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AbstractParvalbumin-positive neurons are inhibitory neurons that release GABA and are mostly represented by fast-spiking basket or chandelier cells. They constitute a minor neuronal population, yet their peculiar profiles allow them to react quickly to any event in the brain under normal or pathological conditions. In this review, we will summarize the current knowledge about the fundamentals of fast-spiking parvalbumin-positive neurons, focusing on their morphology and specific channel/protein content. Next, we will explore their development, maturation, and migration in the brain. Finally, we will unravel their potential contribution to the physiopathology of epilepsy.

PACS:05.45.−a, 42.65.−k, 42.65.Sf ; We introduce a new class of excitable systems with two-dimensional fast dynamics that includes inertia. A novel transition from excitability to relaxation oscillations is discovered where the usual Hopf bifurcation is followed by a cascade of period doubled and chaotic small excitable attractors and, as they grow, by a new type of canard explosion where a small chaotic background erratically but deterministically triggers excitable spikes. This scenario is also found in a model for a nonlinear Fabry-Perot cavity with one pendular mirror. ; This work was partially funded by the European Union ILIAS Project (No. RII3-CT-2003-506222), the CSIC— Spain Grant HIELOCRIS (No. 200530F0052). ; Peer reviewed

Subjective tinnitus is the conscious perception of sound in the absence of any acoustic source. The literature suggests various tinnitus mechanisms, most of which invoke changes in spontaneous firing rates of central auditory neurons resulting from modification of neural gain. Here, we present an alternative model based on evidence that tinnitus is: (1) rare in people who are congenitally deaf, (2) common in people with acquired deafness, and (3) potentially suppressed by active cochlear implants used for hearing restoration. We propose that tinnitus can only develop after fast auditory fiber activity has stimulated the synapse formation between fast-spiking parvalbumin positive (PV+) interneurons and projecting neurons in the ascending auditory path and coactivated frontostriatal networks after hearing onset. Thereafter, fast auditory fiber activity promotes feedforward and feedback inhibition mediated by PV+ interneuron activity in auditory-specific circuits. This inhibitory network enables enhanced stimulus resolution, attention-driven contrast improvement, and augmentation of auditory responses in central auditory pathways (neural gain) after damage of slow auditory fibers. When fast auditory fiber activity is lost, tonic PV+ interneuron activity is diminished, resulting in the prolonged response latencies, sudden hyperexcitability, enhanced cortical synchrony, elevated spontaneous y oscillations, and impaired attention/stress-control that have been described in previous tinnitus models. Moreover, because fast processing is gained through sensory experience, tinnitus would not exist in congenital deafness. Electrical cochlear stimulation may have the potential to reestablish tonic inhibitory networks and thus suppress tinnitus. The proposed framework unites many ideas of tinnitus pathophysiology and may catalyze cooperative efforts to develop tinnitus therapies. ; German Research Foundation (DFG) DFG-Kni-316-4-1 SPP16-08 DFG Comisión Nacional de Investigación Científica y Tecnológica (CONICYT) CONICYT FONDECYT 1161155 Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT) BASAL FB008 ICM P09-015F European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie Grant 764604 722046 National Institute for Health Research (NIHR)

The cell assignment problem is combinatorial, with increased complexity when it is tackled considering resource allocation. This paper models joint cell assignment and resource allocation for cellular heterogeneous networks, and formalizes cell assignment as an optimization problem. Exact algorithms can find optimal solutions to the cell assignment problem, but their execution time increases drastically with realistic network deployments. In turn, heuristics are able to find solutions in reasonable execution times, but they get usually stuck in local optima, thus failing to find optimal solutions. Metaheuristic approaches have been successful in finding solutions closer to the optimum one to combinatorial problems for large instances. In this paper we propose a fast and efficient heuristic that yields very competitive cell assignment solutions compared to those obtained with three of the most widely-used metaheuristics, which are known to find solutions close to the optimum due to the nature of their search space exploration. Our heuristic approach adds energy expenditure reduction in its algorithmic design. Through simulation and formal statistical analysis, the proposed scheme has been proved to produce efficient assignments in terms of the number of served users, resource allocation and energy savings, while being an order of magnitude faster than metaheuritsic-based approaches. ; This paper has been supported by the National Council of Research and Technology (CONACYT) through Grant FONCICYT/272278 and the ERANetLAC (Network of the European Union, Latin America, and the Caribbean Countries) Project ELAC2015/T100761. This paper is partially supported also by the ADVICE Project, TEC2015-71329 (MINECO/FEDER) and the European Union's Horizon 2020 research and innovation programme under Grant Agreement No 777067 (NECOS Project).

Automated profiling of cell morphology is a powerful tool for inferring cell function. However, this technique retains a high barrier to entry. In particular, configuring image processing parameters for optimal cell profiling is susceptible to cognitive biases and dependent on user experience. Here, we use interactive machine learning to identify the optimum cell profiling configuration that maximises quality of the cell profiling outcome. The process is guided by the user, from whom a rating of the quality of a cell profiling configuration is obtained. We use Bayesian optimisation, an established machine learning algorithm, to learn from this information and automatically recommend the next configuration to examine with the aim of maximising the quality of the processing or analysis. Compared to existing interactive machine learning tools that require domain expertise for per-class or per-pixel annotations, we rely on users' explicit assessment of output quality of the cell profiling task at hand. We validated our interactive approach against the standard human trial-and-error scheme to optimise an object segmentation task using the standard software CellProfiler. Our toolkit enabled rapid optimisation of an object segmentation pipeline, increasing the quality of object segmentation over a pipeline optimised through trial-and-error. Users also attested to the ease of use and reduced cognitive load enabled by our machine learning strategy over the standard approach. We envision that our interactive machine learning approach can enhance the quality and efficiency of pipeline optimisation to democratise image-based cell profiling.

Funding Information: The authors thank Dr. Pirkko M Mattila, Dr. Jenni Lahtela and Bhiswa Ghimire for their valuable suggestions on how to improve the web-tool, Olle Hansson for the FIMM cluster server machine to host the web-tool and the database, and all the beta-testers for confirming the smooth operation and reproducibility of the analyses. This work was supported by the Academy of Finland (grants 295504, 310507, 326238, 340141 and 344698 to TA), European Union's Horizon 2020 Research and Innovation Programme (ERA PerMed JAKSTAT-TARGET), the Cancer Society of Finland (TA), the Sigrid Jusélius Foundation (TA), and the Norwegian Cancer Society (grant 216104 to TA). Publisher Copyright: © 2022, The Author(s). ; Identification of cell populations often relies on manual annotation of cell clusters using established marker genes. However, the selection of marker genes is a time-consuming process that may lead to sub-optimal annotations as the markers must be informative of both the individual cell clusters and various cell types present in the sample. Here, we developed a computational platform, ScType, which enables a fully-automated and ultra-fast cell-type identification based solely on a given scRNA-seq data, along with a comprehensive cell marker database as background information. Using six scRNA-seq datasets from various human and mouse tissues, we show how ScType provides unbiased and accurate cell type annotations by guaranteeing the specificity of positive and negative marker genes across cell clusters and cell types. We also demonstrate how ScType distinguishes between healthy and malignant cell populations, based on single-cell calling of single-nucleotide variants, making it a versatile tool for anticancerapplications. The widely applicable method is deployed both as an interactive web-tool (https://sctype.app), and as an open-source R-package. ; Peer reviewed

FOXP3(+) regulatory T cells (Tregs) are central for maintaining peripheral tolerance and immune homeostasis. Because of their immunosuppressive characteristics, Tregs are a potential therapeutic target in various diseases such as autoimmunity, transplantation and infectious diseases like COVID-19. Numerous studies are currently exploring the potential of adoptive Treg therapy in different disease settings and novel genome editing techniques like CRISPR/Cas will likely widen possibilities to strengthen its efficacy. However, robust and expeditious protocols for genome editing of human Tregs are limited. Here, we describe a rapid and effective protocol for reaching high genome editing efficiencies in human Tregs without compromising cell integrity, suitable for potential therapeutic applications. By deletion of IL2RA encoding for IL-2 receptor alpha-chain (CD25) in Tregs, we demonstrated the applicability of the method for downstream functional assays and highlighted the importance for CD25 for in vitro suppressive function of human Tregs. Moreover, deletion of IL6RA (CD126) in human Tregs elicits cytokine unresponsiveness and thus may prevent IL-6-mediated instability of Tregs, making it an attractive target to potentially boost functionality in settings of adoptive Treg therapies to contain overreaching inflammation or autoimmunity. Thus, our rapid and efficient protocol for genome editing in human Tregs may advance possibilities for Treg-based cellular therapies. ; European Research Council (ERC) under the European Union [640116]; SALK-grant from the government of Flanders; Research Foundation Flanders, Belgium (FWO)

Acknowledgments: This study was supported by Instituto de Salud Carlos III (ISCiii) of Spain, co-financed by FEDER funds from European Union, through grants PI18/01557 (to AG), PI18/01556 (to JV), and CIBERNED (CB06/05/1116 to AG and CB06/05/0094 to JV); by Junta de Andalucia through Consejería de Economía y Conocimiento grants UMA18-FEDERJA-211 (to AG), PY18-RT-2233 (to AG) and US-1262734 (to JV) co-financed by Programa Operativo FEDER 2014-2020 and Consejeria de Salud grant PI-0276-2018 (to JAGL). ; Oligodendrocytes (OLs) are highly specialized cells of the central nervous system responsible for myelin production and metabolic support of neurons. Defects in OLs are crucial in several neurodegenerative diseases including multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). Scarce access to primary samples and lack of efficient protocols to generate OLs from human pluripotent stem cells (hPSCs) are hampering our understanding of OL biology and the development of novel therapies. To promote the conversion of hPSCs into OLs, we have screened for a number of transcription factors (TFs) previously reported to be involved in OL generation. We found that the overexpression of SOX10 was sufficient to generate O4+ oligodendrocyte precursor cells (OPCs) from hPSCs only 10 days after SOX10 induction. Generated OPCs expressed mature OL proteins as MBP or MOG. At the transcriptome level, generated OPCs resembled primary OPCs. To test the functionality of generated OPCs, O4+ cells were co-cultured together with neurons, finding that O4+ cells were able to myelinate the neurons. Moreover, O4+ cells were injected intracerebrally in newborn shiverer RAG2-/- mice, finding that generated OLs extended within the corpus callosum and generated functional myelin, demonstrating the functionality of generated cells also in vivo. The protocol also describes an alternative for viral transduction, by incorporating an inducible SOX10 in the safe harbor locus AAVS1, yielding ~100% pure OPCs. O4+ OPCs can be co-cultured with maturing hPSC-derived neurons in 96/384-well- format plates, allowing the screening of pro-myelinating compounds. We have developed a novel methodology for a fast (20 days from hPSC stage) and efficient generation of functional OLs, which allow testing of compounds involved in myelination. This technology will allow further studies to better understand human OL biology and the screening of potential compounds involved in myelination in a human setting. ; Universidad de Málaga. Campus de Excelencia Internacional Andalucía Tech.

We describe a fast, simple and low temperature electrochemical technique for the preparation of zinc oxide layers on rigid and flexible substrates. The layers, prepared from a zinc nitrate precursor, are of high structural and optical quality. They have been optimized to be applied as efficient electron transport layers in CH3NH3PbI3-sensitized perovskite solar cells (PSCs). We show that an electrodeposition time of only two minutes and a low processing temperature are sufficient to fabricate solar cells with a power conversion efficiency close to 11%, with a high short circuit current and a small J–V curve hysteresis. The key parameters of the cell functioning have been analyzed over a large applied voltage range by the impedance spectroscopy technique. The solar cell characteristic changes with the ZnO layer deposition time are explained by the variation of the recombination and charge transfer resistances. ; J.Z. acknowledges the Guangzhou Government for scholarship (Oversea Study Program of the Guangzhou Elite Project). We thank Dr Odile Majerus for the help in Raman spectroscopy measurements.

Cu2ZnSnS4 thin films have been produced via rapid thermal evaporation of off-stoichiometric kesterite powder followed by annealing in an Ar atmosphere. Different heating rates were applied during the thermal treatments. The chemical composition and structural properties of the deposited layers as well as the distribution of the elements through the kesterite thin film have been investigated. The initial growth of a SnS secondary phase during evaporation led to the formation of this secondary phase next to the Mo back contact. Solar cell power conversion efficiencies were limited to values about 3 % due to this secondary phase. Furthermore, an increased open circuit voltage was demonstrated by using a Zn(O,S) buffer layer ; This work was supported by DAAD project (INTERKEST, Ref: 57050358), Marie Curie-ITN (KESTCELLS, GA: 316488) and MINECO project (SUNBEAM, ENE2013-49136-C4-3-R). RC and ES acknowledge financial support from Spanish MINECO within the Ramón y Cajal program (RYC-2011-08521) and (RYC-2011-09212) respectively. SG also thanks the Government of Spain for the FPI fellowship (BES-2014-068533).

R.B. and M.A.M. have been supported by the European Social Fund (EU), Aragón Government (GrantLMP124-18 and Group E24-17R), and the University of Zaragoza-CUD (grant UZCUD2019-CIE-04). R.B. has beensupported by the Spanish Ministry of Economy and Competitiveness (grant PGC2018-096026-B-I00). M.A.M. hasbeen supported by the Spanish Ministry of Economy and Competitiveness (grant DPI2016-75458-R). L.P. has been supported by the Spanish Ministry of Economy and Competitiveness (grant MTM2017-87697-P) and by Programade Ayudas "Severo Ochoa" of Principado de Asturias (Grant PA-18-PF-BP17-072). E.P. has been supported bythe European Research Council (Grant ERC-638284), Spanish Ministry of Economy and Competitiveness (grantDPI2016-75458-R), European Social Fund (EU), and Aragón Government (grant LMP124-18 and Group T39-17).

This work was supported in part by the European Space Agency under Grant ESTEC/AO/1-7064/12/NL/MH, in part by the Ministerio de Economia y Competitividad, Spanish Government, under Grant MIRIIEM TEC2014-54005-P and Grant MYRADA TEC2016-75103-C2-1-R, and in part by the Gobierno del Principado de Asturias/FEDER under Grant GRUPIN14-114

This study was funded in part by the Spanish Ministry of Science and Innovation under Grants DPI2013-46541-R and TIN2014-56967-R and by the Principality of Asturias Government under Project FC-15-GRUPIN14-073.