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OBJECTIVES: To describe the utilization of early ketamine use among patients mechanically ventilated for COVID-19, and examine associations with in-hospital mortality and other clinical outcomes. DESIGN: Retrospective cohort study. SETTING: Six hundred ten hospitals contributing data to the Premier Healthcare Database between April 2020 and June 2021. PATIENTS: Adults with COVID-19 and greater than or equal to 2 consecutive days of mechanical ventilation within 5 days of hospitalization. INTERVENTION: The exposures were early ketamine use initiated within 2 days of intubation and continued for greater than 1 day. MEASUREMENTS: Primary was hospital mortality. Secondary outcomes included length of stay (LOS) in the hospital and ICUs, ventilator days, vasopressor days, renal replacement therapy (RRT), and total hospital cost. The propensity score matching analysis was used to adjust for confounders. MAIN RESULTS: Among 42,954 patients, 1,423 (3.3%) were exposed to early ketamine use. After propensity score matching including 1,390 patients in each group, recipients of ketamine infusions were associated with higher hospital mortality (52.5% vs. 45.9%, risk ratio: 1.14, [1.06-1.23]), longer median ICU stay (13 vs. 12 d, mean ratio [MR]: 1.15 [1.08-1.23]), and longer ventilator days (12 vs. 11 d, MR: 1.19 [1.12-1.27]). There were no associations for hospital LOS (17 [10-27] vs. 17 [9-28], MR: 1.05 [0.99-1.12]), vasopressor days (4 vs. 4, MR: 1.04 [0.95-1.14]), and RRT (22.9% vs. 21.7%, RR: 1.05 [0.92-1.21]). Total hospital cost was higher (median $72,481 vs. $65,584, MR: 1.11 [1.05-1.19]). CONCLUSIONS: In a diverse sample of U.S. hospitals, about one in 30 patients mechanically ventilated with COVID-19 received ketamine infusions. Early ketamine may have an association with higher hospital mortality, increased total cost, ICU stay, and ventilator days, but no associations for hospital LOS, vasopressor days, and RRT. However, confounding by the severity of illness might oc

Intergroup contact occurring through indirect means such as the internet has the potential to improve intergroup relationships and may be especially beneficial in high conflict situations. Here we conducted a three-timepoint online experiment to ascertain whether the use of a conversational agent in E-contact platforms could mitigate interethnic prejudices and hostility among Afghanistan’s historically segregated and persistently conflictual ethnic groups. 128 Afghans of Pashtun, Tajik, and Hazara backgrounds were assigned to one of four E-contact conditions (control with no conversational agent and three experimental groups that varied in the conversational agent settings). Participants in the experimental conditions contributed more ideas and longer opinions and showed a greater reduction in outgroup prejudice and anxiety than those in the control group. These findings demonstrate that E-contact facilitated by a conversational agent can improve intergroup attitudes even in contexts characterized by a long history of intergroup segregation and conflict.

Simultaneous relocation of a group of pollutant sources in a heavily polluted area is a rare event. Such a relocation has been implemented in Hazaribagh, a tannery built-up area with heavy pollution, in Bangladesh. This provides a valuable opportunity to compare the changes in environmental conditions associated with the relocation of multiple putative sources. Our environmental monitoring for a period of 6 years at the stationary areas centered on Hazaribagh geographically revealed trivalent [Cr(III)], hexavalent [Cr(VI)] chromium, lead, iron, and manganese as tannery-related elements after the legal deadline for tannery relocation. The median Cr(III) level in canal water, into which wastewater from tanneries was directly discharged, after the relocation was 97% lower of that before the relocation, indicating a beneficial effect of the relocation. In contrast, the median Cr(VI) level in water samples just after the relocation and 2 years after the relocation were approximately 5-fold and 30-fold higher, respectively, than those before the relocation. These results indicate not only a harmful effect of the relocation but also the possibility of conversion from Cr(III) to Cr(VI) in nature. Although the health hazard indexes considering all of the tannery-related elements in all of the canal water samples before the relocation exceeded the safety thresholds, the percentages of samples in which the indexes exceeded their safety thresholds after the relocation decreased by 32.5%–45.0%. Treatment with our patented hydrotalcite-like compound consisting of magnesium and iron (MF-HT) resulted in decreases in the health hazard indexes in all of the water samples in which the indexes exceeded their safety thresholds to levels lower than their thresholds. Thus, this study shows the double-edged effects associated with the relocation and a potential solution.

Simultaneous relocation of a group of pollutant sources in a heavily polluted area is a rare event. Such a relocation has been implemented in Hazaribagh, a tannery built-up area with heavy pollution, in Bangladesh. This provides a valuable opportunity to compare the changes in environmental conditions associated with the relocation of multiple putative sources. Our environmental monitoring for a period of 6 years at the stationary areas centered on Hazaribagh geographically revealed trivalent [Cr(III)], hexavalent [Cr(VI)] chromium, lead, iron, and manganese as tannery-related elements after the legal deadline for tannery relocation. The median Cr(III) level in canal water, into which wastewater from tanneries was directly discharged, after the relocation was 97% lower of that before the relocation, indicating a beneficial effect of the relocation. In contrast, the median Cr(VI) level in water samples just after the relocation and 2 years after the relocation were approximately 5-fold and 30-fold higher, respectively, than those before the relocation. These results indicate not only a harmful effect of the relocation but also the possibility of conversion from Cr(III) to Cr(VI) in nature. Although the health hazard indexes considering all of the tannery-related elements in all of the canal water samples before the relocation exceeded the safety thresholds, the percentages of samples in which the indexes exceeded their safety thresholds after the relocation decreased by 32.5%–45.0%. Treatment with our patented hydrotalcite-like compound consisting of magnesium and iron (MF-HT) resulted in decreases in the health hazard indexes in all of the water samples in which the indexes exceeded their safety thresholds to levels lower than their thresholds. Thus, this study shows the double-edged effects associated with the relocation and a potential solution.

The advent of Artificial Intelligence (AI) is fostering the development of innovative methods of communication and collaboration. Integrating AI into Information and Communication Technologies (ICTs) is now ushering in an era of social progress that has the potential to empower marginalized groups. This transformation paves the way to a digital inclusion that could qualitatively empower the online presence of women, particularly in conservative and male-dominated regions. To explore this possibility, we investigated the effect of integrating conversational agents into online debates encompassing 240 Afghans discussing the fall of Kabul in August 2021. We found that the agent leads to quantitative differences in how both genders contribute to the debate by raising issues, presenting ideas, and articulating arguments. We also found increased ideation and reduced inhibition for both genders, particularly females, when interacting exclusively with other females or the agent. The enabling character of the conversational agent reveals an apparatus that could empower women and increase their agency on online platforms.

Small leucine-rich repeat proteoglycan (SLRP) family proteins play important roles in a number of biological events. Here, we demonstrate that the SLRP family member Asporin (ASPN) plays a crucial role in the early stages of eye development in Xenopus embryos. During embryogenesis, ASPN is broadly expressed in the neuroectoderm of the embryo. Overexpression of ASPN causes the induction of ectopic eyes. By contrast, blocking ASPN function with a morpholino oligonucleotide (ASPN-MO) inhibits eye formation, indicating that ASPN is an essential factor for eye development. Detailed molecular analyses revealed that ASPN interacts with insulin growth factor receptor (IGFR) and is essential for activating the IGF receptor-mediated intracellular signalling pathway. Moreover, ASPN perturbed the Wnt, BMP and Activin signalling pathways, suggesting that ASPN thereby creates a favourable environment in which the IGF signal can dominate. ASPN is thus a novel secreted molecule essential for eye induction through the coordination of multiple signalling pathways.

Ocular morphogenesis requires several signalling pathways controlling the expression of transcription factors and cell-cycle regulators. However, despite a well-known mechanism, the dialogue between those signals and factors remains to be unveiled. Here, we identify a requirement for MarvelD3, a tight junction transmembrane protein, in eye morphogenesis in Xenopus. MarvelD3 depletion led to an abnormally pigmented eye or even an eye-less phenotype, which was rescued by ectopic MarvelD3 expression. Altering MarvelD3 expression led to deregulated expression of cell-cycle regulators and transcription factors required for eye development. The eye phenotype was rescued by increased c-Jun terminal Kinase activation. Thus, MarvelD3 links tight junctions and modulation of the JNK pathway to eye morphogenesis.

OBJECTIVES: We aimed to 1) describe patterns of beta-blocker utilization among critically ill patients following moderate-severe traumatic brain injury (TBI) and 2) examine the association of early beta-blocker exposure with functional and clinical outcomes following injury. DESIGN: Retrospective cohort study. SETTING: ICUs at 18 level I, U.S. trauma centers in the Transforming Clinical Research and Knowledge in TBI (TRACK-TBI) study. PATIENTS: Greater than or equal to 17 years enrolled in the TRACK-TBI study with moderate-severe TBI (Glasgow Coma Scale of <13) were admitted to the ICU after a blunt TBI. INTERVENTIONS: None. MEASUREMENTS: Primary exposure was a beta blocker during the first 7 days in the ICU, with a primary outcome of 6-month Glasgow Outcome Scale-Extended (GOSE). Secondary outcomes included: length of hospital stay, in-hospital mortality, 6-month and 12-month mortality, 12-month GOSE score, and 6-month and 12-month measures of disability, well-being, quality of life, and life satisfaction. MAIN RESULTS: Of the 450 eligible participants, 57 (13%) received early beta blockers (BB+ group). The BB+ group was on average older, more likely to be on a preinjury beta blocker, and more likely to have a history of hypertension. In the BB+ group, 34 participants (60%) received metoprolol only, 19 participants (33%) received propranolol only, 3 participants (5%) received both, and 1 participant (2%) received atenolol only. In multivariable regression, there was no difference in the odds of a higher GOSE score at 6 months between the BB+ group and BB- group (odds ratio = 0.86; 95% CI, 0.48-1.53). There was no association between BB exposure and secondary outcomes. CONCLUSIONS: About one-sixth of subjects in our study received early beta blockers, and within this group, dose, and timing of beta-blocker administration varied substantially. No significant differences in GOSE score at 6 months were demonstrated, although our ability to draw conclusions is limite

Single-chain monellin (SCM) is an engineered protein that links the two chains of monellin, a naturally sweet-tasting protein. This protein is an attractive candidate for use as a sugar replacement in food and beverages and has numerous other applications. Therefore, generating SCM mutants with improved stability is an active area of research to broaden the range of its potential applications. In this study, we focused on the Cys41 residue of SCM, which is a single cysteine residue present at a structurally important position. This residue is often substituted with Ser. However, this substitution may destabilize SCM because Cys41 is buried in the hydrophobic core of the protein. Therefore, we designed mutants that substituted Ala, Val, and Leu for this residue, namely C41A, C41V, and C41L. We characterized these three mutants, SCM C41S, and wild type (WT). Differential scanning fluorimetric analysis revealed that substituting Cys41 with Ala or Val increased the thermal stability of SCM, while substitution with Ser or Leu decreased its stability. Determination of the crystal structures of SCM C41A and C41V mutants revealed that the overall structures and main chain structures around the 41st residue of both mutants were almost identical to the WT. On the other hand, the orientations of the amino acid side chains near the 41st residue differed among the SCM variants. Taken together, our results indicate that substituting Cys41 with Ala or Val increases the stability of SCM and provide insight into the structural basis of this improvement.

PD-1 blockade exerts clinical efficacy against various types of cancer by reinvigorating T cells that directly attack tumor cells (tumor-specific T cells) in the tumor microenvironment (TME), and tumor-infiltrating lymphocytes (TILs) also comprise nonspecific bystander T cells. Here, using single-cell sequencing, we show that TILs include skewed T cell clonotypes, which are characterized by exhaustion (T-ex) or nonexhaustion signatures (Tnon-ex). Among skewed clonotypes, those in the T-ex, but not those in the Tnon-ex, cluster respond to autologous tumor cell lines. After PD-1 blockade, non-preexisting tumor-specific clonotypes in the T-ex cluster appear in the TME. Tumor-draining lymph nodes (TDLNs) without metastasis harbor a considerable number of such clonotypes, whereas these clonotypes are rarely detected in peripheral blood. We propose that tumor-infiltrating skewed T cell clonotypes with an exhausted phenotype directly attack tumor cells and that PD-1 blockade can promote infiltration of such T-ex clonotypes, mainly from TDLNs.

Measures of sustainability-related participatory programs vary according to social and cultural contexts. Thus, this study proposed a stepwise participatory program in which stakeholders and randomly chosen citizens (citizen panels) were repeatedly and sequentially involved, and the citizen panels discharged discrete functions through all the planning stages. Procedural and outcome fairness was focal to the evaluation of the participatory program because these criteria are widely deemed essential for public acceptance. Evaluation by nonparticipants was imperative because of the limited number of participants, but sustainability plans affect and mandate the cooperation of the general public. Therefore, this study undertaken during the revision of the city of Sapporo's environmental master plan compared evaluations of nonparticipants with those of participants from three stages of the stepwise participatory program applying backcasting scenario workshops. A two-wave mailout survey was administered to test two hypotheses: (a) workshop participants would evaluate the acceptance, process, outcome, and antecedent factors more positively than nonparticipants, and (b) procedural fairness and evaluation of expected outcomes would affect acceptance. The results supported these hypotheses. Procedural fairness was associated with acceptance most robustly and consistently. The study's primary contribution to the extant literature entails accumulating empirical evidence on stepwise participatory programs.

In this note, we prove a lemma for a strong comparison principle of nonlinear parabolic equations. We shall prove a function which is a viscosity subsolution minus a viscosity supersolution of the equation becomes a viscosity subsolution of a parabolic equation which may not coincide with the original equation. Thanks to a strong maximum principle of nonlinear parabolic equations we have a strong comparison principle.

BackgroundEarly hypotension following moderate to severe traumatic brain injury (TBI) is associated with increased mortality and poor long-term outcomes. Current guidelines suggest the use of intravenous vasopressors to support blood pressure following TBI; however, guidelines do not specify vasopressor type, resulting in variation in clinical practice. Minimal data are available to guide clinicians on optimal early vasopressor choice to support blood pressure following TBI. Therefore, we conducted a multicenter study to examine initial vasopressor choice for the support of blood pressure following TBI and its association with clinical and functional outcomes after injury.MethodsWe conducted a retrospective cohort study of patients enrolled in the transforming research and clinical knowledge in traumatic brain injury (TRACK-TBI) study, an 18-center prospective cohort study of patients with TBI evaluated in participating level I trauma centers. We examined adults with moderate to severe TBI (defined as Glasgow Coma Scale score < 13) who were admitted to the intensive care unit and received an intravenous vasopressor within 48 h of admission. The primary exposure was initial vasopressor choice (phenylephrine versus norepinephrine), and the primary outcome was 6-month Glasgow Outcomes Scale Extended (GOSE), with the following secondary outcomes: length of hospital stay, length of intensive care unit stay, in-hospital mortality, new requirement for dialysis, and 6-month Disability Rating Scale. Regression analysis was used to assess differences in outcomes between patients exposed to norepinephrine versus phenylephrine, with propensity weighting to address selection bias due to the nonrandom allocation of the treatment groups and patient dropout.ResultsThe final study sample included 156 patients, of whom 79 (51%) received norepinephrine, 69 (44%) received phenylephrine, and 8 (5%) received an alternate drug as their initial vasopressor. 121 (77%) of patients we

BACKGROUND: Extracranial multisystem organ failure is a common sequela of severe traumatic brain injury (TBI). Risk factors for developing circulatory shock and long-term functional outcomes of this patient subset are poorly understood. OBJECTIVE: To identify emergency department predictors of circulatory shock after moderate-severe TBI and examine long-term functional outcomes in patients with moderate-severe TBI who developed circulatory shock. METHODS: We conducted a retrospective cohort study using the Transforming Clinical Research and Knowledge in TBI database for adult patients with moderate-severe TBI, defined as a Glasgow Coma Scale (GCS) score of <13 and stratified by the development of circulatory shock within 72 hours of hospital admission (Sequential Organ Failure Assessment score ≥2). Demographic and clinical data were assessed with descriptive statistics. A forward selection regression model examined risk factors for the development of circulatory shock. Functional outcomes were examined using multivariable regression models. RESULTS: Of our moderate-severe TBI population (n = 407), 168 (41.2%) developed circulatory shock. Our predictive model suggested that race, computed tomography Rotterdam scores <3, GCS in the emergency department, and development of hypotension in the emergency department were associated with developing circulatory shock. Those who developed shock had less favorable 6-month functional outcomes measured by the 6-month GCS-Extended (odds ratio 0.36, P = .002) and 6-month Disability Rating Scale score (Diff. in means 3.86, P = .002) and a longer length of hospital stay (Diff. in means 11.0 days, P < .001). CONCLUSION: We report potential risk factors for circulatory shock after moderate-severe TBI. Our study suggests that developing circulatory shock after moderate-severe TBI is associated with poor long-term functional outcomes.

In this note, we prove a lemma for a strong comparison principle of nonlinear parabolic equations. We shall prove a function which is a viscosity subsolution minus a viscosity supersolution of the equation becomes a viscosity subsolution of a parabolic equation which may not coincide with the original equation. Thanks to a strong maximum principle of nonlinear parabolic equations we have a strong comparison principle.

Some patients experience mixed response to immunotherapy, whose biological mechanisms and clinical impact have been obscure. We obtained two tumor samples from lymph node (LN) metastatic lesions in a same patient. Whole exome sequencing for the both tumors and single-cell sequencing for the both tumor-infiltrating lymphocytes (TIL) demonstrated a significant difference in tumor clonality and TILs' characteristics, especially exhausted T-cell clonotypes, although a close relationship between the tumor cell and T-cell clones were observed as a response of an overlapped exhausted T-cell clone to an overlapped neoantigen. To mimic the clinical setting, we generated a mouse model of several clones from a same tumor cell line. Similarly, differential tumor clones harbored distinct TILs, and one responded to programmed cell death protein 1 (PD-1) blockade but the other did not in this model. We further conducted cohort study (n = 503) treated with PD-1 blockade monotherapies to investigate the outcome of mixed response. Patients with mixed responses to PD-1 blockade had a poor prognosis in our cohort. Particularly, there were significant differences in both tumor and T-cell clones between the primary and LN lesions in a patient who experienced tumor response to anti-PD-1 mAb followed by disease progression in only LN metastasis. Our results underscore that intertumoral heterogeneity alters characteristics of TILs even in the same patient, leading to mixed response to immunotherapy and significant difference in the outcome. Significance: Several patients experience mixed responses to immunotherapies, but the biological mechanisms and clinical significance remain unclear. Our results from clinical and mouse studies underscore that intertumoral heterogeneity alters characteristics of TILs even in the same patient, leading to mixed response to immunotherapy and significant difference in the outcome.

Measures of sustainability-related participatory programs vary according to social and cultural contexts. Thus, this study proposed a stepwise participatory program in which stakeholders and randomly chosen citizens (citizen panels) were repeatedly and sequentially involved, and the citizen panels discharged discrete functions through all the planning stages. Procedural and outcome fairness was focal to the evaluation of the participatory program because these criteria are widely deemed essential for public acceptance. Evaluation by nonparticipants was imperative because of the limited number of participants, but sustainability plans affect and mandate the cooperation of the general public. Therefore, this study undertaken during the revision of the city of Sapporo's environmental master plan compared evaluations of nonparticipants with those of participants from three stages of the stepwise participatory program applying backcasting scenario workshops. A two-wave mailout survey was administered to test two hypotheses: (a) workshop participants would evaluate the acceptance, process, outcome, and antecedent factors more positively than nonparticipants, and (b) procedural fairness and evaluation of expected outcomes would affect acceptance. The results supported these hypotheses. Procedural fairness was associated with acceptance most robustly and consistently. The study's primary contribution to the extant literature entails accumulating empirical evidence on stepwise participatory programs.

This study aimed to identify determinants of interdependent happiness (IH), with a focus on social capital resources. Using data from a population survey conducted in Sapporo, Japan, we ran hierarchical regressions to compare determinants of IH with determinants of a standard measure of subjective well-being (SWB), namely Diener et al.’s (1985) satisfaction with life scale (SWLS). While we confirmed the relationships of control variables generally associated with SWB also for IH, we found several decisive differences between the two well-being measures regarding social capital. For IH, an overall larger share of variance was predicted by social capital resources than for SWLS. IH is most strongly affected by social affiliation, which measures a sense of belonging to society, followed by interpersonal reliance, and social support. Reciprocal norms and institutional reliance predicted only IH, but not SWLS. Overall, our results imply that IH captures aspects of well-being related to social capital not fully covered by standard measures of SWB. Thus, for societies in which the cultural construal of happiness is more inclined to IH, the specific importance of social capital resources for subjective well-being might be underestimated when relying solely on standard measures of well-being.

The effect of interaction between the magnetic and chemical ordering reactions on the phase equilibria between the bcc phases, A2, B2 and DO3 has been studied by using the four-sublattice Compound Energy Model (CEM) taking account of the magnetic contribution to the Gibbs energy. An interaction between the magnetic and chemical ordering arises when the Curie temperature is formulated as a function of the site fraction of elements on each sublattice. A positive interaction arises from the higher deviation of the Curie temperature of the ordered state from that of the disordered one and leads to a two-phase separation between the ferro- and paramagnetic B2 phases. A lower deviation causes a negative interaction which introduces a convexity in the Gibbs energy curve around the composition of the intersection point between the Curie temperature and the order-disorder transition temperature. As a result, two-phase separations between either para- or ferro-magnetic A2 phase and paramagnetic B2 phase are introduced., QC 20220124

FACT (facilitate chromatin transcription) is involved in heterochromatic silencing, but its mechanisms and function remain unclear. We reveal that the Spt16 recruitment mechanism operates in two distinct ways in heterochromatin. First, Pob3 mediates Spt16 recruitment onto the heterochromatin through its Spt16 dimerization and tandem PH domains. Without Pob3, Spt16 recruitment is partially reduced, exhibiting a silencing defect and impaired H2A/H2B organization. Second, heterochromatin protein 1 (HP1)/Swi6 mediates Spt16 recruitment onto the heterochromatin by physical interaction of the Swi6 chromo-shadow domain (CSD) and Spt16 peptidase-like domains. Several CSD mutants are tested for Spt16 binding activity, and the charged loop connecting beta 1 and beta 2 is critical for Spt16 binding and heterochromatic silencing. Loss of these pathways causes a severe defect in H3K9 methylation and HP1/Swi6 localization in the pericentromeric region, exhibiting transcriptional silencing defects and disordered heterochromatin. Our findings suggest that FACT and HP1/Swi6 work intimately to regulate heterochromatin organization.

Background Patients with cancer benefit from treatment with immune checkpoint inhibitors (ICIs), and those with an inflamed tumor microenvironment (TME) and/or high tumor mutation burden (TMB), particularly, tend to respond to ICIs; however, some patients fail, whereas others acquire resistance after initial response despite the inflamed TME and/or high TMB. We assessed the detailed biological mechanisms of resistance to ICIs such as programmed death 1 and/or cytotoxic T-lymphocyte-associated protein 4 blockade therapies using clinical samples. Methods We established four pairs of autologous tumor cell lines and tumor-infiltrating lymphocytes (TILs) from patients with melanoma treated with ICIs. These tumor cell lines and TILs were subjected to comprehensive analyses and in vitro functional assays. We assessed tumor volume and TILs in vivo mouse models to validate identified mechanism. Furthermore, we analyzed additional clinical samples from another large melanoma cohort. Results Two patients were super-responders, and the others acquired resistance: the first patient had a non-inflamed TME and acquired resistance due to the loss of the beta-2 microglobulin gene, and the other acquired resistance despite having inflamed TME and extremely high TMB which are reportedly predictive biomarkers. Tumor cell line and paired TIL analyses showed high CD155, TIGIT ligand, and TIGIT expression in the tumor cell line and tumor-infiltrating T cells, respectively. TIGIT blockade or CD155-deletion activated T cells in a functional assay using an autologous cell line and paired TILs from this patient. CD155 expression increased in surviving tumor cells after coculturing with TILs from a responder, which suppressed TIGIT+ T-cell activation. Consistently, TIGIT blockade or CD155-deletion could aid in overcoming resistance to ICIs in vivo mouse models. In clinical samples, CD155 was related to resistance to ICIs in patients with melanoma with an inflamed

Members of the genus Borrelia are arthropod-borne spirochetes that are human and animal pathogens. Vertebrate hosts, including wild animals, are pivotal to the circulation and maintenance of Borrelia spirochetes. However, information on Borrelia spirochetes in vertebrate hosts in Zambia is limited. Thus, we aimed to investigate the presence of Borrelia spirochetes in wild animals and cattle in Zambia. A total of 140 wild animals of four species and 488 cattle DNA samples from /near the Kafue National Park were collected for real-time PCR screening, followed by characterization using three different genes with positive samples. Five impalas and 20 cattle tested positive using real-time PCR, and sequence analysis revealed that the detected Borrelia were identified to be Borrelia theileri, a causative agent of bovine borreliosis. This is the first evidence of Borrelia theileri in African wildlife and cattle in Zambia. Our results suggest that clinical differentiation between bovine borreliosis and other bovine diseases endemic in Zambia is required for better treatment and control measures. As this study only included wild and domestic animals in the Kafue ecosystem, further investigations in other areas and with more wildlife and livestock species are needed to clarify a comprehensive epidemiological status of Borrelia theileri in Zambia.

Highly pathogenic avian influenza viruses (HPAIVs) with H5 and H7 hemagglutinin (HA) subtypes are derived from their low pathogenic counterparts following the acquisition of multiple basic amino acids in their HA cleavage site. It has been suggested that consecutive adenine residues and a stem-loop structure in the viral RNA region that encodes the cleavage site are essential for the acquisition of the polybasic cleavage site. By using a reporter assay to detect non-templated nucleotide insertions, we found that insertions more frequently occurred in the RNA region (29 nucleotide-length) encoding the cleavage site of an H5 HA gene that was predicted to have a stem-loop structure containing consecutive adenines than in a mutated corresponding RNA region that had a disrupted loop structure with fewer adenines. In virus particles generated by using reverse genetics, nucleotide insertions that created additional codons for basic amino acids were found in the RNA region encoding the cleavage site of an H5 HA gene but not in the mutated RNA region. We confirmed the presence of virus clones with the ability to replicate without trypsin in a plaque assay and to cause lethal infection in chicks. These results demonstrate that the stem-loop structure containing consecutive adenines in HA genes is a key molecular determinant for the emergence of H5 HPAIVs.

This study aims to demonstrate the significance of the discussion under the “veil of ignorance” in building consensus about the Not In My Back Yard (NIMBY) issue. The Siting for a Contaminated Waste Landfill Game simulating conflicts related to the site selection of a contaminated waste landfill created by the accident at Fukushima nuclear power plant was developed with the veil of ignorance implemented as the prevailing social structure. The game involves two types of players: mayors, who are aware of the interests of their regions but can only engage in discussion; and citizens, who are unaware of the specific concerns of their regions (i.e., under the veil of ignorance) but are tasked with engaging in discussions and making the final decision. The transformations in the ideas of the players were examined through this game relating to building consensus. Ten games were conducted, and no unfair decisions were discerned under the veil of ignorance. A qualitative analysis of the open-ended questions revealed that a) the participants focused on fair viewpoints and avoided obsessions with regional interests after the discussion, and b) the diversity of actors and the multiple value dimensions were consistently emphasized before and after the discussion. Hence, this study succeeded in demonstrating that by participating in discussions under the veil of ignorance, the participants were able to form a shared recognition of the multiple-decision process, which the involvement of a diversity of actors and values was crucial for the formation of a consensus on the NIMBY issue.

Highly pathogenic avian influenza viruses (HPAIVs) with H5 and H7 hemagglutinin (HA) subtypes are derived from their low pathogenic counterparts following the acquisition of multiple basic amino acids in their HA cleavage site. It has been suggested that consecutive adenine residues and a stem-loop structure in the viral RNA region that encodes the cleavage site are essential for the acquisition of the polybasic cleavage site. By using a reporter assay to detect non-templated nucleotide insertions, we found that insertions more frequently occurred in the RNA region (29 nucleotide-length) encoding the cleavage site of an H5 HA gene that was predicted to have a stem-loop structure containing consecutive adenines than in a mutated corresponding RNA region that had a disrupted loop structure with fewer adenines. In virus particles generated by using reverse genetics, nucleotide insertions that created additional codons for basic amino acids were found in the RNA region encoding the cleavage site of an H5 HA gene but not in the mutated RNA region. We confirmed the presence of virus clones with the ability to replicate without trypsin in a plaque assay and to cause lethal infection in chicks. These results demonstrate that the stem-loop structure containing consecutive adenines in HA genes is a key molecular determinant for the emergence of H5 HPAIVs.

This study aims to demonstrate the significance of the discussion under the “veil of ignorance” in building consensus about the Not In My Back Yard (NIMBY) issue. The Siting for a Contaminated Waste Landfill Game simulating conflicts related to the site selection of a contaminated waste landfill created by the accident at Fukushima nuclear power plant was developed with the veil of ignorance implemented as the prevailing social structure. The game involves two types of players: mayors, who are aware of the interests of their regions but can only engage in discussion; and citizens, who are unaware of the specific concerns of their regions (i.e., under the veil of ignorance) but are tasked with engaging in discussions and making the final decision. The transformations in the ideas of the players were examined through this game relating to building consensus. Ten games were conducted, and no unfair decisions were discerned under the veil of ignorance. A qualitative analysis of the open-ended questions revealed that a) the participants focused on fair viewpoints and avoided obsessions with regional interests after the discussion, and b) the diversity of actors and the multiple value dimensions were consistently emphasized before and after the discussion. Hence, this study succeeded in demonstrating that by participating in discussions under the veil of ignorance, the participants were able to form a shared recognition of the multiple-decision process, which the involvement of a diversity of actors and values was crucial for the formation of a consensus on the NIMBY issue.

FACT (facilitate chromatin transcription) is involved in heterochromatic silencing, but its mechanisms and function remain unclear. We reveal that the Spt16 recruitment mechanism operates in two distinct ways in heterochromatin. First, Pob3 mediates Spt16 recruitment onto the heterochromatin through its Spt16 dimerization and tandem PH domains. Without Pob3, Spt16 recruitment is partially reduced, exhibiting a silencing defect and impaired H2A/H2B organization. Second, heterochromatin protein 1 (HP1)/Swi6 mediates Spt16 recruitment onto the heterochromatin by physical interaction of the Swi6 chromo-shadow domain (CSD) and Spt16 peptidase-like domains. Several CSD mutants are tested for Spt16 binding activity, and the charged loop connecting beta 1 and beta 2 is critical for Spt16 binding and heterochromatic silencing. Loss of these pathways causes a severe defect in H3K9 methylation and HP1/Swi6 localization in the pericentromeric region, exhibiting transcriptional silencing defects and disordered heterochromatin. Our findings suggest that FACT and HP1/Swi6 work intimately to regulate heterochromatin organization.

Members of the genus Borrelia are arthropod-borne spirochetes that are human and animal pathogens. Vertebrate hosts, including wild animals, are pivotal to the circulation and maintenance of Borrelia spirochetes. However, information on Borrelia spirochetes in vertebrate hosts in Zambia is limited. Thus, we aimed to investigate the presence of Borrelia spirochetes in wild animals and cattle in Zambia. A total of 140 wild animals of four species and 488 cattle DNA samples from /near the Kafue National Park were collected for real-time PCR screening, followed by characterization using three different genes with positive samples. Five impalas and 20 cattle tested positive using real-time PCR, and sequence analysis revealed that the detected Borrelia were identified to be Borrelia theileri, a causative agent of bovine borreliosis. This is the first evidence of Borrelia theileri in African wildlife and cattle in Zambia. Our results suggest that clinical differentiation between bovine borreliosis and other bovine diseases endemic in Zambia is required for better treatment and control measures. As this study only included wild and domestic animals in the Kafue ecosystem, further investigations in other areas and with more wildlife and livestock species are needed to clarify a comprehensive epidemiological status of Borrelia theileri in Zambia.

C-13 NMR and electrical resistivity of lambda-(BETS)(2)GaBr0.75Cl3.25 [BETS: bis(ethylenedithio) tetraselenafulvalene] were simultaneously measured to clarify the electronic state of the insulating phase near the boundary of the superconducting (SC) phase of lambda-(BETS)(2)GaCl4. We found the divergent peak in the nuclear spin-lattice relaxation rate divided by temperature 1/T1T with the metal-insulator transition at 13 K, below which the appearance of internal fields in NMR spectra was confirmed. Results of this study indicate that lambda-(BETS)(2)GaBr0.75Cl3.25 undergoes spin-density-wave (SDW) ordering. We suggest that the existence of the SDW phase in the vicinity of the SC phase can explain the unexplainable enhancement of 1/T1T at low temperatures observed in lambda-(BETS)(2)GaCl4, and SDW fluctuation plays an important role in the pairing mechanism of lambda-type BETS superconductors.

For the unconventional organic superconductor lambda-(BETS)(2)GaCl4 [BETS = bis(ethylenedithio) tetraselenafulvalene], the importance of both spin and charge degrees of freedom has been discussed based on the broadening of the NMR linewidth due to charge disproportionation and the occurrence of a spin-density-wave phase near the superconducting phase. NMR with the nuclear spin of 1/2, previously used for studying organic conductors, is an effective method for revealing electronic states microscopically; however, it cannot distinguish between charge and spin anomalies. To resolve this problem, in this paper, we performed Ga-69,Ga-71-NMR measurements, which enabled us to study both charge and spin dynamics using different gyromagnetic ratios and quadrupole moments between two isotopes. The spin-lattice relaxation rate is dominated by electric-field gradient fluctuations originating from molecular dynamics above 150 K and, below this temperature, it is dominated by spin fluctuations derived from the pi electrons of BETS layers. This change in the relaxation mechanism is considered to be due to the development of interactions between GaCl4 ions and BETS layers upon freezing of the molecular motion by cooling. Below 150 K, the contribution of spin fluctuations monotonically increases, and no increase in the charge fluctuation was observed, suggesting that the spin degree of freedom plays a major role in low-temperature physical properties. Our findings will aid theoretical studies on superconducting properties.

Hydrodynamic motion can generate a flux of electron-spin’s angular momentum via the coupling between fluid rotation and electron spins. Such hydrodynamic generation, called spin hydrodynamic generation (SHDG), has recently attracted attention in a wide range of fields, especially in spintronics. Spintronics deals with spin-mediated interconversion taking place on a micro or nano scale because of the spin-diffusion length scale. To be fully incorporated into the interconversion, SHDG physics should also be established in such a minute scale, where most fluids exhibit a laminar flow. Here, we report electric voltage generation due to the SHDG in a laminar flow of a liquid-metal mercury. The experimental results show a scaling rule unique to the laminar-flow SHDG. Furthermore, its energy conversion efficiency turns out to be about 105 greater than of the turbulent one. Our findings reveal that the laminar-flow SHDG is suitable to downsizing and to extend the coverage of fluid spintronics.

The disposal of designated radioactive contaminated waste resulting from the Fukushima nuclear accident is a primary issue in Japan. However, residents often strongly oppose siting a repository of designated waste; therefore, a possible site remains undecided. The NIMBY (Not In My Back Yard) aspect, whereby people refuse to build a repository in their hometown, has led to strong opposition. This study examined a public acceptance model for the siting investigation of a repository of designated waste. The model proposes that the antecedents of the three types of fairness, namely, procedural, distributive, and interpersonal fairness, determine public acceptance in addition to affecting evaluation of designated waste. The study investigated the differences of influences of the three types of fairness between residents in possible siting areas and in a non-siting area to compare the cognitive process toward the NIMBY issue. The respondents included 1016 residents in possible siting areas (Miyagi, Tochigi, Gunma, Ibaraki, and Chiba Prefectures), and 1006 residents in a non-siting area (the Tokyo metropolitan area). All respondents completed a web-based questionnaire. The results revealed that the influence of procedural fairness on public acceptance in the non-siting area was stronger than it was in the possible siting areas. Conversely, the influence of distributive fairness was stronger in the possible siting areas than it was in the non-siting area. Furthermore, affect evaluation through antecedents of fairness was more influential for public acceptance in the possible sites than it was in the non-siting area. Therefore, the findings suggest that the strong opposition due to the NIMBY aspect was caused by the differences between the process of fairness and the concept of fairness that people emphasize.

The disposal of designated radioactive contaminated waste resulting from the Fukushima nuclear accident is a primary issue in Japan. However, residents often strongly oppose siting a repository of designated waste; therefore, a possible site remains undecided. The NIMBY (Not In My Back Yard) aspect, whereby people refuse to build a repository in their hometown, has led to strong opposition. This study examined a public acceptance model for the siting investigation of a repository of designated waste. The model proposes that the antecedents of the three types of fairness, namely, procedural, distributive, and interpersonal fairness, determine public acceptance in addition to affecting evaluation of designated waste. The study investigated the differences of influences of the three types of fairness between residents in possible siting areas and in a non-siting area to compare the cognitive process toward the NIMBY issue. The respondents included 1016 residents in possible siting areas (Miyagi, Tochigi, Gunma, Ibaraki, and Chiba Prefectures), and 1006 residents in a non-siting area (the Tokyo metropolitan area). All respondents completed a web-based questionnaire. The results revealed that the influence of procedural fairness on public acceptance in the non-siting area was stronger than it was in the possible siting areas. Conversely, the influence of distributive fairness was stronger in the possible siting areas than it was in the non-siting area. Furthermore, affect evaluation through antecedents of fairness was more influential for public acceptance in the possible sites than it was in the non-siting area. Therefore, the findings suggest that the strong opposition due to the NIMBY aspect was caused by the differences between the process of fairness and the concept of fairness that people emphasize.

C-13 NMR and electrical resistivity of lambda-(BETS)(2)GaBr0.75Cl3.25 [BETS: bis(ethylenedithio) tetraselenafulvalene] were simultaneously measured to clarify the electronic state of the insulating phase near the boundary of the superconducting (SC) phase of lambda-(BETS)(2)GaCl4. We found the divergent peak in the nuclear spin-lattice relaxation rate divided by temperature 1/T1T with the metal-insulator transition at 13 K, below which the appearance of internal fields in NMR spectra was confirmed. Results of this study indicate that lambda-(BETS)(2)GaBr0.75Cl3.25 undergoes spin-density-wave (SDW) ordering. We suggest that the existence of the SDW phase in the vicinity of the SC phase can explain the unexplainable enhancement of 1/T1T at low temperatures observed in lambda-(BETS)(2)GaCl4, and SDW fluctuation plays an important role in the pairing mechanism of lambda-type BETS superconductors.

For the unconventional organic superconductor lambda-(BETS)(2)GaCl4 [BETS = bis(ethylenedithio) tetraselenafulvalene], the importance of both spin and charge degrees of freedom has been discussed based on the broadening of the NMR linewidth due to charge disproportionation and the occurrence of a spin-density-wave phase near the superconducting phase. NMR with the nuclear spin of 1/2, previously used for studying organic conductors, is an effective method for revealing electronic states microscopically; however, it cannot distinguish between charge and spin anomalies. To resolve this problem, in this paper, we performed Ga-69,Ga-71-NMR measurements, which enabled us to study both charge and spin dynamics using different gyromagnetic ratios and quadrupole moments between two isotopes. The spin-lattice relaxation rate is dominated by electric-field gradient fluctuations originating from molecular dynamics above 150 K and, below this temperature, it is dominated by spin fluctuations derived from the pi electrons of BETS layers. This change in the relaxation mechanism is considered to be due to the development of interactions between GaCl4 ions and BETS layers upon freezing of the molecular motion by cooling. Below 150 K, the contribution of spin fluctuations monotonically increases, and no increase in the charge fluctuation was observed, suggesting that the spin degree of freedom plays a major role in low-temperature physical properties. Our findings will aid theoretical studies on superconducting properties.

Cell detachment is essential in culturing adherent cells. Trypsinization is the most popular detachment technique, even though it reduces viability due to the damage to the membrane and extracellular matrix. Avoiding such damage would improve cell culture efficiency. Here we propose an enzyme-free cell detachment method that employs the acoustic pressure, sloshing in serum-free medium from intermittent traveling wave. This method detaches 96.2% of the cells, and increases its transfer yield to 130% of conventional methods for 48 h, compared to the number of cells detached by trypsinization. We show the elimination of trypsinization reduces cell damage, improving the survival of the detached cells. Acoustic pressure applied to the cells and media sloshing from the intermittent traveling wave were identified as the most important factors leading to cell detachment. This proposed method will improve biopharmaceutical production by expediting the amplification of tissue-cultured cells through a more efficient transfer process.

Cell detachment is essential in culturing adherent cells. Trypsinization is the most popular detachment technique, even though it reduces viability due to the damage to the membrane and extracellular matrix. Avoiding such damage would improve cell culture efficiency. Here we propose an enzyme-free cell detachment method that employs the acoustic pressure, sloshing in serum-free medium from intermittent traveling wave. This method detaches 96.2% of the cells, and increases its transfer yield to 130% of conventional methods for 48 h, compared to the number of cells detached by trypsinization. We show the elimination of trypsinization reduces cell damage, improving the survival of the detached cells. Acoustic pressure applied to the cells and media sloshing from the intermittent traveling wave were identified as the most important factors leading to cell detachment. This proposed method will improve biopharmaceutical production by expediting the amplification of tissue-cultured cells through a more efficient transfer process.

Background. Many studies have shown that sanctions promote cooperation in social dilemma situations. However, it has also been suggested that sanctions have a negative effect. The interactions among people and systems need to be considered to examine the consequences of sanctions. Aim. We examined whether rewards and mutual punishment increased non-cooperation. We regarded illegal industrial waste dumping as a social dilemma in which everyone bears the burden of the cost of illegal dumping, legal treatment is cooperative behavior, and illegal dumping is non-cooperative behavior. Method. We used the Industrial Waste Illegal Dumping Game. This game simulates the structure of industrial waste treatment (incomplete surveillance, various industries with different roles and payoffs, cost of cooperation, etc.) in addition to the social dilemma structure. Players take on roles in industrial waste treatment, negotiating and dealing with other players, and treating industrial waste. We set three conditions. In the reward condition, players can earn rewards by rapidly treating industrial waste. In the mutual punishment condition, players can mutually monitor and punish each other. In the control condition, neither reward nor punishment exists. Results. Non-cooperation occurred more frequently in the reward condition than in the control condition. Conversely, there was no difference in non-cooperation between the mutual punishment and control conditions. Players under the reward condition did not gather information proactively, and information on benefits was not shared. Conclusion. This study showed that sanctions caused non-cooperation. Social dynamics should be considered when evaluating the effectiveness of sanctions. Gaming allows us to examine social consequences, including social dynamics, which leads to discoveries not possible through traditional methods.

Background. This study aims to examine the effectiveness of the “persuasion game” in changing environmental attitudes and behaviors in different cultural contexts. Personal communication has been identified as a key facilitator of environmental behaviors, but environmental communication in our daily lives is infrequent. Intervention. This study tested the effects of the persuasion game in Germany, Hong Kong, and Japan. The game divides participants into two groups: persuaders and persuadees. The persuaders were given 10 minutes to persuade as many persuadees as they could to adopt energy-saving behaviors. Further, after 10 minutes, these participants were asked to switch their roles. Method. The study employed a quasi-experimental pretest/posttest design to examine changes in attitudes and behavioral intentions of the participants toward energy-saving before and after their participation in the persuasion game. Participants were university students in Germany (N = 116), Hong Kong (N = 65), and Japan (N = 92). Results. In all three countries, playing the game was associated with increased intention to adopt energy-saving behaviors, perceived seriousness of environmental problems, descriptive norm, and subjective norm. The increase in subjective norm was especially high in Japan, where the increase in intention to adopt energy-saving behavior was particularly pronounced among those who had less environmental communication. Discussion. The results indicate that this game can not only facilitate communication on environmental issues in different cultural contexts but also change how people perceive others’ interest in environmental issues. Conclusion. This study showed that persuasion game can be played in countries other than Japan as well. Moreover, it provides an opportunity to communicate with others on environmental issues, which may contribute to promoting future environmental behaviors.

Background. This study aims to examine the effectiveness of the “persuasion game” in changing environmental attitudes and behaviors in different cultural contexts. Personal communication has been identified as a key facilitator of environmental behaviors, but environmental communication in our daily lives is infrequent. Intervention. This study tested the effects of the persuasion game in Germany, Hong Kong, and Japan. The game divides participants into two groups: persuaders and persuadees. The persuaders were given 10 minutes to persuade as many persuadees as they could to adopt energy-saving behaviors. Further, after 10 minutes, these participants were asked to switch their roles. Method. The study employed a quasi-experimental pretest/posttest design to examine changes in attitudes and behavioral intentions of the participants toward energy-saving before and after their participation in the persuasion game. Participants were university students in Germany (N = 116), Hong Kong (N = 65), and Japan (N = 92). Results. In all three countries, playing the game was associated with increased intention to adopt energy-saving behaviors, perceived seriousness of environmental problems, descriptive norm, and subjective norm. The increase in subjective norm was especially high in Japan, where the increase in intention to adopt energy-saving behavior was particularly pronounced among those who had less environmental communication. Discussion. The results indicate that this game can not only facilitate communication on environmental issues in different cultural contexts but also change how people perceive others’ interest in environmental issues. Conclusion. This study showed that persuasion game can be played in countries other than Japan as well. Moreover, it provides an opportunity to communicate with others on environmental issues, which may contribute to promoting future environmental behaviors.

Background. Many studies have shown that sanctions promote cooperation in social dilemma situations. However, it has also been suggested that sanctions have a negative effect. The interactions among people and systems need to be considered to examine the consequences of sanctions. Aim. We examined whether rewards and mutual punishment increased non-cooperation. We regarded illegal industrial waste dumping as a social dilemma in which everyone bears the burden of the cost of illegal dumping, legal treatment is cooperative behavior, and illegal dumping is non-cooperative behavior. Method. We used the Industrial Waste Illegal Dumping Game. This game simulates the structure of industrial waste treatment (incomplete surveillance, various industries with different roles and payoffs, cost of cooperation, etc.) in addition to the social dilemma structure. Players take on roles in industrial waste treatment, negotiating and dealing with other players, and treating industrial waste. We set three conditions. In the reward condition, players can earn rewards by rapidly treating industrial waste. In the mutual punishment condition, players can mutually monitor and punish each other. In the control condition, neither reward nor punishment exists. Results. Non-cooperation occurred more frequently in the reward condition than in the control condition. Conversely, there was no difference in non-cooperation between the mutual punishment and control conditions. Players under the reward condition did not gather information proactively, and information on benefits was not shared. Conclusion. This study showed that sanctions caused non-cooperation. Social dynamics should be considered when evaluating the effectiveness of sanctions. Gaming allows us to examine social consequences, including social dynamics, which leads to discoveries not possible through traditional methods.

This work demonstrates markedly modified spin dynamics of magnetic insulator (MI) by the spin momentum-locked Dirac surface states of the adjacent topological insulator (TI), which can be harnessed for spintronic applications. As the Bi concentration x is systematically tuned in 5-nm-thick (Bi x Sb1-x )2Te3 TI films, the weight of the surface relative to bulk states peaks at x = 0.32 when the chemical potential approaches the Dirac point. At this concentration, the Gilbert damping constant of the precessing magnetization in 10-nm-thick Y3Fe5O12 MI films in the MI/TI heterostructures is enhanced by an order of magnitude, the largest among all concentrations. In addition, the MI acquires additional strong magnetic anisotropy that favors the in-plane orientation with similar Bi concentration dependence. These extraordinary effects of the Dirac surface states distinguish TI from other materials such as heavy metals in modulating spin dynamics of the neighboring magnetic layer.

This work demonstrates markedly modified spin dynamics of magnetic insulator (MI) by the spin momentum-locked Dirac surface states of the adjacent topological insulator (TI), which can be harnessed for spintronic applications. As the Bi concentration x is systematically tuned in 5-nm-thick (Bi x Sb1-x )2Te3 TI films, the weight of the surface relative to bulk states peaks at x = 0.32 when the chemical potential approaches the Dirac point. At this concentration, the Gilbert damping constant of the precessing magnetization in 10-nm-thick Y3Fe5O12 MI films in the MI/TI heterostructures is enhanced by an order of magnitude, the largest among all concentrations. In addition, the MI acquires additional strong magnetic anisotropy that favors the in-plane orientation with similar Bi concentration dependence. These extraordinary effects of the Dirac surface states distinguish TI from other materials such as heavy metals in modulating spin dynamics of the neighboring magnetic layer.

Cisplatin plus 5‐fluorouracil is regarded as standard neoadjuvant chemotherapy for esophageal squamous cell carcinoma (ESCC) in Japan, but the prognosis remains poor. We have previously described how definitive chemoradiotherapy with docetaxel, nedaplatin, and 5‐fluorouracil (DNF) led to a very high response rate and promising survival times. We therefore undertook a phase II trial to evaluate the feasibility and efficacy of neoadjuvant DNF. The study included patients with clinical stage Ib‐III ESCC. Chemotherapy consisted of i.v. docetaxel (30 mg/m2) and nedaplatin (50 mg/m2) on days 1 and 8, and a continuous infusion of 5‐fluorouracil (400 mg/m2/day) on days 1‐5 and 8‐12, every 3 weeks. After three courses of chemotherapy, esophagectomy was carried out. The primary end‐point was the completion rate of the protocol treatment. Twenty‐eight patients were enrolled (cStage Ib/II/III, 2/3/23) and all received at least two cycles of chemotherapy. Twenty‐five patients underwent surgery, all of whom achieved an R0 resection, leading to a completion rate of 89.3%. The overall response rate was 87.0%. A pathological complete response was confirmed in eight (32.0%) cases. Grade 3/4 adverse events included leukopenia (32.1%), neutropenia (39.3%), febrile neutropenia (10.7%), thrombocytopenia (10.7%), and diarrhea (14.3%), but were manageable. Treatment‐related deaths and major surgical complications did not occur. Estimated 2‐year progression‐free and overall survival rates were 70.4% and 77.2%, respectively. Thus, DNF therapy was well tolerated and deemed feasible, with a strong tumor response in a neoadjuvant setting for ESCC. This trial is registered with the University Hospital Medical Information Network (UMIN ID: 000014305).

The evolution of cooperation is an unsolved research topic and has been investigated from the viewpoint of not only biology and other natural sciences but also social sciences. Much extant research has focused on the evolution of cooperation among peers. While, different players belonging to different organizations play different social roles, and players playing different social roles cooperate together to achieve their goals. We focus on the evolution of cooperation in linear division of labor that is defined as follows: a player in the i-th role interacts with a player in the i + 1-th role, and a player in the n-th role achieves their goal (1 <= i < n) if there are n roles in the division of labor. We take the industrial waste treatment process as an example for illustration. We consider three organizational roles and B-i is the i-th role. The player of B; can choose two strategies: legal treatment or illegal dumping, which can be interpreted as cooperation or defection (i = 1-3). With legally required treatment, the player of B-j pays a cost to ask the player of Bj+1 to treat the waste (j = 1, 2). Then, the cooperator of Bj+1 pays a cost to treat the waste properly. With illegal dumping, the player of Bi dumps the waste and does not pay any cost (i= 1-3). However, the waste dumped by the defector has negative environmental consequences, which all players in all roles suffer from. This situation is equivalent to a social dilemma encountered in common-pool resource management contexts. The administrative organ in Japan introduces two sanction systems to address the illegal dumping problem: the actor responsibility system and the producer responsibility system. In the actor responsibility system, if players in any role who choose defection are monitored and discovered, they are penalized via a fine. However, it is difficult to monitor and detect the violators, and this system does not work well. While, in the producer responsibility system, the player in B-1

The evolution of cooperation is an unsolved research topic and has been investigated from the viewpoint of not only biology and other natural sciences but also social sciences. Much extant research has focused on the evolution of cooperation among peers. While, different players belonging to different organizations play different social roles, and players playing different social roles cooperate together to achieve their goals. We focus on the evolution of cooperation in linear division of labor that is defined as follows: a player in the i-th role interacts with a player in the i + 1-th role, and a player in the n-th role achieves their goal (1 <= i < n) if there are n roles in the division of labor. We take the industrial waste treatment process as an example for illustration. We consider three organizational roles and B-i is the i-th role. The player of B; can choose two strategies: legal treatment or illegal dumping, which can be interpreted as cooperation or defection (i = 1-3). With legally required treatment, the player of B-j pays a cost to ask the player of Bj+1 to treat the waste (j = 1, 2). Then, the cooperator of Bj+1 pays a cost to treat the waste properly. With illegal dumping, the player of Bi dumps the waste and does not pay any cost (i= 1-3). However, the waste dumped by the defector has negative environmental consequences, which all players in all roles suffer from. This situation is equivalent to a social dilemma encountered in common-pool resource management contexts. The administrative organ in Japan introduces two sanction systems to address the illegal dumping problem: the actor responsibility system and the producer responsibility system. In the actor responsibility system, if players in any role who choose defection are monitored and discovered, they are penalized via a fine. However, it is difficult to monitor and detect the violators, and this system does not work well. While, in the producer responsibility system, the player in B-1 is fin