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Primary biliary cholangitis (PBC) is a rare autoimmune disease with a clear predisposition for human leukocyte antigen (HLA)-DR/DQ-associated loss of immune tolerance for the E2 component of the pyruvate dehydrogenase complex. Three-field-resolution HLA imputation of 1,670 Japanese PBC patients and 2,328 healthy controls was conducted using Japanese population-specific HLA reference panels. Eighteen previously reported Japanese PBC-associated HLA alleles were confirmed and extended to 3-field-resolution, including HLA-DRB1*08:03 to HLA-DRB1*08:03:02, HLA-DQB1*03:01 to HLA-DQB1*03:01:01, HLA-DQB1*04:01 to HLA-DQB1*04:01:01 and HLA-DQB1*06:04 to HLA-DQB1*06:04:01. In addition, additional significant novel HLA alleles were identified, including 3 novel susceptible HLA-DQA1 alleles: HLA-DQA1*03:03:01, HLA-DQA1*04:01:01, HLA-DQA1*01:04:01 and 1 novel protective HLA-DQA1 allele, HLA-DQA1*05:05:01. In addition, PBC patients carrying HLA-DRB1*15:01:01 and HLA-DQA1*03:03:01 would have a higher predisposition toward developing concomitant autoimmune hepatitis (AIH). Further, late-stage and symptomatic PBC shared the same susceptible HLA alleles of HLA-A*26:01:01, HLA-DRB1*09:01:02 and HLA-DQB1*03:03:02. Lastly, HLA-DPB1*05:01:01 was identified as a potential risk HLA allele for development of hepatocellular carcinoma (HCC) in PBC patients. In conclusion, we have extended the current knowledge of HLA allele associations to 3-field resolution and identified novel HLA allele associations with predisposition risk, staging, symptomatic state, and AIH and HCC events for Japanese PBC patients.

Adding anti-PD1 antibodies to 5-FU/platinum chemotherapy improves survival in a subset of advanced gastroesophageal adenocarcinoma (GEA) patients. Beyond PD-L1 expression and mismatch repair status we have limited insight into molecular predictors of response, or the relative contribution of PD-1 blockade. We conducted an investigator sponsored phase II trial (n = 47) sequentially adding pembrolizumab to standard 5-FU/platinum in previously untreated advanced GEA (ClinicalTrials.gov: NCT04249739). With an overall response rate of 67% the activity paralleled phase III chemoimmunotherapy trials. To understand on-treatment tumor and immune adaptations patients underwent serial biopsy of the primary tumor, including baseline, after one cycle of 5-FU/platinum, and after the addition of pembrolizumab. We leveraged transcriptional profiling from 358,067 cells to identify multicellular networks of malignant, stromal, and immune cells after chemotherapy and concurrent chemoimmunotherapy. The relative usage of pro-tumor and anti-tumor interaction hubs differed between fast and slow progressing patients. Chemotherapy induced early on-treatment formation of hubs centered on tumor-reactive T-cell and M1-oriented macrophage interactions with pro-inflammatory cytokines in slow progressors. Faster progression was characterized by increased MUC5A and MSLN containing programs in tumor cells and M2-oriented macrophages with immunosuppressive stromal interactions. After adding pembrolizumab we observed increased CD8 T-cell infiltration by scRNAseq and multiplex immunofluorescence and development of an immunity hub involving co-variation of the tumor-reactive CXCL13 program and epithelial interferon-stimulated gene programs enriched in slow progressors. Together this data provides prospective evidence of differential early on-treatment evolution of the gastric immune microenvironment and nominates candidate cellular interactions for clinical targeting.

Adolescent stress can be a risk factor for abnormal social behavior in the postpartum period, which critically affects an individual social functioning. Nonetheless, the underlying mechanisms remain unclear. Using a mouse model with optogenetics and in vivo calcium imaging, we found that adolescent psychosocial stress, combined with pregnancy and delivery, caused hypofunction of the glutamatergic pathway from the anterior insula to prelimbic cortex (AI-PrL pathway), which altered PrL neuronal activity, and in turn led to abnormal social behavior. Specifically, the AI-PrL pathway played a crucial role during recognizing the novelty of other mice by modulating “stable neurons” in PrL, which were constantly activated or inhibited by novel mice. We also observed that glucocorticoid receptor signaling in the AI-PrL pathway had a causal role in stress-induced postpartum changes. Our findings provide functional insights into a cortico-cortical pathway underlying adolescent stress-induced postpartum social behavioral deficits.

Chemotherapy is ubiquitous in first-line treatment of advanced gastric cancer, yet responses are heterogeneous, and little is known about mediators of chemotherapy response. To move forward, an understanding of the effects of standard chemotherapy on the tumor–immune microenvironment (TME) is needed. Coupling whole-exome sequencing, bulk RNA and single-cell transcriptomics from paired pretreatment and on-treatment samples in treatment-naïve patients with HER2-positive and HER2-negative gastric cancer, we define features associated with response to platinum-based chemotherapy. Response was associated with on-treatment TME remodeling including natural killer (NK) cell recruitment, decreased tumor-associated macrophages, M1-macrophage repolarization, and increased effector T-cell infiltration. Among chemotherapy nonresponders, we observed low/absent PD-L1 expression or modulation, on-treatment increases in Wnt signaling, B-cell infiltration, and LAG3-expressing T cells coupled to an exodus of dendritic cells. We did not observe significant genomic changes in early on-treatment sampling. We provide a map of on-treatment TME modulation with standard chemotherapy and nominate candidate future approaches.Significance:Using paired pretreatment and on-treatment samples during standard first-line chemotherapy, we identify chemotherapy-induced NK-cell infiltration, macrophage repolarization, and increased antigen presentation among responders. Increased LAG3 expression and decreased dendritic cell abundance were seen in nonresponders, emphasizing remodeling of the TME during chemotherapy response and resistance.This article is highlighted in the In This Issue feature, p. 873

Supplementary Figure from Early Tumor–Immune Microenvironmental Remodeling and Response to First-Line Fluoropyrimidine and Platinum Chemotherapy in Advanced Gastric Cancer

Adding anti-PD1 antibodies to 5-FU/platinum chemotherapy improves survival in a subset of advanced gastroesophageal adenocarcinoma (GEA) patients. Beyond PD-L1 expression and mismatch repair status we have limited insight into molecular predictors of response or the relative contribution of PD-1 blockade. We conducted an investigator sponsored phase II trial (n = 47) sequentially adding pembrolizumab to standard 5-FU/platinum in previously untreated advanced GEA (ClinicalTrials.gov:NCT04249739). With an overall response rate of 67% the activity paralleled phase III chemoimmunotherapy trials. To understand on-treatment tumor and immune adaptations patients underwent serial biopsy of the primary tumor, including baseline, after one cycle of 5-FU/platinum, and after the addition of pembrolizumab. We leveraged transcriptional profiling from 358,067 cells to identify multicellular networks of malignant, stromal, and immune cells after chemotherapy and concurrent chemoimmunotherapy. The relative usage of pro-tumor and anti-tumor interaction hubs differed between fast and slow progressing patients. Chemotherapy induced early on-treatment formation of hubs centered on tumor-reactive T-cell and M1-oriented macrophage interactions with pro-inflammatory cytokines in slow progressors. Faster progression was characterized by increased MUC5A and MSLN containing programs in tumor cells and M2-oriented macrophages with immunosuppressive stromal interactions. After adding pembrolizumab we observed increased CD8 T-cell infiltration by scRNAseq and multiplex immunofluorescence and development of an immunity hub involving co-variation of the tumor-reactive CXCL13 program and epithelial interferon-stimulated gene programs enriched in slow progressors. Together this data provides prospective evidence of differential early on-treatment evolution of the gastric immune microenvironment and nominates candidate cellular interactions for clinical targeting.

Supplementary Table from Early Tumor–Immune Microenvironmental Remodeling and Response to First-Line Fluoropyrimidine and Platinum Chemotherapy in Advanced Gastric Cancer

Background Adipokines such as leptin and adiponectin are associated with cognitive function. Although adiposity crucially affects adipokine levels, it remains unclear whether the relationship between adipokines and cognition is influenced by obesity. Methods We enrolled 171 participants and divided them into participants with obesity and without obesity to explore the effect of obesity on the relationship between adipokines and cognition. In addition to plasma levels of leptin and adiponectin, multidomain cognitive functions and brain structures were assessed using neuropsychological testing and magnetic resonance imaging. Association between levels of these adipokines and Alzheimer’s disease (AD) was then assessed by logistic regression. Results We found that cognitive function was negatively associated with leptin levels and leptin-to-adiponectin ratio (LAR). Such correlations between leptin and cognitive domains were prominent in participants with obesity but were not observed in those without obesity. Leptin levels were associated with lower hippocampal volumes in participants with obesity. A significant interaction of leptin and obesity was found mostly in the medial temporal lobe. Both leptin and LAR were positively associated with insulin resistance and inflammation markers in all participants. Of note, LAR was associated with a higher risk of AD after adjusting for demographic variables, Apolipoprotein E genotype, and body mass index. Conclusions Obesity might be a factor that determines how adipokines affect brain structure and cognition. Leptin resistance might influence the relationship between adipokines and cognition. In addition, LAR rather than each adipokine levels alone may be a better indicator of AD risk in older adults with metabolic stress.

食支援において大切にしていることおよび課題について，鳥取県内の特別養護老人ホームで勤務する多職種を対象にアンケート調査を行った．現場では，誤嚥や窒息のリスクを考慮するとともに利用者一人ひとりが安全に食べることができ，食事が楽しく豊かな時間となるよう支援していた．よりよい支援にむけて，利用者の摂食嚥下状態の把握に努め安全に食べられるための環境調整や食事介助のスキル向上，専門職の配置と多職種連携の強化を課題としていた．

Background & Aims Tumor necrosis factor alpha (TNFα) is considered a major tissue damage-promoting effector in Crohn’s disease (CD) pathogenesis. Patient-derived intestinal organoid (enteroid) recapitulates the disease-specific characteristics of the intestinal epithelium. This study aimed to evaluate the intestinal epithelial responses to TNFα in enteroids derived from healthy controls and compare them with those of CD patient-derived enteroids. Methods Human enteroids derived from patients with CD and controls were treated with TNFα (30 ng/mL), and cell viability and gene expression patterns were evaluated. Results TNFα induced MLKL-mediated necroptotic cell death, which was more pronounced in CD patient-derived enteroids than in control enteroids. Immunohistochemistry and RNA sequencing revealed that treatment with TNFα caused expansion of the intestinal stem cell (ISC) populations. However, expanded ISC subpopulations differed in control and CD patient-derived enteroids, with LGR5+ active ISCs in control enteroids and reserve ISCs, such as BMI1+ cells, in CD patient-derived enteroids. In single-cell RNA sequencing, LGR5+ ISC-enriched cell cluster showed strong expression of TNFRSF1B (TNFR2) and cyclooxygenase-prostaglandin E2 (PGE2) activation. In TNFα-treated CD patient-derived enteroids, exogenous PGE2 (10 nmol/L) induced the expansion of the LGR5+ ISC population and improved organoid-forming efficiency, viability, and wound healing. Conclusions TNFα increases necroptosis of differentiated cells and induces the expansion of LGR5+ ISCs. In CD patient-derived enteroids, TNFα causes LGR5+ stem cell dysfunction (expansion failure), and exogenous PGE2 treatment restored the functions of LGR5+ stem cells. Therefore, PGE2 can be used to promote mucosal healing in patients with CD., Graphical abstract

研究者が自己評価をすることにより，キャリアデザインを具体化・可視化するシステムであるe ポートフォリオシステム“ENISHI”を開発したので紹介する。“ENISHI”は，個々の研究者が所属する機関や専門性の枠にとどまらず，研究者の主体的な成長を支援し，将来のキャリア形成につながる能力の開発を促すことを目的としている。“ENISHI”は，web ベースで成果物等の広範囲にわたる情報を電子的に取り込み保管するポートフォリオである。研究者は，“ENISHI”の機能である「プロフィール」「能力診断」「ビジョン」「到達目標」「行動計画」「能力アッププログラム」「成果物」「キャリアラダー」「他者評価」を主体的に循環させ，研究者としての成長過程を具体化・可視化しながら成長を目指す。研究者の能力の指標は，Vitae 研究者開発フレームワークを参考に作成し，能力診断として位置づけた。“ENISHI”の活用は，研究者のキャリアデザインの確立を高める支援につながると考える。

今後の実習指導に活かすために，公衆衛生看護学実習における学びの特徴を明らかにすることを目的に，2005 年度以降15 年間に学生が実習報告会で報告した107 テーマをテキスト分析ソフトKHCoder（Ver）.3.0 を用いて分析した。その結果，総抽出語数は1,205 語であり，出現回数が3 回以上の語は，42 語あり，上位5 位で最も多かったのは，「保健」90 回，次いで「活動」37 回，「健康」35 回，「役割」33 回，「住民」23 回の順であった。学生の学びの特徴として以下のことが明らかとなった。1．抽出語上位10 位までの語句と共起ネットワーク，特徴語の分析から，学生は，保健活動や健康づくりについて，主に母子保健や介護予防の活動をとおして，保健師・住民等の役割を学んでいた。2．2010 年度以降は，「保健師に必要とされる力量」や「保健師の専門性」「住民主体」に注目した報告会テーマが多くなっていた。3．実習年代別の報告会テーマの特徴語から，実習目的が報告会テーマに反映されており，学生は，実習目的を意識しながら実習を行うことが出来ていた。4．実習機関の圏域別の特徴語から，学生は，圏域の地域特性をよく捉え，報告会テーマに取り上げ学びを深めることが出来ていた。以上のことから，引き続き，実習目的や地域特性に応じた実習報告会のテーマ設定ができるように実習指導者及び教員による指導が重要であると考えた。

2011 年度から2020 年度までの島根県立大学における公衆衛生看護学実習実施報告集をもとに，学生の実習目標到達度と実習体験内容の実態を明らかにし，新カリキュラムの始動に向けた保健師教育のあり方について検討した。本学の学生は，個人・家族・集団・地域の力量を引き出すケアシステム化と，ケアマネジメントやケアコーディネーションの基本を身につける実習目標に対する到達度が低く，これらを高める教育内容の充実が必要である。公衆衛生看護学実習での学生一人あたりの保健活動体験数は，この10 年で有意に減少傾向にあるが，実習目標の到達度には変化は見られなかったことから，今後も実習では，体験数を重視するのではなく，体験した保健師活動で得た知識を関連づける指導や教育内容の工夫が求められる。

Chemotherapy is ubiquitous in first-line treatment of advanced gastric cancer, yet responses are heterogeneous, and little is known about mediators of chemotherapy response. To move forward, an understanding of the effects of standard chemotherapy on the tumor–immune microenvironment (TME) is needed. Coupling whole-exome sequencing, bulk RNA and single-cell transcriptomics from paired pretreatment and on-treatment samples in treatment-naïve patients with HER2-positive and HER2-negative gastric cancer, we define features associated with response to platinum-based chemotherapy. Response was associated with on-treatment TME remodeling including natural killer (NK) cell recruitment, decreased tumor-associated macrophages, M1-macrophage repolarization, and increased effector T-cell infiltration. Among chemotherapy nonresponders, we observed low/absent PD-L1 expression or modulation, on-treatment increases in Wnt signaling, B-cell infiltration, and LAG3-expressing T cells coupled to an exodus of dendritic cells. We did not observe significant genomic changes in early on-treatment sampling. We provide a map of on-treatment TME modulation with standard chemotherapy and nominate candidate future approaches. Significance: Using paired pretreatment and on-treatment samples during standard first-line chemotherapy, we identify chemotherapy-induced NK-cell infiltration, macrophage repolarization, and increased antigen presentation among responders. Increased LAG3 expression and decreased dendritic cell abundance were seen in nonresponders, emphasizing remodeling of the TME during chemotherapy response and resistance. This article is highlighted in the In This Issue feature, p. 873

Reward design in reinforcement learning (RL) is challenging since specifying human notions of desired behavior may be difficult via reward functions or require many expert demonstrations. Can we instead cheaply design rewards using a natural language interface? This paper explores how to simplify reward design by prompting a large language model (LLM) such as GPT-3 as a proxy reward function, where the user provides a textual prompt containing a few examples (few-shot) or a description (zero-shot) of the desired behavior. Our approach leverages this proxy reward function in an RL framework. Specifically, users specify a prompt once at the beginning of training. During training, the LLM evaluates an RL agent's behavior against the desired behavior described by the prompt and outputs a corresponding reward signal. The RL agent then uses this reward to update its behavior. We evaluate whether our approach can train agents aligned with user objectives in the Ultimatum Game, matrix games, and the DealOrNoDeal negotiation task. In all three tasks, we show that RL agents trained with our framework are well-aligned with the user's objectives and outperform RL agents trained with reward functions learned via supervised learning, International Conference on Learning Representations (ICLR) 2023

Globally, university partnerships and collaborations have been identified as key pillars of the tripartite roles of universities namely; Academics, Research, and Civic Engagement. In Africa, there is intensified effort to strengthen university partnerships with the governments, industry and communities for greater impact to socio-economic development. The role of university partnerships is considered a vital driver of not only research and innovation but also capacity development as well as internationalization. In this paper, multiple case analysis approach was used to explore the strategies being employed by universities in Kenya with a view of teasing out lessons for advancing partnerships and collaborations in universities in Africa. The two main objectives of the study were; to find out the strategies employed by universities in advancing partnerships and (ii) to establish challenges affecting university partnerships in Kenya. Random sampling was used to identify public and private universities for the study in order to establish the objective position across the higher education landscape. Both qualitative and quantitative data was collected. The respondents of the study were purposively selected due to the unique nature of the study. Among various initiatives, the paper highlights some distinctive projects, initiated courtesy of university partnerships in the 21st century. The paper highlights developing partnership policies, creating monitoring systems and capacity building as key ingredients for enhancing resilient and sustainable partnerships and collaborations.

Adolescent stress can be a risk factor for abnormal social behavior in the postpartum period, which critically affects the safety of mothers and children. Nonetheless, the underlying mechanisms remain unclear. Using a newly established mouse model with optogenetics andin vivocalcium imaging, we found that adolescent psychosocial stress, combined with pregnancy and delivery, caused hypofunction of the glutamatergic pathway from the anterior insula to prelimbic cortex (AI-PrL pathway), which altered PrL neuronal activity, and in turn led to abnormal social behavior. Specifically, the AI-PrL pathway played a crucial role during recognizing the novelty of other mice by modulating “stable neurons” in PrL, which were constantly activated or inhibited by novel mice. We also observed that glucocorticoid receptor signaling in the AI-PrL pathway had a causal role in stress-induced postpartum changes. Our findings provide novel and functional insights into a cortico-cortical pathway underlying adolescent stress-induced postpartum social behavioral deficits.

Consider a robot tasked with tidying a desk with a meticulously constructed Lego sports car. A human may recognize that it is not socially appropriate to disassemble the sports car and put it away as part of the "tidying". How can a robot reach that conclusion? Although large language models (LLMs) have recently been used to enable social reasoning, grounding this reasoning in the real world has been challenging. To reason in the real world, robots must go beyond passively querying LLMs and *actively gather information from the environment* that is required to make the right decision. For instance, after detecting that there is an occluded car, the robot may need to actively perceive the car to know whether it is an advanced model car made out of Legos or a toy car built by a toddler. We propose an approach that leverages an LLM and vision language model (VLM) to help a robot actively perceive its environment to perform grounded social reasoning. To evaluate our framework at scale, we release the MessySurfaces dataset which contains images of 70 real-world surfaces that need to be cleaned. We additionally illustrate our approach with a robot on 2 carefully designed surfaces. We find an average 12.9% improvement on the MessySurfaces benchmark and an average 15% improvement on the robot experiments over baselines that do not use active perception. The dataset, code, and videos of our approach can be found at https://minaek.github.io/groundedsocialreasoning.