Effects of recalling place memory on promoting cooperative behaviors in local communities.

AIMS: The present study aimed to develop a theoretical model that explores the influence of recalling place memory on cooperative behaviors in local communities. METHODS: Five hundred ninety-five Japanese residents (mean age = 49.75 years) participated in an online survey, in which they received one of the three interventions: (1) positive memory; (2) neutral memory and (3) negative memory. Participants were instructed to recall their place memories within their living areas and provide ratings for their place attachment, emotional valence, perceived self-interest, and willingness to engage in cooperative behaviors. RESULTS: The results revealed that individuals who recalled positive-valenced place memories exhibited a higher willingness to engage in cooperative behaviors. Additionally, this study reveals the previously unreported mediating role of place attachment and perceived self-interest in promoting cooperative behaviors. CONCLUSION: The findings hold significance in elucidating the relationship between place memory and cooperative behaviors, offering novel insights for community management.

Maximin principle, emotional aversion, and integrative judgment in the NIMBY context, including social dilemma and moral dilemma: The roles of the amygdala, angular gyrus, and ventromedial prefrontal cortex.

Public facilities that have NIMBY (not in my backyard) structure involve both a social dilemma, in which individuals' decisions to prevent the worst outcomes for themselves undermine the public interest, and a moral dilemma focused on the majority versus the minority. This study examined the cognitive-neural processes in judging whether to prioritize the site residents or the citizenry as a whole within the context of NIMBY. Our ROIs were the right angular gyrus being related to concern about the worst possible outcomes for others and oneself, the amygdala associating with emotional aversion to prioritizing the majority, and the vmPFC, which integrates the aversion into "all things considered" judgments. As a result of comparing ingroup conditions for which a NIMBY facility may make participants worst-off position and outgroup conditions for which this possibility is denied, the right angular gyrus was activated in both conditions. The amygdala was activated only in the ingroup, and the vmPFC exhibited a stronger tendency in the ingroup. We concluded that the cognitive-neural processes in judgments on NIMBY facilities are common to both decision-making to avoid the worst-off position for others and for oneself and moral judgments between the majority and the minority.

Why People Stayed Home During the COVID-19 Pandemic: Implications for Health Communication Across Four Countries.

Staying at home substantially reduces the spread of COVID-19. Moreover, understanding why people stayed at home by addressing its social cognitive determinants can help create more effective communication to change behaviors. This study analyzed this outcome through an extended model of the theory of planned behavior based on risk perception and personal norms in four countries: the United States, Japan, Brazil, and Taiwan. 1,196 individuals participated in this study through a questionnaire focused on planned behavior, moral norms, and risk perception. The data showed that intention and perceived behavioral control influenced behavior significantly, while attitude, injunctive norms, perceived behavioral control, personal norms, and risk perception influenced intention. With multigroup analysis and ANOVA, we verified significant differences in the estimates and mean scores across cultures, revealing the need for scholars to analyze outcomes based on geography and local political culture. Given that health communications played a key role in managing the pandemic, this study clarifies the social cognitive determinants of staying at home and how the local political culture can impact their influence. Thus, we provide an evidence-based prescription for focused communications.

Discovery of a Tricyclic ß-Lactam as a Potent Antimicrobial Agent against Carbapenem-Resistant Enterobacterales, Including Strains with Reduced Membrane Permeability and Four-Amino Acid Insertion into Penicillin-Binding Protein 3: Structure-Activity-Relationships and In Vitro and In Vivo Activities.

The current worldwide emergence of carbapenem-resistant enterobacterales (CREs) constitutes an important growing clinical and public health threat. Acquired carbapenemases are the most important determinants of resistance to carbapenems. In the development of the previously reported tricyclic ß-lactam skeleton which exhibits potent antibacterial activities against several problematic ß-lactamase-producing CREs without a ß-lactamase inhibitor, we found that these activities were reduced against clinical isolates with resistance mechanisms other than ß-lactamase production. These mechanisms were the reduction of outer membrane permeability with the production of ß-lactamases and the insertion of four amino acids into penicillin-binding protein 3. Here, we report the discovery of a potent compound that overcomes these resistance mechanisms by the conversion of the alkoxyimino moiety of the aminothiazole side chain in which a hydrophilic functional group is introduced and the carboxylic acid of the alkoxyimino moiety is converted to reduce the negative charge of the whole molecule from 2 to 1. This potent tricyclic ß-lactam is a promising drug candidate for infectious diseases caused by CREs due to its potent therapeutic efficacy in the neutropenic mouse lung infection model and low frequency of producing spontaneously resistant mutants.

Model equations of light scattering properties and a characteristic time of light propagation for polydisperse colloidal suspensions at different volume fractions.

We developed model equations of light scattering properties and a characteristic time of light propagation for polydisperse colloidal suspensions at different volume fractions. By the model equations, we examined numerical results using the first-order (dependent) scattering theory (FST) and radiative transfer theory in 600-980 nm wavelength. The model equations efficiently treat the interference of electric fields scattered from colloidal particles by a single effective coefficient, providing fast computation. Meanwhile, the FST provides accurate but complicated treatment. We found the interference effects on the scattering properties and characteristic time depend linearly on wavelength. Dimensionless analysis showed a simple mechanism of the interference effects, independently of wavelength and source-detector distance.

A novel tricyclic ß-lactam exhibiting potent antibacterial activities against carbapenem-resistant Enterobacterales: Synthesis and structure-activity-relationships.

A series of tricyclic ß-lactams were synthesized and evaluated for in vitro antibacterial activities against carbapenem-resistant Enterobacterales (CREs). Starting from a reported tricyclic ß-lactam that combined the cephalosporin skeleton having a γ-lactone ring with a carboxylic acid group, which was reported as a unique partial structure of Lactivicin, we identified the compound which shows potent antibacterial activities against all tested CREs by introducing sulfoxide. In addition, the sulfoxide-introduced tricyclic ß-lactam also shows a strong therapeutic efficacy in the neutropenic mouse lung infection model. These results indicate that the tricyclic ß-lactam skeleton will show sufficient therapeutic performance in clinical use and therefore can serve as a scaffold in the search for new antibacterial agents against CREs.

Discovery of 2-Sulfinyl-Diazabicyclooctane Derivatives, Potential Oral ß-Lactamase Inhibitors for Infections Caused by Serine ß-Lactamase-Producing Enterobacterales.

Coadministration of ß-lactam and ß-lactamase inhibitor (BLI) is one of the well-established therapeutic measures for bacterial infections caused by ß-lactam-resistant Gram-negative bacteria, whereas we have only two options for orally active BLI, clavulanic acid and sulbactam. Furthermore, these BLIs are losing their clinical usefulness because of the spread of new ß-lactamases, including extended-spectrum ß-lactamases (ESBLs) belonging to class A ß-lactamases, class C and D ß-lactamases, and carbapenemases, which are hardly or not inhibited by these classical BLIs. From the viewpoints of medical cost and burden of healthcare personnel, oral therapy offers many advantages. In our search for novel diazabicyclooctane (DBO) BLIs possessing a thio-functional group at the C2 position, we discovered a 2-sulfinyl-DBO derivative (2), which restores the antibacterial activities of an orally available third-generation cephalosporin, ceftibuten (CTB), against various serine ß-lactamase-producing strains including carbapenem-resistant Enterobacteriaceae (CRE). It can be orally absorbed via the ester prodrug modification and exhibits in vivo efficacy in a combination with CTB.

Introduction of a Thio Functional Group to Diazabicyclooctane: An Effective Modification to Potentiate the Activity of ß-Lactams against Gram-Negative Bacteria Producing Class A, C, and D Serine ß-Lactamases.

By the emergence and worldwide spread of multi-drug-resistant Gram-negative bacteria, there have been growing demands for efficacious drugs to cure these resistant infections. The key mechanism for resistance to ß-lactam antibiotics is the production of ß-lactamases, which hydrolyze and deactivate ß-lactams. Diazabicyclooctane (DBO) analogs play an important role as one of the new classes of ß-lactamase inhibitors (BLIs), and several compounds such as avibactam (AVI) have been approved by the FDA, along with many derivatives under clinical or preclinical development. Although these compounds have a similar amide substituent at the C2 position, we have recently reported the synthesis of novel DBO analogs which possess a thio functional group. This structural modification enhances the ability to restore the antimicrobial activities of cefixime (CMF) against pathogens producing classes A, C, and D serine ß-lactamases compared with AVI and expands the structural tolerance at the six position. Furthermore, some of these analogs showed intrinsic microbial activities based on multipenicillin binding protein (PBP) inhibition. This is the unique feature which has never been observed in DBOs. One of our DBOs had a pharmacokinetic profile comparable to that of other DBOs. These results indicate that the introduction of a thio functional group into DBO is a novel and effective modification to discover a clinically useful new BLI.

Synthesis of 2-Thio-Substituted 1,6-Diazabicyclo[3.2.1]octane Derivatives, Potent ß-Lactamase Inhibitors.

Approval of avibactam by the FDA has led to the recognition of 1,6-diazabicyclo[3.2.1]octane (DBO) derivatives as attractive compounds for ß-lactamase inhibition. We achieved a concise and collective synthesis of 2-thio-substituted DBO derivatives. The synthesis involves diastereoselective photo-induced Barton decarboxylative thiolation, which can be applied to large-scale synthesis. The DBO analogues exhibited strong inhibitory activities against serine ß-lactamases and acceptable solution stabilities for clinical development.

Cefiderocol (S-649266), A new siderophore cephalosporin exhibiting potent activities against Pseudomonas aeruginosa and other gram-negative pathogens including multi-drug resistant bacteria: Structure activity relationship.

The structure-activity relationship (SAR) for a novel series of catechol conjugated siderophore cephalosporins is described with their in vitro activities against multi-drug resistant Gram-negative pathogens including Pseudomonas aeruginosa, Acinetobacter baumannii, Stenotrophomonas maltophilia and Enterobacteriaceae. Cefiderocol (3) was one of the best molecules which displayed well-balanced and potent activities against multi-drug resistant Gram-negative pathogens including carbapenem resistant bacteria among the prepared compounds with the modified C-7 side chain and the modified C-3 side chain. Cefiderocol (3) is a highly promising parenteral cephalosporin for the treatment of multi-drug resistant Gram-negative infection.

Analgesic effects of novel lysophosphatidic acid receptor 5 antagonist AS2717638 in rodents.

Lysophosphatidic acid (LPA) is a bioactive lipid that acts via at least six G protein-coupled receptors, LPA receptors 1-6 (LPA1-6), for various physiological functions. We examined (1) whether LPA5 is involved in pain signaling in the spinal cord; and (2) the pharmacological effects of a novel LPA5 antagonist on intrathecal prostaglandin (PG)- and (S)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-induced allodynia, and neuropathic and inflammatory pain in rodents. Intrathecal injection of a selective LPA5 agonist, geranylgeranyl diphosphate, and a non-selective agonist, LPA, induced allodynia in wild type, but not in LPA5 knockout mice. These novel results suggest that LPA5 is important for pain signal transmission in the spinal cord. AS2717638 (6,7-dimethoxy-2-(5-methyl-1,2-benzoxazol-3-yl)-4-(piperidin-1-ylcarbonyl)isoquinolin-1(2H)-one) bound to the LPA-binding site on LPA5 and selectively inhibited LPA-induced cyclic adenosine monophosphate accumulation in human LPA5-but not LPA1-, 2-, or 3-expressing cells. Further, oral administration of AS2717638 inhibited LPA5 agonist-induced allodynia in mice. AS2717638 also significantly improved PGE2-, PGF2α-, and AMPA-induced allodynia, while both pregabalin and duloxetine alleviated only PGE2-induced allodynia in mice. Similarly, AS2717638 significantly ameliorated static mechanical allodynia and thermal hyperalgesia in rat models of chronic constriction injury (CCI)-induced neuropathic pain. AS2717638 also showed analgesic effects in a rat model of inflammatory pain. These findings suggest that LPA5 antagonists elicit broad analgesic effects against both neuropathic and inflammatory pain. Accordingly, pharmacological LPA5 antagonists are attractive development candidates for potential novel pain therapies.

AS1069562, the (+)-isomer of indeloxazine, exerts analgesic effects in rat models of nociceptive pain.

OBJECTIVES: The (+)-isomer of indeloxazine AS1069562 has multiple pharmacological actions, such as serotonin (5-HIT) and norepinephrine (NE) reuptake inhibition and analgesic effects in animal models of neuropathic pain. Here, we investigated the analgesic effects of AS1069562 in rat models of inflammatory and noninflammatory nociceptive pain. METHODS: Adjuvant-induced arthritis (AIA) and bradykinin-induced knee joint pain were used as rat models of inflammatory pain. The chronic phase of monoiodoacetate-induced arthritis (MIA) was used as a rat model of noninflammatory pain. Analgesic effects were evaluated by weight-bearing deficit in the AIA and MIA models and by pain response in the bradykinin-induced knee joint pain model. RESULTS: In the AIA model and the bradykinin-induced knee joint pain model, AS1069562 significantly ameliorated the pain-related behavior of weight-bearing deficit and the pain response, respectively. AS1069562 also significantly improved the pain-related behavior of weight-bearing deficit in the chronic phase of the MIA model. Further, following monoiodoacetate injection, repeated administration of AS1069562 or duloxetine significantly improved weight-bearing deficit in the MIA model. Interestingly, the analgesic effect of AS1069562 was sustained for 24 hours after the last administration, although the plasma concentration of AS1069562 was reduced to undetectable levels. In contrast, the analgesic effect of duloxetine did not continue after treatment discontinuation. DISCUSSION: AS1069562 exerts analgesic effects on inflammatory and noninflammatory nociceptive pain in rat models of arthritis pain, and repeated administration of AS1069562 exerts a more persistent analgesic effect on arthritis pain than duloxetine. These findings suggest that AS1069562 has an attractive analgesic profile for the treatment of nociceptive pain.

Antinociceptive effects of AS1069562, the (+)-isomer of indeloxazine, on spinal hypersensitivity induced by intrathecal injection of prostaglandin in mice: comparison with duloxetine and amitriptyline.

The (+)-isomer of indeloxazine AS1069562 exerts multiple pharmacological actions including the inhibition of serotonin (5-HT) and norepinephrine reuptake and analgesia in experimental animal pain models. Here, we evaluated the antinociceptive effects of AS1069562 and the antidepressants duloxetine and amitriptyline in mouse models of prostaglandin-induced spinal hypersensitivity. Prostaglandin E2 (PGE2) and F2α (PGF2α) were intrathecally administered to induce spinal hypersensitivity, causing tactile allodynia in mice. Allodynia induced by PGF2α but not by PGE2 was suppressed by desensitization of C-fibers with systemic pretreatment with resiniferatoxin. C-fiber hyperexcitability might therefore play a role in allodynia induced by PGF2α but not PGE2. In the PGE2-induced allodynia model, AS1069562 and duloxetine significantly suppressed allodynia, whereas amitriptyline did not. In the PGF2α-induced allodynia model, AS1069562 and amitriptyline significantly ameliorated allodynia, whereas duloxetine did not. To demonstrate the broad effects of AS1069562 compared to duloxetine, additional studies were conducted to elucidate other target mechanisms of AS1069562 beyond 5-HT and norepinephrine reuptake inhibition. AS1069562 exhibited affinity for both 5-HT1A and 5-HT3 receptors, and the analgesic effect of AS1069562 on PGF2α-induced allodynia was significantly blocked by the 5-HT1A receptor antagonist (S)-WAY100135 and the 5-HT3 receptor agonist SR57227. Taken together, these results indicate that AS1069562 inhibits both C-fiber- and non-C-fiber-dependent prostaglandin-induced allodynia, while duloxetine inhibits only non-C-fiber-triggered allodynia, and amitriptyline inhibits only C-fiber-triggered allodynia. These broad antinociceptive effects of AS1069562 may be due not only to 5-HT and norepinephrine reuptake inhibition but also to its effects on 5-HT receptors such as 5-HT1A and 5-HT3 receptors.

AS1069562, the (+)-isomer of indeloxazine, exerts analgesic effects in a rat model of neuropathic pain with unique characteristics in spinal monoamine turnover.

AS1069562 [(R)-2-[(1H-inden-7-yloxy)methyl]morpholine monobenzenesulfonate] is the (+)-isomer of indeloxazine, which had been used clinically for the treatment of cerebrovascular diseases with multiple pharmacological actions, including serotonin (5-HT) and norepinephrine (NE) reuptake inhibition. Here we investigated the analgesic effects of AS1069562 in a rat model of chronic constriction injury (CCI)-induced neuropathic pain and the spinal monoamine turnover. These effects were compared with those of the antidepressants duloxetine and amitriptyline. AS1069562 significantly elevated extracellular 5-HT and NE levels in the rat spinal dorsal horn, although its 5-HT and NE reuptake inhibition was much weaker than that of duloxetine in vitro. In addition, AS1069562 increased the ratio of the contents of both 5-HT and NE to their metabolites in rat spinal cord, whereas duloxetine slightly increased only the ratio of the content of 5-HT to its metabolite. In CCI rats, AS1069562 and duloxetine significantly ameliorated mechanical allodynia, whereas amitriptyline did not. AS1069562 and amitriptyline significantly ameliorated thermal hyperalgesia, and duloxetine tended to ameliorate it. Furthermore, AS1069562, duloxetine, and amitriptyline significantly improved spontaneous pain-associated behavior. In a gastric emptying study, AS1069562 affected gastric emptying at the same dose that exerted analgesia in CCI rats. On the other hand, duloxetine and amitriptyline significantly reduced gastric emptying at lower doses than those that exerted analgesic effects. These results indicate that AS1069562 broadly improved various types of neuropathic pain-related behavior in CCI rats with unique characteristics in spinal monoamine turnover, suggesting that AS1069562 may have potential as a treatment option for patients with neuropathic pain, with a different profile from currently available antidepressants.

AS1069562, the (+)-isomer of indeloxazine, but not duloxetine has a curative-like analgesic effect in a rat model of streptozotocin-induced diabetic neuropathy.

AS1069562 is the (+)-isomer of indeloxazine, which had been clinically used as a cerebral activator for the treatment of cerebrovascular diseases with serotonin and norepinephrine reuptake inhibition (SNRI) and neuroprotection. Here, we compared the analgesic effects of repeated treatment with AS1069562 and duloxetine, a selective SNRI, on pain-related behavior in a rat model of streptozotocin (STZ)-induced diabetic neuropathy. Further, we also evaluated the effects on the expression of neurotrophic factors and nerve conduction velocity. AS1069562 and duloxetine by single daily administration for 4 weeks significantly improved mechanical allodynia in STZ-induced diabetic rats and did not affect plasma glucose level or body weight. Interestingly, the analgesic effect of AS1069562 continued after a consecutive 1-week treatment discontinuation, although the plasma concentration of AS1069562 was reduced to undetectable levels. In contrast, the efficacy of duloxetine disappeared after treatment discontinuation. Expression analysis demonstrated that AS1069562 significantly restored decreased insulin-like growth factor 1 and fibroblast growth factor 2 mRNA levels in dorsal root ganglion and spinal cord, respectively, whereas duloxetine did not affect the expression levels of neurotrophic factors. In addition, AS1069562 reversed the slowing of nerve conduction velocity. The results of this study indicate that the analgesic effect of repeated dosing of AS1069562 but not duloxetine is persistent even after a 1-week drug discontinuation in STZ-induced diabetic rats. Restoration of neurotrophic factors may be involved in the curative-like pharmacological effect of this agent. Thus, AS1069562 may potentially offer a better treatment option for patients with painful diabetic neuropathy than duloxetine via different mechanisms.

New index of pain triggered by spinal activation of voltage-dependent sodium channels.

Voltage-dependent sodium channels (VDSCs) are crucial for pain generation. Here, to develop a new behavioral index of pain induced by spinal VDSC activation, we examined whether intrathecal veratridine injection produced nociceptive behavior. Intrathecal injection of the VDSC opener veratridine in mice dose-dependently induced nociceptive responses, with response times subsequently reduced by administration of morphine or pregabalin. Systemic administration of lidocaine and mexiletine, but not amitriptyline, also decreased this response time. Taken together, these results demonstrated that response time of nociceptive behavior induced by intrathecal veratridine injection is a quantitative index of pain triggered by spinal VDSC activation.

Potent oxazolidinone antibacterials with heteroaromatic C-ring substructure.

Novel oxazolidinone analogues bearing a condensed heteroaromatic ring as the C-ring substructure were synthesized as candidate antibacterial agents. Analogues 16 and 21 bearing imidazo[1,2-a]pyridine and 18 and 23 bearing [1,2,4]triazolo[1,5-a]pyridine as the C-ring had excellent in vitro antibacterial activities against methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus faecalis (VRE), and penicillin-resistant Streptococcus pneumoniae (PRSP). They also showed promising therapeutic effects in a mouse model of lethal infection. Preliminary safety data (inhibitory effects on cytochrome P450 isoforms and monoamine oxidases) were satisfactory. Further evaluation of 18 and 23 is ongoing.

[A case of UFT-induced complete response against multiple lung metastases of hepatocarcinoma].

There are still no effective treatments against advanced hepatocarcinoma. One case of advanced hepatocarcinoma with multiple lung metastases, successfully treated with UFT, is reported here. After TAE in another hospital, the patient was refered to our hospital for treatment of multiple lung metastases. PIVKA-II and AFP decreased to normal levels after UFT was administered, and the multiple lung metastases disappeared as well. There are 13 cases including this one in which UFT was effective for hepatocarcinoma with multiple lung metastases. UFT is a possible home treatment because it is an orally administered anti-cancer drug that improves the patient's QOL. As UFT is one of the effective treatments for advanced hepatocarcinoma, it will be necessary to accumulate more data concerning its use, to apply it in the future.