapy, some of these ...patients could benefit from initial active surveillance. We aimed to characterise the time to initiation of systemic therapy in patients with metastatic renal-cell carcinoma under active surveillance. Methods In this prospective phase 2 trial, we enrolled patients with treatment-naive, asymptomatic, metastatic renal-cell carcinoma from five hospitals in the USA, Spain, and the UK. Patients were radiographically assessed at baseline, every 3 months for year 1, every 4 months for year 2, then every 6 months thereafter. Patients continued on observation until initiation of systemic therapy for metastatic renal-cell carcinoma; a decision that was made at the discretion of the treating physician and patient. The primary endpoint of the study was time to initiation of systemic therapy in the per-protocol population. The follow-up of patients is ongoing. Findings Between Aug 21, 2008, and June 7, 2013, we enrolled 52 patients. Median follow-up of patients in the study was 38·1 months (IQR 29·4–48·9). In the 48 patients included in analysis, median time on surveillance from registration on study until initiation of systemic therapy was 14·9 months (95% CI 10·6–25·0). Multivariate analysis showed that higher numbers of International Metastatic Database Consortium (IMDC) adverse risk factors (p=0·0403) and higher numbers of metastatic disease sites (p=0·0414) were associated with a shorter surveillance period. 22 (46%) patients died during the study period, all from metastatic renal-cell carcinoma. Interpretation A subset of patients with metastatic renal-cell carcinoma can safely undergo surveillance before starting systemic therapy. Additional investigation is required to further define the benefits and risks of this approach. Funding None.
Three-photon fluorescence microscopy has emerged as one of the leading tools for deep tissue imaging in opaque biological specimens. A recent study by Hontani et al. demonstrated a new strategy for ...multicolor imaging deep in the mouse brain using a single excitation wavelength.
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