Uncovering the neural control of laryngeal activity and subglottic pressure in anaesthetized rats: insights from mesencephalic regions.

To assess the possible interactions between the dorsolateral periaqueductal gray matter (dlPAG) and the different domains of the nucleus ambiguus (nA), we have examined the pattern of double-staining c-Fos/FoxP2 protein immunoreactivity (c-Fos-ir/FoxP2-ir) and tyrosine hydroxylase (TH) throughout the rostrocaudal extent of nA in spontaneously breathing anaesthetised male Sprague-Dawley rats during dlPAG electrical stimulation. Activation of the dlPAG elicited a selective increase in c-Fos-ir with an ipsilateral predominance in the somatas of the loose (p < 0.05) and compact formation (p < 0.01) within the nA and confirmed the expression of FoxP2 bilaterally in all the domains within the nA. A second group of experiments was made to examine the importance of the dlPAG in modulating the laryngeal response evoked after electrical or chemical (glutamate) dlPAG stimulations. Both electrical and chemical stimulations evoked a significant decrease in laryngeal resistance (subglottal pressure) (p < 0.001) accompanied with an increase in respiratory rate together with a pressor and tachycardic response. The results of our study contribute to new data on the role of the mesencephalic neuronal circuits in the control mechanisms of subglottic pressure and laryngeal activity.

Impact of the glutamatergic neurotransmission within the A5 region on the cardiorespiratory response evoked from the midbrain dlPAG.

Stimulation of the dorsolateral periaqueductal grey matter (dlPAG) in rats evokes an active defensive behaviour together with a cardiorespiratory response characterised by tachypnoea, tachycardia and hypertension. The dlPAG neurons involved in these responses are excitatory, presumably glutamatergic, due to the presence of vesicular glutamate transporter VGLUT2 within their axon terminals. Previously, our group described a functional interaction between dlPAG and the pontine A5 region. Accordingly, in the present work, in order to characterize the role of glutamate within this interaction, experiments were carried out in spontaneously breathing anaesthetized rats (sodium pentobarbitone 60 mg/kg i.p., suplemented with 20 mg/kg i.p.). The cardiorespiratory response evoked by electrical stimulation of the dlPAG (1 ms pulses, 20-50 µA, given at 100 Hz, during 5 s) was analysed before and after the microinjection, within the A5 region, of either kynurenic acid (non-specific glutamate receptor antagonist; 5-10 nmol), DAP-5 (NMDA antagonist; 1 pmol), CNQX (non-NMDA antagonist; 1 pmol) or MCPG (metabotropic antagonist; 0,1 nmol). Kynurenic acid decreased the intensity of both the tachypnoea (p < 0,001) and tachycardia (p < 0,001) induced by dl-PAG stimulation. Blockade of no-NMDA receptors reduced the increase of respiratory frequency, heart rate and pressor response to dl-PAG stimulation (p < 0,01, p < 0,001, p < 0,05 respectively). Blockade of either NMDA or metabotropic receptors reduced the dlPAG-evoked tachycardia and pressor response (p < 0,01; p < 0,05 respectively). These results suggest a neuromodulatory role for A5 region via glutamate neurotransmission of the dlPAG-evoked cardiorespiratory response, confirming the role of the ventrolateral pons in the neuronal circuits involved in respiratory and heart rate control.

Fibrous hamartoma of infancy. Radiologic-pathologic study of 21 cases: 8 with predominant pseudoangiomatous pattern.

Fibrous hamartoma of infancy (FHI) is a very rare benign soft tissue lesion that principally affects the axilla, trunk, and upper extremities of children younger than 2 years. It is usually cured by local excision. Histologically, these lesions have a triphasic morphology in an organoid pattern: mature adipose tissue, fibroblastic/myofibroblastic trabeculae, and small round cell nests in a myxoid matrix. However, morphologic variants have recently been described. Focal areas with a pseudoangiomatous pattern have been found in some FHI, but few cases with predominant pseudoangiomatous areas have been previously described in the medical literature. We report 21 new cases of FHI, 8 of them with a predominant pseudoangiomatous pattern. Our cases with a predominant pseudoangiomatous pattern did not present specific radiological findings.

Phylogenetic analyses based on molecular and morphological data reveal a new species of Strigea Abildgaard, 1790 (Digenea: Strigeidae) and taxonomic changes in strigeids infecting Neotropical birds of prey.

Members of the genus Strigea Abildgaard, 1790 are endoparasites of birds distributed worldwide. Adults of an undescribed species of the genus Strigea were collected from the intestines of two hawk species (Rupornis magnirostris and Accipiter coperii). Other species identified as Parastrigea macrobursa that were described in Argentina were also recovered from two hawk species (Buteogallus urubitinga and Buteogallus anthracinus) in three localities along the coasts of Mexico. Specimens of the two species were sequenced for three molecular markers, the internal transcribed spacers locus (ITS1-5.8S rDNA- ITS2) and the domains D1-D3 from the large subunit from nuclear ribosomal DNA and the cytochrome c oxidase subunit 1 from mitochondrial DNA. The newly sequenced specimens were aligned with other strigeids sequences downloaded from GenBank. Maximum likelihood and Bayesian analyses inferred with each molecular marker revealed that our specimens of Strigea sp. formed an independent lineage, which is recognized herein as a new species, Strigea magnirostris n. sp., representing the first species in Mexico and the 16th in the Neotropical region. Morphologically, the new species is distinguished from other congeneric species from the Americas by having an oral sucker with several papillae around it, well-developed pseudosuckers (118-248 µm), a tegument covered with tiny spines, a larger cone genital (193-361 × 296-637) and a larger copulatory bursa (247-531 × 468-784). Our phylogenetic analyses revealed that P. macrobursa is not closely related to other members of the genus Parastrigea and is nested within Strigea, suggesting that P. macrobursa should be transferred to Strigea to form Strigea macrobursa n. comb., expanding its distribution range from Mexico to Argentina. Finally, the analyses also revealed that the taxonomy and systematics of Strigea should be re-evaluated, combining morphological and molecular characteristics.

Molecular and morphological characterization of Andracantha gravida (Alegret, 1941) (Acanthocephala: Polymorphidae) in piscivorous birds from the Gulf of Mexico.

Adult specimens of Andracantha gravida (Alegret, 1941) were recorded from the intestines of the double-crested cormorant Nannopterum auritus (Lesson) (type host) and brown pelican Pelecanus occidentalis L. in two localities from Mexico: Celestún, Yucatan (south-eastern) and Punta Piedra, Tamaulipas (north-eastern). The specimens of A. gravida are morphologically characterized by having a pipe-shaped body without swellings, the absence of small trunk spines between the two fields of spines on the foretrunk and a cylindrical proboscis with 14-16 rows of 10-12 hooks per row. Newly generated partial sequences of the mitochondrial cytochrome c oxidase subunit 1 (cox1) gene were generated from adult isolates of A. gravida from Mexico and compared with one sequence of A. gravida and with sequences of other polymorphid acanthocephalans available in GenBank. Phylogenetic analyses based on maximum likelihood and Bayesian inference methods of the cox1 dataset placed all the species of Andracantha in a single clade, with weak support. The analyses of the cox1 dataset placed Andracantha sigma Presswell, García-Varela & Smales, , as sister to the clade formed by A. gravida, Andracantha phalacrocoracis (Yamaguti, 1939), Andracantha leucocarboi Presswell, García-Varela & Smales, and an unidentified species of Andracantha from Japan. The newly generated cox1 sequences of A. gravida from piscivorous birds of Mexico formed a strongly supported clade with the published sequence of A. gravida from the double-crested cormorant from the south-eastern coast of Mexico. The intraspecific genetic divergence among isolates identified as A. gravida ranged from 0.0% to 2.2%. A cox1 haplotype network inferred with 14 sequences revealed the presence of nine haplotypes, two of which were shared between the populations of piscivorous birds from the north-eastern and south-eastern coasts of Mexico and seven of which were unique. The fixation index between the populations from north-eastern and south-eastern Mexico was low (0.06949), which suggests genetic flow. This can be explained by the migration patterns of the brown pelican and the double-crested cormorant along the coasts of the Gulf of Mexico.

Scaphanocephalus spp. (Trematoda: Opisthorchiidae) in intermediate and definitive hosts of the Yucatán Peninsula, Mexico, with a re-description of Scaphanocephalus expansus.

Scaphanocephalus is a small trematode genus belonging to the family Opistorchiidae. The genus currently contains only three species associated with marine fish as intermediate hosts and fish-eating birds as definitive hosts. Here, specimens of Scaphanocephalus were collected from the Osprey, Pandion haliaetus, and the White mullet, Mugil curema in the Yucatán Peninsula, Mexico. We report for the first-time DNA sequences of adult specimens of Scaphanocephalus, particularly S. expansus, as well as a sequence of a different species sampled as metacercaria. Morphological comparisons of Scaphanocephalus expansus confirmed the identity of the adult specimens, with minor morphological variations; Scanning electron photomicrographs were included, and the species was re-described. Phylogenetic analysis based on 28S rDNA sequences showed that Scaphanocephalus is monophyletic within Opisthorchiidae and consists of three independent lineages. Sequences of adults are identical to those of S. expansus. Instead, the sequence of the metacercaria sampled from the mesentery of Mugil curema nested with specimens reported as Scaphanocephalus sp. from a labrid fish in the Mediterranean Sea, herein named it as Scaphanocephalus sp. 2.

Calcifying aponeurotic fibroma: Radiologic-pathologic analysis of ten cases and review of the literature.

Calcifying aponeurotic fibroma (CAF) is a very rare benign entity that principally affects the volar fascia, tendons, and aponeuroses of the hands and feet with a peak incidence of between 5 and 15 years, although there have been cases found for a wide age range and at various anatomical sites. We present ten CAF cases; consisting of eight children and two adults. CAF occurred in the extremities in nine of the cases and in the chest wall in one case. CAF ultrasound and radiological findings are nonspecific but may help orientate diagnosis. Magnetic resonance imaging should be performed when there are doubtful cases, when occurring in nontypical sites, and when there are cases of nontypical clinical presentation. Histologically, all cases showed two components, a fibromatosis-like component and a nodular component. Chondroid areas were present in five cases. Calcifications were observed in nine cases. ERG immunostaining showed the same patterns in all the cases; diffuse positivity in pericalcified areas, and patchy positivity in areas away from calcifications. CAF has distinctive histopathological features which should aid in the differential diagnoses with other entities.

Clinical presentation, sonographic features and treatment options of segmental stiff skin syndrome.

Segmental stiff skin syndrome is a rare genetic connective tissue disease, which is often misdiagnosed. High-frequency ultrasonography can represent a useful clinical adjunct in the differential diagnosis of this condition, in conjunction with the clinical and histopathological findings. Treatment options are limited and evidence is scarce. We present the clinical, sonographic and histological features of five paediatric patients diagnosed at our institution and discuss their response to treatment.

Phylogenetic affinities of Forticulcitinae (Haploporidae) parasites of mullet from the Americas, with the description of three new species and notes on the genera and key species.

Members of Forticulcitinae Blasco-Costa, Balbuena, Kostadinova & Olson, 2009 include endoparasites of mullet fishes distributed worldwide. Adult specimens were collected from the intestines of white mullet (Mugil curema) and flathead grey mullet (Mugil cephalus) from five localities in the Gulf of Mexico and a single locality in Venezuela. Photogenophores were sequenced for two nuclear molecular markers, the large subunit (LSU) and second internal transcribed spacer (ITS2) of nuclear rDNA. The new sequences were aligned with other sequences downloaded from GenBank. The maximum likelihood and Bayesian inferences were deduced using the combined dataset (LSU + ITS2). The phylogenetic analyses revealed four new lineages belonging to Forticulcitinae. Three new species are described in the present study. Ekuarhuni mexicanus n. sp. can be differentiated from its congeneric species by presenting a longer hermaphroditic sac length (136-180 µm) and a wider testis (91-123 µm). Forticulcita macropharyngis n. sp. and Forticulcita venezuelensis n. sp. are the 8th and 9th species described in Forticulcita. Both species belong to the diminutive morphotype of Forticulcita. Forticulcita macropharyngis n. sp. can be morphologically distinguished from the other congeneric species by the presence of a massive and muscular pharynx (46-110 µm long, 74-106 µm wide). Forticulcita venezuelensis n. sp. is the second species of the studied genus recorded in South America and can be differentiated from congeneric species by possessing the largest testis (138-201 µm long, 83-100 µm wide). Finally, the fourth lineage corresponds to Overstreetoides Andrade-Gómez & García-Varela, 2021; however, few specimens of this lineage were collected, precluding any description of the species. In addition, a key is proposed for differentiating the genera and species of Forticulcitinae.

Morphological and molecular evidence reveals a new species of Lyperosomum Looss, 1899 (Digenea: Dicrocoeliidae) from Melanerpes aurifrons (Wagler, 1829) from northern Mexico.

A new species of the genus Lyperosomum Looss, 1899, from the intestine of the golden-fronted woodpecker (Melanerpes aurifrons) from northern Mexico is described. Lyperosomum cuauhxinqui sp. n. is morphologically distinguished from other congeneric species from the Americas by a higher oral/ventral sucker ratio and its body length and width. The sequences of domains D1-D3 of the large subunit (LSU) of nuclear ribosomal DNA and cytochrome c oxidase subunit 1 (cox 1) from the mitochondrial DNA of the new species were obtained and compared with available sequences from GenBank. The genetic divergence estimated between the new species and other congeneric species ranged from 2 to 6% and 13.4 to 17.3% for LSU and cox 1, respectively. Phylogenetic analyses based on the two (LSU and cox 1) molecular markers consistently showed that L. cuauhxinqui sp. n. was nested within the genus Lyperosomum, with strong bootstrap support (100%) and Bayesian posterior probabilities (1.0). In particular, the LSU tree indicated that the sequence of the new species is closely related to sequences from Zonorchis alveyi, Zonorchis delectans and Zonorchis sp. from Central America, suggesting that these sequences should be transferred to the genus Lyperosomum. The new species represents the first record from Mexico and the fifth species identified in the Americas. Our study also revealed that the taxonomy of the genus Lyperosomum should be re-examined by combining molecular, morphological and ecological characteristics.

The development of proliferative verrucous leukoplakia in oral lichen planus. A preliminary study.

BACKGROUND: Was to describe 14 cases of a proliferative verrucous leukoplakia as a clinical evolution of oral lichen planus. MATERIAL AND METHODS: The clinical and histopathological characteristics of 14 cases of OLP that progress towards a plaque-like and verrucous form were indicated, with monitoring over a period of six to 24.3 years. RESULTS: The female/male ratio was 11/3, (78.6 and 21.4%). The mean age when the first biopsy was undertaken was 56.4 years old. None of the patients smoked during the study. As bilateral reticular was clinically diagnostic criterion, the second most frequent clinical form was the plaque form (n=10; 71.4%), followed by the atrophic (n=6; 42.8%), and erosive forms (n=4; 28.5%). Clinically it spread towards attached gingival mucosa and the hard palate. In the histopathologic study, there were a predominance of hyperkeratosis and verrucous epithelial hyperplasia. Three of the cases progressed to a squamous cell carcinoma, and one patient developed two verrucous carcinoma. CONCLUSIONS: Further research is needed to demonstrate if proliferative multifocal oral lichen planus and proliferative multifocal oral leukoplakia are the same disorder but have different behaviour of malignancy for reasons of origin.

Chronic obstructive pulmonary disease related to wood smoke and impact of the combined exposure to tobacco.

BACKGROUND: Global Initiative for Chronic Obstructive Lung Disease (GOLD) 2023 highlights the need to explore aetiotypes of chronic obstructive pulmonary disease (COPD) beyond the tobacco-smoking COPD. Exposure to wood smoke (WS) is a risk factor for COPD in women, but the effect of the combined exposure to tobacco smoke (TS) in the general population and among COPD patients, and the characteristics of WS-COPD are unclear. METHOD: This was an analysis of data from PREPOCOL (Prevalence of COPD in Five Colombian Cities Situated at Low, Medium, and High Altitude), a random cross-sectional population-based study (n = 5,539) focusing on the effect of combined WS and TS exposure and WS-COPD characterisation. RESULTS: Prevalence of COPD was significantly higher in those exposed to both WS and TS (16.0%) than in those exposed to WS (6.7%) or TS (7.8%) only (P < 0.001). Exposure to WS was associated with COPD in men (OR 1.53, P = 0.017). WS-COPD individuals were more frequently female, older, shorter and had higher forced expiratory volume in 1 sec (FEV1) (all P < 0.05). Those exposed to both WS and TS had more symptoms and worse airflow limitation (P < 0.001). CONCLUSIONS: This was the first random population-based study showing that WS is an associated risk factor for COPD also in men, and that people exposed to both WS and TS have a significantly higher prevalence of COPD. Similarly, COPD subjects exposed to both types of smoke have more symptoms and greater airflow obstruction. This suggests an additive effect of WS and TS.

CONTEXTE: L'Initiative mondiale pour les maladies pulmonaires obstructives chroniques (Global Initiative for Chronic Obstructive Lung Disease, GOLD) 2023 met en évidence l'importance d'explorer les différents étiotypes de la maladie pulmonaire obstructive chronique (COPD, pour l'anglais « chronic obstructive pulmonary disease ¼) en dehors de la COPD liée au tabagisme. L'exposition à la fumée de bois (WS, pour l'anglais « wood smoke ¼) représente un facteur de risque de la COPD chez les femmes, cependant, l'impact de l'exposition simultanée à la fumée de tabac (TS, pour l'anglais « tobacco smoke ¼) chez la population générale et chez les patients atteints de COPD, ainsi que les caractéristiques spécifiques de la WS-COPD, demeurent peu clairs. MÉTHODES: Il s'agit d'une étude transversale aléatoire basée sur la population (n = 5 539) qui analyse les données de PREPOCOL (Prevalence of COPD in Five Colombian Cities Situated at Low, Medium, and High Altitude). L'étude se concentre sur l'effet de l'exposition combinée à la WS et à la TS ainsi que sur la caractérisation de la WS-COPD. RÉSULTATS: La prévalence de la COPD était significativement plus élevée chez les personnes exposées à la fois à la WS et à la TS (16,0%) que chez celles exposées uniquement à la WS (6,7%) ou à la TS (7,8%) (P < 0,001). L'exposition à la WS était associée à la COPD chez les hommes (OR 1,53 ; P = 0,017). Les personnes atteintes de WS-COPD étaient plus fréquemment des femmes, d'un âge plus avancé, de plus petite taille et présentaient un volume expiratoire maximal en 1 seconde (FEV1) plus élevé (tous P < 0,05). Les personnes exposées à la fois à la WS et à la TS ont montré plus de symptômes et une plus grande limitation du débit d'air (P < 0,001). CONCLUSION: Il s'agit de la première étude aléatoire basée sur la population qui démontre que la WS est un facteur de risque lié à la COPD, même chez les hommes, et que les individus exposés à la fois à la WS et à la TS présentent une prévalence significativement plus élevée de la COPD. De plus, les personnes souffrant de COPD qui sont exposés aux deux types de fumée manifestent davantage de symptômes et une obstruction pulmonaire plus sévère. Cela laisse supposer qu'il y a un effet cumulatif de la WS et de la TS.

Determining triple gauge boson couplings from Higgs data.

In the framework of effective Lagrangians with the SU(2)(L)×U(1)(Y) symmetry linearly realized, modifications of the couplings of the Higgs field to the electroweak gauge bosons are related to anomalous triple gauge couplings (TGCs). Here, we show that the analysis of the latest Higgs boson production data at the LHC and Tevatron give rise to strong bounds on TGCs that are complementary to those from direct TGC analysis. We present the constraints on TGCs obtained by combining all available data on direct TGC studies and on Higgs production analysis.

Optical Binding-Driven Micropatterning and Photosculpting with Silver Nanorods.

Controlling the nano- and micropatterning of metal structures is an important requirement for various technological applications in photonics and biosensing. This work presents a method for controllably creating silver micropatterns by laser-induced photosculpting. Photosculpting is driven by plasmonic interactions between pulsed laser radiation and silver nanorods (AgNRs) in aqueous suspension; this process leads to optical binding forces transporting the AgNRs in the surroundings, while electronic thermalization results in photooxidation, melting, and ripening of the AgNRs into well-defined 3D structures. This work call these structures Airy castles due to their structural similarity with a diffraction-limited Airy disk. The photosculpted Airy castles contain emissive Ag nanoclusters, allowing for the visualization and examination of the aggregation process using luminescence microscopy. This work comprehensively examines the factors that define the photosculpting process, namely, the concentration and shape of the AgNRs, as well as the energy, power, and repetition rate of the laser. Finally, this work investigates the potential applications by measuring the metal-enhanced luminescence of a europium-based luminophore using Airy castles.

Prevalence of pulmonary hypertension in COPD patients living at high altitude.

BACKGROUND: Pulmonary hypertension (PH) is associated with poor prognosis for patients with chronic obstructive pulmonary disease (COPD). Most of the knowledge about PH in COPD has been generated at sea level, with limited information associated with high altitude (HA). OBJECTIVES: To assess the prevalence and severity of PH in COPD patients living in a HA city (2,640 m). METHODS: Cross-sectional study in COPD patients with forced expiratory volume in the first second / forced vital capacity ratio (FEV1/FVC) post-bronchodilator <0,7. Transthoracic echocardiography (TTE), spirometry, carbon monoxide diffusing capacity, and arterial blood gasses tests were performed. Patients were classified according to the severity of airflow limitation. PH was defined by TTE as an estimated systolic pulmonary artery pressure (sPAP) > 36 mmHg or indirect PH signs; severe PH as sPAP > 60 mmHg; and disproportionate PH as an sPAP > 60 mmHg with non-severe airflow limitation (FEV1 > 50% predicted). RESULTS: We included 176 COPD patients. The overall estimated prevalence of PH was 56.3% and the likelihood of having PH increased according to airflow-limitation severity: mild (31.6%), moderate (54.9%), severe (59.6%) and very severe (77.8%) (p = 0.038). The PH was severe in 7.3% and disproportionate in 3.4% of patients. CONCLUSIONS: The estimated prevalence of PH in patients with COPD at HA is high, particularly in patients with mild to moderate airflow limitation, and greater than that described for COPD patients at low altitude. These results suggest a higher risk of developing PH for COPD patients living at HA compared to COPD patients with similar airflow limitation living at low altitude.

A multicomponent reaction platform towards multimodal near-infrared BODIPY dyes for STED and fluorescence lifetime imaging.

We report a platform combining multicomponent reaction synthesis and automated cell-based screening to develop biocompatible NIR-BODIPY fluorophores. From a library of over 60 fluorophores, we optimised compound NIRBD-62c as a multimodal probe with suitable properties for STED super-resolution and fluorescence lifetime imaging. Furthermore, we employed NIRBD-62c for imaging trafficking inside cells and to examine how pharmacological inhibitors can alter the vesicular traffic between intracellular compartments and the plasma membrane.

Activation of rye 5RL neocentromere by an organophosphate pesticide.

An interstitial constriction located on the long arm of rye chromosome 5R (5RL) shows neocentromeric activity at meiosis. In some meiocytes this region is strongly stretched orienting with the true centromere to opposite poles at metaphase I, and keeping sister chromatid cohesion at anaphase I. We found previously that the frequency of neocentric activity varied dramatically in different generations suggesting the effect of environmental factors. Here we studied the behavior of the 5RL neocentromere in mono- and ditelosomic 5RL, and mono-, and disomic 5R wheat-rye addition lines, untreated and treated with an organophosphate pesticide. The treated plants form neocentromeres with an about 4.5-fold increased frequency compared to untreated ones, demonstrating that the pesticide promotes neocentric activity. The neocentromere was activated irrespectively of the pairing configuration or the presence of a complete or truncated 5R centromere. Fluorescence in situ hybridization (FISH) with 2 repetitive sequences (UCM600 and pSc119.2) present at the constriction showed kinetic activity at several locations within this region. Immunostaining with anti-α-tubulin showed that treated plants have abnormal spindles in 46% of the metaphase I cells, indicating that disturbances in spindle formation might promote neocentromere activation.

Dynamic Excimer (DYNEX) Imaging of Lipid Droplets.

Unraveling cellular physiological processes via luminescent probes that target specific cellular microenvironments is quite challenging due to the uneven distribution of probes. Herein, we designed a new dynamic excimer (DYNEX) imaging method that involves the sensitive detection of nanosecond-scale dynamic molecular contacts of a fluorescent acridone derivative and reveals the cell microenvironment polarity. Using our method, we specifically tracked cell lipid droplets in fibroblast colon carcinoma cells. These organelles play a central role in metabolic pathways, acting as energy reservoirs in regulatory processes. DYNEX imaging provides the inner polarity of cell lipid droplets, which can be related to lipid contents and metabolic dysfunctions. This new methodology will inspire development of novel multidimensional fluorescent sensors that are able to provide target-specific and orthogonal information at the nanosecond scale.

Chimeric Drug Design with a Noncharged Carrier for Mitochondrial Delivery.

Recently, it was proposed that the thiophene ring is capable of promoting mitochondrial accumulation when linked to fluorescent markers. As a noncharged group, thiophene presents several advantages from a synthetic point of view, making it easier to incorporate such a side moiety into different molecules. Herein, we confirm the general applicability of the thiophene group as a mitochondrial carrier for drugs and fluorescent markers based on a new concept of nonprotonable, noncharged transporter. We implemented this concept in a medicinal chemistry application by developing an antitumor, metabolic chimeric drug based on the pyruvate dehydrogenase kinase (PDHK) inhibitor dichloroacetate (DCA). The promising features of the thiophene moiety as a noncharged carrier for targeting mitochondria may represent a starting point for the design of new metabolism-targeting drugs.