The lymphocyte/monocyte ratio predicts the efficacy of isatuximab plus pomalidomide in multiple myeloma patients.

BACKGROUND: Isatuximab, an anti-CD38 antibody, has been widely used in treatments for patients with relapsed/refractory multiple myeloma (MM). Despite its high efficacy, not all patients achieve a lasting therapeutic response with isatuximab. OBJECTIVE: We tried to identify biomarkers to predict the effectiveness of isatuximab by focusing on the host's immune status before treatment. METHODS: We retrospectively analyzed the cases of 134 relapsed/refractory MM patients in the Kansai Myeloma Forum database who had received only a first isatuximab treatment. RESULTS: Among the 134 patients, an isatuximab, pomalidomide and dexamethasone (Isa-PD) regimen, isatuximab, carfilzomib and dexamethasone (Isa-KD) regimen and isatuximab and/or dexamethasone (Isa-D) regimen were used in 112, 15 and 7 patients, respectively. The median age at treatment, number of prior treatment regimens, and progression-free survival (PFS) were 71, 6, and 6.54 months, respectively. Multivariate analysis showed that the PFS under the Isa-PD regimen was longer in patients with higher lymphocyte/monocyte ratio (LMR ≥ 4), fewer prior treatment regimens (< 6), and no use of prior daratumumab treatment. The OS under the Isa-PD regimen was longer in patients with higher white blood cell counts (WBC counts ≥ 3000/µL) and higher LMR. The PFS under the Isa-D regimen was longer in patients with fewer prior treatment regimens in univariate analysis, but no parameters were correlated with PFS/OS under the Isa-KD regimen. CONCLUSION: We found that the patients with higher LMR (≥ 4) could obtain longer PFS and OS under the Isa-PD regimen. Other cohort studies of isatuximab treatment might be necessary to substantiate our results.

A study on the reliability and validity of the Japanese version of the Scenario Test for people with chronic stroke-induced aphasia: A cross-sectional study.

BACKGROUND: The Scenario Test is recognised for its effectiveness in assessing the interactive aspects of functional communication in people with post-stroke aphasia (PWA). AIMS: To develop a Japanese version of the Scenario Test (Scenario Test-JP) and assess its reliability and validity. METHODS & PROCEDURES: Among 66 participants, we selected 61 individuals: 34 PWA and 27 healthy controls (HCs). We modified the Scenario Test-JP based on the UK version and subsequently evaluated its reliability (internal consistency, test-retest and intra-rater and inter-rater reliabilities) and validity (convergent and discriminant) by comparing PWA and HCs. OUTCOMES & RESULTS: The Scenario Test-JP showed strong reliability with a Cronbach's α of 0.93, test-retest reliability with an intraclass correlation coefficient (ICC) of 0.97, intra-rater reliability with an ICC of 0.95-1.00, and inter-rater reliability with an ICC of 0.96. The validity of the test was confirmed with concurrent scores ranging from ρ = 0.37 to 0.76 (p < 0.05) and known-groups validity (p < 0.001, r = -0.56). CONCLUSIONS & IMPLICATIONS: The reliability and validity of the Scenario Test-JP align with those of the original Dutch version and the UK and Greek versions. Additionally, the assessment can now include extended alternative communication methods, such as digital devices, indicating the potential of the Scenario Test-JP for modern Japanese speech-language therapy. WHAT THIS PAPER ADDS: What is already known on the subject Interactive communication is a facet of functional communication and is crucial for evaluating engagement and participation of people with aphasia (PWA) in speech-language therapy. The Scenario Test provides valuable information for planning speech-language treatment strategies by assessing dialogic communication. What this study adds This study describes the development of the Scenario Test-JP for use with Japanese speakers and Japanese PWA, which is adapted from the Scenario Test UK version. This study evaluated the reliability and validity of this assessment tool and provided supporting evidence. What are the clinical implications of this work? The reliability and validity of the Scenario Test-JP were consistent with those of the Dutch, UK and Greek versions. The Scenario Test-JP contributes to speech-language therapy in Japan, where high-quality support for the activities and participation of PWA is required. PRACTITIONER POINTS: Insights from the Scenario Test The Scenario Test plays a crucial role in evaluating the functional communication skills of people with post-stroke aphasia (PWA). Enhancing functional communication has been linked to improved social engagement among PWA, which in turn influences their overall quality of life (QOL). Issues addressed by the Scenario Test The Scenario Test aids in delineating rehabilitation objectives for activities and participation among PWA, particularly concerning functional communication. The test facilitates tailored support for PWAs' interactive communication and forms the foundation for appropriate speech-language therapy interventions. Transformation of speech-language therapy (SLT) in Japan through the introduction of the Scenario Test-JP The integration of the Scenario Test-JP could enhance the SLT services provided to PWA in Japan. With Japan experiencing an unprecedented ageing population, the prevalence of social isolation and diminished QOL resulting from communication disorders like stroke-induced aphasia is expected to rise. Consequently, the SLT rehabilitation sector in Japan is actively seeking effective interventions to support functional communication among PWA. Hence, the adoption of the Scenario Test-JP is anticipated to streamline the evaluation of functional communication, facilitating the judicious selection and timely provision of assistance to PWA in SLT, including guidance on communication partner support and communication skill training.

Primary analysis of a prospective cohort study of Japanese patients with plasma cell neoplasms in the novel drug era (2016-2021).

The emergence of novel drugs has significantly improved outcomes of patients with plasma cell neoplasms (PCN). The Japanese Society of Hematology conducted a prospective observational study in newly diagnosed PCN patients between 2016 and 2021. The analysis focused on 1385 patients diagnosed with symptomatic PCN between 2016 and 2018. The primary endpoint was the 3-year overall survival (OS) rate among patients requiring treatment (n = 1284), which was 70.0% (95%CI 67.4-72.6%). Approximately 94% of these patients received novel drugs as frontline therapy. The 3-year OS rate was 90.3% (95%CI 86.6-93.1%) in the 25% of patients who received upfront autologous stem cell transplantation (ASCT), versus just 61.4% (95%CI 58.0-64.6%) in those who did not receive upfront ASCT. The only unfavorable prognostic factor that affected OS in ASCT recipients was an age of 65 or higher. For patients who did not receive ASCT, independent unfavorable prognostic factors included frontline treatment with conventional chemotherapies, international staging system score of 2/3, extramedullary tumors, and Freiberg comorbidity index of 2/3. This study unequivocally demonstrates that use of novel drugs improved OS in Japanese myeloma patients, and underscores the continued importance of upfront ASCT as the standard of care in the era of novel drugs.

Diverse B-cell tumors associated with t(14;19)(q32;q13)/IGH::BCL3 identified by G-banding and fluorescence in situ hybridization.

We characterized 5 B-cell tumors carrying t(14;19)(q32;q13) that creates the IGH::BCL3 fusion gene. The patients' ages ranged between 55 and 88 years. Two patients presented with progression or recurrence of B-cell chronic lymphocytic leukemia (B-CLL)/small lymphocytic lymphoma (SLL), two with diffuse large B-cell lymphoma (DLBCL) of non-germinal center B-like phenotype, and the remaining one with composite angioimmunoblastic T-cell lymphoma and Epstein-Barr virus-positive DLBCL. The presence of t(14;19)(q32;q13) was confirmed by fluorescence in situ hybridization (FISH), showing colocalization of 3' IGH and 3' BCL3 probes on der(14)t(14;19) and 5' BCL3 and 5' IGH probes on der(19)t(14;19). One B-CLL case had t(2;14)(p13;q32)/IGH::BCL11A, and 2 DLBCL cases had t(8;14)(q24;q32) or t(8;11;14)(q24;q11;q32), both of which generated IGH::MYC by FISH, and showed nuclear expression of MYC and BCL3 by immunohistochemistry. The IGH::BCL3 fusion gene was amplified by long-distance polymerase chain reaction in 2 B-CLL/SLL cases and the breakpoints occurred immediately 5' of BCL3 exon 1 and within the switch region associated with IGHA1. The 5 cases shared IGHV preferentially used in B-CLL cells, but the genes were unmutated in 2 B-CLL/SLL cases and significantly mutated in the remaining 3. B-cell tumors with t(14;19)(q32;q13) can be divided into B-CLL/SLL and DLBCL groups, and the anatomy of IGH::BCL3 in the latter may be different from that of the former.

Safety of cricotracheostomy with skin and tracheal membrane flaps for severe COVID-19 patients.

OBJECTIVE: Airway surgery is performed for COVID-19 patients who require long-term tracheal intubation and mechanical ventilation. Tracheostomy sometimes causes postoperative complications represented by bleeding at a relatively high rate in COVID-19 patients. As an alternative surgical procedure to tracheostomy, cricotracheostomy may reduce these complications, but few studies have examined its safety. METHODS: Data were retrospectively collected for sixteen COVID-19 patients (11 underwent tracheostomy, 5 underwent modified cricotracheostomy). In addition to patients' backgrounds and blood test data, the frequency of complications and additional care required for postoperative complications were collected. Statistical analysis was conducted by the univariate analysis of Fischer analysis and Mann-Whitney U test. RESULTS: Five cases experienced postoperative bleeding, four cases experienced peristomal infection, and one case experienced subcutaneous emphysema in the tracheostomy patients. These complications were not observed in the cricotracheostomy patients. The number of additional cares for postoperative complications was significantly lower in cricotracheostomy than in tracheostomy patients (p < 0.05). CONCLUSIONS: Modified cricotracheostomy could be a safe procedure in airway surgery for patients with COVID-19 from the point of fewer postoperative complications and additional care. It might be necessary to select the cricotracheostomy depending on patients' background to reduce postoperative complications.

Evolutionary insights into strategy shifts for the safe and effective accumulation of ascorbate in plants.

Plants accumulate high concentrations of ascorbate, commonly in their leaves, as a redox buffer. While ascorbate levels have increased during plant evolution, the mechanisms behind this phenomenon are unclear. Moreover, has the increase in ascorbate concentration been achieved without imposing any detrimental effects on the plants? In this review, we focus on potential transitions in two regulatory mechanisms related to ascorbate biosynthesis and the availability of cellular dehydroascorbate (DHA) during plant evolution. The first transition might be that the trigger for the transcriptional induction of VTC2, which encodes the rate-limiting enzyme in ascorbate biosynthesis, has shifted from oxidative stress (in green algae) to light/photosynthesis (in land plants), probably enabling the continuous accumulation of ascorbate under illumination. This could serve as a preventive system against the unpredictable occurrence of oxidative stress. The second transition might be that DHA-degrading enzymes, which protect cells from the highly reactive DHA in green algae and mosses, have been lost in ferns or flowering plants. Instead, flowering plants may have increased glutathione concentrations to reinforce the DHA reduction capacity, possibly allowing ascorbate accumulation and avoiding the toxicity of DHA. These potential transitions may have contributed to strategies for plants' safe and effective accumulation of ascorbate.

A novel NFKB1 variant in a Japanese pedigree with common variable immunodeficiency.

Recently, heterozygous loss-of-function NFKB1 variants were identified as the primary cause of common variable immunodeficiency (CVID) in the European population. However, pathogenic NFKB1 variants have never been reported in the Japanese population. We present a 29-year-old Japanese woman with CVID. A novel variant, c.136 C > T, p.(Gln46*), was identified in NFKB1. Her mother and daughter carried the same variant, demonstrating the first Japanese pedigree with an NFKB1 pathogenic variant.

Sustained remission after cord blood transplantation for breast cancer with lung metastases and myelodysplastic syndrome.

Allogenic hematopoietic stem cell transplantation (allo-HSCT) is not a standard therapy for solid cancer because of its high toxicity and insufficient evidence levels. However, the potential graft-versus-solid-tumor (GVT) effect of this therapy has been discussed. Many case reports have also described treatment effects of allo-HSCT in patients with hematologic malignancies and active solid tumors. A 38-year-old woman treated with fulvestrant and abemaciclib for recurrent breast cancer with multiple lung metastases was diagnosed with myelodysplastic syndrome (MDS) with increased blasts 2. She was classified as adverse risk by the 2017 European LeukemiaNet risk stratification and as very high risk by the Molecular International Prognostic Scoring System. Breast cancer treatment was interrupted and venetoclax and azacitidine therapy was started. Complete hematologic response was achieved after three cycles. However, multiple lung metastases from the breast cancer remained. The patient then underwent umbilical cord blood transplantation. She has maintained complete remission of MDS as of 1 year post-transplantation, without serious complications. Lung metastatic activity on FDG-PET/CT scan also completely disappeared by half a year post-transplantation, and this response has continued as of 1 year post-transplantation. This favorable treatment course suggests the existence of a GVT effect.

Successful treatment of isolated central nervous system recurrence of primary testicular lymphoma by autologous stem cell transplantation using a conditioning regimen of thiotepa and busulfan.

Primary testicular lymphoma (PTL) frequently relapses in the central nervous system (CNS) despite prophylactic intrathecal chemotherapy, and the outcome for CNS recurrence of PTL is very poor. We report a case of isolated CNS recurrence of bilateral PTL. Our patient achieved complete response (CR) after rituximab-combination chemotherapy for PTL. Approximately five years later, isolated CNS recurrence of PTL occurred. Our patient achieved CR again after high-dose methotrexate therapy and autologous stem cell transplantation (ASCT) with a conditioning regimen of thiotepa and busulfan as a consolidation therapy. The secondary failure of platelet recovery, probably caused by busulfan, occurred after the platelet engraftment. Our patient has remained in CR for over three years. The treatment strategy for CNS recurrence of PTL is mainly whole-brain radiotherapy or high-dose methotrexate-based chemotherapy; however, CNS recurrence of PTL may occur again even after achieving CR. ASCT with a conditioning regimen of thiotepa and busulfan is the optimal consolidation therapy for secondary CNS lymphoma. To the best of our knowledge, this is the second reported case of a patient with isolated CNS recurrence of PTL successfully treated by ASCT with a conditioning regimen of thiotepa and busulfan as a consolidation therapy.

Nasal Packing Materials and Placement Duration on Wound Healing in Nasal Mucosa: An Animal Study.

OBJECTIVE: The histological findings of wound healing depending on different nasal packing materials and replacement periods were lacking. METHODS: Mucosal defects were created in the nasal septum of rabbits and covered with Spongel®, Algoderm®, or Nasopore®, which were cleaned on Day 14. To investigate the effect of replacement durations, Spongel® was removed on Days 3 and 7. All nasal septal specimens were collected on Day 28. Samples without packing material were prepared as controls. Depending on residual packing materials in the regenerated tissue, specimens were classified into the remnant and non-remnant groups, and morphology was compared using epithelium grade score and subepithelial thickness. RESULTS: The epithelium grade score in the Spongel-14d group was lower than that in the other groups (p < 0.05). Subepithelial thickness was higher in the Algoderm-14d and Spongel-14d groups (p < 0.05). Epithelium grade scores were higher and subepithelial thicknesses were lower in the Spongel-3d and -7d groups than in the Spongel-14d group. Epithelium grade score was lower and subepithelial thickness was higher in the remnant group (n = 10) than in the non-remnant group (n = 15; p < 0.05). CONCLUSIONS: Differences in packing materials and placement durations affected wound healing of nasal mucosa. The selection of appropriate packing materials and replacement duration was considered essential for ideal wound healing. LEVEL OF EVIDENCE: NA Laryngoscope, 134:562-568, 2024.

The D-mannose/L-galactose pathway plays a predominant role in ascorbate biosynthesis in the liverwort Marchantia polymorpha but is not regulated by light and oxidative stress.

Ascorbate plays an indispensable role in plants, functioning as both an antioxidant and a cellular redox buffer. It is widely acknowledged that the ascorbate biosynthesis in the photosynthetic tissues of land plants is governed by light-mediated regulation of the D-mannose/L-galactose (D-Man/L-Gal) pathway. At the core of this light-dependent regulation lies the VTC2 gene, encoding the rate-limiting enzyme GDP-L-Gal phosphorylase. The VTC2 expression is regulated by signals via the photosynthetic electron transport system. In this study, we directed our attention to the liverwort Marchantia polymorpha, representing one of the basal land plants, enabling us to conduct an in-depth analysis of its ascorbate biosynthesis. The M. polymorpha genome harbors a solitary gene for each enzyme involved in the D-Man/L-Gal pathway, including VTC2, along with three lactonase orthologs, which may be involved in the alternative ascorbate biosynthesis pathway. Through supplementation experiments with potential precursors, we observed that only L-Gal exhibited effectiveness in ascorbate biosynthesis. Furthermore, the generation of VTC2-deficient mutants through genome editing unveiled the inability of thallus regeneration in the absence of L-Gal supplementation, thereby revealing the importance of the D-Man/L-Gal pathway in ascorbate biosynthesis within M.  polymorpha. Interestingly, gene expression analyses unveiled a distinct characteristic of M. polymorpha, where none of the genes associated with the D-Man/L-Gal pathway, including VTC2, showed upregulation in response to light, unlike other known land plants. This study sheds light on the exceptional nature of M. polymorpha as a land plant that has evolved distinctive mechanisms concerning ascorbate biosynthesis and its regulation.

Impact of cytogenetic abnormalities in symptomatic multiple myeloma; a Japanese real-world analysis from Kansai Myeloma Forum.

To evaluate the specific prognostic value of CAs, we conducted an analysis of 923 symptomatic multiple myeloma patients. Among this cohort, 480 patients had complete data set of high-risk CAs by interphase fluorescent in situ hybridization at diagnosis. In the high-risk group analysis, the median OS of patients without CAs (n = 338, 72 %) was 6.5 years, patients with del(17p) (n = 42, 9 %) was 4.4 years, patients with t(4;14) or t(14;16) (n = 72, 15 %) was 4.4 years, and patients with double-positive CAs(del(17p) and t(4;14) or t(14;16)) (n = 18, 4 %) was 2.1 years (p = 0.032). Patients with double-positive CAs had a significantly worse prognosis.

Lung Involvement in Adult T-Cell Lymphoma Diagnosed Using Bronchoscopic Cryobiopsy: A Case Report and Review of the Literature.

The diagnosis of pulmonary lymphoma using small tissue samples is difficult and often requires surgical procedures; thus, a less invasive sampling method is desirable. Moreover, pulmonary involvement in adult T-cell lymphoma (ATL) is often difficult to diagnose, especially in cases without characteristic flower cells. Here, we present the case of a 78-year-old man, in whom pathological examination of the transbronchial lung biopsy (TBLB) specimen did not reveal malignant findings; therefore, transbronchial lung cryobiopsy (TBLC) in combination with endobronchial ultrasonography (EBUS) was used to diagnose ATL based on the pathological findings. A literature review identified 18 cases of pulmonary lymphomas diagnosed using TBLC. Among the 19 cases, including our own, 16 cases were of B-cell lymphoma (84.2%), and the present case is the first case of ATL diagnosed using TBLC. Eighty percent of the cases underwent a biopsy (more than two samples) of the middle or lower lobe and were diagnosed without major complications. EBUS was used with TBLC in three cases to identify the location of the pulmonary lesions. In the present case, EBUS was also useful for avoiding vascular biopsy. Although large-scale prospective studies are required to establish precise guidelines for diagnosing pulmonary lymphomas using TBLC, our case report and review contributes to a deeper understanding of the diagnosis of rare diseases.

Activity-dependent organization of prefrontal hub-networks for associative learning and signal transformation.

Associative learning is crucial for adapting to environmental changes. Interactions among neuronal populations involving the dorso-medial prefrontal cortex (dmPFC) are proposed to regulate associative learning, but how these neuronal populations store and process information about the association remains unclear. Here we developed a pipeline for longitudinal two-photon imaging and computational dissection of neural population activities in male mouse dmPFC during fear-conditioning procedures, enabling us to detect learning-dependent changes in the dmPFC network topology. Using regularized regression methods and graphical modeling, we found that fear conditioning drove dmPFC reorganization to generate a neuronal ensemble encoding conditioned responses (CR) characterized by enhanced internal coactivity, functional connectivity, and association with conditioned stimuli (CS). Importantly, neurons strongly responding to unconditioned stimuli during conditioning subsequently became hubs of this novel associative network for the CS-to-CR transformation. Altogether, we demonstrate learning-dependent dynamic modulation of population coding structured on the activity-dependent formation of the hub network within the dmPFC.

Surgical strategy for patients with papillary thyroid carcinoma invading the trachea: a comparison of tracheal sleeve resection with end-to-end anastomosis and window resection with tracheocutaneous fistula.

Background: Sleeve resection with end-to-end anastomosis (Procedure A) and window resection with a tracheocutaneous fistula (Procedure B) are the major surgical procedures for patients with papillary thyroid carcinoma (PTC) exhibiting transluminal tracheal invasion. For each procedure, the indications, postoperative course, and treatment results were examined retrospectively. Methods: Of 1,456 patients with PTC (maximum tumor diameter >1 cm) who received initial treatment between 1993 and 2013, we reviewed 51 patients. Of these 51 cases, 45 showed full-layer tracheal invasion, and 6 did not reach the tracheal mucosa, but required full-layer tracheal resection. Twenty-four patients underwent Procedure A, and 27 patients underwent Procedure B. Results: Regarding surgical procedure selection, Procedure B was selected significantly more frequently than Procedure A for cases with preoperative recurrent laryngeal nerve (RLN) palsy, tumor invasion of the esophagus, clinical lymph node metastasis, or a large number of resected tracheal rings. Postoperative airway-related complications were not significantly different between the procedures, but decreased with the use of intraoperative neuromonitoring (IONM). The postoperative hospital stay was significantly longer for Procedure B than for Procedure A. In addition, the rate of a permanent postoperative tracheostoma was higher with Procedure B than with Procedure A. Local recurrence-free survival (LRFS) and cause-specific survival (CSS) did not differ significantly between the two procedures. Conclusions: Certain patients may benefit from Procedure A with IONM in terms of a shorter hospital stay and avoiding the need for a permanent tracheostoma. Although Procedure B was indicated for patients with more advanced disease than Procedure A, treatment outcomes were similar.

Middle meatus microbiome in patients with eosinophilic chronic rhinosinusitis in a Japanese population.

BACKGROUND: Chronic rhinosinusitis (CRS) is a common chronic inflammatory disease and is subdivided into eosinophilic and noneosinophilic forms. There are few reports investigating the nasal microbiome and its pathological functions in patients with CRS. OBJECTIVE: We sought to analyze factors contributing to variations of the nasal microbiome in CRS, and on the basis of these factors, to elucidate whether the bacterial metabolites were related to the pathogenesis. METHODS: Nasal swabs were collected, and the V3 to V4 variable region of the 16S ribosomal RNA gene was amplified and sequenced. Factors contributing to variations of the nasal microbiome in patients with CRS were compared. The most influential factor was whether CRS was eosinophilic, and we compared α- and ß-diversity, bacterial species, and predictive bacterial functions between the 2 patient groups. In addition, the metabolites of the key bacteria were extracted, and we evaluated the predicted bacterial functions in airway epithelial cells. RESULTS: In total, 110 patients with CRS and 33 control subjects were enrolled. On the basis of the factors of variation, it was found that patients with eosinophilic CRS (n = 65) had different microbiomes with weighted UniFrac ß-diversity and lower α-diversity compared with those with noneosinophilic CRS (n = 45). A higher abundance of Fusobacterium nucleatum and an increased LPS pathway were observed in patients with noneosinophilic CRS compared with those with eosinophilic CRS. In airway epithelial cells, LPS derived from F nucleatum suppressed the expression levels of ALOX15 induced by TH2 cytokines. CONCLUSIONS: The differences in the nasal microbiome may play a key role in the pathophysiology of CRS.

Layer 5 Intratelencephalic Neurons in the Motor Cortex Stably Encode Skilled Movement.

The primary motor cortex (M1) and the dorsal striatum play a critical role in motor learning and the retention of learned behaviors. Motor representations of corticostriatal ensembles emerge during motor learning. In the coordinated reorganization of M1 and the dorsal striatum for motor learning, layer 5a (L5a) which connects M1 to the ipsilateral and contralateral dorsal striatum, should be a key layer. Although M1 L5a neurons represent movement-related activity in the late stage of learning, it is unclear whether the activity is retained as a memory engram. Here, using Tlx3-Cre male transgenic mice, we conducted two-photon calcium imaging of striatum-projecting L5a intratelencephalic (IT) neurons in forelimb M1 during late sessions of a self-initiated lever-pull task and in sessions after 6 d of nontraining following the late sessions. We found that trained male animals exhibited stable motor performance before and after the nontraining days. At the same time, we found that M1 L5a IT neurons strongly represented the well-learned forelimb movement but not uninstructed orofacial movements. A subset of M1 L5a IT neurons consistently coded the well-learned forelimb movement before and after the nontraining days. Inactivation of M1 IT neurons after learning impaired task performance when the lever was made heavier or when the target range of the pull distance was narrowed. These results suggest that a subset of M1 L5a IT neurons continuously represent skilled movement after learning and serve to fine-tune the kinematics of well-learned movement.SIGNIFICANCE STATEMENT Motor memory persists even when it is not used for a while. IT neurons in L5a of the M1 gradually come to represent skilled forelimb movements during motor learning. However, it remains to be determined whether these changes persist over a long period and how these neurons contribute to skilled movements. Here, we show that a subset of M1 L5a IT neurons retain information for skilled forelimb movements even after nontraining days. Furthermore, suppressing the activity of these neurons during skilled forelimb movements impaired behavioral stability and adaptability. Our results suggest the importance of M1 L5a IT neurons for tuning skilled forelimb movements over a long period.

Structure-activity relationship of volatile compounds that induce defense-related genes in maize seedlings.

Volatile organic compounds mediate plant-to-plant communication, and plants receiving volatile cues can acquire greater defenses against attackers. It has been expected that volatiles are received by factors that eventually lead to the induction of defense-related gene expression; however, the nature of these factors remain unclear. Structure-activity relationship analysis of gene expression induction by volatiles should provide insights into the nature of these factors. We conducted a structure-activity relationship study using maize seedlings and (Z)-3-hexen-1-yl acetate (Z3HAC) as the lead compound. The acid portion of Z3HAC was not essential, and (Z)-3-hexen-1-ol (Z3HOL), which is formed after the hydrolysis of Z3HAC, is likely the structure essential for the upregulation of the genes. The double bond of Z3HOL is essential; however, its geometry is indistinguishable. Strict specificity was detected regarding the length of the methylene chain on the α- and ω-sides of the double bond, and therefore, the 3-hexen-1-ol structure was found to be the ultimate structure. This finding provides insight into the nature of the factors that interact with a volatile compound and subsequently activate signaling pathways, leading to the upregulation of a subset of defense genes.

Establishment of a novel model of endometriosis-associated ovarian cancer by transplanting uterine tissue from Arid1a/Pten knockout mice.

Although endometriosis is primarily benign, it has been identified as a risk factor for endometriosis-associated ovarian cancer (EAOC). Genetic alterations in ARID1A, PTEN, and PIK3CA have been reported in EAOC; however, an appropriate EAOC animal model has yet to be established. Therefore, the present study aimed to create an EAOC mouse model by transplanting uterine pieces from donor mice, in which Arid1a and/or Pten was conditionally knocked out (KO) in Pax8-expressing endometrial cells by the administration of doxycycline (DOX), onto the ovarian surface or peritoneum of recipient mice. Two weeks after transplantation, gene KO was induced by DOX and endometriotic lesions were thereafter removed. The induction of only Arid1a KO did not cause any histological changes in the endometriotic cysts of recipients. In contrast, the induction of only Pten KO evoked a stratified architecture and nuclear atypia in the epithelial lining of all endometriotic cysts, histologically corresponding to atypical endometriosis. The induction of Arid1a; Pten double-KO evoked papillary and cribriform structures with nuclear atypia in the lining of 42 and 50% of peritoneal and ovarian endometriotic cysts, respectively, which were histologically similar to EAOC. These results indicate that this mouse model is useful for investigating the mechanisms underlying the development of EAOC and the related microenvironment.

Analysis of spontaneous speech in Parkinson's disease by natural language processing.

INTRODUCTION: Patients with Parkinson's disease (PD) encounter a variety of speech-related problems, including dysarthria and language disorders. To elucidate the pathophysiological mechanisms for linguistic alteration in PD, we compared the utterance of patients and that of healthy controls (HC) using automated morphological analysis tools. METHODS: We enrolled 53 PD patients with normal cognitive function and 53 HC, and assessed their spontaneous speech using natural language processing. Machine learning algorithms were used to identify the characteristics of spontaneous conversation in each group. Thirty-seven features focused on part-of-speech and syntactic complexity were used in this analysis. A support-vector machine (SVM) model was trained with ten-fold cross-validation. RESULTS: PD patients were found to speak less morphemes on one sentence than the HC group. Compared to HC, the speech of PD patients had a higher rate of verbs, case particles (dispersion), and verb utterances, and a lower rate of common noun utterances, proper noun utterances, and filler utterances. Using these conversational changes, the respective discrimination rates for PD or HC were more than 80%. CONCLUSIONS: Our results demonstrate the potential of natural language processing for linguistic analysis and diagnosis of PD.