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Tamoxifen, a common adjuvant therapy for hormone receptor-positive breast cancer, is associated with an increased risk of endometrial pathologies, such as hyperplasia, polyps, and carcinoma. This study investigates rapamycin, an mTOR inhibitor, as a potential novel strategy for preventing tamoxifen-induced endometrial proliferation. This in vitro study utilised endometrial stromal cells isolated from infertile women. The cells were treated with tamoxifen alone or in combination with rapamycin, and proliferation was assessed using the CCK-8 assay. The activation of the mTOR pathway, as well as apoptosis and cell cycle markers, was evaluated by Western blotting to elucidate the molecular mechanisms underlying these effects. The study design emphasised simulating clinically relevant exposure levels. Tamoxifen significantly increased endometrial cell proliferation in a dose-dependent manner. Rapamycin effectively inhibited this proliferation, even at concentrations lower than those typically observed in clinical settings. Quantitative analysis by Western blotting showed activation of the mTOR pathway and cell cycle in the tamoxifen group, and inhibition of these pathways in the tamoxifen plus rapamycin combination group, whereas there was no change in apoptosis. In conclusion, rapamycin shows promise as a prophylactic agent against tamoxifen-induced endometrial pathologies, with potential implications for fertility preservation and endometrial protection in breast cancer patients., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

There is insufficient evidence comparing the outcomes of tacrolimus-based remission induction therapy with infliximab in refractory ulcerative colitis (UC) and evidence regarding optimal strategies after tacrolimus-based remission induction therapy. We conducted a multi-institutional retrospective study of patients with UC treated with tacrolimus or infliximab between January 2010 and March 2019. The proportion of clinical remission at week 8 and cumulative colectomy-free rate were examined using propensity score matching analysis. The predictors for colectomy after tacrolimus induction were also investigated. Ninety patients in the tacrolimus group and 151 in the infliximab group were enrolled. The proportion of patients in clinical remission at week 8 was 65.2% in the matched tacrolimus group and 37.3% in the matched infliximab group (P = 0.0016), and the long-term colectomy-free rate was lower in the matched tacrolimus group than in the matched infliximab group (P = 0.0003). After clinical remission with tacrolimus, a serum albumin level of ≤ 3.5 g/dL at week 8 was extracted as a factor predicting colectomy (area under the curve: 0.94). Tacrolimus showed a higher remission induction effect for UC compared to infliximab. However, a high rate of colectomy after transition to maintenance treatment was found to be a concern for tacrolimus therapy., Competing Interests: Competing interests: Takeo Yoshihara received lecture fees from EA Pharma Co., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, and Nippon Kayaku Co., Ltd. Takahiro Amano received lecture fees from Janssen Pharmaceutical K.K. and Mitsubishi Tanabe Pharma Corporation. Shinichiro Shinzaki received personal fees from AbbVie Inc., EA Pharma Co., Ltd., Eisai Co., Ltd., Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, and Nippon Kayaku Co., Ltd., and scholarship grants from AbbVie Inc., EA Pharma Co., Ltd., and Nippon Kayaku Co., Ltd. Satoshi Egawa received lecture fees from Mitsubishi Tanabe Pharma Corporation and Janssen Pharmaceutical K.K. Satoshi Hiyama1 received lecture fees from Mitsubishi Tanabe Pharma Corporation and AbbVie Inc. Hideki Iijima received lecture fees from AbbVie Inc., Janssen Pharmaceutical K.K., EA Pharma Co., Ltd., Eisai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Corporation, and Mochida Pharmaceutical Co., Ltd. Yoshito Hayashi received lecture fees from EA Pharma Co., Ltd and Nippon Kayaku Co., Ltd. Tetsuo Takehara received lecture fees from AbbVie Inc.,consigned/joint research expenses from AbbVie Inc., Janssen Pharmaceutical K.K., and Mitsubishi Tanabe Pharma Corporation, and scholarship donations from AbbVie Inc., EA Pharma Co., Ltd., Nippon Kayaku Co., Ltd. and Mitsubishi Tanabe Pharma Corporation. None of the disclosures mentioned above are related to this study. The remaining authors do not have any conflicts of interest to disclose. Ethics approval: This study was approved by the Ethics Committee of Osaka University Hospital and by the Ethics Committees of the respective institutions (the ethics approval number: 18208). Patient consent: The requirement for written informed consent was waived by allowing the participants to opt out because of the study’s retrospective nature., (© 2024. The Author(s).)

Serum leucine-rich alpha-2 glycoprotein (LRG) can monitor disease activities during biologics treatment in patients with inflammatory bowel disease (IBD). It is unclear whether the pretreatment serum LRG level can predict clinical effectiveness including serum trough levels of ustekinumab in patients with IBD. This multicenter prospective cohort study included 184 patients (Crohn's disease, 104; ulcerative colitis, 80) who received ustekinumab (n = 119) or anti-tumor necrosis factor (n = 65) between January 2019 and March 2023. Multivariate logistic regression analysis revealed serum LRG level at week 0 (0w-LRG, odds ratio 0.12, 95% confidence interval 0.02-0.68) as one of significant factors for clinical remission at week 8. We divided patients into the low- and the high-LRG groups by the median 0w-LRG (18.2 µg/mL) and compared the effectiveness. In patients who received ustekinumab, the proportion of clinical remission at week 8 was significantly different between in the low- (76.9%) and in the high-LRG group (59.3%, P = 0.038), and median serum trough level at week 8 was significantly different between in the low- (10.9 µg/mL, interquartile range 6.7-13.4) and the high-LRG group (5.3 µg/mL, interquartile range 2.4-8.3, P < 0.001). The 0w-LRG can predict the effectiveness including serum trough levels of ustekinumab during induction treatment for patients with IBD., Competing Interests: Declarations. Competing interests: S. Shinzaki received lecture fees from Janssen Pharmaceutical K.K., Mitsubishi Tanabe Pharma Corporation, and lecture fees and grants from AbbVie GK, Sekisui Medical Co., Ltd.; A. Yonezawa: grants from Shimadzu Corporation and Ayumi Pharma Corporation.; H. Iijima: lecture fees from AbbVie GK and Mitsubishi-Tanabe Pharma Corporation; T. Takehara: grants from Mitsubishi-Tanabe Pharma Corporation, and lecture fees and grants from AbbVie GK. None of the aforementioned are related to this study. The remaining authors do not have any conflicts of interest to disclosure. Ethnics approval and consent to participate: This study was carried out in accordance with the Declaration of Helsinki, and approved by the ethics committee of Osaka University Hospital, the ethics committee of National Hospital Organization Osaka National Hospital, the ethics committee of Osaka Rosai Hospital, the ethics committee of Toyonaka Municipal Hospital, the ethics committee of Japan Community Healthcare Organization Osaka Hospital, the ethics committee of Itami City Hospital, the ethics committee of Suita Municipal Hospital, the ethics committee of Ikeda Municipal Hospital, the ethics committee of Otemae Hospital, the ethics committee of Kansai Rosai Hospital, the ethics committee of Higashiosaka City Medical Center, the ethics committee of Osaka General Medical Center, the ethics committee of Osaka Police Hospital, the ethics committee of Yao Municipal Hospital and the ethics committee of Hyogo Prefectural Nishinomiya Hospital. Written informed consent was obtained from all patients., (© 2024. The Author(s).)

Brown adipose tissue (BAT) plays an important role in energy metabolism because it uses fatty acids for thermogenesis during cold exposure. Preclinical studies found that boysenberry anthocyanins (BoyACs) activate BAT. Therefore, the aim of this preliminary study was to evaluate how BoyAC intake affects BAT in humans. We performed an open-label single-arm nonrandomized study in healthy volunteers. Before and after 4 weeks of daily consumption of 100 ml boysenberry juice (BoyJ) containing 61 mg of BoyACs, participants were assessed at 24 °C and then after 1 h of mild cold exposure (18 °C). An infrared thermography camera was used to measure skin surface temperatures in the supraclavicular BAT region (Tscv) and the non-BAT region of the upper chest (Tch). Energy metabolism was measured by indirect calorimetry. For each endpoint, we calculated Δ as the difference between values before and after cold exposure and compared the values before and after BoyJ intake. 10 volunteers participated (age: 36.1 ± 4.1, body mass index (BMI): 20.9 ± 0.6). After BoyJ intake, ΔTscv-ch was significantly higher (p = 0.029), but Δ energy expenditure, Δ fat oxidation, and Δ carbohydrate oxidation were not significantly different. We found a significant positive correlation between BMI and Δfat oxidation with BoyJ intake. The results indicate that 4 weeks of BoyJ intake activates cold-induced thermogenesis in the scv-BAT but does not have a significant effect on energy metabolism. BoyJ intake may increase fat oxidation during cold exposure in individuals with higher BMI.Trial registry number: UMIN000043476, 05/03/2021., (© 2024. The Author(s).)

Diagnosing cardiac sarcoidosis (CS), especially in isolated cases, is challenging, particularly due to the limitations of endomyocardial biopsy, leading to potential undiagnosed cases in pacemaker-implanted patients. This study aims to provide real world findings to support new guideline for CS using 18F-fluoro-deoxyglucose positron-emission tomography computed tomography (FDG-PET/CT) which give a definite diagnosis of isolated CS (iCS) without histological findings. We examined consecutive patients with cardiac pacemakers for atrioventricular block (AV-b) attending our outpatient pacemaker clinic. The patients underwent periodical follow-up echocardiography and were divided into two groups according to echocardiographic findings: those with suspected CS and those without suspected CS. Patients suspected of having nonischemic cardiomyopathy underwent FDG-PET/CT for CS diagnosis. We investigated the utility of the new guideline for CS using FDG-PET/CT. Among the 272 patients enrolled, 97 patients were implanted with cardiac pacemakers for AV-b. Twenty-two patients were suspected of having CS during a median observation period of 5.4 years after pacemaker implantation. Of these, one did not consent, and nine of 21 cases (43%) were diagnosed with definite CS according to the new guidelines. Five of these nine patients were diagnosed with iCS using FDG-PET/CT. The number of patients diagnosed with definite CS using the new guidelines tended to be approximately 2.3 times that of the conventional criteria (p = 0.074). Three of the nine patients underwent steroid treatment. The composite outcome, comprising all-cause death, heart failure hospitalization, and a substantial reduction in left ventricular ejection fraction, were significantly lower in patients receiving steroid treatment compared to those without steroid treatment (p = 0.048). The utilization of FDG-PET/CT in accordance with the new guidelines facilitates the diagnosis of CS, including iCS, resulting in approximately 2.3 times as many diagnoses of CS compared to the conventional criteria. This guideline has the potential to support the early identification of iCS and may contribute to enhancing patient clinical outcomes., (© 2024. The Author(s).)

Catheter ablation for atrial fibrillation (AF) during pulmonary vein isolation (PVI) is performed under general anesthesia (GA) or conscious sedation (CS). GA during PVI may improve treatment outcomes by improving catheter stability. However, the magnitude of GA-derived catheter stability compared with that of CS is unclear. We directly assessed catheter movement and determined the impact of GA compared with that of CS on ablation catheter stability during PVI. Patients who underwent initial ablation using the EnSite Precision™ mapping system were recruited and divided into two groups (GA and CS groups). The two groups were compared for ablation catheter stability during PVI based on the distance traveled by the catheter distal tip per second, clinical periprocedural characteristics, and periprocedural complications. Among 69 consecutively admitted patients, data of 30 patients (17 in the GA group and 13 in the CS group) and the distance traveled per second by the catheter on 148,976 points/patient were evaluated. The GA group had a significantly smaller catheter tip travel distance than the CS group (0.92 [0.82‒1.16] vs. 1.25 [1.14‒1.38], p = 0.01). Therefore, GA during PVI for AF provides greater catheter stability than CS and will contribute to more accessible and safer PVI procedures., (© 2023. Springer Nature Limited.)

A simple, non-invasive algorithm for maximal lactate steady state (MLSS) assessment has not been developed. We examined whether MLSS can be estimated from the sweat lactate threshold (sLT) using a novel sweat lactate sensor for healthy adults, with consideration of their exercise habits. Fifteen adults representing diverse fitness levels were recruited. Participants with/without exercise habits were defined as trained/untrained, respectively. Constant-load testing for 30 min at 110%, 115%, 120%, and 125% of sLT intensity was performed to determine MLSS. The tissue oxygenation index (TOI) of the thigh was also monitored. MLSS was not fully estimated from sLT, with 110%, 115%, 120%, and 125% of sLT in one, four, three, and seven participants, respectively. The MLSS based on sLT was higher in the trained group as compared to the untrained group. A total of 80% of trained participants had an MLSS of 120% or higher, while 75% of untrained participants had an MLSS of 115% or lower based on sLT. Furthermore, compared to untrained participants, trained participants continued constant-load exercise even if their TOI decreased below the resting baseline (P < 0.01). MLSS was successfully estimated using sLT, with 120% or more in trained participants and 115% or less in untrained participants. This suggests that trained individuals can continue exercising despite decreases in oxygen saturation in lower extremity skeletal muscles., (© 2023. The Author(s).)

Glioblastoma is the most common brain tumor with dismal outcomes in adults. Metabolic remodeling is now widely acknowledged as a hallmark of cancer cells, but glioblastoma-specific metabolic pathways remain unclear. Here we show, using a large-scale targeted proteomics platform and integrated molecular pathway-level analysis tool, that the de novo pyrimidine synthesis pathway and serine synthesis pathway (SSP) are the major enriched pathways in vivo for patients with glioblastoma. Among the enzymes associated with nucleotide synthesis, RRM1 and NME1 are significantly upregulated in glioblastoma. In the SSP, SHMT2 and PSPH are upregulated but the upstream enzyme PSAT1 is downregulated in glioblastoma. Kaplan-Meier curves of overall survival for the GSE16011 and The Cancer Genome Atlas datasets revealed that high SSP activity correlated with poor outcome. Enzymes relating to the pyrimidine synthesis pathway and SSP might offer therapeutic targets for new glioblastoma treatments., (© 2022. The Author(s).)

The outcomes of patients with elderly onset (EO) inflammatory bowel disease (IBD) treated with anti-tumor necrosis factor (TNF) remains uncertain. The present study evaluated the efficacy and safety of anti-TNF treatment for bio-naïve EO-IBD. Elderly patients were defined as those 60 years and older, and further divided into those with EO (Elderly-EO) and those with non-elderly onset (Elderly-NEO). A total of 432 bio-naïve patients were enrolled in this multicenter observational study, comprising 55 with Elderly-EO (12.7%), 25 with Elderly-NEO (5.8%), and 352 under age 60 (Non-elderly, 81.5%). After 52 weeks of anti-TNF treatment, clinical and steroid-free remission rates were significantly lower in Elderly-EO than in Non-elderly (37.7% and 60.8%; P = 0.001, and 35.9% and 57.8%; P = 0.003, respectively), and comparable between Elderly-NEO and Non-elderly. Multivariate analysis revealed that elderly onset was a significant factor for both clinical remission (OR, 0.49, 95% CI 0.25-0.96) and steroid-free remission (OR, 0.51, 95% CI 0.26-0.99) after 52 weeks of anti-TNF treatment. The rate of cumulative severe adverse events was significantly higher in Elderly-EO than in Non-elderly (P = 0.007), and comparable between Elderly-NEO and Non-elderly. In conclusion, anti-TNF treatment for bio-naïve EO-IBD may be less effective and raise safety concerns., (© 2022. The Author(s).)

Clinical targeted sequencing allows for the selection of patients expected to have a better treatment response, and reveals mechanisms of resistance to molecular targeted therapies based on actionable gene mutations. We underwent comprehensive genomic testing with either our original in-house CLHURC system or with OncoPrime. Samples from 24 patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer underwent targeted sequencing between 2016 and 2018. Germline and somatic gene alterations and patients' prognosis were retrospectively analyzed according to the response to endocrine therapy. All of the patients had one or more germline and/or somatic gene alterations. Four patients with primary or secondary endocrine-resistant breast cancer harbored germline pathogenic variants of BRCA1, BRCA2, or PTEN. Among somatic gene alterations, TP53, PIK3CA, AKT1, ESR1, and MYC were the most frequently mutated genes. TP53 gene mutation was more frequently observed in patients with primary endocrine resistance compared to those with secondary endocrine resistance or endocrine-responsive breast cancer. Recurrent breast cancer patients carrying TP53-mutant tumors had significantly worse overall survival compared to those with TP53-wild type tumors. Our 160-gene cancer panel will be useful to identify clinically actionable gene alterations in breast cancer in clinical practice.

Habitat fragmentation is considered as major threat to biodiversity worldwide. Biodiversity can be described as taxonomic, functional and phylogenetic diversity. However, the effect of forest fragmentation on taxonomic, phylogenetic and functional diversity is barely understood. We compare the response of taxonomic (species richness), phylogenetic and functional diversity of birds to forest fragmentation. We hypothesised that with increasing forest patch isolation and/or decreasing patch size the diversity of birds decreases but only if certain thresholds of fragmentation metrics are reached. Specifically, we hypothesized that out of the three diversity components the taxonomic diversity is the most sensitive to forest fragmentation, which means that it starts declining at larger patch size and higher connectivity values than phylogenetic and functional diversity do. We compared the three biodiversity metrics of central European bird species in a large set of forest patches located in an agricultural landscape. General additive modeling and segmented regression were used in analyses. Habitat fragmentation differentially affected studied biodiversity metrics. Bird taxonomic diversity was the most responsive towards changes in fragmentation. We observed an increase in taxonomic diversity with increasing patch area, which then stabilized after reaching certain patch size. Functional diversity turned out to be the least responsive to the fragmentation metrics and forest stand characteristics. It decreased linearly with the decreasing isolation of forest patches. Apart from the habitat fragmentation, bird taxonomic diversity but not phylogenetic diversity was positively associated with forest stand age. The lower share of dominant tree species, the highest taxonomic diversity was. While preserving a whole spectrum of forests (in terms of age, fragmentation and size) is important from the biodiversity perspective, forest bird species might need large, intact, old-growth forests. Since the large and intact forest becomes scarcer, our study underscore their importance for the preservation of forest specialist species.

Chronic kidney disease and white matter hyperintensity (WMH) are associated with cognitive decline. The aim of this study was to assess the correlations between estimated glomerular filtration rate (eGFR) or WMH and cognitive function in patients who have undergone carotid endarterectomy (CEA). Cognitive functions were investigated using the Neurobehavioral Cognitive Status Examination (Cognistat) in 83 patients who had undergone CEA. The eGFR at 5 years prior to examination was significantly associated with severe cognitive impairment (odds ratio, 0.89 per 1-mL/min/1.73 m 2 increase, 95% confidence interval 0.82-0.97, p = 0.0004). Receiver operating characteristic analysis revealed that a cutoff eGFR of 46.8 mL/min/1.73 m 2 at 5 years prior to examination offered the most reliable predictor of severe cognitive impairment (sensitivity 88.9%, specificity 76.5%, area under the curve 0.848). The eGFR at 5 years prior to examination showed a significant linear association with total Cognistat score (r 2  = 0.11035, p = 0.0032) compared to eGFR at 3 years prior to examination (r 2  = 0.06455, p = 0.0230) or at examination (r 2  = 0.0210, p = 0.0210). Spearman's correlation coefficient revealed that orientation, comprehension, repetition, construction, memory, and similarity correlated with eGFR at 5 years prior to examination. Conversely, Fazekas grade for deep WMH at examination was associated with total Cognistat score (p = 0.0016), unlike that at 3 years (p = 0.0100) or 5 years prior to examination (p = 0.0172). While eGFR correlates with future cognitive function, deep WMH associates with present cognitive function in patients who have undergone CEA.

A topical medication combining calcipotriol (Cal) and betamethasone dipropionate (BDP) has proven effective in a number of randomized controlled trials performed in patients with psoriasis, but its mechanism of action has not been fully elucidated. We investigated whether the combination of Cal and BDP (Cal/BDP) in this topical medication had a synergistic effect on psoriasis-like dermatitis and explored the underlying immunological mechanisms in a murine psoriasis model induced by application of imiquimod. Cal/BDP synergistically inhibited ear thickening induced by imiquimod compared to monotherapy with either Cal or BDP. In addition, Cal/BDP significantly suppressed the interleukin (IL)-23/IL-17-producing T (T17) pathogenic axis, including expression of IL-17a, IL-23a, IL-22 and TNF-α mRNA in skin lesions and expansion of CCR6 + γδ T17 cells in the draining lymph nodes. Notably, Cal/BDP synergistically induced regulatory CD8 + T cells and also improved the balance between regulatory CD8 + or CD4 + T cells and proinflammatory CCR6 + γδ T17 cells in the draining lymph nodes. These results suggest synergistic anti-psoriatic activity of Cal/BDP with normalization of the imbalance between regulatory CD8 + or CD4 + T cells and proinflammatory CCR6 + γδ T17 cells, which contributes to successful control of psoriasis by Cal-BDP combination therapy.

Accumulation of ubiquitinated protein aggregates is a common pathology associated with a number of neurodegenerative diseases and selective autophagy plays a critical role in their elimination. Although aging-related decreases in protein degradation properties may enhance protein aggregation, it remains unclear whether proteasome dysfunction is indispensable for ubiquitinated-protein aggregation in neurodegenerative diseases. Here, we show that N-oleoyl-dopamine and N-arachidonyl-dopamine, which are endogenous brain substances and belong to the N-acyldopamine (AcylDA) family, generate cellular inclusions through aggresome formation without proteasome inhibition. Although AcylDA itself does not inhibit proteasome activity in vitro, it activates the rearrangement of vimentin distribution to form a vimentin cage surrounding aggresomes and sequesters ubiquitinated proteins in aggresomes. The gene transcription of p62/SQSTM1 was significantly increased by AcylDAs, whereas the transcription of other ubiquitin-dependent autophagy receptors was unaffected. Genetic depletion of p62 resulted in the loss of ubiquitinated-protein sequestration in aggresomes, indicating that p62 is a critical component of aggresomes. Furthermore, AcylDAs accelerate the aggregation of mutant huntingtin exon 1 proteins. These results suggest that aggresome formation does not require proteasome dysfunction and AcylDA-induced aggresome formation may participate in forming cytoplasmic protein inclusions.

Interaction between the epithelium and mesenchyme coordinates patterning and differentiation of oral cavity structures including teeth, palatal rugae and tongue papillae. SHH is one of the key signaling molecules for this interaction. Epithelial expression of Shh in the tooth buds and tongue papillae is regulated by at least two enhancers, MRCS1 and MFCS4. However, it is unclear how the two enhancers cooperate to regulate Shh. Here, we found that simultaneous deletion of MRCS1 and MFCS4 results in the formation of a supernumerary tooth in front of the first molar. Since deletion of either single enhancer barely affects tooth development, MRCS1 and MFCS4 evidently act in a redundant fashion. Binding motifs for WNT signaling mediators are shared by MRCS1 and MFCS4, and play a central role in regulating Shh expression, indicating that the two redundant enhancers additively exert their Shh regulation by responding to WNT signal input.

State-controlled protected areas (PAs) have dominated conservation strategies globally, yet their performance relative to other governance regimes is rarely assessed comprehensively. Furthermore, performance indicators of forest PAs are typically restricted to deforestation, although the extent of forest degradation is greater. We address these shortfalls through an empirical impact evaluation of state PAs, Indigenous Territories (ITs), and civil society and private Conservation Concessions (CCs) on deforestation and degradation throughout the Peruvian Amazon. We integrated remote-sensing data with environmental and socio-economic datasets, and used propensity-score matching to assess: (i) how deforestation and degradation varied across governance regimes between 2006-2011; (ii) their proximate drivers; and (iii) whether state PAs, CCs and ITs avoided deforestation and degradation compared with logging and mining concessions, and the unprotected landscape. CCs, state PAs, and ITs all avoided deforestation and degradation compared to analogous areas in the unprotected landscape. CCs and ITs were on average more effective in this respect than state PAs, showing that local governance can be equally or more effective than centralized state regimes. However, there were no consistent differences between conservation governance regimes when matched to logging and mining concessions. Future impact assessments would therefore benefit from further disentangling governance regimes across unprotected land.

Psychotherapy is often effective for treating psychogenic disorders, but the changes that occur in the brain during such treatments remain unknown. To investigate this, we monitored cerebral activity throughout an entire session using a psychotherapeutic technique in healthy subjects. Since post-traumatic stress disorder (PTSD) is a typical psychogenic psychiatric disorder, we used PTSD-model volunteers who had experienced a moderately traumatic event. The technique used as psychotherapy was eye movement desensitisation and reprocessing (EMDR), a standard method for treating PTSD. The oxygenated haemoglobin concentration ([oxy-Hb]), a sensitive index of brain activation, measured using multi-channel near-infrared spectroscopy, revealed changes in [oxy-Hb] in the superior temporal sulcus (STS) and orbitofrontal cortex (OFC). During a vital therapeutic stage, a significant reduction in the activation by forced eye movements was observed in the right STS, and a trend toward a reduction in the left OFC. The hyperactivation of the right STS on the recall of unpleasant memories, and its normalisation by eye movements, seem to reflect an important neural mechanism of the psychotherapy. These findings suggest that psychotherapy for traumatic symptoms involves brain regions related to memory representation and emotion, and possibly those that link memory and emotion, such as the amygdala.

The presence of salts in biological solution can affect the activity of the reactive species (RS) generated by plasma, and so they can also have an influence on the plasma-induced sterilization. In this work, we assess the influence that diethylammonium dihydrogen phosphate (DEAP), an ionic liquid (IL), and sodium chloride (NaCl), an ionic salt (IS), have on the structural changes in hemoglobin (Hb) in the presence of RS generated using dielectric barrier discharge (DBD) plasma in the presence of various gases [O2, N2, Ar, He, NO (10%) + N2 and Air]. We carry out fluorescence spectroscopy to verify the generation of (•)OH with or without the presence of DEAP IL and IS, and we use electron spin resonance (ESR) to check the generation of H(•) and (•)OH. In addition, we verified the structural changes in the Hb structure after treatment with DBD in presence and absence of IL and IS. We then assessed the structural stability of the Hb in the presence of IL and IS by using molecular dynamic (MD) simulations. Our results indicate that the IL has a strong effect on the conservation of the Hb structure relative to that of IS against RS generated by plasma.

Networks of transcription factors (TFs) are thought to determine and maintain the identity of cells. Here we systematically repressed each of 100 TFs with shRNA and carried out global gene expression profiling in mouse embryonic stem (ES) cells. Unexpectedly, only the repression of a handful of TFs significantly affected transcriptomes, which changed in two directions/trajectories: one trajectory by the repression of either Pou5f1 or Sox2; the other trajectory by the repression of either Esrrb, Sall4, Nanog, or Tcfap4. The data suggest that the trajectories of gene expression change are already preconfigured by the gene regulatory network and roughly correspond to extraembryonic and embryonic fates of cell differentiation, respectively. These data also indicate the robustness of the pluripotency gene network, as the transient repression of most TFs did not alter the transcriptomes.

The generation of induced pluripotent stem cells (iPSCs) by the forced expression of defined transcription factors in somatic cells holds great promise for the future of regenerative medicine. However, the initial reprogramming mechanism is still poorly understood. Here we show that Zscan4, expressed transiently in2-cell embryos and embryonic stem cells (ESCs), efficiently produces iPSCs from mouse embryo fibroblasts when coexpressed with Klf4, Oct4, and Sox2. Interestingly, the forced expression of Zscan4 is required onlyfor the first few days of iPSC formation. Microarray analysis revealed transient and early induction of preimplantation-specific genes in a Zscan4-dependent manner. Our work indicates that Zscan4 is a previously unidentified potent natural factor that facilitates the reprogramming process and reactivates early embryonic genes.