Specifically, CO, in safe dosages, elicits neurorestoration via igniting sGC/cGMP/MAPK signaling and crosstalk between HO‐CO, HIF‐1α/VEGF, and NOS pathways. Xe rescues neurons through NMDA antagonism and PI3K/Akt/HIF‐1α/ERK activation. Primary findings also reveal that the need to utilize cutting‐edge molecular and genetic tactics to validate mechanistic targets and optimize outcome consistency remains urgent; the number of neurotherapeutic investigations is limited, without published results from large in vivo models. Lastly, the broad‐spectrum, concurrent multimodal homeostatic actions of medical gases may represent a novel pharmaceutical approach to treating critical organ failure and neurotrauma.Gaseous molecules have been increasingly explored for therapeutic development. Here, following an analytical background introduction, a systematic review of medical gas research is presented, focusing on tissue protections, mechanisms, data tangibility, and translational challenges. The pharmacological efficacies of carbon monoxide (CO) and xenon (Xe) are further examined with emphasis on intracellular messengers associated with cytoprotection and functional improvement for the CNS, heart, retina, liver, kidneys, lungs, etc. Overall, the outcome supports the hypothesis that readily deliverable “biological gas” (CO, H This systematic review is focused on tissue protections, mechanisms, data qualities, and translational challenges of experimental gas therapies. The outcome suggests that biological/noble gases in safe dosages preserve cells by modulating oxidative, inflammatory, apoptotic, survival, and/or repair processes; it remains urgent to validate therapeutic targets via cutting‐edge molecular/genetic technologies. Gas agents may be developed to treat organ failure and neurotrauma. For the formulated literature search, we sought articles  on experimental mechanistic investigations of medical gases as therapeutics, with relevant clinical reports crosschecked to assess translational potential. Keywords comprising Brain, Medical Gas, Neural, Protection, Preservation, Regeneration, Repair, Spinal Cord, etc. plus their varied combinations (Section  2) Scopus, an abstract and citation database covering topics of life sciences, social sciences, physical sciences, and health sciences provided by Elsevier; and 3) Embase, a biomedical and pharmacological bibliographic database produced by Elsevier that includes published literature designed to support compliance with the regulatory requirements of a licensed drug.A narrative review of literature collected from PubMed and Google Scholar was conducted to analytically compose the historical background of medical gas therapy  as conjunctions to combine or exclude keywords.5 All In total, we retrieved 268 studies from Medline, 488 studies from Embase, and 2139 from Scopus. A total of 2755 papers emerged after removing 140 duplicates. After further evaluation, 223 publications, including 59 reports chosen manually, met inclusion criteria , hydrogen sulfide (H2S), nitric oxide (NO), oxygen (O2), and ozone (O3). Noble gases evaluated consisted of helium (He), argon (Ar), and xenon (Xe). Because of interstudy differences in experimental models, outcome measures, drug deliveries, and research designs, statistical comparison  between studies regarding medical gas efficacy for a particular tissue was deemed biologically invalid. Instead, based on an established rule for systematic reviews, quantitative distributions of all enrolled publications by MG type were displayed in Figure FigureTableFigureBiological gases reviewed were carbon monoxide (CO), hydrogen H, hydroge22.12, N2, N2O, Ar, He, and CO2) and three gaseous mixtures . Therefore, in this review, medical gases are defined as pharmaceutical gaseous molecules that fulfill the therapeutic demands of specific pathophysiologic conditions.Modern medical gases are conventionally described as compressed gases that are used in clinical procedures involving symptom treatment and anesthesia, or driving and conditioning medical devices or tools. Commonly utilized in hospitals are six individual gases .8 Ther MGT has been considered a contemporary clinical discipline. However, our analysis suggested that the origin and evolvement of inhalation of medicinal aerosols likely provided the foundation for MGT development.On account of the relatively short history of industrialized production of gas compounds,9 MGT 2.2 The first known reference to inhaled therapeutics was recorded in an Egyptian medical papyrus scroll  dating back to ≈1554 BCE. It was described in the papyrus that patients with breathing stress were prescribed to inhale the vapor of black henbane (Hyoscyamus niger) plants baked on a hot brick through a stalk of reed that was inserted into a dome jar , containing ephedrine, was prescribed to treat it via smoke, steam vapor, and aromatic sachets. Inhalation of various herb vapors (including tobacco) and resins, sometimes boiled with vinegar and oil, was also widely practiced in other early civilizations beginning in India, Ancient Greece, the Middle East, and North and Central America.Even earlier, the most frequently consumed ventilatory drug probably already existed: the smoking of opium for therapeutic  and recreational purposes, based on documentation written around 1100 BCE.13 In 2.3th century that physicians began integrating MGT into clinical practice with what might be called a modern signature. Carl Wilhelm Scheele first identified oxygen in 1771 and mentioned the discovery in a letter to Antoine Lavoisier in 1774 before submitting his finding for publication in 1775 (in press by 1777). Also published in 1774 and 1775 was characterization work of oxygen performed independently by Joseph Priestly. In contrast to other gases identified earlier or at a similar time  that were adapted to help patients much later, the therapeutic potential of O2 was speculated soon after its discovery.It was not until the discovery of oxygen in the late 18Priestly.16 In 2 inhalation on tuberculosis was observed by M. Caillens. Ten years afterward, Dr. Beddoes started using O2 for asthma, tuberculosis, chronic lung disease, palsy, dropsy, and various other conditions. In the early 1800s, O2 was recognized as the essential element that humans obtain through respiration. Over the following 200 years, therapeutic administration of O2 and other gases fluctuated but, in general, increased remarkably over time. Toward the middle of the 20th century, O2 therapy finally became rational and scientific.In 1783, benefits of OCaillens.17 Ten2 in inspired air  under normobaric and hyperbaric conditions. It is worth noting that, more recently, intermittent hypoxia  has been under intensive investigation for its potential in tissue protection, neuroplasticity, and functional improvement. The establishment of this unconventional approach was aided by advances in the understanding of molecular specifics underlying cell stress, trophic factor expression, survival and death, and the tissue sparing effect of other gaseous molecules as secondary messengers (see below).Standard acute therapies for patients utilize 24–100% Onditions.20 It 33.1To understand these naturally occurring molecules for their multiplicity of action and interaction with biological targets to modulate cell survival and function, research efforts were first focused on determining the dose range of a particular gas that was able to ignite a set of signaling events to produce a specific biological effect not only in gas‐generator cells, but also in cells not synaptically coupled with them.243.1.1 Despite its lethal poisoning potency in high concentrations (human adjusted 0.5 h [h] LC: 4000 ppm (CF: 1); cdc.gov/niosh/idlh/630 080.htm), a low level of CO has been known to exist in the blood of healthy humans and animals since the late 19th century. In 1968, Tenhunen, Marver, and Schmidt determined that heme oxygenase (HO) was the rate‐limiting enzyme to catabolize heme degradation to produce CO, ferrous iron, and biliverdin; biliverdin‐reductase then converted biliverdin to bilirubin. CO, bilirubin, and biliverdin were later found to have antioxidative and cell protective qualities. CO, in particular, could multimodally affect neurotransmission, vasodilation, and suppression of platelet aggregation. Accordingly, HO‐1 and CO have been deemed crucial endogenous homeostatic, signaling, and cell protective agents with desirable therapeutic value.Joseph Priestley was credited for the isolation of CO during 1772–1799.16 Des HO is mainly located in the endoplasmic reticulum (ER), as well as the cell nucleus, mitochondria, and plasma membrane. Heme has high affinity to NO, CO, and O2, and operates as a gas sensor and signal transducer. For both prokaryotes and eukaryotes, gas sensing is pivotal for survival and function. The heme‐based sensor proteins such as HO and NPAS2 thereupon play important roles in regulating cellular responses to gaseous environment changes  through coupling a “regulatory” heme binding site to a “functional” signal‐transmitter site. Distinctly, CO, NO, and H2S are members of the growing family of molecules termed “gasotransmitters” that influence functional, metabolic, and genetic events.Biochemically, HO belongs to the heat shock protein (HSP) family as a heme‐containing member named HSP32. In mammals, there are three isoforms of HO: an inducible form of HO‐1 that is produced throughout the body, two constitutively expressed forms of HO‐2 in the brain, testes, and endothelial cells of other organs, and HO‐3, a heme‐binding sensor due to its catalytic inactivity.30 HO −1, resulting in the normal baseline human carboxyhemoglobin level of 0.4–1%. The activity of HO accounts for 86–80% of endogenous CO production. The remaining 14–20% is derived from nonheme sources . CO, in physiological concentrations  acts as a ubiquitous second messenger affecting a wide range of physiological and pathophysiological processes. This concept appears to have been widely accepted, albeit with some disputes . Challenged by stress , cells increase HO and CO production to restore homeostasis for tissue protection. To date, most reports have shown that safe dosage CO inhalation therapy reduced cell death in the brain, spinal cord, heart, retina, kidneys, lungs, etc. and enhanced functional recovery in established models of trauma, cerebral ischemia, myocardial infarction, ischemia‐reperfusion injury (IRI), etc. (Table The human body's average rate of CO generation is ≈20 µmol h marrow).35 CO,−1, p.o.) or HO‐1 inducer cobalt protoporphyrin IX  was administered at 24 and 3 h, respectively, before coronary artery ligation (3 min). Compared to controls, pretreatment of CO donor activated stem/progenitor cells to migrate into the infarct area to differentiate into vascular smooth muscle cells. The healing process was associated with augmented expression of HIF‐1α, SDF‐1α, and VEGF‐B, molecules impacting stem/progenitor cell migration, differentiation, vasculogenesis, and myocardial regeneration. Additionally, heightened HO‐1 production improved SDF‐1α (a progenitor mobilizer) expression and vascular density, suggesting that CO and HO‐1 cooperatively evoked required mechanisms for cardiac repair.In male Wistar rats, CO‐donor methylene chloride (500 mg kg (3 min).45 Com In contrast, in people with coronary artery disease histories, low concentrations of CO inhalation  exacerbated myocardial ischemia during graded physical exercise.In terms of safety, experimental in vivo inhalations typically utilized 100–500 ppm CO for bolus administrations with or without consecutive exposures . Animals all tolerated these exposures well without discernible toxic responses , synthetic air (placebo) or 500 ppm CO was given for 1 h, followed by a safe bolus of LPS, an inflammation inducer . Compared to the experimental anti‐inflammatory results shown in Table  The discrepancy might be attributable to pharmacological differences: animals had higher LPS doses  plus CO treatment both pre‐ and post‐LPS injection without body fluid maintenance, whereas human volunteers received systemic hydration protection, a 78% lower dose of LPS, and post‐LPS CO inhalation only.In a small size pilot clinical study (in Table 47 The Different types of CO‐releasing molecules (CORMs) have been experimentally investigated. In a rat acute lung injury model induced by hemorrhagic shock and resuscitation where interstitial macrophage demise was detrimental, hydrophilic CORM‐3  significantly ameliorated lung injury, pulmonary edema, macrophage apoptotic or pyroptotic death and expressions of p‐p38MAPK. When given at 1 h after acetaminophen‐induced liver injury in mice, lipophilic CORM‐2  suppressed M1 (proinflammation)/M2  ratios of microglia polarization by decreasing HIF‐1α and increasing HO‐1 to reduce oxidative damage and inflammation. The treatment also promoted liver regeneration by activating hepatic progenitor cells via igniting the PI3K/Akt/mTOR pathway.Since the early 2000s, synthetic pharmaceuticals which release CO have been invented to enhance targeting, controlled release, and potential systemic toxicity prevention; the precision level of these pharmacological parameters will be further optimized by the development of gas‐producing nanoplatforms.48 Dif−1, i.p.) done 2 h before LPS injection  appeared necessary in order to impede ROS‐Fyn‐ER stress signaling in nephric cells. Notably, CO exhibited a partly similar mechanistic profile when effecting as a neurotherapeutic (see below).The data suggested that, unlike conventional cytoprotectants  that exclusively act through specific receptors, CO, under varied pathogenic milieus, could differentially affect the same type of target cells  by concurrently modulating multiple second messengers to promote homeostasis and repair . Conversely, to attain a direct antioxidant effect on a murine acute kidney injury model, a pretreatment of CORM‐2 , or p.o. (CO liquid HBI‐002: 0.2 mg kg−1), was nephroprotective in a model of bilateral kidney IRI in mice through modulating purinergic signaling. The treatment augmented CD39 ectonucleotidase expression, reduced expression of Adora1 (adenosine receptor A1); there was a concomitant increase in Adora2a/2b. These changes were associated with marked elevations of the circadian rhythm protein Period 2 (Per2) and serum erythropoietin (EPO), which jointly impeded kidney IRI (see details in CO reference #7 in Section S2: Supporting Information).A more recent report showed that CO administered via inhalation (250 ppm for 1 h before injury), i.p.  This fact has made administration of CO or CORM a valuable approach to managing acute tissue or organ lesions.Also demonstrated was that either CO treatment or HO‐1 elevation induced by endogenous heme increased cellular CO production,54 sug ↑IRG1/↓TNFα): modulation of the HO‐CO axis, HIF‐1α dependent and independent induction of VEGF expression, and crosstalk with NO and other messengers. Among them, activation of the HO‐CO system was determined as a major player in rallying multiple mechanisms of tissue repair  imposing a “pseudo” intracellular hypoxia environment that upregulated VEGF expression to increase circulating endothelial progenitor cells; 3) reducing endothelial apoptosis via activating PERK, which is a key transducer of ER stress and cell death/survival regulation; 4) inducing production of hypoxia‐responsive microRNA‐101, which, via stabilizing Nrf2, promoted Nrf2‐dependent HO‐1 synthesis to augment VEGF and eNOS‐derived NO levels; and 5) modulating L‐type Ca2+ channel activity to either activate AMPKα/SIRT1‐PGC‐1α/ERRα signaling to increase VEGF, or reduce Ca2+ influx. Importantly, CO‐evoked crosstalk with NO signaling pathway has been shown to mobilize NSCs  was also discovered by Carl Wilhelm Scheele in 1777. Commonly produced from the microbial process of anaerobic digestion, volcanic gases, etc., H2S had occupationally been regarded as a toxic, corrosive, and flammable hazard. However, since Stipanuk and Beck reported that small quantities of H2S were produced by human cells in 1982, H2S has been investigated and gained acceptance as a gasotransmitter and neuromodulator.Hydrogen sulfide . H2S exercises important roles in intra‐ and intercellular communication in mammals. Due to lipid‐solubility, gasotransmitters are not regulated by vesicle‐mediated storage and release transitions. Instead, their signals are gated by metabolism‐ and/or physical diffusion‐controlled concentration fluctuations. In this manner, H2S, working in consortium with NO, modulates ureteral smooth muscle activity in urodynamics and affects relaxation of the sphincters.Apart from its production by the intestinal microbiota, Hsferase).67 H2S2S and its donor (NaHS) have been examined for their tissue protection potential in the brain, spinal cord, heart, retina, blood vessels, etc., against excitotoxicity, neurotrauma, heart failure, and IRI. Data suggested that H2S treatment strengthened tissue repair through modulating specific signaling pathways. Specifically, H2S induced HIF‐1α and VEGF expression through both NOS dependent and independent pathways , which partially overlapped with CO pathways  protected rat pheochromocytoma PC12 cells, which were used to proximate neurons, against scratch‐caused decrease of cystathionine‐β‐synthetase, a key enzyme for H2S generation, and attenuated depolarization of mitochondrial membrane, intracellular accumulation of ROS, and cell death. The effects were diminished by blocking the PI3K/Akt pathway with LY294002 (5 × 10−6m x 24 h). H2S exposure  impeded inflammation and oxidative stress by inhibiting NF‐κB activation and downstream proinflammatory mediators iNOS and ICAM‐1 to improve hippocampal neuron protection, neurological recovery, and animal survival. Recently, it was reported that CSE/cystathionase, another crucial biosynthetic enzyme of H2S, failed to bind Tau P301L, a mutant Tau related to AD pathogenesis. CSE‐produced H2S normally prevents hyperphosphorylation of Tau by sulfhydrating its kinase GSK3β. In both 3xTg‐AD mice and in human AD brains, CSE was depleted. Treating the AD mice (6 m/o) with NaGYY, a slow‐releasing H2S donor  mitigated motor and cognitive deficits through sulfhydrating GSK3β.For neuroprotection, H 5 × 10−6m x 24 h. 5 × 10−6m x 24 h. 5 × 10−6m x 24 h.2S also included Bcl‐2 and surviving for cell survival; cyclin D1, mTOR, Bax, and caspases for cell death; IL‐6 and IL‐12 for immune and inflammatory responses; and GABAA receptor for neuroplasticity. Taken together, H2S may divergently  and convergently  regulate cell survival, death, homeostasis, and function  was perhaps first encountered by Jan Baptista van Helmont around 1620.77 It  When administering NMDA, an agonist of a glutamate receptor subtype, to rat hippocampal slices, researchers noticed that NO concentrations in the CA1 and CA3 pyramidal cell layer were increased from ≈2–10 to ≈200 × 10−9m. Furthermore, for any newly elevated NO doses to facilitate neuronal long‐term potentiation, a tonic endogenous low concentration of NO was required, suggesting that cell production of NO was dependent on the functional level of the glutamate NMDA receptor. Since NMDA receptors mediate excitatory neurotransmission that detonates important signaling cascades to regulate neurogenesis, development, neuronal plasticity, neural cell interaction, senescence, cell death, and disease, the finding validated a role of NO in modulating these processes. NO was subsequently determined to be a controller of vascular tone and integrity, inflammatory response of endothelial cells and leukocytes, and platelet function.The role of NO as a gaseous messenger was not validated until the 1980s.81 Whe However, NO is a free radical when possessing an unpaired electron. The feature makes it highly reactive with the thiol/sulfhydryl groups that usually exist in disulfide linkages to sustain the tertiary and quaternary structures of proteins. Consequently, NO inhalation has not been approved for therapeutic application in most organ disorders, except for those of the lungs  and heart  in short‐term and low concentration  formulas to limit its action range and harmful effect. NO dose‐dependently reduces PAP and pulmonary vascular resistance for PAH but not for pulmonary circulation systems in normal vascular tone.By 1991, Frostell et al. reported that inhalation of NO in low doses reduced pulmonary artery pressure (PAP) in an unanesthetized lamb pulmonary arterial hypertension (PAH) model.82 Howα synthesis to mediate cardiovascular and other tissue protection or destruction , depending on the dose level and time course of NO exposure. Second, NO modified protein thiol/sulfhydryl residues via S‐nitrosylation, exerting a major ubiquitous influence on cellular signal transductions and fate/function of proteins, including the activity and stability of enzymes and transcription factors, functions of receptors and ion channels, protein phosphorylation, ubiquitylation and degradation, cellular redox equilibrium, and apoptosis. Third, NO modified prosthetic metals in proteins  and iron‐related gene expression to maintain iron homeostasis and trigger regulatory effects . Conversely, heme proteins , allosterically activated by heme coordination changes post‐NO binding, carried out a variety of vital functions . For neuroprotection, it was reported that nitrite, an ischemic reservoir of NO and a potent S‐nitrosating agent, ameliorated brain injury after asphyxial cardiac arrest in rats by S‐nitrosylation of brain mitochondria to reduce reperfusion ROS and maintain ATP generation. Such an effect was NO dependent but not involving the cGC/cGMP signaling pathway. In addition, when rat hippocampal neurons were stressed by sublethal OGD, NO, derived from donor and NOS activation, provided partial neuroprotection by indirect stimulation of ATP‐sensitive K+ channels via turning on the Ras/MAPK pathway. In a murine MCAO (for 1 h) and reperfusion (for 47 h) model, inhalation of NO  significantly reduced group average infarct size, likely through enhanced blood flow during reperfusion and anti‐inflammation  that adversely causes oxidative damage. The reaction may also exhaust normal NO bioactivity. Clearly, a judiciously designed treatment to properly control NO level and application time is important for mitigating these potential side effects.The NO/sGC/cGMP axis may promote epidermal stem cell proliferation in wound healing and angiogenesis. It operated through NO‐regulated FOXG1 expression via cGMP pathway and FOXG1‐heightened c‐Myc promoter activity, which could be enhanced by H, ↑cGMP).83 Forsion for 7 h model3.1.42: the primary existence form of hydrogen) was likely first experimentally produced by Robert Boyle in 1671. Henry Cavendish recognized hydrogen (H) as a distinct element a century later. The pilot test of treating tuberculosis with H2 was led by Thomas Beddoes around 1793. Yet, H2 production within the human body was not confirmed until 1969. In 1975, Dole et al. demonstrated that treatment with a hyperbaric (8 ATA) H2 mixture (97.5% H2 and 2.5% O2 × 2 weeks) caused regression of squamous cell carcinoma in mice, mainly through catalyzing free radical decay.Hydrogen , the most abundant element, composes ≈90% of the visible universe. Molecular hydrogen gas  without interruption of physiological oxidation, H2‐based treatments hold excellent potential for tissue protection against toxicological pathology, diabetes, neurotrauma, and IRI of the brain, heart, intestine, kidney, liver, and lungs , down‐regulation of Bax expression and caspase 3 activation, and upregulation of Bcl‐2, SIRT1 and HO‐1. Administering H2‐rich saline in rodent perinatal cerebral IRI  and cardiac arrest models reduced pro‐inflammatory cytokines , microRNA‐21/‐210 , HMGB1, caspase 3 activation, NF‐κB response, and microglia toxicity; the treatment increased activity of antioxidant enzymes  and the number of regulatory T (Treg) cells to conjugatively protect neural tissue. Treatment with H2 saline  and H2 inhalation  significantly reduced brain edema and infarct size by reducing ER stress (via ↓GRP78 and C/EBP homologous protein), in HIBI neonatal mice and mitigated neuronal loss and motor deficits by decreasing extracellular glutamate level (via ↓GluT1) in rats with spinal cord IRI, respectively , pre‐, intra‐, and post‐injury inhalation of 2.9% H2 all failed to significantly reduce infarct volume and brain concentration of MDA, an end‐product of lipid peroxidation. In addition, H2 pretreatment was associated with increased infarct area in neonatal hypoxic brains and cerebral MDA level in non‐ischemic neonates. Compared to the beneficial outcomes observed in the neonatal mice with HIBI after H2 saline administration and an earlier work where 2% H2 inhalation showed marked neuroprotection in a mild Rice‐Vannucci model (90 min hypoxia), the data suggested that the impact of H2 on oxidative damages is defined by the balance between selective antioxidant effect and circumstantial prooxidant influence of H2, and the local and global free radical dynamics of superoxide anion (O2•‐), nitric oxide (•NO), and hydroxyl (•OH) radicals. Accordingly, the pharmacodynamics of these oxidants and H2 could be modified by pathophysiological aspects of a particular injury or disease model, lesion severity, injury time course, and the age of the subject.In terms of negative results (Table neonates.102 Co3.1.5th atomic number and a symbol of “O”), not the “oxygen” as a clinical term . As described above, O2 is a traditional medical gas valued for its essential role in sustaining aerobes on the earth. This signature has made the application profile of O2 in hospitals different from all other medical gases. For this review, hyperbaric O2 (HBO) therapy was focused on for its prevalent use in promoting recovery for patients with ischemic and/or hypoxic lesions in various organs, drug resistant microbial infections, or/and full thickness wounds. HBO increases O2 concentration in the blood and interstitial space to counteract hypoxic lesions, maintains cellular reservoirs of O2, and attenuates adverse consequences , as well as exerts direct bactericidal effects on anaerobic pathogens to provide tissue protection ; oxygen refers to elemental oxygen (with the 8rm of O).16 As 2, by definition, is an oxidative stimulus that increases the production of ROS and RNS and initiates cell survival signaling and antioxidant reactions. In fact, HBO has been shown to promote tissue remodeling and functional restoration through interaction with other gaseous messengers to modulate multiple signaling pathways. As examples, the level of SDF‐1, a pivotal factor in mobilizing various progenitors, was elevated by HBO treatment via improving stability and activity of HIF‐1α, which reciprocally increased SDF‐1 and dermal fibroblast proliferation. HBO therapy also stimulated the IL‐6/STAT3 pathway in an early phase of a muscle injury model.HBO‐elevated interstitial pOgenitors,45 was Since administering hemin also augmented HO‐1 production, the HBO‐induced HO‐1 elevation might have resulted from an immediate inhibition of protein synthesis, leading to an accumulation of heme, rather than a direct antagonism to oxidative insult. Data from a clinical study supported this conclusion: exposure to HBO  produced DNA damage in lymphocytes of the participants. Yet, induction of DNA breakage only occurred after the first HBO treatment but not in subsequent sessions. There were discernibly elevated levels of HO‐1 in lymphocytes 24 h after HBO treatment. In contrast, superoxide dismutase, catalase, DNA repair enzyme apurinic endonuclease, and DNA polymerase beta were not increased. Importantly, blood lymphocytes collected 24 h after HBO exposure were significantly protected against DNA destruction caused by H2O2, but not by gamma‐irradiation, suggesting that the survival adaptation was enabled by the HBO‐induced antioxidant defense.HBO treatment broke DNA strands and caused an initial inhibition of HO‐1 synthesis that was later increased  in cultured rabbit lens epithelial cells.108 Si HBO preconditioning also markedly protected cultured rat spinal cord neurons from oxidative and OGD insults by upregulating ROS, NO, and HO‐1 and activation of MEK1/2, ERK1/2, p38 MAPK, CREB, Bach1 and Nrf2 pathways. Among them, the ROS/p38 MAPK/Nrf2 pathway functioned to augment HO‐1 expression; MEK1/2/Bach1 signaling, in contrast, negatively regulated this process. HBO also increased HO‐1 in a myocardium IRI model through activating the PI3K/Akt/Nrf2‐dependent system against oxidants. Thus, interactions between O2, CO, and NO intracellular signaling pathways may collectively decide cell survival or death, and HO‐1, the primary producer of endogenous CO, may serve as a mediator between these pathways.  improved diaphragm‐specific force production and muscle fiber integrity in rats with lateral C3/4 contusion. The effect was mainly derived from HBO‐mediated mitochondrial protection and ROS modulation. In rodent TBI models, HBO protected neural cells by increasing expression of IL‐10, Bcl‐2, and Bcl‐xL. It is noteworthy that a systematic review of clinical data (40 years through 2017) revealed that when HBO was given ≤30 d of an acute severe TBI, it enhanced clinical recovery signs with no major toxicity. For moderate‐to‐severe TBI, the majority of results favored HBO treatment compared to “standard care.” While limited analysis of placebo effect and tissue preservation were conducted on mild TBI (mTBI) with no statistically significant differences being reported between HBO and sham arms in all trials, Walker et al. found that for military service members with post‐mTBI sleep‐wake disturbances, HBO relative to sham significantly improved certain aspects of sleep quality. For people suffering from chronic neuro‐cognitive impairment from concussion TBI, HBO therapy enhanced angiogenesis to benefit blood perfusion in the damaged brain area and general cognitive function.For SCI, a recent paper described that HBO therapy (1 h of 100% Odulation.115 In3.1.63) produced by electrical discharge through ambient air was noticed in 1785 by Martin van Marum. Fifty‐four years later (1839), Christian Friedrich Schönbein sensed the same peculiar odor from the oxygen generated during electrolysis of acidulated water. He named it ozone (from the Greek verb “ozein”: to smell), as a discrete gas. O3 is dynamically unstable due to the presence of mesomeric states. Despite its hazardous properties, O3 has been studied for therapeutic purposes since the 1890s. For example, Dr. Henry Norris, in 1892, prescribed O3 dissolved in water (termed “Aquozone”) to treat tuberculosis. Considering the known serious adverse effects, the U.S. FDA banned O3 use “in any medical condition for which there is no proof of safety and effectiveness"  in April 2016.The odor of ozone , a eustress‐dependent activation of Nrf2 was observed, followed by induction of HO‐1 and NQO1 (an antioxidant enzyme) to evoke anti‐inflammation responses. O3 pre‐exposure (2 ppm x 3 h) enhanced the innate immune response in the lungs by decreasing MIP‐1α and TNFα and increasing the expression of CXCL‐1, IL‐6, and TLRs in macrophages. Furthermore, a wound healing study reported that administration of 400 µL O3 oil topically (b.i.d. × 12) activated the PI3K/Akt/mTOR pathway to promote the epithelial‐mesenchymal transition  toward other elements or compounds. Despite said inertness and a relatively limited understanding of their mechanism of action, noble gases have been utilized for various purposes in hospitals and extensively investigated for applications in anesthesia, IRI amelioration, tissue preservation, and neural repair.1253.2.1 By 1946, the anesthetic effect of normobaric Xe was observed in mice. The general anesthetic effect of Xe inhalation in humans was reported by Cullen and Gross in 1951, which was subsequently adopted as a clinical anesthetic gas. Around the early 2010s, experimental and clinical research began to reveal the tissue protective effect of Xe on the nervous and cardiovascular systems, especially under ischemic and hypoxic circumstances.William Ramsay and Morris Travers first isolated xenon (Xe), the fifth of the noble elements in 1898.126 By As an anesthetic and cytoprotectant, Xe interacts with the glycine binding site to block the NMDA subtype of glutamate receptors in excitatory neurotransmission, suggesting that Xe may hold high potential as a neurotherapeutic  and ATP‐sensitive K+ channels, and multiple signaling transductions, such as PI3K/Akt, MAPK, mTOR/HIF‐1α, and mitochondrial apoptosis pathways. Specifically, in a mouse model of renal IRI, Xe pretreatment provided renoprotection via mTOR pathway‐mediated HIF‐1α upregulation , Williams Ramsay and John William Strutt separated Argon , the third noble element (atomic number 18), from liquified atmospheric air and recognized that it was responsible for the residue noticed by Cavendish. Ar is the most abundant noble gas in Earth's atmosphere.Henry Cavendish, in 1785, found a small amount of an unknown, unreacted gas remaining after he removed O the air.140 Mo Ar lasers have been applied in surgeries for tissue welding , ablating tumors, correcting vision defects, and treating various eye conditions including diabetic eye complications and glaucoma. Because of its low cost, excellent safety record, and easy application, Ar has been actively studied for therapeutic potentials in several systems, involving cell cultures under LPS, hypoxic or OGD exposure, and animal models of IRI, MCAO, subarachnoid hemorrhage, and multiorgan failure. Overall, post‐insult systemic administration of Ar ameliorated inflammation, reduced apoptosis, enhanced cell proliferation and survival, and improved function in the nervous, cardiac, retinal, renal, and hepatic systems by modulating apoptotic and pro‐survival pathways and reducing blood levels of IL‐6 and HMGB1  has been used to kill cancer cells.141 Ar−1 LPS‐triggered ERK‐1/2 activation and inflammatory cytokine induction in cultured microglia. Since the study did not examine any longer‐term effect of Ar on microglia, future investigations should verify if Ar would augment beneficial polarization of microglia to enhance tissue repair. In a PND 7 rat model of asphyxia, treatment of 70% (vol) Ar  distinctly improved cell survival, brain structural integrity, and neurological function on PND 40 in both moderate and severe hypoxia‐ischemia groups, compared to those treated with 70% N2/30% O2. Ar inhalation increased the expression of Bcl‐2 to hinder apoptosis in the non‐directly injured hemisphere.As examples, 50% (vol) Ar exposure to plain microglial cell (line BV‐2) cultures for 30 min significantly increased levels of pERK‐1/2, stimulating cell proliferation and survival. In contrast, administration of U0126, an inhibitor of MEK (an upstream activator of ERK), abolished Ar‐induced ERK‐1/2 phosphorylation, indicating that Ar activates microglial ERK‐1/2 via turning on the upstream kinase MEK. However, Ar did not significantly affect 50 ng mLmisphere.146A receptors at high pressure, because pretreatment with the competitive GABAA receptor antagonist gabazine (0.2 nmol) but not the GABAB receptor antagonist 2‐hydroxysaclofen (10 nmol) significantly increased the argon threshold pressure to induce loss‐of‐righting‐reflex (p < 0.005) in rats. This mechanism can also contribute to neural protection and neuroplasticity in certain neurological abnormalities  Ar for 2 h reduced the expression and density of TLR2 and TLR4 (transmembrane mediator of major immune responses) in human neuroblastoma cells. The effect was associated with suppression of the TLR2 and TLR4‐induced downstream STAT3/NF‐κB activation in combination with activation of the ERK‐1/2/Akt pathway. Furthermore, Ar inhalation significantly ameliorated apoptosis of animal retina ganglion cells after IRI in vivo via attenuating TLR2 and 4/STAT3/NF‐κB‐induced retinal IL‐8 expression, and preservation of mitochondrial membrane potential to reduce ROS generation  x 3 h) neither exhibited protection nor modified survival gene expression in human tubular kidney (HK2) cells after 3 h of OGD. In the same study, whereas He exposure worsened the OGD injury, Xe treatment improved cell survival through upregulating expression of pAkt, HIF‐1α and Bcl‐2. Factors interfering with the cell protection potential of Ar might be related to the two long intervals (24 h/each) between Ar exposure and OGD onset, and between the end of OGD and beginning of data collection.For the effect of Ar, some data discrepancies persisted  of Ar treatment blocked and increased tPA enzymatic and thrombolytic efficacy, respectively. The concentration of Ar used to manage acute ischemic stroke should be judiciously tailored, factoring in the impact of drug administration timing .Based on data obtained from an ex vivo rat brain slice model of OGD and a rat MCAO model, investigators recommended that postischemic Ar treatment be administered during but not after ischemia  to provide cortical neuroprotection and avoid worsening subcortical brain damage.149 On3.2.3ηλιος/romanized: Helios, lit: sun) was originally detected as a bright yellow spectral line in sunlight during a solar eclipse in 1868 by Pierre Janssen and Joseph Norman Lockyer. Helium , the first in the noble gas group in the periodic table and the second most abundant element in the universe, was isolated on Earth by William Ramsay in 1895. For its distinct physicochemical characteristics , helium has been clinically applied as an adjunct therapeutic and investigated for cytoprotective effects.Helium  can generate high quality images of the pulmonary airspaces. Unlike Ar and Xe, helium is a non‐immobilizer, due to its incapability to induce anesthesia. Still, helium treatment was found to lessen the heart and brain lesions associated with IRI and hypoxia. For neuronal protection, helium pre‐ and post‐conditioning of rats  significantly decreased neuronal apoptosis in the hippocampal CA‐1 region, compared to controls treated with 70% N2/30% O2  that contain caveolin (Cav). They serve as epicenters of cellular signal transduction. Caveolins, the structural proteins of caveolae and hexokinase II that promotes cell survival by facilitating glycolysis, mediate the effect of cardiac and brain protection of helium. In a rat cardiac IRI model , 15 min of post conditioning with 70% (vol) helium  ventilation significantly heightened amounts of Cav‐1 and Cav‐3 in cardiomyocyte membrane of tissues within the area‐at‐risk, and serum Cav‐3 . The treatment also significantly raised phosphorylation levels of RISK pathway's cytosolic proteins pERK1/2 and pAkt  played main roles.160 Mot Figure . for 30 min – 24 h) applied ≈5 min after mechanical injury significantly preserved CA1 region, compared to controls treated with N2, He, Ne, and Kr. Notably, administration of glycine could reverse the neuroprotective outcome of Xe, but not Ar, suggesting Xe's competitive suppression of the NMDA receptor's glycine‐binding site.The primary neuroprotective mechanism of Xe, based on the following data, was its competitive inhibition of NMDA receptors. In an organotypic murine hippocampal slice model of focal brain trauma, Xe or Ar , a L‐glutamate transporter inhibitor. The neuronal rescue was enabled by the NMDA receptor antagonizing effect of Xe since memantine, an uncompetitive NMDA blocker, mimicked the benefit. Xe treatment also decreased spontaneous neuronal death in standard cell cultures through inducing paracrine neuroprotection of astrocyte‐produced neurotrophic factors. These effects were Xe specific: unlike what was attained from the hippocampal slice assays, they were not reproducible by Ar in the same setting. Through inhibition of overactive NMDA receptors to interrupt cytotoxic Ca2+ influx, Xe was able to protect neurons in models of excitotoxicity, OGD, stroke, and hypoxia.Incubation of E15.5 Wistar rat ventral midbrain tissue with 75% (vol) Xe/20% O2 decreased group average infarct size resulting from asphyxia , followed with hypoxia (8% O2/37°C/3.5 h), and improved long‐term (30 d after ischemia) rotarod performance. The effect of Xe inhalation was associated with enhanced CREB signaling. A similar regimen when combined with hypothermia produced synergistic neuroprotection based on morphological criteria, hemispheric weight, and rotarod performance assessed up to 30 d.p.i. In a murine model of focal stroke, Xe pre‐conditioning  significantly lowered group average cerebral infarct volume in both male and female mice that had 1 h of MCAO at 24 h after Xe pre‐exposure and were allowed to recover for 24 h. Xe treatment quantitatively upregulated HIF‐1α and pAkt.In vivo, preconditioning (120 min) of PND 7 rats with 75% (vol) Xe/25% Oignaling.137 A −1, i.a.) done 2–5 h post a transient MCAO (2 h) in adult rats significantly lowered group mean infarct volume, relative to control treatment, by activating the MAPK and Akt pathways and augmenting BDNF expression  for 6 h. Exposure to 1 or 2 MAC Xe triggered marked neuronal death (>40%) in CA1, CA3, and dentate regions. Replicative investigations will be required to validate this finding before mechanistic assays can be done to reach a conclusion.Lastly, systemic injection of Xe‐containing echogenic liposomes  and rostral (more prominently at 16 h p.i.) to the injury epicenter. Western blot results showed similar upregulations of HO‐1 and HO‐2 proteins after SCI. Furthermore, IHC assays determined that HO‐1 and HO‐2 were mainly expressed by the ventral horn motor neurons, with HO‐2 being also augmented in neurons of the Clarke's Nucleus (located in Rexed lamina VII and involved in unconscious proprioception), oligodendrocytes, and ependymal cells. HO enzymatic activity measurements corroborated the protein expression data. The investigators hypothesized that HO‐1 might counteract cell intrinsic suicide programs, and HO‐2 might suppress RNS‐ignited inflammatory response.The rationale of developing CO‐based interventions was partly built upon data collected in the early 2000s. It was exhibited that there were injury site‐specific inductions of HO‐1 and HO‐2 after a 9–10th thoracic spinal cord compression (clip: 15 g x 30 min) in adult male and female mice.176 HO CORM‐3 (8 mg kg−1 d−1), given immediately after injury until the end of the study, resulted in inhibition of inflammasome signaling and pyroptosis, partly through modulating clip injury‐activated IRE1, an important proximal ER stress sensor (note: prolonged IRE1 activation causes apoptosis) and a central mediator of the unfolded protein response (UPR) for cell fate adaptation, and XBP1, a nuclear transcription factor that, downstream of IRE1α, is a key component of the UPR. However, the presented post‐euthanasia (≥28 d.p.i.) histopathology showed near epicenter lesion volume only within the dorsal funiculus of the spinal cord. With sparing of the propriospinal, raphespinal, reticulospinal, rubrospinal and vestibulospinal tracts, and ventral and dorsolateral corticospinal tracts, it is unclear why the control T9‐compression rats manifested severe locomotor deficits .The effect of CO on neural recovery was recently examined in a rat T9 clip compression model (30 g x 1 min).177 CO4.3.2−1; n = 48) post TBI, compared to a control group . Notably, the amount of HO‐1 increase was positively correlated with the injury severity and unfavorable neurological outcome levels (p < 0.05 for both). Infants appeared to have higher HO‐1 increases than older children after TBI, suggesting that HO‐1, a cell protectant .181 In−1, via retro‐orbital injection at 1 h p.i.) and CO inhalation  had a dual effect on pericytes and neurogenesis, resulting in neurological behavioral benefits in C57Bl/6 mice  after TBI . CO significantly reduced pericyte death and maintained vascular integrity through impeding HIF‐1α and Caspase‐3 activation. Further, post‐CO exposure pericytes exhibited signs of signaling crosstalk with NSCs via nNOS phosphorylation, which increased proliferating NSC numbers and neurological recovery. In contrast, administration of free radical scavenger  alone did not result in functional improvement, despite mitigation of apoptosis, suggesting the pro‐neurogenic effect of CO might be crucial.By 2016, it was reported that treatment with CORM‐3 (4 mg kg cortex).44 CO −6m) increased neuronal differentiation rate. Thus, CO‐elevated NSC proliferation and subsequent NSC‐derived neurons might have aided post‐TBI recovery. To this end, it has been uncovered that proliferating NSCs and NPCs possess functional multipotency that enables them to secrete trophic factors , exosomes, and pro‐recovery cytokines , as well as form gap junctions to promote homeostasis and functional restoration  administered at the initiation of reperfusion or 1 and 2 h after reperfusion, significantly reduced motor neuron death and hindlimb locomotor deficit in adult rats 4, 24, and 48 h after IRI, compared to the control treatment given immediately after ischemia .For the defined timeframe, we did not find any reports that described the neurotherapeutic effects and mechanisms of Xe treatment against traumatic SCI. A study published in 2014, nevertheless, explored the cytoprotective impact of Xe on spinal cord IRI . Briefly, Xe inhalation (50% Xe/50% Oh group).184The same team later showed that rats in the IRI + Xe group had significantly better locomotion scores, more spared motor neurons, fewer apoptotic neurons, and higher levels of pAkt and pERK at 6, 12, 24, and 48 h after reperfusion, relative to the control group. The data, verified via applying specific antagonists of PI3K‐Akt and ERK messengers, indicated that Xe treatment strengthened neurological recovery by activating these signaling pathways  treated with 75% Xe and 25% O2 for 3 h starting 15 min p.i., exhibited significantly improved mean neurological score and contusion volume determined at 24 h after trauma, compared to the control group receiving 75% N2/25% O2 (n = 22). Discernible locomotor enhancement was too observed in Xe‐treated mice 1 month after TBI. The benefits of Xe treatment were associated with lessened secondary brain tissue lesion.In a controlled cortical impact model of TBI, adult male C57BL/6N mice  g; e lesion.185p < 0.05 and 0.01, respectively; n = 9/each group) at 24 h post TBI. Moreover, at 20 months after TBI, Xe treatment blocked development of late‐onset memory deficits , which was correlated with mitigated chronic white matter degeneration in the contralateral corpus callosum and neuronal death in the contralateral hippocampal CA1/dentate gyrus regions . The long‐term neuroprotective effects were confirmed by a significant reduction in levels of reactive gliosis and microglial numbers in the brain areas influencing the behavioral tests. Future investigations should verify whether such therapeutic effects of Xe and CO (see above) on TBI are replicable in adult female mice.In a follow‐up study, the same regimen of Xe inhalation for adult male C57BL/6N mice  with TBI significantly reduced acute neurological dysfunction and lesion volume  and CO (22%: 50 papers) were the most frequently investigated, compared to 4–12% of other 4 biological gases . There were 11 reports with negative findings (11/223 = 5%), and another 3 papers  described both negative and positive data of different gases simultaneously studied  only conventional methods  were used to verify putative target molecules. In addition, no reports on combinatorial MGT were qualified for enrollment. Therefore, it is urgent to exploit cutting‐edge technologies of functional genomics, proteomics, next generation gene sequencing, and gene knock‐in, silencing, knockdown, knockout or editing to authenticate key mechanisms of MGT. Furthermore, protocols to administer multiple gas molecules and newly emerged ex‐vivo models, especially 3D cell cultures and organ‐modeling organoids derived from disease/condition‐specific hiPSCs, should be utilized to expedite MGT research.In terms of challenges, all in vivo investigations reviewed were conducted in small animal models, without fully factoring in sex and age as biological variables.187 Ex In spite of a long history concerning various clinical applications of medical gases, only oxygen therapy is currently prescribed in standardized manners for clinical problems of patients. Applying MGT to effectively manage serious diseases and traumas remains an unmet medical demand. In the coming decades, the atmosphere, with its vast capacity, will likely become the newest frontier for the discovery of therapeutics in general, and neurotherapeutics in particular.For pharmacological logistics, direct inhalation has been the most extensively adopted drug delivery method in the field. This approach appears to be promoted by the physiological route of gas intake, lipophilic feature of gas molecules, practicability of general dose adjustment, and historical influence from inhalation therapies (see above). Yet, pragmatic management perspectives can be drastically different between medical gases, particularly regarding rarity, cost, and risk . Furthermore, inhalation as a method has several drawbacks such as high cost of gas storage, difficulties in precisely controlling gas concentration, and possible off‐site adverse effects. Developing pharmaceutical grade pro‐drugs will thereby be a more effective strategy to enable traditional route delivery of medical gases .190 InThe authors declare no conflict of interest.Supporting InformationClick here for additional data file.


Although 2D PtS2 is intrinsically non-magnetic, a stable ferromagnetic phase is found for a wide range of hole densities, owing to the so-called Stoner instabilities. Besides spontaneous magnetization, half-metallicity is additionally observed. The majority and minority spin states exhibit insulating and metallic nature, respectively, allowing a fully polarized spin transport in 2D PtS2. Lastly, hole doping resulting from substitutional doping is investigated. For As-doped PtS2 shallow spin-polarized states close to the valence band edge are observed, and among all studied group-V dopants, As replacing S, is the most promising one to induce p-type conductivity and a subsequent ferromagnetic order in PtS2.Using first principles calculations based on density functional theory, we study the impact of hole doping on the magnetic and electronic properties of two dimensional PtS 2 is studied.Using first principles calculations based on density functional theory the impact of hole doping on the magnetic and electronic properties of two dimensional PtS To overcome such limitations, new materials that can sustain aggressive scaling and/or new technologies should be introduced. The “marriage” of two dimensional materials with spintronics1–3 may bring a revolution in today's transistor technology.Over the past decades, the technological advances yielded to smaller transistors and subsequently to devices integrating an increasing number of them. However, as the physical dimensions of the transistors are scaled down, quantum effects start to dominate the device operation. In particular, transistors with very short channel lengths experience source to drain tunneling currents, 3 and Cr2Ge2Te6.4,5 In addition, spontaneous magnetization has been predicted in monolayer metal chalcogenides, such as GaS, GaSe and InSe, upon hole doping.6–9 Such magnetization arises from an exchange splitting of the electronic states at the valence band edge, where the density of states exhibits a sharp van Hove singularity, leading to the so-called Stoner instability.To realize spintronic nanodevices the selection of materials is critical. For instance, the spin states should be easily established and conveniently manipulated, whereas long-distance spin transport and efficient spin injection should be achieved. Although various spintronic nanodevices have been realized in the last years, the quest for optimal materials is still an open issue. Remarkably, recent experimental observations revealed a long-range ferromagnetic order in 2D compounds like CrI2 is a relatively unexplored member of the transition metal dichalcogenide (TMD) family. Its thermodynamically stable structure consists of one hexagonal metal plane sandwiched between two hexagonal chalcogen planes with an octahedral coordination, forming the so-called 1T phase.10,11 Interestingly, a high mobility of 1107 cm2 V−1 s−1 is theoretically predicted for 2D PtS2, which is larger compared to other well-studied TMDs like MoS2.12 In addition, theoretical investigations reveal a transition from a non-magnetic to a ferromagnetic phase upon hydrogenation, and the magnetic moments mainly arise from the Pt 5d orbitals.13Two dimensional PtS2 are studied, using first principles calculations based on density functional theory (DFT). Although 2D PtS2 is intrinsically non-magnetic, a stable ferromagnetic phase is found for a wide range of hole densities. Hole doping resulting from substitutional doping is also investigated.In this paper, the magnetic and electronic properties of hole-doped 2D PtS2.2 are performed using the spin polarized DFT, as implemented in the Vienna ab initio simulation package (VASP).14,15 The generalized gradient approximation, developed by Perdew, Burke and Ernzerhof (PBE), is used for the exchange correlation functional,16 and long-range van der Waals corrections are applied, using the DFT-D3 Grimme method.17 The projected augmented wave (PAW) pseudopotentials are employed,18 along with a kinetic energy cutoff of 400 eV. The Brillouin zone is sampled by a 4 × 4 × 1 k-point grid for the atomic relaxations, whereas a denser grid is considered for the electronic structure calculations. Note that in order to get well-converged magnetic moments, a grid of 18 × 18 × 1 k-points is adopted. The atomic positions are optimized using the conjugate gradient method, with 10−2 eV Å−1 force convergence criteria on the ionic optimization. For our calculations we used the tetrahedron method with Bloch's corrections whereas for the calculations of the total magnetic moments of hole-doped systems, different smearing methods were tested, like the Methfessel–Paxton method and the Gaussian smearing, leading to identical results.First principles calculations of monolayer PtS19 along with the standard mixing (25% Fock exchange) and range-separation parameters. Note that for the HSE calculations, we used a less dense k-point grid as compared to the PBE calculations.We additionally performed hybrid functional calculations, using the VASP code. The functional proposed by Heyd, Scuseria and Ernzerhof (HSE) was adopted,We constructed 5 × 5 single-layer supercells consisting of one hexagonal Pt plane sandwiched between two hexagonal S planes, with ∼17.8 × 17.8 Å lateral dimensions and 75 atoms in total. Periodic boundary conditions were applied, and a vacuum layer larger than 15 Å was used in the out-of-plane direction, to avoid any artificial interactions between periodic images. Hole doping was achieved by changing the number of electrons of the supercell and by adding a compensating jellium background of opposite charge.3.3.1.2 is shown in 20 The S–Pt bond length, S–Pt–S bond angle, and S–S vertical distance are found to be 2.40 Å, 84.1°, and 2.47 Å, respectively.The relaxed atomic structure of monolayer PtS2 is a semiconductor with an indirect band gap of Eg = 1.83 eV. The valence band (VB) maximum lies along the Γ–K direction, whereas the conduction band (CB) minimum is located between the Γ and M points, in agreement with previously reported theoretical calculations.21 The inclusion of spin–orbit coupling (SOC) reduces the gap by less than 0.1 eV, and retains the indirect nature of the gap. Interestingly, the topmost VB resembles an inverted Mexican-hat-like dispersion. This peculiar VB dispersion leads to a divergence in the density of states, corresponding to sharp van Hove singularities. When the Fermi level lies close to such singularities, the large electronic density of states favors the formation of a ferromagnetic order, since the Stoner criterion is satisfied.22–24 Thus, hole-doped 2D PtS2 can be a ferromagnetic material, similar to other 2D metal chalcogenides.6–8 Note that the inclusion of SOC preserves the sombrero shape VB and the subsequent van Hove singularity at the top of the VB and for the calculations of the magnetic and electronic properties of doped systems, this relativistic interaction is not included.As observed in n). The spin polarization energy is defined as the energy difference between the non-magnetic and the ferromagnetic phase, and positive values reveal a stable ferromagnetic phase. As observed in μB per carrier. Although the magnetic moment per carrier remains constant up to high hole densities, the spin polarization energy per carrier significantly varies. In particular, for low hole densities, it increases by increasing the density, whereas for n = 3.5 × 1014/cm2, it reaches the maximum value of about 12 meV per carrier. Further increase of the hole density results in the reduction of the spin polarization energy.Initially, we consider charged supercells and we compute the magnetic moment and the spin polarization energy for different hole densities  and Etot(PtS2) are the total energies of the doped and pristine systems, respectively, whereas μS and μX are the chemical potentials of sulfur and dopant atoms, respectively. Note that the sulfur chemical potential refers to the solid structure of sulfur, i.e., μS = μsolS + ΔμS, and the dopant chemical potential corresponds to solid phosphorus and arsenic, but molecular nitrogen. The N, P, and As formation energies are found to be 3.1 + ΔμS, 0.9 + ΔμS, and 1.1 + ΔμS eV, respectively, i.e., P and As have fairly similar formation energies whereas the N formation energy is significantly larger, which is consistent with the larger lattice distortion.To evaluate the thermodynamic stability of these dopants, we calculate the dopant formation energies using the equationμB. The spin polarization energies are found to be 0.27, 0.10, and 0.06 eV, for N, P, and As, respectively, where the positive values reveal a stable  magnetic moment. The charge density differences as well as the spin density differences for all doped systems are shown in ρc = ρ2:XPtS − ρ2:VSPtS − ρX where ρ2:XPtS, ρ2:VSPtS, and ρX are the charge densities of doped PtS2 (i.e. PtS2 with a S substituent), bare PtS2:VS (i.e. PtS2 with a S vacancy), and isolated X dopants, respectively. Accordingly, the spin density difference, which is used to visualize the magnetic moment distribution around the dopant atom, is computed by Δρs = ρ↑ − ρ↓ where ρ↑ and ρ↓ are the spin up and spin down charge densities, respectively. To further describe the magnetic moment distribution, the ratio between the magnetic moment of the dopant atom and the total magnetic moment  is computed. We find Mr,N ≈ 66%, Mr,P ≈ 32%, and Mr,As ≈ 26%, i.e., the magnetic moment is less localized in the P and As doped systems, compared to the N doped one, as expected from the much deeper in-gap states for N doping.Next, the magnetic and electronic properties of doped systems are discussed. All substitutional dopants lead to magnetic ground states with total magnetic moments of 1 25,26 Overall, among all three dopants, As is the most promising one to induce p-type conductivity (provided a sufficient dopant concentration can be achieved), since the unoccupied gap state lies close to the VB edge. Our projected density of states calculations reveal that for all doped systems, the opposite spin states within the gap are mainly derived from the group-V p orbitals as well as the 5d orbitals of Pt atoms neighboring the group-V atom.Regarding the electronic properties, as observed in 4.2. Upon hole doping, a transition from a non-magnetic to a ferromagnetic phase along with a half-metallic behavior were observed. Therefore, hole-doped 2D PtS2 presenting one conducting and one insulating spin channel, could be highly promising for future spin-based nanodevices. Hole doping resulting from substitutional doping was also investigated. We found that group-V atoms replacing S atoms create spin polarized states within the gap. By increasing the dopant atomic number, these states move towards the valence band edge and their spin splitting reduces, potentially forming a ferromagnetic phase in monolayer PtS2.Based on first principles calculations, we studied the magnetic and electronic properties of hole-doped monolayer PtSThere are no conflicts to declare.RA-010-C9RA09756B-s001


Variable-angle spectroscopic ellipsometry was used tostudy their optical properties in the 0.5–3.5 eV spectral range.The optical constants were accurately obtained using a model thatcombines Drude and Tauc–Lorentz oscillators with Bruggemaneffective medium approximations, allowing the inclusion of a roughnesslayer in the optical model. The effect of Zr doping (ca. 1.9–4.4atom %) was then investigated in both as-prepared samples and samplesannealed in the temperature range of 100–300 °C. All ofthe films exhibited good optical transparency (ca. 70–90% inthe visible region). For doping levels below 2.7 atom %, the realpart of the dielectric permittivity reveals a semiconductor-to-metaltransition in the near-infrared (NIR) region, as the permittivitygoes from positive to negative. Besides, the plasma energy increaseswith increasing Zr concentration, and both resistivity and carrierconcentration exhibit slightly parabolic behaviors, with a minimumof ∼1.5 × 10–3 Ω cm and a maximumof 2.4 × 1020 cm–3, respectively,at the same critical Zr concentration (2.7 atom %). In contrast, thecarrier mobility decreases rapidly from 76.0 to 19.2 cm2/(V s) with increasing Zr content, while conductivities and carriermobilities worsen when the annealing temperature increases, probablydue to the segregation of ZnO crystals. Finally, the optical bandgap is very stable, revealing its interesting independence of substratecomposition and annealing temperature, as it collapses to a singlemaster curve when band gap energy is plotted versus free carrier concentration,following the Burstein–Moss effect. Overall, the Zr-doped ZnOfilms studied here would be a highly desirable system for developingthermally stable transparent conductive oxides (TCOs).This work reports the ellipsometryanalysis of atomic layer deposition(ALD) films of ZnO doped with Zr to determine parameters like freecarrier concentration and mobility. Thin films of zinc oxide (ZnO)and Zr-doped ZnO of thickness ∼100 nm were prepared by atomiclayer deposition on sapphire, SiO Asa promising substitute for ITO films, ZnO exhibits a hexagonal wurtzitecrystal structure, relatively soft mechanical properties , and a direct and wide band gap of about3.3 eV at room temperature. In addition, ZnO exhibits high chemicalstability, good surface uniformity, and a large exciton binding energyof 60 meV. ZnO also has excellent electrical conductivity generatedby its high concentration of donor native point defects, such as oxygenvacancies (VO) and zinc interstitials (Zni),enhanced by doping with group IV elements including titanium,7 zirconium,8 hafnium,10 and ruthenium.11 Furthermore, Zr incorporationin ZnO lattice is chemically favorable due to the comparable ionicradii of Zn2+ and Zr4+ ions for the four-coordinate tetrahedral substitution, which generatestwo extra electrons by each ionic substitution.13 Consequently, Zr doping increases the electrical conductivity ofZnO at least until an overdoping limit is reached, from which theelectrical resistivity, ρ, can increase or be limited, suchas is reported for Al doping.15 Furthermore, Ellmeret al. previously reported that overdoping generates a critical limitfor ρ of 2 × 10–4 Ω cm that remainsconstant. Besides, the mobility of free carriers did not overcomea value of 50 cm2/(V s).16 Ingeneral, this effect is a well-known property of TCO films,17 possibly due to the formation of dopant ionsclusters near grain boundaries that increase carrier scattering.1818 On the other hand, the optical absorptionof ZnO takes place throughout the superimposition of two separateabsorption processes, attributed to the interband transitions in thenear-UV region and to the free-electron transitions at the near-infrared(NIR) region.20 The first process is essentiallygoverned by the band gap, which obeys the Burstein–Moss (BM)effect, while the plasma resonance of electron gas causes the secondone in the conduction band. So far, ZnO optical response can be accuratelymodeled by combining Drude and Tauc–Lorentz (TL) oscillators,thus allowing the determination of all of the physically significantparameters involved in the absorption–conduction processes,such as free carrier density, mobility, concentration, resistivity,plasma frequency, and relaxation time.Transparentconductive oxide (TCO) films such as indium tin oxide(ITO), tin oxide ). This work used Tauc–Lorentz oscillatorsand simplified Herzinger–Johs oscillators; they also addeda Gaussian oscillator in some thin films. The excitonic direct-gappeak is strongly broadened and weakened in thinner ZnO layers. Incontrast, with fixed thickness, Fujiwara studied the electronic propertiesthrough ellipsometric spectroscopy in Ga-doped ZnO and ZnO thin films.20 They combined the Drude and Tauc–Lorentzoscillators to model the dielectric function. They found that by increasingthe concentration of free electrons (through doping), there is a shiftin ε1 from ∼3 eV toward higher energies. Inε2, the absorption increases at low energies dueto these free electrons. In the case of Zr-doped ZnO thin films grownby ALD,26 ellipsometry has been used but only to determine the thickness ofthe films but not to determine optical or electronic parameters.In previous ellipsometricreports of ZnO films, the dielectricfunction and the optical constants 27 Thus, we firstmodeled the ZnO pure films and, second, the Zr-doped ZnO films depositedonto several substrates, both as-prepared and annealed at differenttemperatures ranging from 100 to 300 °C. The band gap evolutions,depending on these preparation conditions, were then studied. On theother hand, the critical limit of different parameters, such as freecarrier concentration, resistivity, mobility, and relaxation timeas a function of Zr doping level, was determined. We also show thepotential of using the proposed optical model to map these parametersover a broad sample region as a function of film thicknesses. Finally,an example of a resistivity map is provided in this work.In this work, we appeal to a realistic model based on the Drude–TLcombination in which a roughness layer, determined from atomic forcemicroscopy (AFM) topography measurements, is also taken into accountsubsequently in the optical model as a Bruggeman effective mediumapproximation (EMA) layer.22/Si(100) substrates through a Beneq TFSALD reactor.25 For the last substrates,the SiO2 layer was thermally grown on Si(100) at 1200 °Cin an oxygen atmosphere until obtaining a thickness of 300 nm. Theprecursors for Zn and Zr were diethylzinc  (Strem 95%)28 andtetrakis(dimethylamido)-zirconium  (Strem 98%), respectively. High-purity nitrogen(N2), with O2 traces below 10–6 ppm was used as a carrier gas to purge the growth chamber.23 Zr doping of ZnO films consisted of a definednumber of supercycles composed of n cycles of ZnOby one cycle of Zr (labeled as n:1), with a growthrate of 1.8 Å for ZnO and 0.8 Å for Zr. Four Zr-doped ZnOfilms were prepared with cycle ratios of 20:1, 15:1, 10:1, and 5:1,applying 27, 36, 53, and 102 supercycles, respectively, to obtainsimilar thicknesses (2 as the carrier gas at a flowof 3 mL/min.Undoped ZnO andZnO/Zr films were prepared onto sapphire(0001),Si(100), and SiOcknesses 1. An undD, was calculated with the Scherrer equationK is the Scherrer constant,λ is the X-ray wavelength, β is the full width at half-maximum(FWHM) of diffraction peaks, and θ is the Bragg angle. High-resolution(HREM) and scanning transmission electron microscopy (STEM) imagingwere performed using a TEM/STEM FEI Talos F200X G2 microscope  equipped with a high-angle annulardark-field (HAADF) detector, which was operated at 200 kV and witha camera length of 11.5 cm. X-ray energy-dispersive spectrometry (XEDS)mappings were performed using the 4 Super-X detector system integratedin the equipment. The beam current and the dwell time per pixel were190 pA and 50 μs, respectively. To improve the visual qualityof the elemental maps obtained, these were filtered using a Gaussianblur of 0.8 using Velox software. Phase identification was carriedout using Eje Z software.29 The TEM specimenwas prepared with a Thermo Scientific Helios Hydra DualBeam, whichis a last-generation plasma focused ion beam scanning electron microscope(FIB-SEM). This equipment allowed us to prepare the ultrathin samplesthat are required for S/TEM studies. The film thicknesses and opticalproperties were determined by reflection through spectroscopic ellipsometry(SE). Before the ZnO synthesis on SiO2/Si(100) substrates,the thickness of the SiO2 layer was measured by SE analyzingthe oxidized silicon substrates used to synthesize the ZnO films,with optical constants for c-Si and SiO2 provided withthe WVASE software. SE spectra of Ψ and Δ were measuredover a range of 0.5–3.5 eV with steps of 0.05 eV, at room temperature,using a Woollam v-VASE spectroscopic ellipsometer; it is a rotatinganalyzing ellipsometer (RAE) with a Berek computer-controlled adjustableMgF2 waveplate retarder (Automatic Retarder), which isused to accurately introduce a beam path delay over a wide spectralrange. The variable retarder allows to adjust the input polarizationto provide a reflected beam, which is always close to circularly polarized,and the system will measure Δ accurately over the entire rangeof 0–360°. Additionally, the autoretarder ellipsometerconfiguration permits the measurement of the % depolarization, whichcan be correlated with thickness nonuniformities of the samples, enablinga better fitting of the ellipsometric angles ψ and Δ inthese cases. The data analysis was performed with the WVASE softwarefrom J.A. Woollam.30Phase, crystallite size, and lattice parametersof the films werecharacterized by X-ray diffraction (XRD) on a PANalytical X’PertPRO MRD with a Cu Kα (λ = 1.540 Å) line excitationsource in-plane diffraction conditions. The mean size of the crystallites, 27 The optical transmission spectra were obtainedusing a UV–vis–NIR spectrophotometer from the thin filmsgrown on sapphire.To estimatethe roughness layer thickness used in the optical model,the accumulated height distribution  was obtained from the atomicforce microscopy (AFM) images of the undoped ZnO and ZnO/Zr films.We used a Bruker MultiMode NanoScope 8 AFM operated in tapping mode,using a SuperSharp SNL probe . The accumulated height distributions fitted the sigmoidal Boltzmannequation for each sample studied and introduced afterward in the opticalmodel as a function-based effective medium approximation (EMA) layer.33.12/Si(100) are summarized in 31a-direction to the c-direction. c of the wurtzite structure withoutexhibiting variations by increasing Zr concentration in samples. Furthermore,according to the literature, for films synthesized by ALD, the growthtemperature, not the substrate atomic plane, defines its crystallineorientation because the ALD technique operates at higher depositionrates than required to generate an epitaxial growth.33 In this work, all syntheses were carried out at the same growthtemperature and with the same doses to maintain the same growth rate,so we inferred that there are no differences between the three substratesused.These results show that the (100) diffraction peakdominated inintensity on XRD patterns of all samples except the ZnO/Zr (5:1) sample,which exhibited higher intensity on the (002) peak, revealing thatZr impurification at very high concentrations modifies the preferentialgrowth of ZnO/Zr films from the To gain information onthe distribution of Zr cations in the film,EDS–STEM experiments were carried out and are included in 3.22/Si(100) array shown in tA presentonto the surface of a ZnO film, with thickness tZ, grown on a SiO2 layer with thickness t0 = 300 nm and a silicon substrate with infinitethickness. The roughness layer, modeled as a ZnO/void ratio, was determinedfrom the AFM topography images by fitting the cumulative height distributionas a function of the height to the sigmoidal Boltzmann equationA1, A2, z0, and dz as shown in v(z) % represents thepercentage of voids as a function of height, expressedin turn as a percentage of the surface roughness layer thickness, z %, v(z = 0) % being0% at the ZnO bulk layer.27The optical modelused for spectroscopy ellipsometry (SE) measurementsconsisted of the ZnO/SiON) relatively high .20 Under such conditions of high dopinglevel,the ZnO Fermi energy (EF) exhibits anupward shift toward the conduction band, filling it with free electronsand generating a semiconductor–metal transition. Due to thispartially electron-occupied conduction band, the optical transitionfrom the valence to the conduction band in such semiconductors doesnot occur at energies close to their band gap energies (Eg), behaving then as a quasi-transparent material. Furthermore,since interband optical transitions occur between unoccupied conductionband states with energies higher than EF, the photon energy required to generate such interband transitions(Einter) becomes higher than Eg. This effect observed in degenerate semiconductors isknown as the Burstein–Moss shift.33 In contrast, FCA processes in semiconductors with high carrier concentrationincrease at longer wavelengths (or lower energies), and the extinctioncoefficient, k, increases significantly in this region.Therefore, the ZnO layer dielectric function can be modeled by combiningthe Drude, εD, and the Tauc–Lorentz (TL),εTL, oscillators to represent the FCA and the interbandtransitions, respectively.The optical model parameters werecalculated by fitting the dielectricfunction of the ZnO bulk layer, composed of two terms that correspondto two separate absorption processes: interband optical transitionand free carrier absorption (FCA), observed in ZnO films with freecarrier concentrations , broadening parameter (C), TLoptical gap (Eg), peak transition energy(En0), andenergy-independent contribution to ε1(E) [ε1∞].The TL model combines the empirical Tauc expressionfor the bandedge onset with the absorption around band gap energy given by theclassical Lorentz oscillator.1(E), can be derived using the Kramers–Kronig relationshipgiventhat ε1(E) and ε2(E) (n and k)must be Kramers–Kronig consistent. The fitting procedure todetermine the unknown optical model parameters was: (i) ZnO bulk layerthickness is first extracted for the optically transparent region(500–800 nm) followed by (ii) a point-by-point fit to generatethe initial spectra in all measured regions, and finally, (iii) fittingof TL and Drude oscillator models to the final spectra and regressionbetween the generated and measured data is performed. Therefore, aLevenberg–Marquardt regression algorithm was used to find theoptical model parameters fitting the SE data until a minimum valueof the mean-squared error (MSE) was obtained. The validity of themodel was confirmed by the good values of MSE shown in the fittings(MSE < 5). This exact procedure was applied for the doped samples;the corresponding adjustments are shown in The expression for the real part, ε3.32/Si(100)with the ellipsometric angles Ψ and Δ obtained at wavelengthsbetween 350 and 2500 nm, at an incidence angle of 75°, besidestheir accurate fitting achieved with the TL–Drude model. n, and extinction coefficient, k, are shown in k to higher wavelengths attributed to free-electron transitions.32T values between 73and 97% of external transmission (transmission can increase with propercoating), and (iii) an absorptive region in the NIR (900 nm ≤λ ≤ 2500 nm) generated by the presence of free carriersin the films. The absorption coefficient of a crystalline semiconductoris expected to behave as35hν is the photon energy. Thus, the bandgap energy Eg is calculated by fittingthe curves α2–hν witha Boltzmann sigmoidal function using nonlinear regression .gression 7b and ca1, and ε2, as a functionof the photon energy, ofthe undoped ZnO and ZnO/Zr films synthesized on Si(100), and SiO2/Si(100) substrates are shown in 21 . The peak of the real partε1 that corresponds to free carrier and interbandabsorption appears at almost the same position and broadens due tothe thickness when the film is compared to the bulk sample. The curvesof 1 and ε2 peaks at E > 3.5 eV exhibit a slightshifttoward higher energies with Zr doping; (ii) at lower energies, ε2 increases following the series of the ZnO/Zr films: 5:1,20:1, 15:1, and 10:1, that is, it does not increase with Zr doping,while ε1 decreases in the same order. In addition,the plasma energy value Ep, obtained fromε1 = 0, exhibits a slight increase accordingly withthis sequence, indicating that samples are becoming increasingly electricallyconductive. Similar behavior has been reported for Ga-doped ZnO thinfilms.20The curves of the complex dielectricfunction, ε3.42/Si(100) substratesdeduced from the optical measurements, the free carrier concentration Nopt, resistivity ρ, mobility μ,and relaxation times τ were obtained by applying the classicalDrude model expressions38P is the screenedplasma resonance frequency given by∞ and ε0 are thedielectric constants of the medium and free space,respectively, and me* is the effective mass of the charge carriers.Furthermore, Nopt, ρ, and μ,τ exhibit the following relationships: 1/τ = −e/(me*μ)] and ρ = 1/(Nopt e μ). 2/Si(100)a decrease in their resistivity from 1.7 × 10–3 Ω cm, observed for undoped ZnO, to 1.0 × 10–3 Ω cm in Zr-doped films with concentrations lower than 3 atom%, besides an increase to 2.8 × 10–3 Ωcm in the ZnO/Zr film with Zr concentration of 4.4 atom %. Nopt exhibits a maximum valueat 2.73 atom % both for ZnO/Zr films grown on Si(100) and SiO2/Si(100) substrates, in agreement with the results reportedby Ye et al.100 Then, it decreases sinceno more extra free electrons are now generated when Zn2+ is substituted by Zr4+ impurities, i.e., when the overdoping-likebehavior appears.15To investigate the electrical properties of theundoped ZnO andZnO/Zr films synthesized on Si(100), and SiO2/(V s), where the Zr atom % corresponds to 0 and 4.4,mainlydue to the increase of carrier scattering and the formation of Zr4+ impurities. For the interpretation of the ZnO Zr dopingefficiencies, 2) region of the ZnO/Zr (20:1) sample (1.9 Zr atom%). Here, the optoelectronic properties can be nondestructively characterized,and it allows modeling the resistivity within the layer while providinginformation about the thickness homogeneity. For example, it may beseen that the ZnO/Zr (20:1) film with an average thickness of 119nm shows a thickness variation of 5% with lower ρ values inthe thinner regions.On the other hand, the mobility decreases from 76.0 to 19.2cmTs, the saturation temperature. This effect is mainly produced becausethe annealing treatment enhances the oxygen atom content in the films,which is absorbed by the interstitials Zn-rich surface to form insulatorZnO molecules. Consequently, the number of native oxygen vacanciesacting as donors in ZnO decreases, making the film more resistive.At Ts, most of the oxygen atoms are absorbedand resistivity remains constant.40 Interestingly,all of the studied Zr-doped ZnO films saturate at the same resistivityvalue of 2 × 10–2 Ω cm. Furthermore,the electron mobility exhibited a substantial decrease in ZnO/Zr filmsthermally treated at temperatures higher than 250 °C  studied films, both as-prepared andannealed ones, which reveals that the absorption edge of all Zr-dopedZnO films shifts toward high photon energies, regardless of the typeof substrate and annealing treatment applied. This Eg widening has its origin in the fact that the high electronconcentrations involved in the absorption processes cause the Fermi-levelposition to move upward due to the increase of free electrons causingthe absorption axis to shift toward higher photon energies, i.e., Eg is blue-shifted. This behavior is describedas the effect of Burstein–Moss (BM), which is expressed byh/2π) and m* isthe electron effective mass. Although band gap widening by BM effectcan be calculated from Eg –ΔEg, does not follow this equation,as it can be observed in the inset of 41 It is well known that in heavily doped semiconductors, band gapwidening and narrowing can exist simultaneously, with BGN being competitivewith the BM shift. Therefore, it can be stated that the Zr-doped ZnOsamples in this work present a band gap shift that is affected byboth BM and BGN effects.Finally, 42/Si(100), and Si(100) substratesusing the ALD technique. The optical transmission of the films isgood, with transmittances higher than 70% in the visible range forall cases and reaching a maximum of 85% for the 20–1 sample.We employed Drude–TL oscillators to model the films’optical response and their optical constants. The absorption observedat the NIR region indicates a metallic behavior due to the presenceof free carriers to 2.73 atom % doping. Furthermore, resistivity andcarrier concentration exhibit a parabolic dependence with Zr concentration.Both yield minimum and maximum values, respectively, at the same criticalvalue of 2.73 atom % Zr. Meanwhile, annealing temperature decreasesthe conductivity and carrier mobility of the films. Then, by controllingthe doping level during the preparation of the films and annealingtemperature during postprocessing, the electrical and optical propertiesof these Zr-doped ZnO thin films can be tuned.In thisstudy, we have prepared ZnO and Zr-doped ZnO films of thickness∼100 nm on sapphire, SiOFinally, ourresults show that the band gap energy follows theBurstein–Moss effect for all of the substrates and annealingtemperatures. The relatively large stability of the main electro-opticalparameters with annealing treatments demonstrates their applicabilityto develop TCOs to be used in high-power electronic devices.


N = 179, ageM = 13.94, 49.2% female) reported emotional events using experience sampling via a smartphone application for 14 days. Multilevel modeling revealed that adolescents used less expressive suppression when they were alone compared with when they were with people, and used more expressive suppression when they were with their peers compared with when they were with family. In addition, more closeness with family predicted less overall expressive suppression use, while closeness with peers did not influence the level of expressive suppression use within the peer context. We discuss the importance of peer relations in adolescence and the relationship between closeness and emotional expression.Adolescence is characterized by frequent emotional challenges, intense emotions, and higher levels of expressive suppression use than found in older populations. While evidence suggests that contingent expressive suppression use based on context is the most functional, it remains unclear whether adolescents use expressive suppression differentially based on social context. Because the peer relationship is highly salient in adolescence, the current study was designed to assess whether adolescents use expressive suppression differentially based on their social context. Adolescents ( Previous studies of regulatory habits have relied on trait-based assessments of suppression or social context, and these measures fail to capture variations in emotion regulation and instead rely on assumptions . Thus, capturing suppression and social context using ESM allows the assessment of individual variations in daily life. Because adults  and chilSecond, we considered individual difference factors in suppression use that have not been previously studied. Specifically, we were interested in exploring how closeness with others might affect general and context-dependent suppression use. Adults use suppression less when they are around people they feel close to , and theThird, we considered gender differences in context-dependent suppression use that are not well understood. Males use suppression more than females , as pareMage = 13.94, SD = 0.88). Participants were recruited from a university participant database maintained by child development researchers located in southern Ontario, Canada. This database contains families from the community that volunteered to be included and consented to be contacted for developmental research studies. To be recruited for the current study, adolescents had to be 12–15 years old, and they had to have access to a mobile device . Parents of participants provided consent and participants provided assent prior to participating in the study. Ethnic background was reported as follows: White (86.2%), Asian (13.7%), Black (2.3%), Latin American (2.9%), and other (2.3%). Ethnic background was representative of the city in which the study took place. Participants received $10 as compensation for completing the questionnaire portion of the study, plus participants received an additional $1 for every prompt they completed during the experience-sampling portion of the study, for a total possible compensation of $52. This study was approved by the Queen’s University General Research Ethics Board (GPSYC-817-17).Participants for this study included 179 typically developing adolescents , 12–15 years old  Participant did not use suppression or (1) Participant did use suppression.For each mobile prompt, participants first reported which negative emotionParticipants reported who they were with during their most recent experience of a negative emotion. Participants were able to select any number of options from the following list: parents, siblings, teacher, students at school, staff at school, friends, boyfriend/girlfriend, boss, coworkers, other, I was alone.Dummy coding was used to create four variables for Social Context: Alone, Peers, Family, and Peers versus Family. For the Alone variable, instances in which participants selected “alone” were coded as 1, and instances in which participants selected any other social context were coded as 0. Thus, this variable will compare being alone (1) versus not being alone (0). For the Peers variable, instances in which participants selected “friends,” “students at school” and/or “boyfriend/girlfriend” were coded as 1, and instances in which participants selected “siblings,” “teacher,” “staff at school,” “boss,” “coworkers,” and/or “other” were coded as 0. If participants selected “parents,” this variable was coded as missing. Thus, this variable will compare being with peers (1) versus being with others, not including parents (0). For the Parents variable, instances in which participants selected “parents” were coded as 1, and instances in which participants selected “siblings,” “teacher,” “staff at school,” “boss,” “coworkers,” and/or “other” were coded as 0. If participants selected “friends,” “students at school,” and/or “boyfriend/girlfriend,” this variable was coded as missing. Thus, this variable will compare being with parents (1) versus being with others, not including peers (0). For the Peers versus Parents variable, instances in which participants selected “friends,” “students at school,” and/or “boyfriend/girlfriend” were coded as 1, and instances in which participants selected “parents” were coded as 0. If participants selected “siblings,” “teacher,” “staff at school,” “boss,” “coworkers,” and/or “other,” this variable was coded as missing. Thus, this variable will compare being with peers (1) versus being with parents (0).plus 8 using a multilevel framework due to the nested data4  (Hypothesis 1a). Model equations were as follows:Level 1In Model 2a, we assessed the effect of being with peers compared with being with others (not including parents). At Level 1, Suppression was predicted by Peers (0/1) (Hypothesis 1b), and at Level 2 Friend Closeness predicted Suppression (Hypothesis 2a), and the slope of Peers on Suppression (Hypothesis 2b). Model equations were as follows:Level 1Level 2In Model 2b, we assessed the effect of being with parents compared with being with others (not including peers). At Level 1, Suppression was predicted by Parents (0/1) (Hypothesis 1c), and at Level 2 Parent Closeness predicted Suppression (Hypothesis 2a) and the slope of Parents on Suppression (Hypothesis 2b). Model equations are the same as above, replacing any Peer variables with Parent variables.In Model 3, we assessed the effect of being with peers compared with being with parents. At Level 1, Suppression was predicted by Peers versus Parents (Hypothesis 1d), and at Level 2 Friend and Parent Closeness predicted Suppression (Hypothesis 2a), and the slope of Peers versus Parents on Suppression (Hypothesis 2b). Model equations are as follows:Level 1Level 25 Models 1 to 3 were each run for males only and for females only (Hypothesis 3).Finally, we also assessed gender differences in suppression use by running all four models separated by gender,SD = 0.21), indicating that on average, participants used suppression at 27% of their prompts. Second, each participant’s proportion of Suppression prompts in which they were Alone, with Peers, and with Parents were calculated. We then calculated the means and standard deviations for these three variables, which could range from 0  to 1 . The mean indicates the average proportion of an individual’s suppression prompts in which they were in a given social context. The average proportion of suppression prompts in which participants were alone was 11%, M = 0.11, SD = 0.22. The average proportion of suppression prompts in which participants were with peers was 33%, M = 0.33, SD = 0.33. The average proportion of suppression prompts in which participants were with parents was 37%, M = 0.37, SD = 0.32. Third, the correlation between Friend Closeness, M = 3.81, SD = 0.72, and Parent Closeness, M = 3.71, SD = 0.77, was positive, r = .39, p < .01.Preliminary analyses were run in SPSS . Individuals may have different thresholds for suppression use, so at a given prompt, what might be considered suppression use for one person may not be considered suppression use for another. Recent studies have tested multiple Likert-type scale items to capture emotion regulation strategy use and have found within and between person reliability . In addiWe have demonstrated that adolescents engage in suppression based on social context and how close they feel with others. This study warrants replication and expansion, specifically, analyzing specific social groups independently  to better understand the nuance of this distinction in adolescence. Likewise, research making comparisons from childhood to adulthood could establish when context-dependent suppression use is developed. The current study represents an important first step in understanding social influences on expressive habits in adolescence.