Click Synthesis of Tweezer Dyads for H-Bond Assisted Cooperativity in Tandem Uncaging Systems.

"Tandem" uncaging systems, in which a photolabile protecting group (PPG) is sensitized by an energy-harvesting antenna, may increase the photosensitivity of PPGs by several orders of magnitude for two-photon (2P) photorelease. Yet, they remain poorly accessible because of arduous multi-step synthesis. In this work, we design efficient tandem uncaging systems by (i) using a convenient assembly of the building blocks relying on click chemistry, (ii) H-bonding induced proximity thus facilitating (iii) photoinduced electron transfer (PeT) as a cooperative mechanism. A strong two-photon absorber electron-donating quadrupolar antenna and various electron-accepting PPGs (mDEAC, MNI or MDNI) were clicked stepwise onto a "tweezer-shaped" pyrido-2,6-dicarboxylate platform whose H-bonding and p-stacking abilities were exploited to keep the antenna and the PPGs in close proximity. The different electron acceptor ability of the PPGs led to dyads with wildly different behaviors. Whilst the MDNI and MNI dyads showed poor dark stability or no photo-uncaging ability due to their too high electron accepting character, the mDEAC dyad benefited from optimum redox potentials to promote PeT and slow down charge recombination, resulting in enhanced uncaging quantum yield (Fu=0.38) compared to mDEAC (Fu=0.014). The unique resulted in large 2P photo-sensitivity in the near-infrared window (240 GM at 710 nm).

Triphenylamine Sensitized 8-Dimethylaminoquinoline: An Efficient Two-Photon Caging Group for Intracellular Delivery.

Triphenylamine-sensitized 8-dimethylaminoquinoline (TAQ) probes showed fair two-photon absorption and fragmentation cross sections in releasing kainate and GABA ligands. The water-soluble PEG and TEG-analogs allowed cell internalization and efficient light-gated liberation of the rhodamine reporter under UV and two-photon (NIR) irradiation conditions.

Stealth Luminescent Organic Nanoparticles Made from Quadrupolar Dyes for Two-Photon Bioimaging: Effect of End-Groups and Core.

Molecular-based Fluorescent Organic Nanoparticles (FONs) are versatile light-emitting nano-tools whose properties can be rationally addressed by bottom-up molecular engineering. A challenging property to gain control over is the interaction of the FONs' surface with biological systems. Indeed, most types of nanoparticles tend to interact with biological membranes. To address this limitation, we recently reported on two-photon (2P) absorbing, red to near infrared (NIR) emitting quadrupolar extended dyes built from a benzothiadiazole core and diphenylamino endgroups that yield spontaneously stealth FONs. In this paper, we expand our understanding of the structure-property relationship between the dye structure and the FONs 2P absorption response, fluorescence and stealthiness by characterizing a dye-related series of FONs. We observe that increasing the strength of the donor end-groups or of the core acceptor in the quadrupolar (D-π-A-π-D) dye structure allows for the tuning of optical properties, notably red-shifting both the emission (from red to NIR) and 2P absorption spectra while inducing a decrease in their fluorescence quantum yield. Thanks to their strong 1P and 2P absorption, all FONs whose median size varies between 11 and 28 nm exhibit giant 1P (106 M-1.cm-1) and 2P (104 GM) brightness values. Interestingly, all FONs were found to be non-toxic, exhibit stealth behaviour, and show vanishing non-specific interactions with cell membranes. We postulate that the strong hydrophobic character and the rigidity of the FONs building blocks are crucial to controlling the stealth nano-bio interface.

Electron Kinetic Entropy across Quasi-Perpendicular Shocks.

We use Magnetospheric Multiscale (MMS) data to study electron kinetic entropy per particle Se across Earth's quasi-perpendicular bow shock. We have selected 22 shock crossings covering a wide range of shock conditions. Measured distribution functions are calibrated and corrected for spacecraft potential, secondary electron contamination, lack of measurements at the lowest energies and electron density measurements based on plasma frequency measurements. All crossings display an increase in electron kinetic entropy across the shock ΔSe being positive or zero within their error margin. There is a strong dependence of ΔSe on the change in electron temperature, ΔTe, and the upstream electron plasma beta, ße. Shocks with large ΔTe have large ΔSe. Shocks with smaller ße are associated with larger ΔSe. We use the values of ΔSe, ΔTe and density change Δne to determine the effective adiabatic index of electrons for each shock crossing. The average effective adiabatic index is ⟨γe⟩=1.64±0.07.

Behind the clock: elucidating factors contributing to longer clinic appointment duration and patient wait time.

BACKGROUND: Longer wait time in ambulatory clinics can disrupt schedules and decrease satisfaction. We investigated factors associated with patient wait time (WT, check-in to examination room placement), approximate clinician time (ACT, completion of nurse assessment to check-out), and total appointment length (TAL, check-in to check-out). METHODS: A single-institution retrospective study was conducted of breast surgery clinic patients, 2017-2019, using actual encounter times. A before/after analysis compared a five-day 8 hour/day (from a four-day 10 hour/day) advanced practice provider (APP) work-week. Non-parametric tests were used, and medians with interquartile ranges (IQRs) reported. RESULTS: 15,265 encounters were identified. Overall WT was 15.0 minutes (IQR:6.0-32.0), ACT 49.0 minutes (IQR:31.0-79.0) and TAL 84.0 minutes (IQR:57.0-124.0). Trainees were associated with 30.0 minutes longer ACT (p < 0.0001); this increased time was greatest for follow-up appointments, least for new patients. Patients arriving > 5 minutes late (versus on-time) experienced shorter WT (11.0 vs. 15.0 minutes, p < 0.0001) and ACT (43.0 vs. 53.0 minutes, p < 0.0001). Busier days (higher encounter volume:APP ratios) demonstrated increased encounter times. After transitioning to a five-day APP work-week, ACT decreased. CONCLUSIONS: High-volume clinics and trainee involvement prolong ambulatory encounters. Increasing APP assistance, altering work schedules, and assigning follow-up appointments to non-trainees may decrease encounter time.

Photophysics, Electrochemistry and Efficient Electrochemiluminescence of Trigonal Truxene-Core Dyes.

We synthesized and characterized a series of dyes built from a spirofluorene or truxene core. The quadrupolar spirofluorene system is the initial building unit for the design and preparation of more complex star-shaped dyes consisting of a truxene core bearing three di- or triphenylamine moieties with or without a thiophene connector. Their photophysical, electrochemical, and electrochemiluminescence (ECL) properties were first investigated in solution. Structure/activity relationships were derived and rationalized by comparing the quadrupolar system and trigonal truxene-core derivatives using computational studies. The photophysical and redox characteristics are drastically tuned by the introduction of a thiophene bridge and electron-donor substituents at their terminal branches. These comparative studies show the essential role of the stability of both radical cations and anions to obtain efficient ECL dyes. The stabilization of the radicals is directly related to the charge delocalization due to the π-conjugation by the thiophene bridge. The brightest ECL is achieved by annihilation and coreactant (benzoyl peroxide) pathways with the blue-emitting truxene dye, which is 2- and 4.5-times greater than that of the quadrupolar compound and reference [Ru(bpy)3 ]2+ emitter, respectively. Such an extensive study on these extended π-conjugated molecules presenting different core structures may guide the design and synthesis of new ECL dyes with a strong efficiency.

Harnessing Lysosomal pH through PLGA Nanoemulsion as a Treatment of Lysosomal-Related Neurodegenerative Diseases.

Most neurodegenerative disorders are characterized by deposits of misfolded proteins and neuronal degeneration in specific brain regions. Growing evidence indicates that lysosomal impairment plays a primary pathogenic role in these diseases, in particular, the occurrence of increased lysosomal pH. Thus, therapeutic development aiming at restoring lysosomal function represents a novel, precise, and promising strategy for the treatment of these pathologies. Herein we demonstrate that acidic oil-in-water nanoemulsions loaded with poly(dl-lactide- co-glycolide) (PLGA) are able to rescue impaired lysosomal pH in genetic cellular models of Parkinson's disease. For in vivo assays, nanoemulsions were labeled with an original synthetic hydrophobic far red-emitting dye to allow fluorescence monitoring. Following stereotaxic injection in the mouse brain, widespread diffusion of the nanocarrier was observed, up to 500 µm from the injection site, as well as internalization into the lysosomal compartment in brain cells. Finally, promising preliminary assays of systemic administration demonstrate that a fraction of the formulation crosses the blood brain barrier, penetrates the brain parenchyma, is internalized by cells, and colocalizes with lysosomal markers. Overall, these results suggest the feasibility and the therapeutic potential of this new nanoformulation as an effective drug delivery tool to the brain, with the potential to rescue pathological lysosomal deficits.

Bright Electrogenerated Chemiluminescence of a Bis-Donor Quadrupolar Spirofluorene Dye and Its Nanoparticles.

A series of symmetric fluorescent dyes built from a spirofluorene core bearing electroactive end groups and having different conjugated linkers were prepared with a view to their use as building blocks for the preparation of electrochemiluminescent (ECL) dyes and nanoparticles. Their electrochemical, spectroelectrochemical, and ECL properties were first investigated in solution, and structure/activity relationships were derived. The electrochemical and ECL properties show drastic variation that could be tuned by means of the nature of the π-conjugated system, the end groups, and the core. In this series, highly fluorescent dye 1 based on a spirofluorene core and triphenylamine end groups connected via thiophene moieties shows the most promising and intriguing properties. Dye 1 is reversibly oxidized in three well-separated steps and generates a very intense and large ECL signal. Its ECL efficiency is 4.5 times higher than that of the reference compound [Ru(bpy)3 ](2+) (bpy=2,2'-bipyridine). This remarkably high efficiency is due to the very good stability of the higher oxidized states and it makes 1 a very bright organic ECL luminophore. In addition, thanks to its molecular structure, this dye retains fluorescence after nanoprecipitation in water, which leads to fluorescent organic nanoparticles (FONs). The redox behavior of these FONs shows oxidation waves consistent with the initial molecular species. Finally, ECL from FONs made of 1 was recorded in water and strong ECL nanoemitters are thus obtained.

Evaluation of germline BRCA1 and BRCA2 mutations in a multi-ethnic Asian cohort of ovarian cancer patients.

OBJECTIVE: Despite the discovery of breast and ovarian cancer predisposition genes BRCA1 and BRCA2 more than two decades ago, almost all the available data relate to women of European ancestry, with only a handful of studies in Asian populations. In this study, we determined the frequency of germline alterations in BRCA1 and BRCA2 in ovarian cancer patients from a multi-ethnic cross-sectional cohort of Asian ovarian cancer patients from Malaysia. METHODS: From October 2008 to February 2015, we established a hospital-based cohort of ovarian cancer patients and the germline status of all 218 women with invasive epithelial ovarian cancer was tested using targeted amplification and sequencing of the intron-exon junctions and exonic sequences of BRCA1, BRCA2, PALB2 and TP53. RESULTS: BRCA1 and BRCA2 mutations were found in 8% (17 cases) and 3% (7 cases) of the ovarian cancer patients, respectively. Mutation carriers were diagnosed at a similar age to non-carriers, but were more likely to be Indian, have serous ovarian cancer, and have more relatives with breast or ovarian cancer. Nonetheless, 42% (10/24) of mutation carriers did not have any family history of breast or ovarian cancer and offering genetic counselling and genetic testing only to women with family history would mean that 35% (6/17) of BRCA1 mutation carriers and 57% (4/7) of BRCA2 mutation carriers would not be offered genetic testing. CONCLUSIONS: Our data suggest that, similar to Caucasians, a significant proportion of Asian ovarian cancer was attributed to germline mutations in BRCA1 and to a lesser extent in BRCA2.

Molecular-Based Fluorescent Nanoparticles Built from Dedicated Dipolar Thienothiophene Dyes as Ultra-Bright Green to NIR Nanoemitters.

Fluorescent Organic Nanoparticles (FONs), prepared by self-aggregation of dedicated dyes in water, represent a promising green alternative to the toxic quantum dots (QDs) for bioimaging purposes. In the present paper, we describe the synthesis and photophysical properties of new dipolar push-pull derivatives built from thieno[3,2-b]thiophene as a π-conjugated bridge that connects a triphenylamine moiety bearing various bulky substituents as electron-releasing moiety to acceptor end-groups of increasing strength (i.e., aldehyde, dicyanovinyl and diethylthiobarbiturate). All dyes display fluorescence properties in chloroform, which shifts from the green to the NIR range depending on the molecular polarization (i.e., strength of the end-groups) as well as a large two-photon absorption (TPA) band response in the biological spectral window (700-1000 nm). The TPA bands show a bathochromic shift and hyperchromic effect with increasing polarization of the dyes with maximum TPA cross-section reaching 2000 GM for small size chromophore. All dyes are found to form stable and deeply colored nanoparticles (20-45 nm in diameter) upon nanoprecipitation in water. Although their fluorescence is strongly reduced upon aggregation, all nanoparticles show large one-photon (up to 108 M(-1)·cm(-1) in the visible region) and two-photon (up to 106 GM in the NIR) brightness. Interestingly, both linear and non-linear optical properties are significantly affected by interchromophoric interactions, which are promoted by the molecular confinement and modulated by both the dipolar strength and the presence of the bulky groups. Finally, we exploited the photophysical properties of the FONs to design optimized core-shell nanoparticles built from a pair of complementary dipolar dyes that promotes an efficient core-to-shell FRET process. The resulting molecular-based core-shell nanoparticles combine large two-photon absorption and enhanced emission both located in the NIR spectral region, thanks to a major amplification (by a factor of 20) of the core fluorescence quantum yield. These novel nanoparticles, which combine huge one-and two-photon brightness, hold major promise for in vivo optical bioimaging.

Epiglottitis as a presentation of leukemia in an adolescent.

Epiglottitis is a life-threatening entity that can present in children or adults. Although the incidence has declined since the introduction of the Haemophilus influenzae type B vaccine in 1985, cases continue to be identified in high-risk populations. In pediatric oncology patients specifically, epiglottitis has been reported after initiation of chemotherapy. We report the first case of epiglottits as the initial presentation of leukemia in a pediatric patient.

Video-assisted thoracoscopic surgery retrieval of a migrated unilateral hypoglossal nerve stimulator sensor lead.

Obstructive sleep apnea is a common chronic condition typically treated with positive airway pressure. However, many patients have difficulty with adherence to this therapy, and for some, implantation of a hypoglossal nerve stimulator has become an option. Though device implantation is generally well-tolerated, a minority of patients will experience serious adverse events. Here we report the unusual complication of the sensor lead migrating to the costophrenic angle and invading the pleural space. Nine months after original implantation, the sensor lead malfunctioned and was found to be displaced. Initial explantation and reimplantation of a new device resulted in the inability to find a portion of the lead. Reimaging showed the missing lead at the costophrenic angle, and the patient underwent thoracoscopic removal. He resumed therapy with the new device without difficulty. This case demonstrates the ability of the lead to migrate far from the implantation site, which has rarely been reported.

Two-photon Dye-Based Fluorogenic Organic Nanoparticles as Intracellular Thiols Sensors.

Optical bioimaging is an ever-growing field that benefits both from the fast progress of optical instrumentation and modalities, and from the development of light-emitting probes. The efficacy of molecular fluorescent dyes is crucial, yet hindered by limited brightness and hydrophilicity. Addressing these challenges, self-stabilized fluorogenic organic nanoparticles only made of pure dyes (dFONs) are introduced in this work. Comprising thiol-sensitive fluorogenic chromophores, these dFONs exhibit enhanced brightness exclusively in the presence of biological thiols, notably glutathione, overcoming the need for water-solubilizing moieties. Importantly, these nanoparticles demonstrate large fluorescence and one- and two-photon brightness, enabling sensitive bioimaging of intracellular thiols at micromolar concentrations. Notably, only the pristine fluorogenic nanoparticles can penetrate the cells and does not require to wash the cells before imaging, emphasizing their unique role as dye carriers, fluorogenic probes and ease of use. This work highlights the transformative potential of dFONs in advancing optical bioimaging, paving the way for the use of dFONs not just as tracers, but also now as biosensors and ultimately in the future as biomarkers.

Hydrophilic Biocompatible Fluorescent Organic Nanoparticles as Nanocarriers for Biosourced Photosensitizers for Photodynamic Therapy.

Most photosensitizers of interest for photodynamic therapy-especially porphyrinoids and chlorins-are hydrophobic. To circumvent this difficulty, the use of nanocarriers is an attractive strategy. In this perspective, we have developed highly water-soluble and biocompatible fluorescent organic nanoparticles (FONPs) made from citric acid and diethyltriamine which are then activated by ethlynene diamine as nanoplatforms for efficient photosensitizers (PSs). Purpurin 18 (Pp18) was selected as a biosourced chlorin photosensitizer combining the efficient single oxygen generation ability and suitable absorption in the biological spectral window. The simple reaction of activated FONPs with Pp18, which contains a reactive anhydride ring, yielded nanoparticles containing both Pp18 and Cp6 derivatives. These functionalized nanoparticles combine solubility in water, high singlet oxygen generation quantum yield in aqueous media (0.72) and absorption both in the near UV region (FONPS) and in the visible region (Soret band approximately 420 nm as well as Q bands at 500 nm, 560 nm, 660 nm and 710 nm). The functionalized nanoparticles retain the blue fluorescence of FONPs when excited in the near UV region but also show deep-red or NIR fluorescence when excited in the visible absorption bands of the PSs (typically at 520 nm, 660 nm or 710 nm). Moreover, these nanoparticles behave as efficient photosensitizers inducing colorectal cancer cell (HCT116 and HT-29 cell lines) death upon illumination at 650 nm. Half maximal inhibitory concentration (IC50) values down to, respectively, 0.04 and 0.13 nmol/mL were observed showing the potential of FONPs[Cp6] for the PDT treatment of cancer. In conclusion, we have shown that these novel biocompatible nanoparticles, which can be elaborated from biosourced components, both show deep-red emission upon excitation in the red region and are able to produce singlet oxygen with high efficiency in aqueous environments. Moreover, they show high PDT efficiency on colorectal cancer cells upon excitation in the deep red region. As such, these functional organic nanoparticles hold promise both for PDT treatment and theranostics.

Sensorineural hearing loss after cardiac surgery: a systematic review.

BACKGROUND: Sensorineural hearing loss (SNHL) may occur following cardiac surgery. Although preventing post-operative complications is vitally important in cardiac surgery, there are few guidelines regarding this issue. This review aimed to characterize SNHL after cardiac surgery. METHOD: This systematic review was registered on PROSPERO and conducted in accordance with PRISMA guidelines. A systematic search of the PubMed, Embase and Cochrane Library were conducted from inception. Eligibility determination, data extraction and methodological quality analysis were conducted in duplicate. RESULTS: There were 23 studies included in the review. In the adult population, there were six cohort studies, which included 36 cases of hearing loss in a total of 7135 patients (5.05 cases per 1000 operations). In seven cohort studies including paediatric patients, there were 88 cases of hearing loss in a total of 1342 operations. The majority of cases of hearing loss were mild in the adult population (56.6%). In the paediatric population 59.2% of hearing loss cases had moderate or worse hearing loss. The hearing loss most often affected the higher frequencies, over 6000 Hz. There have been studies indicating an association between hearing loss and extracorporeal circulation, but cases have also occurred without this intervention. CONCLUSION: SNHL is a rare but potentially serious complication after cardiac surgery. This hearing loss affects both paediatric and adult populations and may have significant long-term impacts. Further research is required, particularly with respect to the consideration of screening for SNHL in children after cardiac surgery.

Acidic nanoparticles protect against α-synuclein-induced neurodegeneration through the restoration of lysosomal function.

Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by the loss of dopaminergic neurons in the substantia nigra, associated with the accumulation of misfolded α-synuclein and lysosomal impairment, two events deemed interconnected. Protein aggregation is linked to defects in degradation systems such as the autophagy-lysosomal pathway, while lysosomal dysfunction is partly related to compromised acidification. We have recently proven that acidic nanoparticles (aNPs) can re-acidify lysosomes and ameliorate neurotoxin-mediated dopaminergic neurodegeneration in mice. However, no lysosome-targeted approach has yet been tested in synucleinopathy models in vivo. Here, we show that aNPs increase α-synuclein degradation through enhancing lysosomal activity in vitro. We further demonstrate in vivo that aNPs protect nigral dopaminergic neurons from cell death, ameliorate α-synuclein pathology, and restore lysosomal function in mice injected with PD patient-derived Lewy body extracts carrying toxic α-synuclein aggregates. Our results support lysosomal re-acidification as a disease-modifying strategy for the treatment of PD and other age-related proteinopathies.

Microbiome-by-ethanol interactions impact Drosophila melanogaster fitness, physiology, and behavior.

The gut microbiota can affect how animals respond to ingested toxins, such as ethanol, which is prevalent in the diets of diverse animals and often leads to negative health outcomes in humans. Ethanol is a complex dietary factor because it acts as a toxin, behavioral manipulator, and nutritional source, with both direct effects on the host as well as indirect ones through the microbiome. Here, we developed a model for chronic, non-intoxicating ethanol ingestion in the adult fruit fly, Drosophila melanogaster, and paired this with the tractability of the fly gut microbiota, which can be experimentally removed. We linked numerous physiological, behavioral, and transcriptional variables to fly fitness, including a combination of intestinal barrier integrity, stored triglyceride levels, feeding behavior, and the immunodeficiency pathway. Our results reveal a complex tradeoff between lifespan and fecundity that is microbiome-dependent and modulated by dietary ethanol and feeding behavior.

Tinea capitis caused by dermatophytes: a 15-year retrospective study from a Mississippi Dermatology Clinic.

Tinea capitis is a highly contagious disorder occurring predominantly in children. Presentation is variable and, as such, mycologic confirmation of dermatophyte infection would be useful in targeting specific therapy and implementing preventive measures to interrupt spread of infection. This retrospective study was performed at an outpatient dermatology clinic in Jackson, Mississippi, over a 15-year period (1983-1998). Dermatophyte infections were confirmed using scalp scrapings cultured on Mycosel Agar containing cycloheximide and chloramphenicol. Cultures were performed on 1220 patients of all ages presenting with signs and symptoms suggestive of tinea capitis. Of the total patients meeting the inclusion criteria, 66% were younger than 13 years. Overall, 39% (478/1220) had positive cultures for dermatophytes, with black individuals having the highest percentage of positive cultures (87% [414/478]). In addition to a review of findings, we examine the impact of a cultural diagnosis of dermatophyte infection on the treatment and prevention of this highly contagious infection.

A Bottom-Up Approach to Red-Emitting Molecular-Based Nanoparticles with Natural Stealth Properties and their Use for Single-Particle Tracking Deep in Brain Tissue.

Fluorescent nanoparticles dedicated to bioimaging applications should possess specific properties that have to be maintained in the aqueous, reactive, and crowded biological environment. These include chemical and photostability, small size (on the scale of subcellular structures), biocompatibility, high brightness, and good solubility. The latter is a major challenge for inorganic nanoparticles, which require surface coating to be made water soluble. Molecular-based fluorescent organic nanoparticles (FONs) may prove a promising, spontaneously water-soluble alternative, whose bottom-up design allows for the fine-tuning of individual properties. Here, the critical challenge of controlling the interaction of nanoparticles with cellular membranes is addressed. This is a report on bright, size-tunable, red-emitting, naturally stealthy FONs that do not require the use of antifouling agents to impede interactions with cellular membranes. As a proof of concept, single FONs diffusing up to 150 µm deep in brain tissue are imaged and tracked.