STPP-UP: An alternative method for drug target identification using protein thermal stability.

Thermal proteome profiling (TPP) has significantly advanced the field of drug discovery by facilitating proteome-wide identification of drug targets and off-targets. However, TPP has not been widely applied for high-throughput drug screenings, since the method is labor intensive and requires a lot of measurement time on a mass spectrometer. Here, we present Single-tube TPP with Uniform Progression (STPP-UP), which significantly reduces both the amount of required input material and measurement time, while retaining the ability to identify drug targets for compounds of interest. By using incremental heating of a single sample, changes in protein thermal stability across a range of temperatures can be assessed, while alleviating the need to measure multiple samples heated to different temperatures. We demonstrate that STPP-UP is able to identify the direct interactors for anticancer drugs in both human and mice cells. In summary, the STPP-UP methodology represents a useful tool to advance drug discovery and drug repurposing efforts.

Which patients benefit from adding short-term psychodynamic psychotherapy to antidepressants in the treatment of depression? A systematic review and meta-analysis of individual participant data.

BACKGROUND: Adding short-term psychodynamic psychotherapy (STPP) to antidepressants increases treatment efficacy, but it is unclear which patients benefit specifically. This study examined efficacy moderators of combined treatment (STPP + antidepressants) v. antidepressants for adults with depression. METHODS: For this systematic review and meta-analysis (PROSPERO registration number: CRD42017056029), we searched PubMed, PsycINFO, Embase.com, and the Cochrane Library from inception to 1 January 2022. We included randomized clinical trials comparing combined treatment (antidepressants + individual outpatient STPP) v. antidepressants in the acute-phase treatment of depression in adults. Individual participant data were requested and analyzed combinedly using mixed-effects models (adding Cochrane risk of bias items as covariates) and an exploratory machine learning technique. The primary outcome was post-treatment depression symptom level. RESULTS: Data were obtained for all seven trials identified (100%, n = 482, combined: n = 238, antidepressants: n = 244). Adding STPP to antidepressants was more efficacious for patients with high rather than low baseline depression levels [B = -0.49, 95% confidence interval (CI) -0.61 to -0.37, p < 0.0001] and for patients with a depressive episode duration of >2 years rather than <1 year (B = -0.68, 95% CI -1.31 to -0.05, p = 0.03) and than 1-2 years (B = -0.86, 95% CI -1.66 to -0.06, p = 0.04). Heterogeneity was low. Effects were replicated in analyses controlling for risk of bias. CONCLUSIONS: To our knowledge, this is the first study that examines moderators across trials assessing the addition of STPP to antidepressants. These findings need validation but suggest that depression severity and episode duration are factors to consider when adding STPP to antidepressants and might contribute to personalizing treatment selection for depression.

A Psychoanalytic-Derived Brief Psychotherapeutic Approach in the Treatment of Major Depression: Monotherapy Studies.

Over the years, short term psychodynamic therapy (STPP) has been broadly researched in order to evaluate its efficacy in the treatment of major psychiatric disorders. In particular, a consistent number of studies focused on assessing clinical outcomes of the principal psychodynamic techniques in treating depressive disorders. We conducted a narrative review in which we aimed to evaluate the efficacy of STPP in monotherapy in major depressive disorder and to assess possible features that may correlate with its clinical use. Databases searched were PubMed, Ovid, Scopus, PsycINFO and Cochrane Libraries from inception to July 2022. Our research underlined that STPP in monotherapy is particularly effective in moderately severe depression and in preventing depressive relapses. Moreover, a case-by-case evaluation of its efficacy should be performed when considering STPP for the treatment of major depression with other comorbid psychiatric conditions. Although such key points emerged from scientific evidence, STPP should be better studied in the long-term perspective; further research is needed to define the clinical scenarios in which STPP can be considered a first-line approach as monotherapy in major depressive disorder compared to medications or other types of psychotherapy.

Encoding of vestibular and optic flow cues to self-motion in the posterior superior temporal polysensory area.

KEY POINTS: Neurons in the posterior superior temporal polysensory area (STPp) showed significant directional selectivity in response to vestibular, optic flow and combined visual-vestibular stimuli. By comparison to the dorsal medial superior temporal area, the visual latency was slower in STPp but the vestibular latency was faster. Heading preferences under combined stimulation in STPp were usually dominated by visual signals. Cross-modal enhancement was observed in STPp when both vestibular and visual cues were presented together at their heading preferences. ABSTRACT: Human neuroimaging data implicated that the superior temporal polysensory area (STP) might be involved in vestibular-visual interaction during heading computations, but the heading selectivity has not been examined in the macaque. Here, we investigated the convergence of optic flow and vestibular signals in macaque STP by using a virtual-reality system and found that 6.3% of STP neurons showed multisensory responses, with visual and vestibular direction preferences either congruent or opposite in roughly equal proportion. The percentage of vestibular-tuned cells (18.3%) was much smaller than that of visual-tuned cells (30.4%) in STP. The vestibular tuning strength was usually weaker than the visual condition. The visual latency was significantly slower in STPp than in the dorsal medial superior temporal area (MSTd), but the vestibular latency was significantly faster than in MSTd. During the bimodal condition, STP cells' response was dominated by visual signals, with the visual heading preference not affected by the vestibular signals but the response amplitudes modulated by vestibular signals in a subadditive way.

Efficacy of short-term psychodynamic psychotherapy (STPP) with depressed breast cancer patients: results of a randomized controlled multicenter trial.

BACKGROUND: There is a lack of trials of psychodynamic treatments of depression in breast cancer patients. The purpose of this trial was to determine the efficacy of short-term psychodynamic psychotherapy (STPP) in non-metastatic breast cancer patients diagnosed with depression, one of the most frequent mental comorbidities of breast cancer. PATIENTS AND METHODS: In a multicenter prospective trial, 157 breast cancer patients with comorbid depression were randomized to either individual STPP (intervention group, N=78) or 'treatment as usual' (control group, TAU, N=79). As our primary outcome measure, we hypothesized a higher rate of remission defined as no diagnosis of depression (Structured Clinical Interview for DSM-IV) and reduction in depression score by at least 2 points (Hospital Anxiety and Depression Scale, HADS-D) in STPP versus TAU at treatment termination. Secondary outcomes mainly refer to quality of life (QoL). RESULTS: In the intention to treat (ITT) analysis, 44% of the STPP group achieved highly significantly more remission than TAU (23%). STPP treatment (OR=7.64; P<0.001) was the strongest predictor for remission post-treatment; time was also significant (OR=0.96; P<0.05). A high effect favoring STPP (d=0.82) was observed for the HADS-D score post-treatment (secondary outcome). Regarding further secondary outcomes (QoL), analyses of covariance yielded main effects for group (favoring STPP with an effect size of at least d=0.5) for global QoL, role, emotional and social functioning, pain, treatment side-effects, breast symptoms and upset by hair loss. CONCLUSIONS: STPP is an effective treatment of a broad range of depressive conditions in breast cancer patients improving depression and functional QoL. Findings are limited by the drop-out rate (∼1/3) and delayed post-treatment assessments. Future trials may consider stepped-care approaches, tailored to patients' needs and requirements in the acute treatment phase.

The catalytic subunit of type 2A protein phosphatase negatively regulates conidiation and melanin biosynthesis in Setosphaeria turcica.

Northern corn leaf blight caused by Setosphaeria turcica is a major fungal disease responsible for significant reductions in maize yield worldwide. Eukaryotic type 2A protein phosphatase (PP2A) influences growth and virulence in a number of pathogenic fungi, but little is known about its roles in S. turcica. Here, we functionally characterized S. turcica StPP2A-C, which encodes the catalytic C subunit of StPP2A. StPP2A-C deletion slowed colony growth, conidial germination, and appressorium formation but increased conidiation, melanin biosynthesis, glycerol content, and disease lesion size on maize. These effects were associated with expression changes in genes related to calcium signaling, conidiation, laccase activity, and melanin and glycerol biosynthesis, as well as changes in intra- and extracellular laccase activity. A pull-down screen for candidate StPP2A-c interactors revealed an interaction between StPP2A-c and StLac1. Theoretical modeling and yeast two-hybrid experiments confirmed that StPP2A-c interacted specifically with the copper ion binding domain of StLac1 and that Cys267 of StPP2A-c was required for this interaction. StPP2A-C expression thus appears to promote hyphal growth and reduce pathogenicity in S. turcica, at least in part by altering melanin synthesis and laccase activity; these insights may ultimately support the development of novel strategies for biological management of S. turcica.

Effects of sodium chloride and sodium tripolyphosphate on the prooxidant properties of hemoglobin in washed turkey muscle system.

This study examined the effects of sodium chloride (NaCl) and sodium tripolyphosphate (STPP) on lipid oxidation induced by oxyhemoglobin (oxyHb) in washed turkey muscle (WTM) model. To explore the reasons for observed effects, the pro-oxidant abilities of Hb derivatives (e.g., metHb, oxyHb, hemin, Fe2+, and Fe3+), pH change, and antioxidation of Hb in the presence of NaCl or STPP were also analyzed. The observed lipid oxidation capacity in WTM followed the order metHb > hemin > oxyHb > Fe2+ > Fe3+. Added Fe2+ accelerated auto-oxidation of oxyHb and oxyHb-mediated lipid oxidation. Hb auto-oxidation to metHb increased as the pH decreased from 6.6 to 5.0. NaCl promoted oxyHb-mediated lipid oxidation due to NaCl causing decreased pH value and increased formation of metHb. STPP inhibited oxyHb-mediated lipid oxidation and weakened the pro-oxidative effect of NaCl. This could be attributed to STPP increasing the pH, inactivating free iron, and inhibiting formation of metHb.

Examining Psychotherapeutic Processes with Depressed Adolescents: A Comparative Study of Two Psychodynamic Therapies.

To understand processes associated with better or poorer psychotherapy outcomes is vital. This study examined and contrasted interaction patterns between one therapist and two depressed 17-year-old girls, Johanna (good outcome) and Sonja (poor outcome), in short-term psychoanalytic therapies selected from an RCT. Outcome data were collected regarding level of inter- and intra-personal functioning and symptoms of depression. Process data were obtained using the Adolescent Psychotherapy Q-Set on all available sessions. Analyses yielded five relational patterns or "interaction structures" in the two therapy processes; Three explained most of the variance in sessions with Johanna (i.e., 'positive working alliance', 'therapist's active use of psychodynamic techniques', and 'a receptive patient') and two explained more of the variance in sessions with Sonja (i.e., 'therapist using a more problem-solving and symptom-oriented approach' and 'patient displaying limited capacity for mentalization'). The processes in the two cases presented differences related to mentalization, psychological mindedness, and attachment style of the patients. The therapist used different therapeutic approaches, favouring more psychodynamic interventions in the good outcome case and a more problem-solving and symptom-oriented approach with the poor outcome case. In the latter case, the relationship seemed to be more of a struggle.

Insights into the similarities and differences of whiteleg shrimp pre-soaked with sodium tripolyphosphate and sodium trimetaphosphate during frozen storage.

In this study, similarities and differences of sodium tripolyphosphate (STPP) and sodium trimetaphosphate (STMP) pre-soaking on the stability of muscle proteins in shrimp were investigated during 12 weeks of frozen storage (-30 °C). The physicochemical analysis indicated significant improvements in the WHC, springiness, chewiness, and thermal stability of STPP and STMP pre-soaked samples when compared to the control. Interestingly, STMP pre-soaking showed better cryoprotective effects than the STPP treatment when the storage period reached the end of the 12 weeks. Furthermore, the label-free based proteomics results indicated that 62 upregulated differentially abundant proteins (DAPs) were detected in STMP when compared to STPP. These identified DAPs specifically included 40S ribosomal proteins, actin-related proteins, heat shock proteins, myosin heavy chain, and tubulin beta chain. Additionally, the gene ontology (GO) and eukaryotic clusters of orthologous group (KOG) analyses verified that the incorporation of STMP molecules enhanced the resistance of cytoskeleton proteins to cold-temperature stress.

The efficacy of adding short-term psychodynamic psychotherapy to antidepressants in the treatment of depression: A systematic review and meta-analysis of individual participant data.

PURPOSE: We examined the efficacy of adding short-term psychodynamic psychotherapy (STPP) to antidepressants in the treatment of depression by means of a systematic review and meta-analysis of individual participant data, which is currently considered the most reliable method for evidence synthesis. RESULTS: A thorough systematic literature search resulted in 7 studies comparing combined treatment of antidepressants and STPP versus antidepressant mono-therapy (n = 3) or versus antidepressants and brief supportive psychotherapy (n = 4). Individual participant data were obtained for all these studies and totaled 482 participants. Across the total sample of studies, combined treatment of antidepressants and STPP was found significantly more efficacious in terms of depressive symptom levels at both post-treatment (Cohen's d = 0.26, SE = 0.10, p = .01) and follow-up (d = 0.50, SE = 0.10, p < .001). This effect was most apparent at follow-up and in studies examining STPP's specific treatment efficacy. Effects were still apparent in analyses that controlled for risk of bias and STPP quality in the primary studies. CONCLUSIONS: These findings support the evidence-base of adding STPP to antidepressants in the treatment of depression. However, further studies are needed, particularly assessing outcome measures other than depression and cost-effectiveness, as well as examining the relative merits of STPP versus other psychotherapies as added to antidepressants.

Topical delivery of acetazolamide by encapsulating in mucoadhesive nanoparticles.

The intent of this study was to provide topical delivery of acetazolamide by preparing chitosan-STPP (sodium tripolyphosphate) nanoparticles of acetazolamide and evaluate the particle size, zeta potential, drug entrapment, particle morphology; in vitro drug release and in vivo efficacy. The particles showed sustained in vitro drug release which followed the Higuchi kinetic model. The results indicate that the nanoparticles released the drug by a combination of dissolution and diffusion. The optimised formulation was having particle size 188.46 ± 8.53 nm and zeta potential + 36.86 ± 0.70 mV. The particles were spherical with a polydispersity index of 0.22 ± 0.00. Powder X-ray diffraction and differential scanning calorimetry indicated diminished crystallinity of drug in the nanoparticle formulation. In the in vitro permeation study, the nanoparticle formulation showed elevated permeation as compared to that of drug solution with negative signs of corneal damage. In vitro mucoadhesion studies showed 90.34 ± 1.12% mucoadhesion. The in vivo studies involving ocular hypotensive activity in rabbits revealed significantly higher hypotensive activity (P < 0.05) as compared with plain drug solution with no signs of ocular irritation. The stability studies revealed that formulation was quite stable.

Development and Characterization of Gefitinib Loaded Polymeric Nanoparticles by Ionic Gelation Method.

BACKGROUND: There is a rapidly growing interest in the development of nanoparticle drug delivery mainly for anticancer drugs as it promises to solve several problems associated with anticancer drugs such as poor water solubility, low therapeutic index, nonspecific distribution and higher systemic toxicity, etc. OBJECTIVE: The objective of the study was to investigate the effect of various critical variables like, concentration of chitosan, concentration of sodium tripolyphosphate (STPP) and volume of STPP on various characteristics of gefitinib loaded nanoparticles. METHODS: Thirteen formulations of the polymeric nanoparticles were prepared using various concentrations of chitosan (0.1-1% w/v), STPP (0.2-1.5% w/v) and different volumes of STPP (8-20 ml) by ionic gelation method. Mannitol (5% w/v) was used as cryoprotectant. The prepared nanoparticle formulations were characterized for various parameters like particle size, zeta potential, process yield, encapsulation efficiency, drug content, and in vitro drug release. RESULTS: The nanoparticle formulation NF-1 containing 0.1% w/v of chitosan and 10 ml volume of 0.2% w/v STPP showed best results in terms of particle size (123.8nm), polydispersity index (0.247), zeta potential (+30.4 mV), process yield (68.09%), drug content (74.32%), encapsulation efficiency (70.52%) and released (56.2 %) drug over a period of 24 h. The in vitro drug release analysis showed sustained release of gefitinib from nanoparticles and followed Korsmeyer-Peppas model. CONCLUSION: The nanoparticle formulation with desired characteristics can be prepared at low concentration of chitosan and STPP along with low volume of STPP. The formulated nanoparticles may prove to be the best option for the treatment of cancer.

Therapeutic alliance and treatment outcome in psychodynamic psychotherapy of depressed breast cancer patients: the same old story or different from other populations?

BACKGROUND: A good therapeutic alliance is associated with better treatment outcomes in diverse types of psychotherapy and patient populations, but little is known about therapeutic alliance in psychotherapies with cancer patients. This study examines the association of therapeutic alliance and treatment outcome in short term psychodynamic psychotherapy (STPP) for breast cancer patients. METHODS: Within a randomized controlled trial, 47 completers of STPP could be included in the analyses. The therapeutic alliance was assessed by patients and therapists at treatment termination with the Helping Alliance Questionnaire. Outcome was defined as no diagnosis of depression assessed with Structured Clinical Interview for DSM-IV (SCID-I) and a reduction of the HADS-depression score by at least two points at treatment termination. RESULTS: Patients' alliance ratings were significantly associated with outcome (r = 0.46, p = 0.015), while, in contrast to findings in non-cancer populations, therapists' ratings were unrelated. There was no association between patients' and therapists' ratings of therapeutic alliance. Especially success and working related aspects of patients' alliance scores were associated with outcome. Patients' and therapists' alliance scores were unrelated to any of their baseline characteristics, therapist characteristic or treatment variables. CONCLUSION: We conclude that therapists should regularly assess the quality of patients' perceived therapeutic alliance in the course of psychotherapy with breast cancer patients to improve psychotherapy outcome. The breast cancer patients' perspective should be actively inquired and considered throughout treatment by therapists. Possible discrepancies between both judgements can be addressed in treatment.

The efficacy of short-term psychodynamic psychotherapy for depression: A meta-analysis update.

OBJECTIVES: The efficacy of short-term psychodynamic psychotherapy (STPP) for depression is debated. Recently, a number of large-scale and high-quality studies have been conducted. We examined the efficacy of STPP by updating our 2010 meta-analysis. RESULTS: After a thorough literature search, 54 studies (33 randomized clinical trials) totaling 3946 subjects were included. STPP was significantly more effective than control conditions at post-treatment on depression, general psychopathology and quality of life measures (d=0.49 to 0.69). STPP pre-treatment to post-treatment changes (d=0.57 to 1.18) indicated significant improvements on all outcome measures, which either significantly improved further (d=0.20 to 1.04) or were maintained from post-treatment to follow-up. No significant differences were found between individual STPP and other psychotherapies at post-treatment (d=-0.14) and follow-up (d=-0.06) in analyses that were adequately powered to detect a clinically relevant difference. STPP was significantly more efficacious than other psychotherapies on anxiety measures at both post-treatment (d=0.35) and follow-up (d=0.76). CONCLUSION: We found clear indications that STPP is effective in the treatment of depression in adults. Although more high-quality studies are needed, particularly to assess the efficacy of STPP compared to control conditions at follow-up and to antidepressants, these findings add to the evidence-base of STPP for depression.

Alginate coated chitosan core shell nanoparticles for oral delivery of enoxaparin: in vitro and in vivo assessment.

The objective of present research work was to develop alginate coated chitosan core shell nanoparticles (Alg-CS-NPs) for oral delivery of low molecular weight heparin, enoxaparin. Chitosan nanoparticles (CS-NPs) were synthesized by ionic gelation of chitosan using sodium tripolyphosphate. Core shell nanoparticles were prepared by coating CS-NPs with alginate solution under mild agitation. The Alg-CS-NPs were characterized for surface morphology, surface coating, particle size, polydispersity index, zeta potential, drug loading and entrapment efficiency using SEM, Zeta-sizer, FTIR and DSC techniques. Alginate coating increased the size of optimized chitosan nanoparticles from around 213 nm to about 335 nm as measured by dynamic light scattering in zeta sizer and further confirmed by SEM analysis. The performance of optimized enoxaparin loaded Alg-CS-NPs was evaluated by in vitro drug release studies, in vitro permeation study across intestinal epithelium, in vivo venous thrombosis model, particulate uptake by intestinal epithelium using fluorescence microscopy and pharmacokinetic studies in rats. Coating of alginate over the CS-NPs improved the release profile of enoxaparin from the nanoparticles for successful oral delivery. In vitro permeation studies elucidated that more than 75% enoxaparin permeated across the intestinal epithelium with Alg-CS-NPs. The Alg-CS-NPs significantly increased (p<0.05) the oral bioavailability of enoxaparin in comparison to plain enoxaparin solution as revealed by threefold increase in AUC of plasma drug concentration time curve and around 60% reduction in thrombus formation in rat venous thrombosis model. The core shell Alg-CS-NPs showed promising potential for oral delivery and significantly enhanced the in vivo oral absorption of enoxaparin.