An ATP13A1-assisted topogenesis pathway for folding multi-spanning membrane proteins.

Many multi-spanning membrane proteins contain poorly hydrophobic transmembrane domains (pTMDs) protected from phospholipid in mature structure. Nascent pTMDs are difficult for translocon to recognize and insert. How pTMDs are discerned and packed into mature, muti-spanning configuration remains unclear. Here, we report that pTMD elicits a post-translational topogenesis pathway for its recognition and integration. Using six-spanning protein adenosine triphosphate-binding cassette transporter G2 (ABCG2) and cultured human cells as models, we show that ABCG2's pTMD2 can pass through translocon into the endoplasmic reticulum (ER) lumen, yielding an intermediate with inserted yet mis-oriented downstream TMDs. After translation, the intermediate recruits P5A-ATPase ATP13A1, which facilitates TMD re-orientation, allowing further folding and the integration of the remaining lumen-exposed pTMD2. Depleting ATP13A1 or disrupting pTMD-characteristic residues arrests intermediates with mis-oriented and exposed TMDs. Our results explain how a "difficult" pTMD is co-translationally skipped for insertion and post-translationally buried into the final correct structure at the late folding stage to avoid excessive lipid exposure.

De novo GRIN variants in M3 helix associated with neurological disorders control channel gating of NMDA receptor.

N-methyl-D-aspartate receptors (NMDARs) are members of the glutamate receptor family and participate in excitatory postsynaptic transmission throughout the central nervous system. Genetic variants in GRIN genes encoding NMDAR subunits are associated with a spectrum of neurological disorders. The M3 transmembrane helices of the NMDAR couple directly to the agonist-binding domains and form a helical bundle crossing in the closed receptors that occludes the pore. The M3 functions as a transduction element whose conformational change couples ligand binding to opening of an ion conducting pore. In this study, we report the functional consequences of 48 de novo missense variants in GRIN1, GRIN2A, and GRIN2B that alter residues in the M3 transmembrane helix. These de novo variants were identified in children with neurological and neuropsychiatric disorders including epilepsy, developmental delay, intellectual disability, hypotonia and attention deficit hyperactivity disorder. All 48 variants in M3 for which comprehensive testing was completed produce a gain-of-function (28/48) compared to loss-of-function (9/48); 11 variants had an indeterminant phenotype. This supports the idea that a key structural feature of the M3 gate exists to stabilize the closed state so that agonist binding can drive channel opening. Given that most M3 variants enhance channel gating, we assessed the potency of FDA-approved NMDAR channel blockers on these variant receptors. These data provide new insight into the structure-function relationship of the NMDAR gate, and suggest that variants within the M3 transmembrane helix produce a gain-of-function.

Alice (and Bob) in Flatland.

2D quantum materials have opened infinite doors, hosting intriguing phenomena and featuring incredible engineering potential. Whether these qualities can boost the use of 2D crystals for quantum applications remains an open field with yet unexplored paths.

Reversible Transition of Semiconducting PtSe2 and Metallic PtTe2 for Scalable All-2D Edge-Contacted FETs.

Two-dimensional (2D) transition metal dichalcogenide (TMD) layers are highly promising as field-effect transistor (FET) channels in the atomic-scale limit. However, accomplishing this superiority in scaled-up FETs remains challenging due to their van der Waals (vdW) bonding nature with respect to conventional metal electrodes. Herein, we report a scalable approach to fabricate centimeter-scale all-2D FET arrays of platinum diselenide (PtSe2) with in-plane platinum ditelluride (PtTe2) edge contacts, mitigating the aforementioned challenges. We realized a reversible transition between semiconducting PtSe2 and metallic PtTe2 via a low-temperature anion exchange reaction compatible with the back-end-of-line (BEOL) processes. All-2D PtSe2 FETs seamlessly edge-contacted with transited metallic PtTe2 exhibited significant performance improvements compared to those with surface-contacted gold electrodes, e.g., an increase of carrier mobility and on/off ratio by over an order of magnitude, achieving a maximum hole mobility of ∼50.30 cm2 V-1 s-1 at room temperature. This study opens up new opportunities toward atomically thin 2D-TMD-based circuitries with extraordinary functionalities.

The N-region sequence context impacts the chloroplast import efficiency of multi-TMD protein.

Targeting heterologous multi-transmembrane domain (TMD) proteins to plant chloroplasts requires sequences in addition to the chloroplast transit peptide (cTP). The N-terminal domain (N-region), located C-terminal to the cTP in chloroplast inner envelope membrane proteins, is an essential region for import. However, it was unclear if the N-region functions solely as a spacer sequence to facilitate cTP access or if it plays an active role in the import process. This study addresses the N-region's role by using combinations of cTPs and N-regions from Arabidopsis chloroplast inner envelope membrane proteins to direct the cyanobacterial protein SbtA to the chloroplast. We find that the sequence context of the N-region affects the chloroplast import efficiency of SbtA, with particular sequences mis-targeting the protein to different cellular sub-compartments. Additionally, specific cTP and N-region pairs exhibit varying targeting efficiencies for different heterologous proteins. Substituting individual N-region motifs did not significantly alter the chloroplast targeting efficiency of a particular cTP and N-region pair. We conclude that the N-region exhibits contextual functioning and potentially functional redundancy in motifs.

Doping Ability Modulated by Interlayer Coupling in AA' and AB Stacked Bilayer V-WS2 Grown with Chemical Vapor Deposition.

Doping in transition metal dichalcogenide (TMD) has received extensive attention for its prospect in the application of photoelectric devices. Currently researchers focus on the doping ability and doping distribution in monolayer TMD and have obtained a series of achievements. Bilayer TMD has more excellent properties compared with monolayer TMD. Moreover, bilayer TMD with different stacking structures presents varying performance due to the difference in interlayer coupling. Herein, this work focuses on doping ability of dopants in different bilayer stacking structures that has not been studied yet. Results of this work show that the doping ability of V atoms in bilayer AA' and AB stacked WS2 is different, and the doping concentration of V atoms in AB stacked WS2 is higher than in AA' stacked WS2. Moreover, dopants from top and bottom layer can be distinguished by scanning transmission electron microscopy (STEM) image. Density functional theory (DFT) calculation further confirms the doping rule. This study reveals the mechanism of the different doping ability caused by stacking structures in bilayer TMD and lays a foundation for further preparation of controllable-doping bilayer TMD materials.

Ruddlesden-Popper 2D Perovskite-MoS2 Hybrid Heterojunction Photocathodes for Efficient and Scalable Photo-Rechargeable Li-Ion Batteries.

Photo-rechargeable batteries (PRBs) can provide a compact solution to power autonomous smart devices located at remote sites that cannot be connected with the grid. The study reports the Ruddlesden-Popper (RP) metal halide perovskite (MHP) and molybdenum disulfide (MoS2) hybrid heterojunction-based photocathodes for Li-ion photo-rechargeable battery (Li-PRB) applications. Hybrid Lithium-ion batteries (LIBs) have demonstrated an average discharge specific capacity of 144.46 and 129.17 mAhg-1 for 50 cycles when operating at 176 and 294 mAg-1, respectively compared to the pristine LIBs which have shown specific capacity of 37.48 and 25.60 mAhg-1 under similar conditions. Hybrid Li-PRB has achieved an average dark discharge specific capacities of 128.66 mAhg-1 (capacity retention: 96.56%) which enhanced to 180.67 mAhg-1 under illumination (capacity retention: 97.39%; photo-enhancement: 40.42%) at 64 mAg-1. Excellent performance of hybrid Li-PRB is attributed to the formation of type-II heterojunction that leads to improved crystallinity and film morphology. The PRB has demonstrated a high photo conversion and storage efficiency (PC-SE) of 0.52% under standard 1 Sun illumination, which outperforms other previously reported MHP based LIBs and PRBs. This work provides a novel approach of harnessing the potential of MHPs for PRBs and offers new avenues for MHP photocathodes for various applications beyond PRBs.

Strain engineering of Zeeman and Rashba effects in transition metal dichalcogenide nanotubes and their Janus variants: anab initiostudy.

We study the influence of mechanical deformations on the Zeeman and Rashba effects in transition metal dichalcogenide nanotubes and their Janus variants from first principles. In particular, we perform symmetry-adapted density functional theory simulations with spin-orbit coupling to determine the variation in the electronic band structure splittings with axial and torsional deformations. We find significant effects in molybdenum and tungsten nanotubes, for which the Zeeman splitting decreases with increase in strain, going to zero for large enough tensile/shear strains, while the Rashba splitting coefficient increases linearly with shear strain, while being zero for all tensile strains, a consequence of the inversion symmetry remaining unbroken. In addition, the Zeeman splitting is relatively unaffected by nanotube diameter, whereas the Rashba coefficient decreases with increase in diameter. Overall, mechanical deformations represent a powerful tool for spintronics in nanotubes.

Structure of Ycf1p reveals the transmembrane domain TMD0 and the regulatory region of ABCC transporters.

ATP binding cassette (ABC) proteins typically function in active transport of solutes across membranes. The ABC core structure is composed of two transmembrane domains (TMD1 and TMD2) and two cytosolic nucleotide binding domains (NBD1 and NBD2). Some members of the C-subfamily of ABC (ABCC) proteins, including human multidrug resistance proteins (MRPs), also possess an N-terminal transmembrane domain (TMD0) that contains five transmembrane α-helices and is connected to the ABC core by the L0 linker. While TMD0 was resolved in SUR1, the atypical ABCC protein that is part of the hetero-octameric ATP-sensitive K+ channel, little is known about the structure of TMD0 in monomeric ABC transporters. Here, we present the structure of yeast cadmium factor 1 protein (Ycf1p), a homolog of human MRP1, determined by electron cryo-microscopy (cryo-EM). A comparison of Ycf1p, SUR1, and a structure of MRP1 that showed TMD0 at low resolution demonstrates that TMD0 can adopt different orientations relative to the ABC core, including a ∼145° rotation between Ycf1p and SUR1. The cryo-EM map also reveals that segments of the regulatory (R) region, which links NBD1 to TMD2 and was poorly resolved in earlier ABCC structures, interacts with the L0 linker, NBD1, and TMD2. These interactions, combined with fluorescence quenching experiments of isolated NBD1 with and without the R region, suggest how posttranslational modifications of the R region modulate ABC protein activity. Mapping known mutations from MRP2 and MRP6 onto the Ycf1p structure explains how mutations involving TMD0 and the R region of these proteins lead to disease.

Genetic change investigation in DOCK1 gene in an Iranian family with sign and symptoms of temporomandibular joint disorder (TMD).

OBJECTIVES: Temporomandibular joint disorder (TMD) is a complex condition with pain and dysfunction in the temporomandibular joint and related muscles. Scientific evidence indicates both genetic and environmental factors play a crucial role in TMD. In this study, we aimed to discover the genetic changes in individuals from 4 generations of an Iranian family with signs and symptoms of TMD and malocclusion Class III. MATERIALS AND METHODS: Whole Exome Sequencing (WES) was performed in 4 patients (IV-8, IV-9, V-4, and V-6) with TMD according to (DC/TMD), along with skeletal Class III malocclusion. Then, PCR sequencing was performed on 23 family members to confirm the WES. RESULTS: In the present study, WES results analysis detected 6 heterozygous non-synonymous Single Nucleotide Variants (SNVs) in 5 genes, including CRLF3, DNAH17, DOCK1, SEPT9, and VWDE. A heterozygous variant, c.2012T > A (p.F671Y), in Exon 20 of the DOCK1 (NM_001290223.2) gene was identified. Then, this variant was investigated in 19 other members of the same family. PCR-Sequencing results showed that 7/19 had heterozygous TA genotype, all of whom were accompanied by malocclusion and TMD symptoms and 12/19 individuals had homozygous TT genotype, 9 of whom had no temporomandibular joint problems or malocclusion. The remaining 3 showed mild TMD clinical symptoms. The 5 other non-synonymous SNVs of CRLF3, DNAH17, SEPT9, and VWDE were not considered plausible candidates for TMD. CONCLUSIONS: The present study identified a heterozygous nonsynonymous c.2012T > A (p.F671Y) variant of the DOCK1 gene is significantly associated with skeletal class III malocclusion, TMD, and its severity in affected individuals in the Iranian pedigree. CLINICAL RELEVANCE: The role of genetic factors in the development of TMD has been described. The present study identified a nonsynonymous variant of the DOCK1 gene as a candidate for TMD and skeletal class III malocclusion in affected individuals in the Iranian pedigree.

Optical Gain Spectrum and Confinement Factor of a Monolayer Semiconductor in an Ultrahigh-Quality Cavity.

Two-dimensional (2D) semiconductors have attracted great attention as a novel class of gain materials for low-threshold, on-chip coherent light sources. Despite several experimental reports on lasing, the underlying gain mechanism of 2D materials remains elusive due to a lack of key information, including modal gain and the confinement factor. Here, we demonstrate a novel approach to directly determine the absorption coefficient of monolayer WS2 by characterizing the whispering gallery modes in a van der Waals microdisk cavity. By exploiting the cavity's high intrinsic quality factor of 2.5 × 104, the absorption coefficient spectrum and confinement factor are experimentally resolved with unprecedented accuracy. The excitonic gain reduces the WS2 absorption coefficient by 2 × 104 cm-1 at room temperature, and the experimental confinement factor is found to agree with the theoretical prediction. These results are essential for unveiling the gain mechanism in emergent, low-threshold 2D-semiconductor-based laser devices.

Awake bruxism in temporomandibular disorders patients referred to tertiary care: A retrospective study on its assessment and TMD management.

BACKGROUND: Bruxism is defined as a repetitive jaw-muscle activity characterised by clenching or grinding of the teeth and/or by bracing or thrusting of the mandible. Bruxism can occur during sleep (sleep bruxism, SB) or during wakefulness (awake bruxism, AB). To date, the effect of AB on the purported negative consequences of bruxism has remained unclear. OBJECTIVES: The assessment of AB, its relation to temporomandibular disorders (TMD) treatment modalities, and their possible outcomes were investigated among TMD patients resistant to treatment in primary care and referred to a tertiary care clinic. METHODS: The records of 115 patients were studied. Patients were referred to the Head and Neck Centre, Department of Oral and Maxillofacial Diseases, Helsinki University Central Hospital, for TMD treatment between 2017 and 2020. The data derived from the eligible patients' records included the following: background data (age and sex), referral data (reason and previous treatment), medical background (somatic and psychiatric), clinical and possible radiological diagnoses at a tertiary care clinic, treatment modalities for masticatory muscle myalgia, bruxism assessment, its possible treatment modalities and their outcomes, and overall management outcome. We analysed the outcomes of single treatment modalities and combined groups of modalities. For the demographic data, the Chi-squared test and Fischer's Exact test were used to determine the associations between the categorical variables. A Sankey-diagram was used to describe the flow of treatment. RESULTS: Temporomandibular joint-pain-dysfunction syndrome (K07.60) was the most frequent single reason to refer a patient to tertiary care (17.4%). At referral, men had myalgia (M79.1) significantly more often (p = .034) than women. Similarly, men had depression (p = .002) more often and other psychiatric diagnoses (p = .034). At tertiary care, the presence of AB was assessed in 53.9%, and self-reported AB was recorded in 48.7%. In patients with possible AB, those who were prescribed neuropathic pain medication showed significantly less improvement in symptoms (p = .021) than those who underwent splint therapy (p = .009). Overall, half of the patients showed overall improvement in their TMD symptoms from the treatment combinations. CONCLUSION: Despite several treatment modalities, only half of the patients showed improvement in their symptoms in the present study. A standardised assessment method encompassing all factors contributing to bruxism behaviours and their consequences is suggested.

Follow-up clarifications concerning the authors' reply to the 'look at the elephant!' comment on 'prevalence of temporomandibular disorders in adult obstructive sleep apnoea patients: A cross-sectional controlled study'.

OSAS and TMDs represent multifactorial nosologic entities, whose central, functional and psycho-social aspects are gaining growing attention within the scientific community. In our previous commentary, we wanted to point out that structural aspects should not be forgotten in a clinical and research context. The inherent complexity of the matter could make it difficult to quantify the exact contribution of every single factor. The multifaceted nature of OSAS and TMDs pathophysiology could sustain several phenotypes in both conditions, and the anatomic parameters may assume different weights according to each phenotype, possibly justifying literature discrepancies. Thus, a patient with a co-existing OSAS and TMD (umbrella terms per se, each of them including different pathophysiological and clinical characteristics) represents an even greater challenge to researchers and practitioners. The scientific and therapeutic community should keep on looking for evidence to offer the best possible answers to such daring questions, in the most collaborative and fruitful way.

Prevalence of temporomandibular disorders in clear aligner patients using orthodontic intermaxillary elastics assessed with diagnostic criteria for temporomandibular disorders (DC/TMD) axis II evaluation: A cross-sectional study.

BACKGROUND: The objective of this investigation is to assess the relationship between the utilisation of orthodontic intermaxillary elastics and temporomandibular disorder (TMD) symptoms in clear aligner patients and to examine the correlation between the elastic usage time with the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD)-Axis II Evaluation Forms. METHODS: This study was carried out on a total of 40 clear aligner patients using intermaxillary elastics in the experimental group and 30 clear aligner patients who did not use any intermaxillary elastics in the control group. The data were evaluated using the Mann-Whitney U, chi-square, Fisher's exact chi-square, and Fisher Freeman Halton exact chi-square tests. RESULTS: The characteristic pain intensity, mastication, mobility, communication, global and PHQ-9 scores of the experimental group were significantly higher than those of the control group (p < .05). The characteristic pain intensity score, interference score and chronic pain grade score of patients using Class III elastics were statistically significantly higher than those of patients using Class II elastics (p < .05). Patients who used elastics for less than 6 months had statistically significantly higher PHQ-9 scores than those who used elastics for more than 6 months (p < .05). CONCLUSIONS: Orthodontic treatment may affect occlusion, bite force and jaw movement, which may cause or worsen TMD symptoms, and the DC/TMD questionnaires can determine if orthodontic patients acquire TMD by assessing their psychosocial state and pain-related problems.

Efficacy of hyaluronic acid in temporomandibular disorders evaluated with diagnostic criteria for temporomandibular disorders (DC/TMD).

BACKGROUND: The study aimed to retrospectively assess the efficacy of hyaluronic acid (HA) in managing temporomandibular disorders (TMD) using the diagnostic criteria for temporomandibular disorders (DC/TMD). There has been an ongoing debate regarding the effectiveness of HA as a treatment option for TMD, which necessitated a thorough evaluation. METHODS: The review adhered to PRISMA guidelines conducted across eight different databases, including PubMed, Embase, Web of Science, Cochrane Library, Scopus, ScienceDirect, PsycINFO and CINAHL. The selection criteria included studies that evaluated the efficacy of HA in TMD patients, utilised DC/TMD, and were published in English. Data extraction and quality assessment were performed independently by two reviewers. ROB-2 tool was employed to assess methodological quality of the assessed studies. RESULTS: A total of 10 studies met the inclusion criteria. They demonstrated that HA was effective in improving various symptoms of TMD, such as pain, mouth opening and joint sounds over control group. But on the other end, platelet-rich plasma (PRP) was found to be better than HA intervention in alleviation of TMD symptoms. However, the degree of improvement varied across the studies. Some studies reported adverse effects, but these were typically minor and transient. Risk of bias assessment was low in all the included studies. CONCLUSION: The findings suggest that HA can be an effective treatment for TMD when evaluated with DC/TMD. However, the variation in effectiveness across studies indicates the need for individualised treatment planning and careful monitoring of adverse effects. Further research is needed to refine the treatment protocols and understand the long-term effectiveness and safety of HA in TMD management.

Temporomandibular Joint Discectomy in Patients With Disc Displacement: Assessment of Osteoarthritis at 10- and 30-Year Follow-Up.

BACKGROUND: Few ≥ 10-year follow-up studies of temporomandibular joint (TMJ) discectomy without replacement in patients with disc displacement (DD) analyse the relationship between the surgery and osteoarthritis (OA) exist. OBJECTIVES: To radiologically evaluate bony joint changes and OA development 10 and 30 years after TMJ discectomy as well as 30-year clinical outcome. METHODS: Twenty-two discectomy patients at the University of Oslo, Norway, with records confirming initial TMJ diagnosis and attendance of 10-year radiological follow-up were evaluated and eligible for 30-year follow-up. Primary variables: discectomy and CT-/CBCT-diagnosed OA at follow-ups. Secondary variables: perioperative TMJ diagnoses and remodelling at follow-up. Unoperated TMJs (Unop-TMJs) in unilaterally operated patients were controls. Statistical association and correlation analyses were performed for the 10-year follow-up (significance level p < 0.05). RESULTS: Twenty-two patients attended the 10-year follow-up (mean follow-up 11 years) with 27 operated TMJs (Op-TMJs) and 17 Unop-TMJs. OA perioperatively was associated with DD without reduction (p = 0.001) and additional disc abnormalities (p = 0.016). Although statistically non-significant, the number of TMJs with OA had increased at 10-year follow-up (p = 0.114, Op-TMJs: 14 to 20 joints; Unop-TMJs: 2 to 5 joints). Remodelling was correlated with discectomy (p = 0.003) and to OA (p = 0.006). Nine patients attended the 30-year follow-up (mean follow-up 32 years, 11 Op-TMJs). All TMJs with OA at 30-year follow-up had OA at 10-year follow-up. Mean maximal interincisal opening was 39 mm. No DC-TMD-diagnosed arthralgia was found. CONCLUSION: Osteoarthritis developed similarly between Op- and Unop-TMJs. Only remodelling, not OA, was correlated to the surgery. The clinical results were still favourable at final follow-up.

Comparison of force profiles from two musculoskeletal palpation methods: A methodological study.

BACKGROUND: The Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) protocol recommends a 5 s and 1 kg force dynamic palpation around the lateral condylar pole of the temporomandibular joint. However, the accuracy and precision of the generated force are not known. OBJECTIVE: To assess and compare the force profiles generated from dynamic palpation manually and using a palpometer, based on the forces and time recommendations suggested by the DC/TMD protocol. METHODS: Nineteen healthy adults applied forces of 0.5 kg, 1.0 kg and 2.0 kg on a calibrated force sensor in a circular motion within target times of 2 s and 5 s. Participants used their right index finger for manual palpation and a calibrated palpometer for device-assisted palpation. Ten repetitions of each target force at both target times were applied. Time taken to complete each application was recorded. Repeated measures analysis of variance was used for analysis of accuracy measured as the relative difference between targeted force and actual force values and precision measured as the coefficient of variation (CV) within the 10 repeated measurements. RESULTS: Accuracy was significantly lower (better) and precision higher (lower CV) with the palpometer than with manual palpation (p < .001). There were significant differences in accuracy and precision between the different forces but not palpation times. Most participants could not achieve the target times and tended to be faster, irrespective of the palpation method (p > .063). CONCLUSION: A palpometer is a more accurate and precise palpation method for dynamic force assessment compared to manual palpation; however, it remains difficult to standardize the palpation duration.

Genetic influence on treatment outcomes in patients with pain-related temporomandibular disorders.

BACKGROUND: Single nucleotide polymorphisms (SNPs) may influence pain susceptibility and impact treatment response in pain-related temporomandibular disorders (TMDp). OBJECTIVE: Explore the role of COMT (rs4646310, rs6269, rs4818, rs4680) and OPRM1 (rs1799971) genotypes in regulating treatment response. METHODS: Sixty TMDp patients (55 females and 5 males), diagnosed with the Diagnostic Criteria for TMD (DC/TMD), underwent standardised treatment (information and education, home physical therapy, occlusal splint) for 6 months. Treatment outcomes included: pain intensity, pain-free mouth opening, jaw functional limitation, depression, and anxiety. Genotyping for COMT and OPRM1 SNPs was performed using DNA from buccal mucosa swabs and TaqMan assays. Statistical analysis was carried out to compare the changes in treatment outcomes and the influence of genotypes on treatment response. RESULTS: Significantly less pain reduction was observed in minor allele carriers of rs4646310, and rs4680 compared to dominant homozygous (p < .025). Minor allele carriers of rs1799971 and rs4646310 demonstrated worsening in pain-free mouth opening while dominant homozygous exhibited improvement (p < .025). Significantly less anxiety reduction was observed in minor allele carriers of rs4646310 compared to dominant homozygous (p = .003). Of the all variables assessed in the regression model, carrying a minor allele of rs1799971 predicted a poorer treatment response considering pain-free mouth opening while carrying a minor allele of rs4646310 predicted less pain and less anxiety reduction. CONCLUSION: Our findings indicate that certain SNP variants of the COMT and OPRM1 genes were associated with poorer treatment response and may therefore play a significant role in the classification of TMDp patients. Also, assessment of patient genotype could potentially aid in predicting treatment response.

Pain and salivary biomarkers of stress in temperomandibular disorders were affected by maxillary splints.

BACKGROUND: Longitudinal intervention studies on treatment options in temporomandibular dysfunction (TMD) including self reports and salivary biomarkers of stress are rare and the exact therapeutic function of occlusal splints widely unknown. METHODS: We examined the therapeutic effects of a Michigan splint with occlusal relevance in patients with TMD using a placebo-controlled, delayed-start design. Two intervention groups received a Michigan splint, while one of them had a placebo palatine splint for the first 3 weeks. We collected pain intensities (at rest and after five occlusal movements), salivary measures associated with stress (cortisol and alpha-amylase) and self-reported psychological distress (stress, anxiety, catastrophizing) at baseline and 3 and 7 weeks after onset of intervention. RESULTS: At baseline, we observed increased pain intensity and psychological distress in TMD patients compared to 11 matched healthy controls. Baseline anxiety was linked to movement pain intensity through stress. Over therapy reductions in pain intensity and morning cortisol were more pronounced in those patients starting immediately with the Michigan splint, while psychological distress decreased similarly in both groups. CONCLUSION: Our results suggest that perceived stress plays a role for the association between anxiety and TMD pain and underlines the need for an interdisciplinary perspective on the pathogenesis and therapy of TMD in a setting where psychotherapeutic knowledge is still scarce or rarely applied.

Salivary Biomarkers and Temporomandibular Disorders: A Systematic Review conducted according to PRISMA guidelines and the Cochrane Handbook for Systematic Reviews of Interventions.

BACKGROUND: The present review aimed to investigate the association between salivary biomarkers and temporomandibular disorders (TMD). TMD is a multifactorial condition characterised by pain and dysfunction in the temporomandibular joint (TMJ) and surrounding structures. Salivary biomarkers have emerged as potential diagnostic tools due to their non-invasiveness and easy accessibility. However, the literature on salivary biomarkers in relation to TMD is limited and inconsistent. METHODS: Electronic databases of Pubmed, Embase, Web of Science, Scopus, Cochrane Library, PsychINFO, CINAHL and Medline were searched using specific search terms and Boolean operators. The search was limited to articles published in English that assessed salivary biomarkers in individuals diagnosed with TMD. Two reviewers independently screened the articles and extracted data. ROB-2 was used to assess the risk of bias. RESULTS: Eleven clinical papers met the inclusion criteria and were included in the review. The findings provided consistent evidence of a clear association between salivary biomarkers and TMD. Various biomarkers, including cortisol, IL-1, glutamate and several others, were assessed. Some studies reported higher levels of cortisol and IL-1 in TMD patients, indicating potential involvement in stress and inflammation. Glutamate levels were found to be elevated, suggesting a role in pain modulation. Other biomarkers also showed alterations in TMD patients compared to controls: CONCLUSION: The findings from the included studies suggest that salivary biomarkers may play a role in TMD pathophysiology. Though a definitive conclusion can be drawn regarding the specific salivary biomarkers and their association with TMD, the results must be interpreted with caution considering the heterogeneity of the biomarkers assessed. Further research with larger sample sizes, standardised methodology and rigorous study designs is needed to elucidate the role of salivary biomarkers in TMD.