Noise or signal? Spontaneous activity of dorsal horn neurons: patterns and function in health and disease.

Spontaneous activity refers to the firing of action potentials by neurons in the absence of external stimulation. Initially considered an artifact or "noise" in the nervous system, it is now recognized as a potential feature of neural function. Spontaneous activity has been observed in various brain areas, in experimental preparations from different animal species, and in live animals and humans using non-invasive imaging techniques. In this review, we specifically focus on the spontaneous activity of dorsal horn neurons of the spinal cord. We use a historical perspective to set the basis for a novel classification of the different patterns of spontaneous activity exhibited by dorsal horn neurons. Then we examine the origins of this activity and propose a model circuit to explain how the activity is generated and transmitted to the dorsal horn. Finally, we discuss possible roles of this activity during development and during signal processing under physiological conditions and pain states. By analyzing recent studies on the spontaneous activity of dorsal horn neurons, we aim to shed light on its significance in sensory processing. Understanding the different patterns of activity, the origins of this activity, and the potential roles it may play, will contribute to our knowledge of sensory mechanisms, including pain, to facilitate the modeling of spinal circuits and hopefully to explore novel strategies for pain treatment.

Analysis of the Attitudes towards Sexuality in People with Intellectual Disabilities: A Cross-Sectional Study.

The barriers faced by people with intellectual disabilities are many. One of the areas in which many problems have been identified is the sexual domain. This descriptive study aims to analyze the attitudes of the family environment, professional carers, and the general population toward their sexuality. A cross-sectional descriptive study was carried out between 2022 and 2023, using convenience sampling among family members and carers from different centers working with people with intellectual disabilities in Spain, and among the general population not related to people with intellectual disabilities. A total of 583 responses were received and significant differences were found for all variables, with the variables related to family or work proximity being those that provided the most significant and relevant results. It was observed that the male sex has a more paternalistic attitude and that in rural areas there is a more permissive attitude towards the sexuality of people with intellectual disabilities. People who work with people with disabilities have more positive attitudes towards this group, while direct relatives have more paternalistic attitudes. Nursing care in the community and specialized centers should be based on an adequate therapeutic relationship and personalized care.

Impedance-Frequency Response of Closed Electrolytic Cells.

The electric AC response of electrolytic cells with DC bias is analyzed solving numerically the Poisson-Nernst-Planck equations and avoiding the commonly used infinite solution approximation. The results show the presence of an additional low-frequency dispersion process associated with the finite spacing of the electrodes. Moreover, we find that the condition of fixed ionic content inside the electrolytic cell has a strong bearing on both the steady-state and the frequency response. For example: the characteristic frequency of the high-frequency dispersion decreases when the DC potential increases and/or the electrode spacing decreases in the closed cell case, while it remains essentially insensitive on these changes for open cells. Finally, approximate analytic expressions for the dependences of the main parameters of both dispersion processes are also presented.

Synchronous firing of dorsal horn neurons at the origin of dorsal root reflexes in naïve and paw-inflamed mice.

Spinal interneurons located in the dorsal horn induce primary afferent depolarization (PAD) controlling the excitability of the afferent's terminals. Following inflammation, PAD may reach firing threshold contributing to maintain inflammation and pain. Our aim was to study the collective behavior of dorsal horn neurons, its relation to backfiring of primary afferents and the effects of a peripheral inflammation in this system. Experiments were performed on slices of spinal cord obtained from naïve adult mice or mice that had suffered an inflammatory pretreatment. Simultaneous recordings from groups of dorsal horn neurons and primary afferents were obtained and machine-learning methodology was used to analyze effective connectivity between them. Dorsal horn recordings showed grouping of spontaneous action potentials from different neurons in "population bursts." These occurred at irregular intervals and were formed by action potentials from all classes of neurons recorded. Compared to naïve, population bursts from treated animals concentrated more action potentials, had a faster onset and a slower decay. Population bursts were disrupted by perfusion of picrotoxin and held a strong temporal correlation with backfiring of afferents. Effective connectivity analysis allowed pinpointing specific neurons holding pre- or post-synaptic relation to the afferents. Many of these neurons had an irregular fast bursting pattern of spontaneous firing. We conclude that population bursts contain action potentials from neurons presynaptic to the afferents which are likely to control their excitability. Peripheral inflammation may enhance synchrony in these neurons, increasing the chance of triggering action potentials in primary afferents and contributing toward central sensitization.

Active Microbial Airborne Dispersal and Biomorphs as Confounding Factors for Life Detection in the Cell-Degrading Brines of the Polyextreme Dallol Geothermal Field.

Determining the precise limits of life in polyextreme environments is challenging. Studies along gradients of polyextreme conditions in the Dallol proto-volcano area (Danakil salt desert, Ethiopia) showed the occurrence of archaea-dominated communities (up to 99%) in several hypersaline systems but strongly suggested that life did not thrive in the hyperacidic (pH ∼0), hypersaline (∼35% [wt/vol],) and sometimes hot (up to 108°C) ponds of the Dallol dome. However, it was recently claimed that archaea flourish in these brines based on the detection of one Nanohaloarchaeotas 16S rRNA gene and fluorescent in situ hybridization (FISH) experiments with archaea-specific probes. Here, we characterized the diversity of microorganisms in aerosols over Dallol, and we show that, in addition to typical bacteria from soil/dust, they transport halophilic archaea likely originating from neighboring hypersaline ecosystems. We also show that cells and DNA from cultures and natural local halophilic communities are rapidly destroyed upon contact with Dallol brine. Furthermore, we confirm the widespread occurrence of mineral particles, including silica-based biomorphs, in Dallol brines. FISH experiments using appropriate controls show that DNA fluorescent probes and dyes unspecifically bind to mineral precipitates in Dallol brines; cellular morphologies were unambiguously observed only in nearby hypersaline ecosystems. Our results show that airborne cell dispersal and unspecific binding of fluorescent probes are confounding factors likely affecting previous inferences of archaea thriving in Dallol. They highlight the need for controls and the consideration of alternative abiotic explanations before safely drawing conclusions about the presence of life in polyextreme terrestrial or extraterrestrial systems. IMPORTANCE Determining the precise limits of life in polyextreme environments is challenging. Confounding factors such as exogenous contamination and the abiotic formation of structures resembling cells need to be considered before concluding on the unambiguous development of microbial life in low-biomass environments. Here, we explored how these factors can affect contrasting reports about microbial life thriving in the hypersaline and hyperacidic brines of the Dallol geothermal field (Danakil Depression, Ethiopia). We show not only that aerosols actively transport a wide diversity of prokaryotic and eukaryotic cells over Dallol but also that, upon contact with the chaotropic hyperacidic brine, cells and DNA are rapidly degraded. We also show the extant occurrence of mineral (mostly silica-based) biomorphs that unspecifically bind fluorescent probes and dyes. Our study highlights the need for controls and the consideration of alternative abiotic explanations before safely drawing conclusions on the presence of life in polyextreme terrestrial or extraterrestrial systems.

Central sensitization of dorsal root potentials and dorsal root reflexes: An in vitro study in the mouse spinal cord.

BACKGROUND: Axo-axonic contacts onto central terminals of primary afferents modulate sensory inputs to the spinal cord. These contacts produce primary afferent depolarization (PAD), which serves as a mechanism for presynaptic inhibition, and also produce dorsal root reflexes (DRRs), which may regulate the excitability of peripheral terminals and second order neurons. We aimed to identify changes in these responses as a consequence of peripheral inflammation. METHODS: In vitro spinal cord recordings of spontaneous activities in dorsal and ventral roots were performed in control mice and following paw inflammation. We also used pharmacological assays to define the neurotransmitter systems implicated in such responses. RESULTS: Paw inflammation increased the frequency and amplitude of spontaneous dorsal root depolarizations, the occurrence of DRRs and the amplitude of ventral roots depolarizations. PAD was classified in two different patterns based on their relation to ventral activity: time-locked and independent events. Both patterns increased in amplitude after paw inflammation, and independent events also increased in frequency. The circuits that were responsible for this activity implicated both glutamatergic and GABAergic transmission. Adrenergic modulation differentially affected both types of PAD, and this modulation changed after paw inflammation. CONCLUSIONS: Our findings suggest the existence of independent spinal circuits at the origin of PAD and DRRs. Inflammation modulates these circuits differentially, unveiling varied mechanisms of spinal sensitization. This in vitro approach provides an isolated model for the study of the mechanisms of central sensitization and for the performance of pharmacological assays with the purpose of identifying and testing novel antinociceptive targets. SIGNIFICANCE: Spinal circuits modulate activity of primary afferents acting on central terminals. Under in vitro conditions, dorsal roots show spontaneous activity in the form of depolarizations and action potentials. Our findings are consistent with the existence of several independent generator circuits. Experimental paw inflammation reduced mechanical withdrawal threshold and significantly increased the spontaneous activity of dorsal roots, which may be secondary to an enhanced output of spinal generators. This can be considered as a novel sign of central sensitization.

Changes in the constituents of the "Bosque de Agua" of the Sierra Cruces-Ajusco-Chichinautzín, Mexico, an area with payment for environmental services.

The "Bosque de Agua", to the west and south of Mexico City, which is the fifth largest city in the world, has historically suffered disturbances in forest cover, with a consequent reduction in the environmental services provided. Changes in the state of the forests between 1994 and 2017 are here analyzed in terms of the annual net change in area of the different cover densities and the different change processes. In general, the net change was favorable in all cases: forest improvement vs. forest degradation, reforestation vs. deforestation, and afforestation vs. land use change. There were changes in 16.03% of the Bosque de Agua: recovery in 11.09% and disturbance in 4.94%. This marked recovery is the result of the protected status of two-thirds of the forest, the payment for hydrological environmental services in 29.33% of the forest, as of 2003, and the continuous programs of reforestation, fire control and surveillance by the local communities, circumstances that have allowed the recovery to exceed the disturbance in most of the Bosque de Agua. One-third of the forest disturbance is concentrated in six of the 35 municipalities in the southern region, caused by clandestine logging by organized gangs, due to the state of ungovernability that reigns in these municipalities. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12665-021-10025-w.

Archaeal overdominance close to life-limiting conditions in geothermally influenced hypersaline lakes at the Danakil Depression, Ethiopia.

The Dallol protovolcanic area on the Danakil Depression (Afar region, Ethiopia) exhibits unique hydrothermal manifestations in hypersaline context, yielding varied polyextreme physicochemical conditions. Previous studies identified a wide archaeal diversity in less extreme brines but failed to identify microorganisms thriving in either high-chaotropicity, low-water-activity brines or hyperacidic-hypersaline Na-Fe-rich brines. Recently, we accessed several small lakes under intense degassing activity adjacent to the Round Mountain, west to the Dallol dome [Western Canyon Lakes (WCL); WCL1-5]. They exhibited intermediate parameter combinations (pH ~ 5, 34%-41% (weight/volume) NaCl-dominated salts with relatively high levels of chaotropic Mg-Ca salts) that should allow to better constrain life limits. These lakes were overwhelmingly dominated by Archaea, encompassing up to 99% of prokaryotic 16S rRNA gene amplicon sequences in metabarcoding studies. The majority belonged to Halobacteriota and Nanohaloarchaeota, the latter representing up to half of prokaryotic sequences. Optical and epifluorescence microscopy showed active cells in natural samples and diverse morphotypes in enrichment cultures. Scanning electron microscopy coupled with energy-dispersive X-ray spectroscopy revealed tiny cells (200-300 nm diameter) epibiotically associated with somewhat larger cells (0.6-1 µm) but also the presence of silica-dominated precipitates of similar size and shape, highlighting the difficulty of distinguishing microbes from mineral biomorphs in this kind of low-biomass systems.

Discovering Effective Connectivity in Neural Circuits: Analysis Based on Machine Learning Methodology.

As multielectrode array technology increases in popularity, accessible analytical tools become necessary. Simultaneous recordings from multiple neurons may produce huge amounts of information. Traditional tools based on classical statistics are either insufficient to analyze multiple spike trains or sophisticated and expensive in computing terms. In this communication, we put to the test the idea that AI algorithms may be useful to gather information about the effective connectivity of neurons in local nuclei at a relatively low computing cost. To this end, we decided to explore the capacity of the algorithm C5.0 to retrieve information from a large series of spike trains obtained from a simulated neuronal circuit with a known structure. Combinatory, iterative and recursive processes using C5.0 were built to examine possibilities of increasing the performance of a direct application of the algorithm. Furthermore, we tested the applicability of these processes to a reduced dataset obtained from original biological recordings with unknown connectivity. This was obtained in house from a mouse in vitro preparation of the spinal cord. Results show that this algorithm can retrieve neurons monosynaptically connected to the target in simulated datasets within a single run. Iterative and recursive processes can identify monosynaptic neurons and disynaptic neurons under favorable conditions. Application of these processes to the biological dataset gives clues to identify neurons monosynaptically connected to the target. We conclude that the work presented provides substantial proof of concept for the potential use of AI algorithms to the study of effective connectivity.

Lyophilized Autologous Serum Eyedrops: Experimental and Comparative Study.

PURPOSE: To analyze the biological stability of autologous serum eyedrops after lyophilization. DESIGN: Prospective, comparative experimental study. METHODS: This was a comparative study with serum obtained from 12 healthy volunteers. The concentrations of different epitheliotropic factors (eg, transforming growth factor-ß [TGF-ß1], epidermal growth factor [EGF], platelet-derived growth factor AB [PDGF-AB], and albumin) were measured in fresh and lyophilized serum. The samples were studied after serum preparation (fresh serum) and immediately after saline solution reconstitution of lyophilized serum (0), 15, and 30 days later. The biological effects of both serum samples were also compared on conjunctival and corneal cell cultures. The pH, osmolarity, and serum density were also determined. RESULTS: No significant differences were found in the concentration of growth factors between fresh serum and re-dissolved serum samples after lyophilization. The concentration of growth factors remained stable during 1 month at 4°C in re-dissolved lyophilized form with saline solution. No differences were found related to osmolarity, pH, and density between fresh and lyophilized serum. In addition, no differences were found on the conjunctival and corneal cells proliferation and differentiation in cells cultures between either serum preparation. CONCLUSIONS: The properties of autologous serum remain after lyophilization. The lyophilized serum can be easily stored without temperature restrictions and easily reconstituted for preparation of eyedrops for standard clinical use.

Hyperdiverse archaea near life limits at the polyextreme geothermal Dallol area.

Microbial life has adapted to various individual extreme conditions; yet, organisms simultaneously adapted to very low pH, high salt and high temperature are unknown. We combined environmental 16S/18S ribosomal RNA gene metabarcoding, cultural approaches, fluorescence-activated cell sorting, scanning electron microscopy and chemical analyses to study samples along such unique polyextreme gradients in the Dallol-Danakil area in Ethiopia. We identified two physicochemical barriers to life in the presence of surface liquid water defined by (1) high chaotropicity-low water activity in Mg2+/Ca2+-dominated brines and (2) hyperacidity-salt combinations (pH ~0/NaCl-dominated salt saturation). When detected, life was dominated by highly diverse ultrasmall archaea that were widely distributed across phyla with and without previously known halophilic members. We hypothesize that a high cytoplasmic K+-level was an original archaeal adaptation to hyperthermophily, subsequently exapted during several transitions to extreme halophily. We detect active silica encrustment/fossilization of cells but also abiotic biomorphs of varied chemistry. Our work helps circumscribing habitability and calls for cautionary interpretations of morphological biosignatures on Earth and beyond.

Implication of Kv7 Channels in the Spinal Antinociceptive Actions of Celecoxib.

Celecoxib is a nonsteroidal anti-inflammatory drug (NSAID) commonly used to treat pain conditions in humans. In addition to its blocking activity on cyclooxygenase (COX) enzymes, several other targets could contribute to its analgesic activity. Here we explore the spinal antinociceptive actions of celecoxib and the potential implication of Kv7 channels in mediating its effects. Spinal cord in vitro preparations from hind paw-inflamed animals were used to assess the segmental sensory-motor and the early sensory processing of nociceptive information. Electrophysiological recordings of ventral roots and dorsal horn neurones were obtained, and the effects of celecoxib and Kv7 modulators on responses to repetitive dorsal root stimulation at C-fiber intensity were assessed. Celecoxib applied at clinically relevant concentrations produced depressant effects on responses to dorsal root stimulation recorded from both ventral roots and individual dorsal horn neurones; by contrast, the non-nociceptive monosynaptic reflex was unaffected. The NSAID indomethacin had no effect on spinal reflexes, but further coapplication of celecoxib still produced depressant effects. The depressant actions of celecoxib were abolished after Kv7 channel blockade and mimicked by its structural analog dimethyl-celecoxib, which lacks COX-blocking activity. The present results identify Kv7 channels as novel central targets for celecoxib, which may be relevant to its analgesic effect. This finding contributes to better understand the pharmacology of celecoxib and reinforces both the role of Kv7 channels in modulating the excitability of central pain pathways and its validity as target for the design of analgesics.

Changes in Corneal Expression of MUC5AC after Autologous Serum Eyedrop Treatment in Patients with Limbal Stem Cell Deficiency.

Purpose: To evaluate the effect of autologous serum eyedrops treatment on corneal expression of the MUC5AC in patients with limbal deficiency. Methods: A prospective and comparative interventional case series study of 42 eyes of 21 patients was performed before and 8 weeks after treatment with autologous serum. All patients underwent a complete ophthalmic assessment of the tear film and ocular surface, corneal impression cytology (IC) and MUC5AC detection by Reverse Transcription-Polymerase Chain Reaction (RT-PCR). Results: Forty-one of the 42 eyes studied were available for both conventional cytology and MUC5AC analysis prior to and after treatment. Differences between outcomes obtained by impression cytology and MUC5AC detection were found in 9 of 82 samples (11%). We found changes in the corneal expression of MUC5AC after treatment in 19 of 41 eyes (46.3%): 18 of them (94.7%) changed from positive to negative expression, and 1 eye (5.3%) changed from negative to positive MUC5AC expression after autologous serum eyedrops. These changes were related with the corneal involvement prior to treatment (15 of them (78.9%) occurred in patients with slight corneal involvement), and with the improvement in the degree of squamous metaplasia after treatment (P = .001 and P = .003, respectively). Conclusions: The treatment significantly improved tear stability, squamous metaplasia, and subjective patient perception. Autologous serum eyedrops treatment diminished the corneal expression of MUC5AC mainly in patients with slight corneal involvement before treatment.

A Polyextreme Hydrothermal System Controlled by Iron: The Case of Dallol at the Afar Triangle.

One of the latest volcanic features of the Erta Ale range at the Afar Triangle (NE Ethiopia) has created a polyextreme hydrothermal system located at the Danakil depression on top of a protovolcano known as the dome of Dallol. The interaction of the underlying basaltic magma with the evaporitic salts of the Danakil depression has generated a unique, high-temperature (108 °C), hypersaline (NaCl supersaturated), hyperacidic (pH values from 0.1 to -1.7), oxygen-free hydrothermal site containing up to 150 g/L of iron. We find that the colorful brine pools and mineral patterns of Dallol derive from the slow oxygen diffusion and progressive oxidation of the dissolved ferrous iron, the iron-chlorine/-sulfate complexation, and the evaporation. These inorganic processes induce the precipitation of nanoscale jarosite-group minerals and iron(III)-oxyhydroxides over a vast deposition of halite displaying complex architectures. Our results suggest that life, if present under such conditions, does not play a dominant role in the geochemical cycling and mineral precipitation at Dallol as opposed to other hydrothermal sites. Dallol, a hydrothermal system controlled by iron, is a present-day laboratory for studying the precipitation and progressive oxidation of iron minerals, relevant for geochemical processes occurring at early Earth and Martian environments.

Numerical Solution of the Electrokinetic Equations for Multi-ionic Electrolytes Including Different Ionic Size Related Effects.

One of the main assumptions of the standard electrokinetic model is that ions behave as point-like entities. In a previous work (López-García, et al., 2015) we removed this assumption and analyzed the influence of finite ionic size on the dielectric and electrokinetic properties of colloidal suspensions using both the Bikerman and the Carnahan⁻Starling equations for the steric interactions. It was shown that these interactions improved upon the standard model predictions so that the surface potential, electrophoretic mobility, and the conductivity and permittivity increment values were increased. In the present study, we extend our preceding works to systems made of three or more ionic species with different ionic sizes. Under these conditions, the Bikerman and Carnahan⁻Starling expressions cease to be valid since they were deduced for single-size spheres. Fortunately, the Carnahan⁻Starling expression has been extended to mixtures of spheres of unequal size, namely the "Boublik⁻Mansoori⁻Carnahan⁻Starling⁻Leland" (BMCSL) equation of state, making it possible to analyze the most general case. It is shown that the BMCSL expression leads to results that differ qualitatively and quantitatively from the standard electrokinetic model.

Origin and classification of spontaneous discharges in mouse superficial dorsal horn neurons.

Superficial laminae of the spinal cord possess a considerable number of neurons with spontaneous activity as reported in vivo and in vitro preparations of several species. Such neurons may play a role in the development of the nociceptive system and/or in the spinal coding of somatosensory signals. We have used electrophysiological techniques in a horizontal spinal cord slice preparation from adult mice to investigate how this activity is generated and what are the main patterns of activity that can be found. The results show the existence of neurons that fire regularly and irregularly. Within each of these main types, it was possible to distinguish patterns of spontaneous activity formed by single action potentials and different types of bursts according to intra-burst firing frequency. Activity in neurons with irregular patterns was blocked by a mixture of antagonists of the main neurotransmitter receptors present in the cord. Approximately 82% of neurons with a regular firing pattern were insensitive to synaptic antagonists but their activity was inhibited by specific ion channel blockers. It is suggested that these neurons generate endogenous activity due to the functional expression of hyperpolarisation-activated and persistent sodium currents driving the activity of irregular neurons.

The Influence of Recognition and Social Support on European Health Professionals' Occupational Stress: A Demands-Control-Social Support-Recognition Bayesian Network Model.

Healthcare professionals undergo high levels of occupational stress as a result of their working conditions. Thus, the aim of this study is to develop a model that focuses on healthcare professionals so as to analyze the influence that job demands, control, social support, and recognition have on the likelihood that a worker will experience stress. The data collected correspond to 2,211 healthcare workers from 35 countries, as reported in the sixth European Working Condition Survey (EWCS). The results obtained from this study allow us to infer stress under several working condition scenarios and to identify the more relevant variables in order to reduce this stress in healthcare professionals, which is of paramount importance to managing the stress of workers in this sector. The Bayesian network proposed indicates that emotional demands have a greater influence on raising the likelihood of stress due to workload than do family demands. The results show that the support of colleagues, in general, has less effect on reducing stress than social support from superiors. Furthermore, the sensitivity analysis shows that, in high-demand and low-control situations, recognition clearly impacts stress, drastically reducing it.

Modified lateral tarsal strip for involutional entropion and ectropion surgery.

PURPOSE: Our purpose was to assess our outcomes in involutional lower eyelid ectropion and entropion surgery after horizontal eyelid tightening by a modified tarsal strip technique. METHODS: A prospective study of 88 eyelids with ectropion and 96 with entropion was performed. Patients were randomly distributed into two groups: the control group included 90 eyelids (46 entropion and 44 ectropion) and the other group of 94 eyelids (50 entropion and 44 ectropion). The control group was treated with a conventional tarsal strip, whereas the second group underwent the same surgery except for a modified suture placement of the tarsal strip different in patients with ectropion and entropion. The mean follow-up was 5.4 years. Horizontal eyelid laxity, orbicularis muscle and lower eyelid retractors function were measured prior and after surgery. Recurrence rate was also evaluated. RESULTS: Recurrent entropion occurred in eight eyelids (17.4 %) treated with conventional tarsal strip, while only two eyelids (4 %) showed recurrence after surgery in the group treated with the modified technique. Recurrence ectropion was only found in one eyelid (2.3 %) in the control group. Pathological horizontal laxity was present in all patients at the baseline study. After surgery, the horizontal laxity improved in both groups, we found significant differences in the patients treated with the modified technique (P=0.04). CONCLUSIONS: The modified suture placement of the tarsal strip reported in this work improves the lower eyelid stability and prevents future recurrences after surgery. This modified technique is useful for the management of patients with entropion and moderate eyelid dysfunction retractors without other surgical procedures.