Feedback control of organ size precision is mediated by BMP2-regulated apoptosis in the Drosophila eye.

Biological processes are intrinsically noisy, and yet, the result of development-like the species-specific size and shape of organs-is usually remarkably precise. This precision suggests the existence of mechanisms of feedback control that ensure that deviations from a target size are minimized. Still, we have very limited understanding of how these mechanisms operate. Here, we investigate the problem of organ size precision using the Drosophila eye. The size of the adult eye depends on the rates at which eye progenitor cells grow and differentiate. We first find that the progenitor net growth rate results from the balance between their proliferation and apoptosis, with this latter contributing to determining both final eye size and its variability. In turn, apoptosis of progenitor cells is hampered by Dpp, a BMP2/4 signaling molecule transiently produced by early differentiating retinal cells. Our genetic and computational experiments show how the status of retinal differentiation is communicated to progenitors through the differentiation-dependent production of Dpp, which, by adjusting the rate of apoptosis, exerts a feedback control over the net growth of progenitors to reduce final eye size variability.

Onset of differentiation is post-transcriptionally controlled in adult neural stem cells.

Whether post-transcriptional regulation of gene expression controls differentiation of stem cells for tissue renewal remains unknown. Quiescent stem cells exhibit a low level of protein synthesis1, which is key to maintaining the pool of fully functional stem cells, not only in the brain but also in the bone marrow and hair follicles2-6. Neurons also maintain a subset of messenger RNAs in a translationally silent state, which react 'on demand' to intracellular and extracellular signals. This uncoupling of general availability of mRNA from translation into protein facilitates immediate responses to environmental changes and avoids excess production of proteins, which is the most energy-consuming process within the cell. However, when post-transcriptional regulation is acquired and how protein synthesis changes along the different steps of maturation are not known. Here we show that protein synthesis undergoes highly dynamic changes when stem cells differentiate to neurons in vivo. Examination of individual transcripts using RiboTag mouse models reveals that whereas stem cells translate abundant transcripts with little discrimination, translation becomes increasingly regulated with the onset of differentiation. The generation of neurogenic progeny involves translational repression of a subset of mRNAs, including mRNAs that encode the stem cell identity factors SOX2 and PAX6, and components of the translation machinery, which are enriched in a pyrimidine-rich motif. The decrease of mTORC1 activity as stem cells exit the cell cycle selectively blocks translation of these transcripts. Our results reveal a control mechanism by which the cell cycle is coupled to post-transcriptional repression of key stem cell identity factors, thereby promoting exit from stemness.

A systematic review on the application of machine learning models in psychometric questionnaires for the diagnosis of attention deficit hyperactivity disorder.

Attention deficit hyperactivity disorder is one of the most prevalent neurodevelopmental disorders worldwide. Recent studies show that machine learning has great potential for the diagnosis of attention deficit hyperactivity disorder. The aim of the present article is to systematically review the scientific literature on machine learning studies for the diagnosis of attention deficit hyperactivity disorder, focusing on psychometric questionnaire tools. The Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines were adopted. The review protocol was registered in the PROSPERO database. A search was conducted in three databases-Web of Science Core Collection, Scopus and Pubmed-with the aim of identifying studies that apply ML techniques to support the diagnosis of attention deficit hyperactivity disorder. A total of 17 empirical studies were found that met the established inclusion criteria. The results showed that machine learning can be used to increase the accuracy of attention deficit hyperactivity disorder diagnosis. Machine learning techniques are useful and effective strategies that can complement traditional diagnostics in patients with attention deficit hyperactivity disorder.

Occupational Lead Exposure Ototoxicity Evaluated With Distortion-Product Otoacoustic Emissions.

OBJECTIVES: To evaluate the extent of hearing loss among pottery workers in Mexico exposed to lead. DESIGN: The authors conducted a cross-sectional study including 315 adult pottery workers. Auditory function was evaluated by air conduction pure-tone audiometry (pure-tone average) and distortion-product otoacoustic emission (DPOAE) levels (amplitude and signal-to-noise ratio). Lead exposure was assessed with a single blood sample test and classified as low, medium, and high according to blood lead tertiles. Logistic regression models were calculated for the association between blood lead levels, pure-tone average, and DPOAE records. RESULTS: Median (25th-75th) blood lead levels were 14 µg/dL (7.5-22.6 µg/dL). The audiometric pattern and DPOAE records were similar across blood lead levels groups in all frequencies, and no statistically significant differences were found. Adjusted logistic regression models showed no increase in the odds for hearing thresholds >25 dB (HL) and DPOAE absence associated with blood lead levels, and no dose-response pattern was observed ( p > 0.05). CONCLUSIONS: Given the results from this cross-sectional study, no association was found between blood lead levels and hearing loss assessed with DPOAE. Future longitudinal work should consider chronic lead exposure estimates among underrepresented populations, which can potentially inform safer work practices to minimize the risk of ototoxicity.

Standardized vs. Relative Intensity in CrossFit.

CrossFit is characterized by being a standardized training program that improves physical performance through the provision of several stimuli regardless of the participant's strength level. This study aimed to compare the acute response in total repetitions as a measurement of performance, jump ability, physiological demand (heart rate and blood lactate), and perceived effort considering the participants' strength level with individualized intensity in CrossFit. Thirty-five participants were assessed and asked to participate on two separate days in a standardized and relative 'As Many Repetitions As Possible' (AMRAP) CrossFit circuit. Both AMRAPs comprised strength, gymnastic and aerobic exercises, although only strength was individualized according to the participant's level. Before the statistical analysis, participants were allocated to higher- or lower-strength groups following the one-repetition maximum-bodyweight ratio in the push press exercise. Results support the existence of a strong relationship between strength level and total repetitions in both AMRAPs. In addition, differences in total repetitions and rate of perceived exertion between strength groups are discarded when AMRAP intensity is individualized while physiological demand and jump ability are maintained. Thus, the higher-strength participants may benefit from similar responses with a lower number of repetitions. Therefore, CrossFit trainers should be encouraged to prescribe strength tasks based on the percentage of 1RM for every training.

Granulocyte Colony Stimulating Factor-Mobilized Peripheral Blood Mononuclear Cells: An Alternative Cellular Source for Chimeric Antigen Receptor Therapy.

Lymphocyte collection by apheresis for CAR-T production usually does not include blood mobilized using granulocyte colony stimulating factor (G-CSF) due to the widespread knowledge that it causes a decrease in the number and functionality of lymphocytes. However, it is used for stem cell transplant, which is a common treatment for hematological malignancies. The growing demand for CAR therapies (CAR-T and NK-CAR), both in research and clinics, makes it necessary to evaluate whether mobilized PBSC products may be potential candidates for use in such therapies. This review collects recent works that experimentally verify the role and functionality of T and NK lymphocytes and the generation of CAR-T from apheresis after G-CSF mobilization. As discussed, T cells do not vary significantly in their phenotype, the ratio of CD4+ and CD8+ remains constant, and the different sub-populations remain stable. In addition, the expansion and proliferation rates are invariant regardless of mobilization with G-CSF as well as the secretion of proinflammatory cytokines and the cytotoxic ability. Therefore, cells mobilized before apheresis are postulated as a new alternative source of T cells for adoptive therapies that will serve to alleviate high demand, increase availability, and take advantage of the substantial number of existing cryopreserved products.

The Biology and Genomics of Human Hair Follicles: A Focus on Androgenetic Alopecia.

Androgenetic alopecia is a highly prevalent condition mainly affecting men. This complex trait is related to aging and genetics; however, multiple other factors, for example, lifestyle, are also involved. Despite its prevalence, the underlying biology of androgenetic alopecia remains elusive, and thus advances in its treatment have been hindered. Herein, we review the functional anatomy of hair follicles and the cell signaling events that play a role in follicle cycling. We also discuss the pathology of androgenetic alopecia and the known molecular mechanisms underlying this condition. Additionally, we describe studies comparing the transcriptional differences in hair follicles between balding and non-balding scalp regions. Given the genetic contribution, we also discuss the most significant risk variants found to be associated with androgenetic alopecia. A more comprehensive understanding of this pathology may be generated through using multi-omics approaches.

Optimizing Antimony Speciation Analysis via Frontal Chromatography-ICP-MS to Explore the Release of PET Additives.

Antimony (Sb) contamination poses significant environmental and health concerns due to its toxic nature and widespread presence, largely from anthropogenic activities. This study addresses the urgent need for an accurate speciation analysis of Sb, particularly in water sources, emphasizing its migration from polyethylene terephthalate (PET) plastic materials. Current methodologies primarily focus on total Sb content, leaving a critical knowledge gap for its speciation. Here, we present a novel analytical approach utilizing frontal chromatography coupled with inductively coupled plasma mass spectrometry (FC-ICP-MS) for the rapid speciation analysis of Sb(III) and Sb(V) in water. Systematic optimization of the FC-ICP-MS method was achieved through multivariate data analysis, resulting in a remarkably short analysis time of 150 s with a limit of detection below 1 ng kg-1. The optimized method was then applied to characterize PET leaching, revealing a marked effect of the plastic aging and manufacturing process not only on the total amount of Sb released but also on the nature of leached Sb species. This evidence demonstrates the effectiveness of the FC-ICP-MS approach in addressing such an environmental concern, benchmarking a new standard for Sb speciation analysis in consideration of its simplicity, cost effectiveness, greenness, and broad applicability in environmental and health monitoring.

Development and content validity of EVAD: A novel tool for evaluating and classifying the severity of adverse events for psychotherapeutic clinical trials.

OBJECTIVE: Develop and obtain content validity of a new tool for Evaluating and Classifying the Severity of Adverse Events for Psychotherapeutic Clinical Trials (EVAD). METHOD: Study of the development process of EVAD in four stages: (1) identify the domain and concept definition through a literature review, (2) instrument design, (3) expert judgment of the EVAD items through Gwent's concordance coefficient, and (4) applicability. RESULTS: In the absence of a consistent conceptual framework of adverse events in psychotherapeutic clinical trials, we have developed a framework and defined it. We have designed EVAD items and their complementary tool for rating adverse events. Content validation by expert judges resulted in CVR = 1.0 for each item and CVI = 0.79 in sufficiency, 0.76 in clarity, 0.91 in coherence and 0.95 in relevance for all items (p < 0.001). Final version of EVAD were applied to three participants for 7 weeks. Overall EVAD seems to be clear and meaningful for participants. CONCLUSIONS: EVAD is a semistructured interview based on a consistent conceptual framework, and proven content validity following the most important guidelines described in the literature. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03878186.

Routine Outcome Monitoring from Psychotherapists' Perspectives: A Framework Analysis Study of Expected Benefits and Difficulties.

Psychotherapists' attitudes and expectations towards routine outcome monitoring can impact the likelihood of its fruitful implementation. While existing studies have predominantly focused on Europe and North America, research in Latin America remains limited. The aim of this study is to explore therapists' expected benefits and difficulties prior to implementing a routine outcome monitoring system in a university psychotherapy service in Ecuador. An exploratory and descriptive cross-sectional qualitative study was carried out with 20 participants aged 21 to 47. Semi-structured interviews were conducted to explore participants' knowledge about routine outcome monitoring, their expectations of the difficulties, benefits, usability and risks of using a monitoring system, as well as their expectations about their role in the process. The data analysis adhered to the framework analysis methodology, leading to the identification of six overarching themes, 36 specific themes and 82 subthemes. The interviews highlighted a spectrum of positive and negative expectations at several levels: institutional/general, therapeutic process, therapists, and clients. Perceived benefits encompassed various aspects, including the availability of supplementary information, continuous adaptation of the therapeutic process, facilitation of organization and treatment planning, opportunities for professional development, and fostering patient trust and empowerment. On the other hand, anticipated difficulties comprised concerns such as discomfort among therapists and clients, increased workload, system usage and technical difficulties, and the risk of excessive quantification. Overall, participants expressed more anticipated benefits than difficulties. We present recommendations that can support and optimize the current local implementation efforts of routine outcome monitoring, both within this service and in other settings. These recommendations consider ways to meet positive expectations and address or mitigate negative ones.

Enhancement of the CO2 adsorption and hydrogenation to CH4 capacity of Ru-Na-Ca/γ-Al2O3 dual function material by controlling the Ru calcination atmosphere.

Integrated CO2 capture and utilization (ICCU) technology requires dual functional materials (DFMs) to carry out the process in a single reaction system. The influence of the calcination atmosphere on efficiency of 4% Ru-8% Na2CO3-8% CaO/γ-Al2O3 DFM is studied. The adsorbent precursors are first co-impregnated onto alumina and calcined in air. Then, Ru precursor is impregnated and four aliquotes are subjected to different calcination protocols: static air in muffle or under different mixtures (10% H2/N2, 50% H2/N2 and N2) streams. Samples are characterized by XRD, N2 adsorption-desorption, H2 chemisorption, TEM, XPS, H2-TPD, H2-TPR, CO2-TPD and TPSR. The catalytic behavior is evaluated, in cycles of CO2 adsorption and hydrogenation to CH4, and temporal evolution of reactants and products concentrations is analyzed. The calcination atmosphere influences the physicochemical properties and, ultimately, activity of DFMs. Characterization data and catalytic performance discover the acccomodation of Ru nanoparticles disposition and basic sites is mostly influencing the catalytic activity. DFM calcined under N2 flow (RuNaCa-N2) shows the highest CH4 production (449 µmol/g at 370°C), because a well-controlled decomposition of precursors which favors the better accomodation of adsorbent and Ru phases, maximizing the specific surface area, the Ru-basic sites interface and the participation of different basic sites in the CO2 methanation reaction. Thus, the calcination in a N2 flow is revealed as the optimal calcination protocol to achieve highly efficient DFM for integrated CO2 adsorption and hydrogenation applications.

Exploiting Ambipolarity in Graphene Field-Effect Transistors for Novel Designs on High-Frequency Analog Electronics.

Exploiting ambipolar electrical conductivity based on graphene field-effect transistors has raised enormous interest for high-frequency (HF) analog electronics. Controlling the device polarity, by biasing the graphene transistor around the vertex of the V-shaped transfer curve, enables to redesign and highly simplify conventional analog circuits, and simultaneously to seek for multifunctionalities, especially in the HF domain. This study presents new insights for the design of different HF applications such as power amplifiers, mixers, frequency multipliers, phase shifters, and modulators that specifically leverage the inherent ambipolarity of graphene-based transistors.

Hybrid Heterostructures of a Spin Crossover Coordination Polymer on MoS2 : Elucidating the Role of the 2D Substrate.

Controlling the deposition of spin-crossover (SCO) materials constitutes a crucial step for the integration of these bistable molecular systems in electronic devices. Moreover, the influence of functional surfaces, such as 2D materials, can be determinant on the properties of the deposited SCO film. In this work, ultrathin films of the SCO Hofmann-type coordination polymer [Fe(py)2 {Pt(CN)4 }] (py = pyridine) onto monolayers of 1T and 2H MoS2 polytypes are grown. The resulting hybrid heterostructures are characterized by GIXRD, XAS, XPS, and EXAFS to get information on the structure and the specific interactions generated at the interface, as well as on the spin transition. The use of a layer-by-layer results in SCO/2D heterostructures, with crystalline and well-oriented [Fe(py)2 {Pt(CN)4 }]. Unlike with conventional Au or SiO2 substrates, no intermediate self-assembled monolayer is required, thanks to the surface S atoms. Furthermore, it is observed that the higher presence of Fe3+ in the 2H heterostructures hinders an effective spin transition for [Fe(py)2 {Pt(CN)4 }] films thinner than 8 nm. Remarkably, when using 1T MoS2 , this transition is preserved in films as thin as 4 nm, due to the reducing character of this metallic substrate. These results highlight the active role that 2D materials play as substrates in hybrid molecular/2D heterostructures.

Automatic Discrimination of Species within the Enterobacter cloacae Complex Using Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry and Supervised Algorithms.

The Enterobacter cloacae complex (ECC) encompasses heterogeneous clusters of species that have been associated with nosocomial outbreaks. These species may have different acquired antimicrobial resistance and virulence mechanisms, and their identification is challenging. This study aims to develop predictive models based on matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) profiles and machine learning for species-level identification. A total of 219 ECC and 118 Klebsiella aerogenes clinical isolates from three hospitals were included. The capability of the proposed method to differentiate the most common ECC species (Enterobacter asburiae, Enterobacter kobei, Enterobacter hormaechei, Enterobacter roggenkampii, Enterobacter ludwigii, and Enterobacter bugandensis) and K. aerogenes was demonstrated by applying unsupervised hierarchical clustering with principal-component analysis (PCA) preprocessing. We observed a distinctive clustering of E. hormaechei and K. aerogenes and a clear trend for the rest of the ECC species to be differentiated over the development data set. Thus, we developed supervised, nonlinear predictive models (support vector machine with radial basis function and random forest). The external validation of these models with protein spectra from two participating hospitals yielded 100% correct species-level assignment for E. asburiae, E. kobei, and E. roggenkampii and between 91.2% and 98.0% for the remaining ECC species; with data analyzed in the three participating centers, the accuracy was close to 100%. Similar results were obtained with the Mass Spectrometric Identification (MSI) database developed recently (https://msi.happy-dev.fr) except in the case of E. hormaechei, which was more accurately identified with the random forest algorithm. In short, MALDI-TOF MS combined with machine learning was demonstrated to be a rapid and accurate method for the differentiation of ECC species.

The Combined Expression of the Nonstructural Protein NS1 and the N-Terminal Half of NS2 (NS21-180) by ChAdOx1 and MVA Confers Protection against Clinical Disease in Sheep upon Bluetongue Virus Challenge.

Bluetongue, caused by bluetongue virus (BTV), is a widespread arthropod-borne disease of ruminants that entails a recurrent threat to the primary sector of developed and developing countries. In this work, we report modified vaccinia virus Ankara (MVA) and ChAdOx1-vectored vaccines designed to simultaneously express the immunogenic NS1 protein and/or NS2-Nt, the N-terminal half of protein NS2 (NS21-180). A single dose of MVA or ChAdOx1 expressing NS1-NS2-Nt improved the protection conferred by NS1 alone in IFNAR(-/-) mice. Moreover, mice immunized with ChAdOx1/MVA-NS1, ChAdOx1/MVA-NS2-Nt, or ChAdOx1/MVA-NS1-NS2-Nt developed strong cytotoxic CD8+ T-cell responses against NS1, NS2-Nt, or both proteins and were fully protected against a lethal infection with BTV serotypes 1, 4, and 8. Furthermore, although a single immunization with ChAdOx1-NS1-NS2-Nt partially protected sheep against BTV-4, the administration of a booster dose of MVA-NS1-NS2-Nt promoted a faster viral clearance, reduction of the period and level of viremia and also protected from the pathology produced by BTV infection. IMPORTANCE Current BTV vaccines are effective but they do not allow to distinguish between vaccinated and infected animals (DIVA strategy) and are serotype specific. In this work we have develop a DIVA multiserotype vaccination strategy based on adenoviral (ChAdOx1) and MVA vaccine vectors, the most widely used in current phase I and II clinical trials, and the conserved nonstructural BTV proteins NS1 and NS2. This immunization strategy solves the major drawbacks of the current marketed vaccines.

Diastereoselective and Scalable Synthesis of 6-(S)-Hydroxycannabidivarin.

The synthesis of 6-(S)-hydroxycannabidivarin was required to assess its biological activity in the treatment of neurological disorders. A novel and scalable synthesis has been developed where the key step involves a Friedel-Crafts alkylation of phloroglucinol with (1S,2R,5R)-2-hydroxy-2-methyl-5-(prop-1-en-2-yl)cyclohex-3-en-1-ylbenzoate. Careful optimization of the reaction conditions identified trifluoromethanesulfonic acid in isopropyl acetate as the best catalyst/solvent combination, providing optimum regioselectivity, diastereoselectivity, and yield for this step. This enabled the multigram synthesis of 6-(S)-hydroxycannabidivarin in 10 steps from S-(+)-carvone.

Comprehensive rehabilitation and job reintegration of people with severe mental illness in a Latin American country: REINTEGRA study protocol.

BACKGROUND: Despite the increasing use of comprehensive rehabilitation models for people with severe mental illness (SMI), there are still limitations to their implementation and replicability in a consensual way, particularly in Latin American countries. The REINTEGRA program aims to be a standardized model of comprehensive rehabilitation focused on psychosocial and cognitive improvement through a set of interventions on different areas of people's functionality, with the goal of reintegrating people with SMI into the labour market. In this paper we summarize the protocol for its subsequent implementation in a mental health institution in Mexico. METHOD: The protocol is based on a quasi-experimental, prospective longitudinal study, with a pragmatic or naturalistic control group. It will be carried out in three phases. Phase 1 consists of a series of interventions focused on psychosocial improvement; Phase 2 focuses on cognitive and behavioral improvement treatments; and Phase 3 targets psychosocial recovery through rehabilitation and reintegration into the labour market. The overall procedure will be monitored with standarized evaluations at different stages of the program. DISCUSSION: This study presents a model of integral rehabilitation of people with SMI. At the moment, one of the obstacles to overcome is the organization and procedural control of the different actors needed for its implementation (nurses, psychologists, doctors, companies, institutions, etc.). REINTEGRA will be the first comprehensive rehabilitation model that includes systematized procedures for job reinsertion for people with SMI in Mexico, which aims to be a standardized tool of easy adaptation and the replicability for other mental health centers and institutions.

Resilience and risk factors associated to depressive symptoms in Mexican healthcare workers during the Covid-19 pandemic.

OBJECTIVE: Report the prevalence of depression, resilience, and risk factors among healthcare workers (HCW) during Co-vid-19. MATERIALS AND METHODS: This is an observational cross-sectional study derived from the ongoing international, prospective multicentric study "The COVID-19 HEalth caRe wOrk-Ers Study" (HEROES). A convenience sample of 2 127 HCW was obtained from Chiapas and Jalisco between May 19th and July 24th 2020. Depression was assessed using the Patient Health Questionnaire, resilience with the Brief Resilience Scale and a Covid risk scale was developed. Model-adjusted prevalence ratios (PRs) and an additive interaction model were performed. RESULTS: Moderate-severe depression was found in 16.6% of HCW. Those from Jalisco, physicians, in hospitals, with chronic illness and mental health history were more depressed. The interaction between resilience and risk showed that, compared to those with no risk and medium/high resilience, HCW at risk with medium/high resilience had a 2.38 PR for depression while those at risk and low resilience had a PR of 5.83. CONCLUSION: This evidence points the need to develop strategies to enhance resilience and reduce the risk in HCW.

Use, Validity and Reliability of Inertial Movement Units in Volleyball: Systematic Review of the Scientific Literature.

The use of inertial devices in sport has become increasingly common. The aim of this study was to examine the validity and reliability of multiple devices for measuring jump height in volleyball. The search was carried out in four databases (PubMed, Scopus, Web of Sciences and SPORTDiscus) using keywords and Boolean operators. Twenty-one studies were selected that met the established selection criteria. The studies focused on determining the validity and reliability of IMUs (52.38%), on controlling and quantifying external load (28.57%) and on describing differences between playing positions (19.05%). Indoor volleyball was the modality in which IMUs have been used the most. The most evaluated population was elite, adult and senior athletes. The IMUs were used both in training and in competition, evaluating mainly the amount of jump, the height of the jumps and some biomechanical aspects. Criteria and good validity values for jump counting are established. The reliability of the devices and the evidence is contradictory. IMUs are devices used in volleyball to count and measure vertical displacements and/or compare these measurements with the playing position, training or to determine the external load of the athletes. It has good validity measures, although inter-measurement reliability needs to be improved. Further studies are suggested to position IMUs as measuring instruments to analyze jumping and sport performance of players and teams.

Compact Modeling of Two-Dimensional Field-Effect Biosensors.

A compact model able to predict the electrical read-out of field-effect biosensors based on two-dimensional (2D) semiconductors is introduced. It comprises the analytical description of the electrostatics including the charge density in the 2D semiconductor, the site-binding modeling of the barrier oxide surface charge, and the Stern layer plus an ion-permeable membrane, all coupled with the carrier transport inside the biosensor and solved by making use of the Donnan potential inside the ion-permeable membrane formed by charged macromolecules. This electrostatics and transport description account for the main surface-related physical and chemical processes that impact the biosensor electrical performance, including the transport along the low-dimensional channel in the diffusive regime, electrolyte screening, and the impact of biological charges. The model is implemented in Verilog-A and can be employed on standard circuit design tools. The theoretical predictions obtained with the model are validated against measurements of a MoS2 field-effect biosensor for streptavidin detection showing excellent agreement in all operation regimes and leading the way for the circuit-level simulation of biosensors based on 2D semiconductors.