Two novel synthetic xanthenodiones as antimicrobial, anti-adhesive and antibiofilm compounds against methicillin resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) is widely recognized as a causative agent for various infections acquired in healthcare settings as well as in the community. Given the limited availability of effective antimicrobial agents to combat MRSA infections, there is an increasing need to explore alternative therapeutic strategies. This study aimed to assess the antimicrobial, anti-adhesive, anti-biofilm properties, and toxicity of 175 newly synthesized compounds, belonging to seven different classes, against MRSA. Initially, the compounds underwent screening for antimicrobial activity using the agar diffusion method. Subsequently, active compounds underwent further evaluation to determine their minimum inhibitory concentrations through microdilution. Anti-biofilm and anti-adhesive properties were assessed using the crystal violet method, while toxicity was tested using the alternative infection model Galleria mellonella. Among the tested compounds, two xanthenodiones exhibited the most promising activities, displaying bactericidal effects along with anti-adhesive and anti-biofilm properties. Moreover, the observed non-toxicity in G. mellonella larvae suggests that these compounds hold significant potential as alternative therapeutic options to address the escalating challenge of MRSA resistance in both hospital and community settings.

INJURY EPIDEMIOLOGY IN BEACH TENNIS: INCIDENCE AND RISK FACTORS.

Introduction: Due to the growing increase in beach tennis practice in Brazil and the lack of studies on the injuries that occur in this sport, it has become necessary to develop more research on the subject. Objective: to identify risk and protection factors for injuries in beach tennis, in order to generate prevention strategies for musculoskeletal injuries. Method: A cross-sectional epidemiological study, level 3 of evidence, was carried out through an electronic form with 698 Beach Tennis players, who answered questions about their relationship with the practice of the sport and occurrences of injuries. We researched the prevalence of injuries, their types, and their relation with personal physical characteristics and the practice of other sports. Results: We found a positive relationship between injuries when associated with longer exposure time and the presence of a previous injury. We did not find differences regarding BMI, gender, and stretching and muscle strengthening performance. Conclusion: the most frequent non-traumatic injuries were to the elbow and shoulder (tendonitis) and traumatic (sprain) injuries to the knee and ankle. Level of Evidence II; Cohort Study.

Introdução: Devido ao crescente aumento da prática de Beach Tennis no Brasil e a carência de estudos sobre as lesões que ocorrem nesse esporte se faz necessário o desenvolvimento de mais pesquisas sobre o tema. Objetivo: identificar fatores de risco e de proteção para lesões no Beach Tennis, afim de gerar estratégias de prevenção às injurias musculoesqueléticas. Método: realizado estudo epidemiológico transversal nível 3 de evidência através de um formulário eletrônico com 698 praticantes de Beach Tennis, que responderam questionamentos sobre sua relação com a prática do esporte e ocorrências de lesões. Pesquisamos a prevalência das lesões e seus tipos, assim como sua relação com as características físicas pessoais e prática de outros esportes. Resultados: encontramos relação de positividade para lesões quando associadas a maior tempo de exposição e presença de lesão prévia. Não encontramos diferença quanto ao IMC, sexo e a realização de alongamento e fortalecimento muscular. Conclusão: as lesões mais frequentes não traumáticas foram no cotovelo e ombro (tendinite) e traumáticas (entorse) de joelho e tornozelo. Nível de Evidência II; Estudo de Coorte.

Environment geometry alters subiculum boundary vector cell receptive fields in adulthood and early development.

Boundaries to movement form a specific class of landmark information used for navigation: Boundary Vector Cells (BVCs) are neurons which encode an animal's location as a vector displacement from boundaries. Here we characterise the prevalence and spatial tuning of subiculum BVCs in adult and developing male rats, and investigate the relationship between BVC spatial firing and boundary geometry. BVC directional tunings align with environment walls in squares, but are uniformly distributed in circles, demonstrating that environmental geometry alters BVC receptive fields. Inserted barriers uncover both excitatory and inhibitory components to BVC receptive fields, demonstrating that inhibitory inputs contribute to BVC field formation. During post-natal development, subiculum BVCs mature slowly, contrasting with the earlier maturation of boundary-responsive cells in upstream Entorhinal Cortex. However, Subiculum and Entorhinal BVC receptive fields are altered by boundary geometry as early as tested, suggesting this is an inherent feature of the hippocampal representation of space.

Injury epidemiology in beach tennis: incidence and risk factors / Epidemiologia das lesões no beach tennis: incidência e fatores de risco

ABSTRACT Introduction: Due to the growing increase in beach tennis practice in Brazil and the lack of studies on the injuries that occur in this sport, it has become necessary to develop more research on the subject. Objective: to identify risk and protection factors for injuries in beach tennis, in order to generate prevention strategies for musculoskeletal injuries. Method: A cross-sectional epidemiological study, level 3 of evidence, was carried out through an electronic form with 698 Beach Tennis players, who answered questions about their relationship with the practice of the sport and occurrences of injuries. We researched the prevalence of injuries, their types, and their relation with personal physical characteristics and the practice of other sports. Results: We found a positive relationship between injuries when associated with longer exposure time and the presence of a previous injury. We did not find differences regarding BMI, gender, and stretching and muscle strengthening performance. Conclusion: the most frequent non-traumatic injuries were to the elbow and shoulder (tendonitis) and traumatic (sprain) injuries to the knee and ankle. Level of Evidence II; Cohort Study.

RESUMO Introdução: Devido ao crescente aumento da prática de Beach Tennis no Brasil e a carência de estudos sobre as lesões que ocorrem nesse esporte se faz necessário o desenvolvimento de mais pesquisas sobre o tema. Objetivo: identificar fatores de risco e de proteção para lesões no Beach Tennis, afim de gerar estratégias de prevenção às injurias musculoesqueléticas. Método: realizado estudo epidemiológico transversal nível 3 de evidência através de um formulário eletrônico com 698 praticantes de Beach Tennis, que responderam questionamentos sobre sua relação com a prática do esporte e ocorrências de lesões. Pesquisamos a prevalência das lesões e seus tipos, assim como sua relação com as características físicas pessoais e prática de outros esportes. Resultados: encontramos relação de positividade para lesões quando associadas a maior tempo de exposição e presença de lesão prévia. Não encontramos diferença quanto ao IMC, sexo e a realização de alongamento e fortalecimento muscular. Conclusão: as lesões mais frequentes não traumáticas foram no cotovelo e ombro (tendinite) e traumáticas (entorse) de joelho e tornozelo. Nível de Evidência II; Estudo de Coorte.

Topical antimicrobial formulations using medicinal plant-derived essential oils targeting methicillin resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA) causes a variety of healthcare-associated and community-acquired infections. Due to limited availability of effective antimicrobials for treating MRSA infections, there is a growing need to explore alternative therapeutic approaches. Here, the antimicrobial activities of 19 oils, popularly used for their medicinal properties, were tested against MRSA USA300. Oils obtained from cinnamon, clove, tangerine, and coriander showed the most promising activities, demonstrating bactericidal, anti-adhesive and anti-biofilm activities, and synergistic properties with common antibiotics. Given that clove and cinnamon oils showed the best activities, they were incorporated into topical formulations. Not only did the formulations with oils maintain antimicrobial and anti-adhesive activities, but their anti-biofilm property was potentiated. Tests on Galleria mellonella larvae suggested that the formulation is non-toxic. The formulations proposed here are a great alternative for the decolonisation of surfaces containing MRSA and can help circumventing antimicrobial resistance, a growing threat in the hospital environment.

Synergism between molecules derived from Garcinia brasiliensis and antimicrobial drugs on field isolates of Mycoplasma hyopneumoniae.

Mycoplasma hyopneumoniae (M. hyopneumoniae) is one of the smallest free-living bacteria found in nature; it has an extremely small genome and lacks a cell wall. It is the main etiological agent of porcine enzootic pneumonia (EP), a chronic respiratory disease with worldwide distribution that causes significant losses in swine production. Due to the great economic impact caused by EP, new strategies for treating and controlling this agent are researched. The objective of this study was to verify the anti-M. hyopneumoniae activity of compounds derived from Garcinia brasiliensis and the synergism with the main antimicrobials used in the treatment of EP; this is the first study assessing the synergism between bioactive molecules and antimicrobial compounds in vitro against isolates of M. hyopneumoniae. The minimum inhibitory concentrations (MICs) of the antimicrobials tiamulin, valnemulin, and enrofloxacin, as well as the bioactive compounds guttiferone-A (Gut-A), 7-epiculsone (7-Epic), copper 7-epiculsone (7-Epic-Cu), and benzophenone, were determined. Subsequently, the interactions of antibiotics with the compounds were evaluated using the checkerboard method. Three field M. hyopneumoniae isolates were used, and the J strain was used as a control. The MIC values of the antimicrobials compared to the field isolates were equal to and lower than those of the reference strain J. Among the compounds used, 7-Epic-Cu showed the lowest MIC value. Synergistic association was observed for Gut-A with tiamulin and valnemulin, whereas 7-Epic and 7-Epic-Cu showed synergistic action with enrofloxacin. No synergistic effect was observed for benzophenone. Despite being an initial study, the results suggest that these combinations hold promise for the treatment of infections caused by M. hyopneumoniae.

Trunk variability and local dynamic stability during gait after generalized fatigue induced by incremental exercise test in young women in different phases of the menstrual cycle.

Purpose: The purpose of this study was to identify how generalized fatigue along with hormonal changes throughout the menstrual cycle affects trunk variability and local dynamic stability during gait. Methods: General fatigue was induced by an incremental test on a treadmill, and the menstrual cycle was divided into three phases: follicular, ovulatory, and luteal. Twenty-six healthy, young volunteers (aged 18 to 28 years) who did not use oral contraceptives or other hormonal drugs with a regular menstrual cycle participated in the study. They walked on the treadmill for 4 min at the preferred speed, before the incremental test, followed by four sets of 4 min alternating between walking, also at preferred speed, and resting. From trunk kinematic data, the following were extracted: the mean of the standard deviation along strides, as a measure of variability, and the maximum Lyapunov exponent, as a measure of local dynamic stability (LDS). Results: After the incremental test, variability increased, and LDS decreased. However, they showed a tendency to return to the initial value faster in women compared to previous results for men. In the follicular phase, which has less hormonal release, the volunteers had an almost complete recovery in LDS soon after the first rest interval, suggesting that female hormones can interfere with fatigue recovery. Nevertheless, concerning the LDS, it was significantly lower in the luteal phase than in the follicular phase. Conclusion: Women that are not taking oral contraceptives should be aware that they are susceptible to increased gait instabilities in the pre-menstrual phase after strenuous activities.

Aspen Plus simulation for effluent reuse in thermomechanical pulp mills.

The objective of this study was to evaluate the closing of the water circuit and reusing the treated effluent in the production of TMP, using simulations performed with the Aspen Plus®. The treated effluent was reused to replace 50, 75 and 100% of the well water. An adaptation of the Aspen Plus® program simulating the TMP production process and a dynamic simulation test to verify the accumulation of non-process elements (NPEs) in industrial processes at different proportions of reuse were evaluated. The quality of the final product was assessed in laboratory bleaching tests for pulp brightness and brightness reversion. The concentrations of the NPE were 0.00097, 0.00122 and 0.00145 kmol/h for Mn2+, 0.012929, 0.018368 and 0.023595 kmol/h for Fe2+ and 0.000542, 0.000722 and 0.000948 kmol/h for Cu2+, with the recycling of the treated effluent of 50, 75 and 100%, respectively. The brightness and brightness reversion of the pulp were similar with the different proportions of effluent reuse and with the use of fresh industrial water, with values ranging from 83.37 to 83.97% ISO and 5.43 to 6.38 ISO units, respectively. The use of treated effluent did not affect the pulp quality, which could diminish the water use a pulp mil.

Applications of fluorescence spectroscopy in protein conformational changes and intermolecular contacts.

Emission fluorescence is one of the most versatile and powerful biophysical techniques used in several scientific subjects. It is extensively applied in the studies of proteins, their conformations, and intermolecular contacts, such as in protein-ligand and protein-protein interactions, allowing qualitative, quantitative, and structural data elucidation. This review, aimed to outline some of the most widely used fluorescence techniques in this area, illustrate their applications and display a few examples. At first, the data on the intrinsic fluorescence of proteins is disclosed, mainly on the tryptophan side chain. Predominantly, research to study protein conformational changes, protein interactions, and changes in intensities and shifts of the fluorescence emission maximums were discussed. Fluorescence anisotropy or fluorescence polarization is a measurement of the changing orientation of a molecule in space, concerning the time between the absorption and emission events. Absorption and emission indicate the spatial alignment of the molecule's dipoles relative to the electric vector of the electromagnetic wave of excitation and emitted light, respectively. In other words, if the fluorophore population is excited with vertically polarized light, the emitted light will retain some polarization based on how fast it rotates in solution. Therefore, fluorescence anisotropy can be successfully used in protein-protein interaction investigations. Then, green fluorescent proteins (GFPs), photo-transformable fluorescent proteins (FPs) such as photoswitchable and photoconvertible FPs, and those with Large Stokes Shift (LSS) are disclosed in more detail. FPs are potent tools for the study of biological systems. Their versatility and wide range of colours and properties allow many applications. Finally, the application of fluorescence in life sciences is exposed, especially the application of FPs in fluorescence microscopy techniques with super-resolution that enables precise in vivo photolabeling to monitor the movement and interactions of target proteins.

Criteria for selection and classification of studies in medical events.

OBJECTIVE: The aim of this study was to evaluate the impact of study methodology and evaluation type on the selection of studies during the presentation of scientific events. METHODS: A prospective, observational, transversal approach was applied to a cohort of studies that were submitted for presentation at the 2021 Brazilian Breast Cancer Symposium. Three forms of criteria (CR) were presented. CR1 was based on six criteria (method, ethics, design, originality, promotion, and social contribution); CR2 graded the studies from 0 to 10 for each study, and CR3 was based on five criteria (presentation, method, originality, scientific knowledge, and social contribution). To evaluate the item correlation, Cronbach's alpha and factorial analysis were performed. For the evaluation of differences between the tests, we used the Kruskal-Wallis and post-hoc Dunn tests. To determine the differences in the study classifications, we used the Friedman test and Namenyi's all-pairs comparisons. RESULTS: A total of 122 studies were evaluated. There was also a good correlation with the items concerning criterion 1 (α=0.730) and 3 (α=0.937). Evaluating CR1 methodology, study design and social contribution (p=0.741) represents the main factor and CR3 methodology, and the scientific contribution (p=0.994) represents the main factor. The Kruskal-Wallis test showed differences in the results (p<0.001) for all the criteria that were used [CR1-CR2 (p<0.001), CR1-CR3 (p<0.001), and CR2-CR3 (p=0.004)]. The Friedman test showed differences in the ranking of the studies (p<0.001) for all studies (p<0.01). CONCLUSION: Methodologies that use multiple criteria show good correlation and should be taken into account when ranking the best studies.

Formulations of essential oils obtained from plants traditionally used as condiments or traditional medicine active against Staphylococcus aureus isolated from dairy cows with mastitis.

The prophylactic and therapeutic overuse of antimicrobials on the farm has contributed to the emergence of hard-to-fight bacterial strains causing bovine mastitis. Aiming at alternative therapies, this study evaluated the antimicrobial activity of 20 essential oils against clinical Staphylococcus aureus strains. Of them, five with strong activities were selected and evaluated for their minimum inhibitory concentrations (MIC) in culture medium and milk, cytotoxicity against bovine mammary cells (MAC-T), antiadhesive properties, and interactions among themselves and with cefoperazone. The oils remained active on milk, were not cytotoxic, and some concentrations stimulated MAC-T cells growth, suggesting healing potential. Subinhibitory concentrations of Coriandrum sativum, Origanum vulgare, Syzygium aromaticum, and Thymus vulgaris reduced biofilm formation by at least 80%. Several oil and cefoperazone combinations displayed additive interaction, with O. vulgare and C. sativum showing the most promising results. We developed formulations for being used as prophylactic postdipping solutions in the field, containing different concentrations (1% or 3%) of the active oils, alone or in combination, with 3% glycerin, 1% Tween 80, and water. The formulations showed strong antimicrobial activity in milk and enhanced antiadhesive properties, specially when two oils were combined in the formula, indicating promising biotechnological and therapeutical applications.

First case report of feline sporotrichosis caused by Sporothrix brasiliensis in the state of Ceará - Brazil.

Feline sporotrichosis is a zoonotic mycosis caused by fungi belonging to the Sporothrix schenckii complex. In the state of Ceará, there are no reports of isolation of this fungus in cats. This study presents the first report of feline sporotrichosis caused by the species Sporothrix brasiliensis in the state of Ceará - Brazil. The diagnosis was made through cytopathological examination, mycological culture and PCR. The findings were compatible with feline sporotrichosis caused by Sporothrix brasiliensis.

Photoantibacterial Poly(vinyl)chloride Films Applying Curcumin Derivatives as Bio-Based Plasticizers and Photosensitizers.

Herein we describe the design of natural curcumin ester and ether derivatives and their application as potential bioplasticizers, to prepare photosensitive phthalate-free PVC-based materials. The preparation of PVC-based films incorporating several loadings of newly synthesized curcumin derivatives along with their standard solid-state characterization is also described. Remarkably, the plasticizing effect of the curcumin derivatives in the PVC material was found to be similar to that observed in previous PVC-phthalate materials. Finally, studies applying these new materials in the photoinactivation of S. aureus planktonic cultures revealed a strong structure/activity correlation, with the photosensitive materials reaching up to 6 log CFU reduction at low irradiation intensities.

Chemical composition variation of essential oils of Copaifera langsdorffii Desf. from different vegetational formations.

This study aims to provide information about the chemical profile of the essential oil from C. langsdorffii resin in areas of Cerradão, Carrasco, and Humid Forest. In order to obtain the essential oils, oil-resin was submitted to hydrodistillation process, and the chemical components were analyzed by gas chromatography coupled to mass spectrometry (GC/MS). Twenty-six constituents were identified in the essential oil of C. langsdorffii resin, of which 12 were present in Cerradão, 15 in Carrasco and 18 in Humid Forest, with ß-bisabolene, caryophyllene oxide, γ-muurolene, α-caryophyllene and ß-caryophyllene common to the three phytophysiognomies. Among the studied areas, the resin collection varied from 2.652 g to 20.263 g, while the essential oil yield varied from 2.216 % to 11.764 %. A concentration range of 0.60 % to 84.57 % was recorded among the compounds in the three study areas. There was variation in chemical composition both among phytophysiognomies and among individuals from the same location, where ß-caryophyllene showed to be the majority for all areas studied, being present in all individuals from Cerradão, Carrasco and Humid Forest.

Protective Effects of Halite to Vacuum and Vacuum-Ultraviolet Radiation: A Potential Scenario During a Young Sun Superflare.

Halite (NaCl mineral) has exhibited the potential to preserve microorganisms for millions of years on Earth. This mineral was also identified on Mars and in meteorites. In this study, we investigated the potential of halite crystals to protect microbial life-forms on the surface of an airless body (e.g., meteorite), for instance, during a lithopanspermia process (interplanetary travel step) in the early Solar System. To investigate the effect of the radiation of the young Sun on microorganisms, we performed extensive simulation experiments by employing a synchrotron facility. We focused on two exposure conditions: vacuum (low Earth orbit, 10-4 Pa) and vacuum-ultraviolet (VUV) radiation (range 57.6-124 nm, flux 7.14 W/m2), with the latter representing an extreme scenario with high VUV fluxes comparable to the amount of radiation of a stellar superflare from the young Sun. The stellar VUV parameters were estimated by using the very well-studied solar analog of the young Sun, κ1 Cet. To evaluate the protective effects of halite, we entrapped a halophilic archaeon (Haloferax volcanii) and a non-halophilic bacterium (Deinococcus radiodurans) in laboratory-grown halite. Control groups were cells entrapped in salt crystals (mixtures of different salts and NaCl) and non-trapped (naked) cells, respectively. All groups were exposed either to vacuum alone or to vacuum plus VUV. Our results demonstrate that halite can serve as protection against vacuum and VUV radiation, regardless of the type of microorganism. In addition, we found that the protection is higher than provided by crystals obtained from mixtures of salts. This extends the protective effects of halite documented in previous studies and reinforces the possibility to consider the crystals of this mineral as potential preservation structures in airless bodies or as vehicles for the interplanetary transfer of microorganisms.

Criteria for selection and classification of studies in medical events

SUMMARY OBJECTIVE: The aim of this study was to evaluate the impact of study methodology and evaluation type on the selection of studies during the presentation of scientific events. METHODS: A prospective, observational, transversal approach was applied to a cohort of studies that were submitted for presentation at the 2021 Brazilian Breast Cancer Symposium. Three forms of criteria (CR) were presented. CR1 was based on six criteria (method, ethics, design, originality, promotion, and social contribution); CR2 graded the studies from 0 to 10 for each study, and CR3 was based on five criteria (presentation, method, originality, scientific knowledge, and social contribution). To evaluate the item correlation, Cronbach's alpha and factorial analysis were performed. For the evaluation of differences between the tests, we used the Kruskal-Wallis and post-hoc Dunn tests. To determine the differences in the study classifications, we used the Friedman test and Namenyi's all-pairs comparisons. RESULTS: A total of 122 studies were evaluated. There was also a good correlation with the items concerning criterion 1 (α=0.730) and 3 (α=0.937). Evaluating CR1 methodology, study design and social contribution (p=0.741) represents the main factor and CR3 methodology, and the scientific contribution (p=0.994) represents the main factor. The Kruskal-Wallis test showed differences in the results (p<0.001) for all the criteria that were used [CR1-CR2 (p<0.001), CR1-CR3 (p<0.001), and CR2-CR3 (p=0.004)]. The Friedman test showed differences in the ranking of the studies (p<0.001) for all studies (p<0.01). CONCLUSION: Methodologies that use multiple criteria show good correlation and should be taken into account when ranking the best studies.

Tratamento da síndrome da artéria mesentérica superior / Treatment of superior mesenteric artery syndrome

Introdução: A síndrome da artéria mesentérica superior (SMAS) resulta da compressão extrínseca dela e obstrução sintomática da terceira porção do duodeno anteriormente, e pela aorta posteriormente. Esse estreitamento leva à compressão extrínseca e à obstrução do duodeno, impedindo a passagem do conteúdo intestinal. Objetivo: Por meio de revisão integrativa, sintetizar evidências sobre o tratamento dessa síndrome. Métodos: Revisão integrativa da literatura com síntese de evidências. A base de dados escolhida para seleção dos trabalhos foi o PUBMED, utilizando a seguinte estratégia de busca: "superior mesenteric artery syndrome"[title] AND (treatment[title] OR surgical[title]). Foram considerados para revisão os trabalhos publicados entre os anos de 2018 e 2023. Resultados: Inicialmente foram identificados 13 trabalhos que atenderam à estratégia de busca previamente estabelecida. Após a leitura dos títulos e resumos, 4 textos foram excluídos por não discutirem o tema proposto, restando 9 trabalhos para revisão. Conclusão: As modalidades cirúrgicas disponíveis para o tratamento da SMA foram consideradas seguras, com baixos índices de recidiva, além de eficazes no controle de sintomas e no manejo da síndrome.

Introduction: Superior mesenteric artery syndrome (SMAS) results from extrinsic compression and symptomatic obstruction of the third portion of the duodenum by it anteriorly, and by the aorta posteriorly. This narrowing leads to extrinsic compression and obstruction of the duodenum, preventing the passage of intestinal contents. Objective: Through an integrative review, to synthesize evidence on the treatment of SMAS. Methods: Integrative literature review with evidence synthesis. The database chosen for the selection of papers was PUBMED, using the following search strategy: "superior mesenteric artery syndrome"[title] AND (treatment[title] OR surgical[title]). Papers published between the years 2018 and 2023 were considered for review. Results: Initially, 13 papers were identified that met the previously established search strategy. After reading the titles and abstracts, 4 were excluded for not discussing the proposed theme, leaving 9 papers for review. Conclusion: The surgical modalities available for SMA treatment were considered safe, with low recurrence rates, and effective in symptom control and management of the syndrome.

Altered low-frequency brain rhythms precede changes in gamma power during tauopathy.

Neurodegenerative disorders are associated with widespread disruption to brain activity and brain rhythms. Some disorders are linked to dysfunction of the membrane-associated protein Tau. Here, we ask how brain rhythms are affected in rTg4510 mouse model of tauopathy, at an early stage of tauopathy (5 months), and at a more advanced stage (8 months). We measured brain rhythms in primary visual cortex in presence or absence of visual stimulation, while monitoring pupil diameter and locomotion to establish behavioral state. At 5 months, we found increased low-frequency rhythms during resting state in tauopathic animals, associated with periods of abnormally increased neural synchronization. At 8 months, this increase in low-frequency rhythms was accompanied by a reduction of power in the gamma range. Our results therefore show that slower rhythms are impaired earlier than gamma rhythms in this model of tauopathy, and suggest that electrophysiological measurements can track the progression of tauopathic neurodegeneration.

Unraveling the Pivotal Role of Atropisomerism for Cellular Internalization.

The intrinsic challenge of large molecules to cross the cell membrane and reach intracellular targets is a major obstacle for the development of new medicines. We report how rotation along a single C-C bond, between atropisomers of a drug in clinical trials, improves cell uptake and therapeutic efficacy. The atropisomers of redaporfin (a fluorinated sulfonamide bacteriochlorin photosensitizer of 1135 Da) are separable and display orders of magnitude differences in photodynamic efficacy that are directly related to their differential cellular uptake. We show that redaporfin atropisomer uptake is passive and only marginally affected by ATP depletion, plasma proteins, or formulation in micelles. The α4 atropisomer, where meso-phenyl sulfonamide substituents are on the same side of the tetrapyrrole macrocycle, exhibits the highest cellular uptake and phototoxicity. This is the most amphipathic atropisomer with a conformation that optimizes hydrogen bonding (H-bonding) with polar head groups of membrane phospholipids. Consequently, α4 binds to the phospholipids on the surface of the membrane, flips into the membrane to adopt the orientation of a surfactant, and eventually diffuses to the interior of the cell (bind-flip mechanism). We observed increased α4 internalization by cells of the tumor microenvironment in vivo and correlated this to the response of photodynamic therapy when tumor illumination was performed 24 h after α4 administration. These results show that properly orientated aryl sulfonamide groups can be incorporated into drug design as efficient cell-penetrating motifs in vivo and reveal the unexpected biological consequences of atropisomerism.