Intermuscular Coherence during Quiet Standing in Sub-Acute Patients after Stroke: An Exploratory Study.

Asymmetrically impaired standing control is a prevalent disability among stroke patients; however, most of the neuromuscular characteristics are unclear. Therefore, the main purpose of this study was to investigate between-limb differences in intermuscular coherence during quiet standing. Consequently, 15 patients who had sub-acute stroke performed a quiet standing task without assistive devices, and electromyography was measured on the bilateral tibialis anterior (TA), soleus (SL), and medial gastrocnemius (MG). The intermuscular coherence of the unilateral synergistic (SL-MG) pair and unilateral antagonist (TA-SL and TA-MG) pairs in the delta (0-5 Hz) and beta (15-35 Hz) bands were calculated and compared between the paretic and non-paretic limbs. The unilateral synergistic SL-MG coherence in the beta band was significantly greater in the non-paretic limb than in the paretic limb (p = 0.017), while unilateral antagonist TA-MG coherence in the delta band was significantly greater in the paretic limb than in the non-paretic limb (p < 0.01). During quiet standing, stroke patients showed asymmetry in the cortical control of the plantar flexor muscles, and synchronous control between the antagonistic muscles was characteristic of the paretic limb. This study identified abnormal muscle activity patterns and asymmetrical cortical control underlying impaired standing balance in patients with sub-acute stroke using an intermuscular coherence analysis.

Diagonal-couplet gaits on discontinuous supports in Japanese macaques and implications for the adaptive significance of the diagonal-sequence, diagonal-couplet gait of primates.

OBJECTIVES: Diagonal-sequence, diagonal-couplet (DSDC) gaits have been proposed as an adaptation to travel on discontinuously arranged arboreal branches. Only a few studies have examined primate gait adjustment to support discontinuity. We analyzed the gaits of Japanese macaques walking on the "ground" and two discontinuous conditions, "circle" and "point," to better understand the advantages of DSDC gaits on discontinuous supports. MATERIALS AND METHODS: Seventy-eight vertical posts, each with a circular upper surface, were arranged in four rows at a spacing of 200 mm. The diameter of the circular upper surface was 150 mm ("circle condition") or 50 mm ("point condition"). We calculated the limb phase, duty factor, and time interval from hindlimb touchdown to ipsilateral forelimb liftoff. The supports the fore- and hindlimbs landed on during walking were identified in the circle and point condition. RESULTS: The macaques predominantly used DSDC gaits in the ground and circle conditions and lateral-sequence, diagonal-couplet (LSDC) gaits in the point condition. The macaques usually placed their hindlimbs on the same supports as their ipsilateral forelimbs during the gait cycle. DISCUSSION: Japanese macaques overlapped the ipsilateral fore- and hindlimb stance phase in all DSDC and some LSDC gaits to proximate the ipsilateral limbs on the discontinuous support, allowing the forelimb to guide the hindlimb placement to the support. The overlap duration of the ipsilateral limb stance phases may be extended by DSDC gaits longer than by LSDC gaits, allowing for a direct pass of the support being held by the prehensile hand to the prehensile foot.

Effects of orthoses on muscle activity and synergy during gait.

An orthosis is often used in rehabilitation to improve kinetic and kinematic parameters during gait. However, whether changes in neural control depend on wearing an orthosis during gait is unclear. We measured the muscle activity and synergy of the lower limb muscles without orthosis and with two types of orthoses: ankle-foot orthosis (AFO) and knee-ankle-foot orthosis (KAFO). Muscle activity during gait was measured in 15 healthy adults, and muscle synergies were extracted using non-negative matrix factorization. The results revealed that some muscle activities were significantly different among the three conditions. Post-hoc analysis indicated differences between each condition. Knee extensor muscle activity related to the loading response was significantly increased by wearing the AFO. In the KAFO condition, hip abductor muscle activity related to weight bearing was significantly decreased, and ankle dorsiflexor muscle activity was increased to secure clearance during the swing phase. However, the number of muscle synergies and complexity of muscle synergy did not significantly change among these conditions. However, along with changes in muscle activity, the activation pattern and weightings of muscle synergies tended to change with the use of orthoses. Each muscle activity was changed by wearing the orthosis; however, the immediate mechanical constraint did not change the framework of muscle synergy.

Identification of osteoporosis using ensemble deep learning model with panoramic radiographs and clinical covariates.

Osteoporosis is becoming a global health issue due to increased life expectancy. However, it is difficult to detect in its early stages owing to a lack of discernible symptoms. Hence, screening for osteoporosis with widely used dental panoramic radiographs would be very cost-effective and useful. In this study, we investigate the use of deep learning to classify osteoporosis from dental panoramic radiographs. In addition, the effect of adding clinical covariate data to the radiographic images on the identification performance was assessed. For objective labeling, a dataset containing 778 images was collected from patients who underwent both skeletal-bone-mineral density measurement and dental panoramic radiography at a single general hospital between 2014 and 2020. Osteoporosis was assessed from the dental panoramic radiographs using convolutional neural network (CNN) models, including EfficientNet-b0, -b3, and -b7 and ResNet-18, -50, and -152. An ensemble model was also constructed with clinical covariates added to each CNN. The ensemble model exhibited improved performance on all metrics for all CNNs, especially accuracy and AUC. The results show that deep learning using CNN can accurately classify osteoporosis from dental panoramic radiographs. Furthermore, it was shown that the accuracy can be improved using an ensemble model with patient covariates.

Hip medial rotator action of gluteus medius in Japanese macaque (Macaca fuscata) and implications to adaptive significance for quadrupedal walking in primates.

The gluteus medius (GM) muscle in quadrupedal primates has long been thought to mainly act as a hip extensor. However, previous reports argue that it may be a prime hip medial rotator and functions to rotate the pelvis in the horizontal plane, suggesting the functional differentiation between the GM and other hip extensors as hamstrings. In this study, we aim to quantify the muscle actions of the GM and hamstrings using muscle moment arm lengths and discuss the functional differentiation among hip extensors. Muscle attachment sites of eight specimens of Japanese macaque (Macaca fuscata) were digitized, and musculoskeletal models were constructed. Flexor-extensor, abductor-adductor, and medial-lateral rotator moment arms were calculated as the models were moved following the experimentally acquired kinematic data during walking on a pole substrate. Using electromyography, we also recorded the pattern of muscle activation. The GM showed a larger medial rotator moment arm length than the extensor moment arm length when it was activated, suggesting this muscle acts mainly as a hip medial rotator rather than as a hip extensor. The medial rotator action of the GM in the early support phase may rotate the pelvis in the horizontal plane and function to help contralateral forelimb reaching as a previous study suggested and facilitate contralateral hindlimb swinging to place the foot near the ipsilateral forelimb's hand.

Efficacy and safety of fixed doses of intranasal Esketamine as an add-on therapy to Oral antidepressants in Japanese patients with treatment-resistant depression: a phase 2b randomized clinical study.

BACKGROUND: Esketamine nasal spray (Spravato) in conjunction with oral antidepressants (ADs) is approved in the European Union, United States, and other markets for treatment-resistant depression (TRD). Efficacy, safety, and tolerability of esketamine nasal spray in Japanese patients with TRD needs to be assessed. METHODS: This Phase 2b, randomized, double-blind (DB), placebo-controlled study was conducted in adult Japanese patients with TRD meeting the Diagnostic and Statistical Manual of Mental Disorders (fifth edition) criteria of major depressive disorder with nonresponse to ≥ 1 but < 5 different ADs in the current episode at screening. Patients were treated with a new oral AD for 6 weeks (prospective lead-in phase); nonresponders were randomized (2:1:1:1) to placebo or esketamine (28-, 56-, or 84-mg) nasal spray along with the continued use of AD for 4 weeks (DB induction phase). Responders (≥50% reduction from baseline in the Montgomery-Asberg Depression Rating Scale [MADRS] total score) from the DB induction phase continued into the 24-week posttreatment phase and patients who relapsed could participate in a 4-week open-label (OL) second induction (flexibly-dosed esketamine). The primary efficacy endpoint, change from baseline in the MADRS total score at Day 28 in the DB induction phase, was based on mixed-effects model using repeated measures pairwise comparisons using a Dunnett adjustment. RESULTS: Of the 202 patients randomized in the DB induction phase (esketamine [n = 122] or placebo [n = 80]), the MADRS total scores decreased from baseline to Day 28 of the DB induction phase (- 15.2, - 14.5, - 15.1, and - 15.3 for esketamine 28 mg, 56 mg, 84 mg, and placebo groups, respectively), indicating an improvement in depressive symptoms; however, the difference between the esketamine and placebo groups was not statistically significant. The most common treatment-emergent adverse events during the DB induction phase in the combined esketamine group (incidences ranging from 12.3 to 41.0%) were blood pressure increased, dissociation, dizziness, somnolence, nausea, hypoaesthesia, vertigo, and headache; the incidence of each of these events was > 2-fold higher than the corresponding incidence in the placebo group. CONCLUSIONS: Efficacy of esketamine plus oral AD in Japanese TRD patients was not established; further investigation is warranted. All esketamine doses were safe and tolerated. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02918318 . Registered: 28 September 2016.

Artificial intelligence improves the accuracy of residents in the diagnosis of hip fractures: a multicenter study.

BACKGROUND: Less experienced clinicians sometimes make misdiagnosis of hip fractures. We developed computer-aided diagnosis (CAD) system for hip fractures on plain X-rays using a deep learning model trained on a large dataset. In this study, we examined whether the accuracy of the diagnosis of hip fracture of the residents could be improved by using this system. METHODS: A deep convolutional neural network approach was used for machine learning. Pytorch 1.3 and Fast.ai 1.0 were applied as frameworks, and an EfficientNet-B4 model (a pre-trained ImageNet model) was used. We handled the 5295 X-rays from the patients with femoral neck fracture or femoral trochanteric fracture from 2009 to 2019. We excluded cases in which the bilateral hips were not included within an image range, and cases of femoral shaft fracture and periprosthetic fracture. Finally, we included 5242 AP pelvic X-rays from 4851 cases. We divided these 5242 images into two images per image, and prepared 5242 images including fracture site and 5242 images without fracture site. Thus, a total of 10,484 images were used for machine learning. The accuracy, sensitivity, specificity, F-value, and area under the curve (AUC) were assessed. Gradient-weighted class activation mapping (Grad-CAM) was used to conceptualize the basis for the diagnosis of the fracture by the deep learning algorithm. Secondly, we conducted a controlled experiment with clinicians. Thirty-one residents;young doctors within 2 years of graduation from medical school who rotate through various specialties, were tested using 300 hip fracture images that were randomly extracted from the dataset. We evaluated the diagnostic accuracy with and without the use of the CAD system for each of the 300 images. RESULTS: The accuracy, sensitivity, specificity, F-value, and AUC were 96.1, 95.2, 96.9%, 0.961, and 0.99, respectively, with the correct diagnostic basis generated by Grad-CAM. In the controlled experiment, the diagnostic accuracy of the residents significantly improved when they used the CAD system. CONCLUSIONS: We developed a newly CAD system with a deep learning algorithm from a relatively large dataset from multiple institutions. Our system achieved high diagnostic performance. Our system improved the diagnostic accuracy of residents for hip fractures. LEVEL OF EVIDENCE: Level III, Foundational evidence, before-after study. CLINICAL RELEVANCE: high.

Recent structural insights into the mechanism of lysozyme hydrolysis.

Lysozyme hydrolyzes the glycosidic bonds between N-acetylmuramic acid and N-acetylglucosamine in peptidoglycans located in the bacterial cell wall. The mechanism of the hydrolysis reaction of lysozyme was first studied more than 50 years ago; however, it has not yet been fully elucidated and various mechanisms are still being investigated. One reaction system that has commonly been proposed is that the lysozyme intermediate undergoes covalent ligand binding during hydrolysis. However, these findings resulted from experiments performed under laboratory conditions using fluorine-based ligands, which facilitate the formation of covalent bonds between the ligands and the catalytic side chain of lysozyme. More recently, high-resolution X-ray structural analysis was used to study the complex of lysozyme with an N-acetylglucosamine tetramer. As a result, the carboxyl group of Asp52 was found to form a relatively strong hydrogen-bond network and had difficulty binding covalently to C1 of the carbohydrate ring. To confirm this hydrogen-bond network, neutron test measurements were successfully performed to a resolution of better than 1.9 Å.

A comparison of axial trunk rotation during bipedal walking between humans and Japanese macaques.

OBJECTIVES: Human walking involves out-of-phase axial rotations of the thorax and pelvis. It has long been believed that this rotational capability is a distinctive feature of the genus Homo. However, Thompson et al. (2015) showed that chimpanzees also counter-rotate their thorax relative to the pelvis during bipedal walking, which raised questions regarding the origins and development of this characteristic. In this study, we measured the axial rotation of the trunk during bipedal walking in humans and macaques to investigate if intra-trunk axial rotations are observed in non-hominoid primate species. MATERIALS AND METHODS: We collected three-dimensional trunk kinematic data during bipedal walking in six humans and five Japanese macaques. The human subjects walked on a treadmill, and the animal subjects walked on a 5-m runway. During walking, the positions of cluster markers, which defined trunk segments, were recorded by multiple video cameras. Segmental xyz coordinates were digitized, and transverse rotations were calculated using motion analysis software. RESULTS: Although trunk rotations in the global coordinate system were greater in macaques than in humans, the intra-trunk rotation and range of motion showed a similar pattern in the two species. CONCLUSIONS: Thoracic rotation relative to the pelvis during bipedal walking is not unique to the hominid lineage but rather a characteristic generated by the mechanical requirements of bipedal walking. The fact that the range of motion of counter rotation is similar in these species infers that an optimal range of rotation exists for bipedal walking.

Deep Learning for Osteoporosis Classification Using Hip Radiographs and Patient Clinical Covariates.

This study considers the use of deep learning to diagnose osteoporosis from hip radiographs, and whether adding clinical data improves diagnostic performance over the image mode alone. For objective labeling, we collected a dataset containing 1131 images from patients who underwent both skeletal bone mineral density measurement and hip radiography at a single general hospital between 2014 and 2019. Osteoporosis was assessed from the hip radiographs using five convolutional neural network (CNN) models. We also investigated ensemble models with clinical covariates added to each CNN. The accuracy, precision, recall, specificity, negative predictive value (npv), F1 score, and area under the curve (AUC) score were calculated for each network. In the evaluation of the five CNN models using only hip radiographs, GoogleNet and EfficientNet b3 exhibited the best accuracy, precision, and specificity. Among the five ensemble models, EfficientNet b3 exhibited the best accuracy, recall, npv, F1 score, and AUC score when patient variables were included. The CNN models diagnosed osteoporosis from hip radiographs with high accuracy, and their performance improved further with the addition of clinical covariates from patient records.

Influences of passive intervertebral range of motion on cervical vertebral form.

OBJECTIVES: The cervical spine is the junction between the head and trunk, and it therefore facilitates head mobility and stability. The goal of this study is to test several predictions regarding cervical morphology and intervertebral ranges of motion. MATERIALS AND METHODS: Intervertebral ranges of motion for 12 primate species were collected via radiographs or taken from the literature. Morphometric data describing functionally relevant aspects of cervical vertebral morphology were obtained from museum specimens representing these species. We tested for correlations between intervertebral movement and vertebral form using phylogenetic generalized least-squares regression. RESULTS: Results demonstrate limited support for the hypothesis that range of motion (ROM) is influenced by cervical vertebral morphology. Few morphological variables correlate with ROM and no relationship is consistently significant across cervical joints. DISCUSSION: These results indicate that the relationship between vertebral morphology and joint ranges of motion is, at most, weak, providing little support the use of bony morphology to reconstruct axial mobility in fossil specimens. Future work should investigate the role of soft tissues in vertebral joint stability.

Resveratrol suppresses nociceptive jaw-opening reflex via 5HT3 receptor-mediated GABAergic inhibition　.

Systemic administration of the dietary constituent, resveratrol, was previously shown to inhibit the nociceptive jaw-opening reflex (JOR) via the endogenous opioid system. The present study investigated whether resveratrol could similarly affect the JOR under in vivo conditions via 5HT3 receptor-mediated GABAergic inhibition. We used electrical stimulation of the tongue in pentobarbital-anesthetized rats to evoke the JOR, which was recorded as the anterior belly of the digastric muscle electromyograms (dEMG). Intravenous administration of resveratrol (2 mg/kg) reduced the dEMG amplitude in response to three times the determined threshold electrical stimulation, with maximum inhibition reached within approximately 10 min. These inhibitory effects on the JOR were reversible to control levels after approximately 20 min. Pretreatment of rats with either 5HT3 receptor antagonist, ondansetron (0.25-1 mg/kg, i.p.), or GABAA receptor antagonist, bicuculline (0.5-1 mg/kg, i.p.), significantly and dose-dependently attenuated the inhibitory effects of resveratrol on dEMG amplitude compared with untreated controls. These findings suggest that resveratrol also attenuates the nociceptive JOR via 5HT3 receptor-mediated GABAergic inhibition. The present study therefore provides new insight into a possible mechanism underlying resveratrol-induced trigeminal antinociception via the descending pain control system and highlights a potential therapeutic agent for complementary alternative medicine.

Efficacy and Safety of Guselkumab in Japanese Patients With Palmoplantar Pustulosis: A Phase 3 Randomized Clinical Trial.

IMPORTANCE: Palmoplantar pustulosis (PPP) causes erythematous, scaly plaques with recurrent sterile pustules refractory to treatment and with few randomized clinical trials conducted. Evidence points to involvement of interleukin 23 in the pathogenesis of PPP. OBJECTIVE: To determine the efficacy and safety of guselkumab, an anti-IL-23 monoclonal antibody, in Japanese patients with PPP. DESIGN, SETTING, AND PARTICIPANTS: A phase 3 randomized clinical trial was conducted from December 15, 2015, to December 12, 2017. A total of 159 enrolled patients (aged ≥20 years) had an inadequate response to conventional therapies, with a diagnosis of PPP for 24 or more weeks before screening. Intention-to-treat analysis was performed. INTERVENTIONS: Subcutaneous injections of guselkumab, 100 or 200 mg, at weeks 0, 4, and 12, and every 8 weeks thereafter were administered; placebo was given at weeks 0, 4, and 12. MAIN OUTCOMES AND MEASURES: Changes from baseline in PPP Area and Severity Index (PPPASI) score (possible score range, 0-72, with higher scores indicating greater area and severity), PPP severity index (PPSI) score (possible score range, 0-12, with higher scores indicating greater severity), and proportion of PPPASI-50 (≥50% reduction) responders at weeks 16 and 52 were assessed. Safety was monitored through week 52. RESULTS: A total of 159 patients (mean [SD] age at diagnosis, 46.8 [11.9] years; 126 women [79.2%]) were enrolled. Treatment groups comprised guselkumab, 100 mg (n = 54), guselkumab, 200 mg (n = 52), or placebo (n = 53). Both guselkumab groups demonstrated significant improvement in least-squares mean changes in PPPASI score compared with placebo: -15.3 and -11.7 in the guselkumab 100-mg and 200-mg groups, respectively, and -7.6 in the placebo group (difference [SE] vs placebo: -7.7 [1.7] in the 100-mg group, P < .001; 95% CI, -11.00 to -4.38; and -4.1 [1.7] in the 200-mg group, P < .017; 95% CI, -7.47 to -0.75]). Least-squares mean changes in PPSI score showed significant improvement in both guselkumab groups (100 mg: -2.0 [0.5]; P < .001; 95% CI, -2.96 to -0.95; 200 mg: -1.0 [0.5; P = .04; 95% CI, -2.06 to -0.03). A significantly higher proportion of patients in the guselkumab 100-mg group (31 [57.4%]) achieved a PPPASI-50 response at week 16 vs placebo (18 [34.0%]; P = .02); however, the result was not significant for the guselkumab 200-mg group (19 [36.5%]) vs placebo; P = .78). Each efficacy end point improved consistently through week 52. Health-related quality of life improved significantly as indicated by a reduction in the Dermatology Life Quality Index score (100 mg: -2.6; 95% CI, -4.0 to -1.2; P < .001; 200 mg: -1.6; 95% CI, -3.1 to -0.2; P = .03). Serious treatment-emergent adverse events were observed in 8 patients (placebo group, 2 of 53 [3.8%]; combined guselkumab group, 6/157≠10.5%). No serious infections were reported. CONCLUSIONS AND RELEVANCE: Targeting interleukin 23 with guselkumab may be an effective and safe treatment option for a recalcitrant disease such as PPP. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02641730.

Tat-exported peptidoglycan amidase-dependent cell division contributes to Salmonella Typhimurium fitness in the inflamed gut.

Salmonella enterica serovar Typhimurium (S. Tm) is a cause of food poisoning accompanied with gut inflammation. Although mucosal inflammation is generally thought to be protective against bacterial infection, S. Tm exploits the inflammation to compete with commensal microbiota, thereby growing up to high densities in the gut lumen and colonizing the gut continuously at high levels. However, the molecular mechanisms underlying the beneficial effect of gut inflammation on S. Tm competitive growth are poorly understood. Notably, the twin-arginine translocation (Tat) system, which enables the transport of folded proteins outside bacterial cytoplasm, is well conserved among many bacterial pathogens, with Tat substrates including virulence factors and virulence-associated proteins. Here, we show that Tat and Tat-exported peptidoglycan amidase, AmiA- and AmiC-dependent cell division contributes to S. Tm competitive fitness advantage in the inflamed gut. S. Tm tatC or amiA amiC mutants feature a gut colonization defect, wherein they display a chain form of cells. The chains are attributable to a cell division defect of these mutants and occur in inflamed but not in normal gut. We demonstrate that attenuated resistance to bile acids confers the colonization defect on the S. Tm amiA amiC mutant. In particular, S. Tm cell chains are highly sensitive to bile acids as compared to single or paired cells. Furthermore, we show that growth media containing high concentrations of NaCl and sublethal concentrations of antimicrobial peptides induce the S. Tm amiA amiC mutant chain form, suggesting that gut luminal conditions such as high osmolarity and the presence of antimicrobial peptides impose AmiA- and AmiC-dependent cell division on S. Tm. Together, our data indicate that Tat and the Tat-exported amidases, AmiA and AmiC, are required for S. Tm luminal fitness in the inflamed gut, suggesting that these proteins might comprise effective targets for novel antibacterial agents against infectious diarrhea.

Guselkumab, an anti-interleukin-23 monoclonal antibody, for the treatment of moderate to severe plaque-type psoriasis in Japanese patients: Efficacy and safety results from a phase 3, randomized, double-blind, placebo-controlled study.

Previous global studies of guselkumab have demonstrated clinical benefits in patients with psoriasis. The aim of this 52-week, phase 3 study was to evaluate efficacy and safety of guselkumab in Japanese patients with moderate to severe plaque-type psoriasis. Patients randomly received guselkumab 50 mg or 100 mg at weeks 0, 4 and every 8 weeks, or placebo with cross-over to guselkumab 50 mg or 100 mg at week 16. Co-primary end-points were the proportion of patients achieving Investigator's Global Assessment (IGA) cleared/minimal (0/1) and 90% or more improvement in Psoriasis Area and Severity Index (PASI-90) at week 16. Overall, 192 patients were randomized to placebo, guselkumab 50 mg or 100 mg. At week 16, patients in the placebo group were crossed over to guselkumab 50 mg or 100 mg. At week 16, a significantly (P < 0.001) higher proportion of patients receiving guselkumab 50 mg and 100 mg versus placebo achieved IGA 0/1 (92.3% and 88.9% vs 7.8%) and PASI-90 (70.8% and 69.8% vs 0%). Patients in guselkumab 50 mg and 100 mg groups achieved significant improvement versus placebo in PASI-75 (89.2% and 84.1% vs 6.3%, P < 0.001) at week 16; improvement was maintained through week 52. Incidences of treatment-emergent adverse events were comparable among the groups through week 16; the most commonly reported was nasopharyngitis. No new safety concerns were observed until week 52. In conclusion, guselkumab treatment demonstrated superior efficacy over placebo and was well tolerated in Japanese patients with moderate to severe plaque-type psoriasis.

Salmonella enterica Serovar Typhimurium CpxRA Two-Component System Contributes to Gut Colonization in Salmonella-Induced Colitis.

Salmonella enterica, a common cause of diarrhea, has to colonize the gut lumen to elicit disease. In the gut, the pathogen encounters a vast array of environmental stresses that cause perturbations in the bacterial envelope. The CpxRA two-component system monitors envelope perturbations and responds by altering the bacterial gene expression profile. This allows Salmonella to survive under such harmful conditions. Therefore, CpxRA activation is likely to contribute to Salmonella gut infection. However, the role of the CpxRA-mediated envelope stress response in Salmonella-induced diarrhea is unclear. Here, we show that CpxRA is dispensable for the induction of colitis by S. enterica serovar Typhimurium, whereas it is required for gut colonization. We prove that CpxRA is expressed during gut infection and that the presence of antimicrobial peptides in growth media activates the expression of CpxRA-regulated genes. In addition, we demonstrate that a S Typhimurium strain lacking the cpxRA gene is able to cause colitis but is unable to continuously colonize the gut. Finally, we show that CpxRA-dependent gut colonization requires the host gut inflammatory response, while DegP, a CpxRA-regulated protease, is dispensable. Our findings reveal that the CpxRA-mediated envelope stress response plays a crucial role in Salmonella gut infection, suggesting that CpxRA might be a promising therapeutic target for infectious diarrhea.

Guselkumab, a human interleukin-23 monoclonal antibody in Japanese patients with generalized pustular psoriasis and erythrodermic psoriasis: Efficacy and safety analyses of a 52-week, phase 3, multicenter, open-label study.

Generalized pustular psoriasis (GPP) and erythrodermic psoriasis (EP) are the rare and severe subtypes of psoriasis, which are often difficult to treat. The aim of this phase 3, open-label study was to evaluate efficacy and safety of guselkumab, a human interleukin-23 monoclonal antibody, in Japanese patients with GPP and EP. Guselkumab 50 mg was administrated to GPP (n = 10) and EP (n = 11) patients at weeks 0, 4 and thereafter every 8 weeks (q8w). Beginning at week 20, patients were escalated to 100 mg q8w if they met the dose escalation criteria. The primary end-point was the proportion of patients achieving treatment success (Clinical Global Impression score of "very much improved", "much improved" or "minimally improved") at week 16. Safety evaluations included assessment of treatment-emergent adverse events (TEAE) through week 52. At week 16, the proportions of GPP and EP patients achieving treatment success were 77.8% (7/9) and 90.9% (10/11), respectively. Furthermore, guselkumab treatment consistently showed improvement in responses of secondary end-points such as Psoriasis Area and Severity Index, Investigator's Global Assessment, Japanese Dermatological Association severity index and improvement in body surface area involvement. Improvements in quality of life, as assessed by the Dermatology Life Quality Index, were also observed through week 52. The most commonly reported TEAE was nasopharyngitis (28.6%, 6/21). Safety findings were consistent with those observed previously in other studies. In conclusion, guselkumab treatment demonstrated efficacy and showed no safety concerns in Japanese patients with GPP and EP through week 52.

Intra-individual variation in hand postures during terrestrial locomotion in Japanese macaques (Macaca fuscata).

The primate hand adopts a variety of postures during locomotion. Habitually terrestrial cercopithecine primates are known to use a palmigrade posture at faster speeds to possibly mitigate stresses on the hand skeleton; however, it is unclear whether arboreal or semi-terrestrial species use a similar strategy for adjusting hand posture. Here, we explored intra-individual variation in hand contact patterns during terrestrial locomotion in the Japanese macaque (Macaca fuscata), a semi-terrestrial cercopithecine primate. Two monkeys were required to walk on the ground at their own preferred speeds or were encouraged to move faster for food rewards. The contact area under the hand and ground reaction forces (GRFs) were measured simultaneously using a tactile pressure sensor, and then hand pressures were calculated offline. We found that hand contact patterns could vary within individuals. The monkeys used predominantly a palmigrade posture within the range of speeds covered in this study (0.72-2.56 m s-1). There were two subtypes of palmigrade posture. In one subtype, the hypothenar pad did not contact the substrate, whereas the entire hand contacted the substrate in the other. The palm of the palmigrade hand with total-hand contact experienced similar or lower peak pressure and pressure-time integral than those of the palmigrade hand without hypothenar pad contact even though it experienced higher peak GRFs. The moderate peak pressure experienced by the palmigrade hand with total-hand contact was due to increased contact area under the palm. The total contact area of the fingers and peak GRF to the fingers were relatively unchanged with different patterns of hand contact. These findings provide evidence that when walking on the ground, semi-terrestrial Japanese macaques use a palmigrade posture with total-hand contact to attenuate stresses on hand bones, as do habitually terrestrial species.

Salmonella Typhimurium PagP- and UgtL-dependent resistance to antimicrobial peptides contributes to the gut colonization.

Mucosal barrier formed by cationic antimicrobial peptides (CAMPs) is believed to be crucial for host protection from pathogenic gut infection. However, some pathogens can develop resistance to the CAMPs to survive in hosts. Salmonella enterica is a common cause of acute diarrhea. During the course of this disease, the pathogen must continuously colonize the gut lumen, which contains CAMPs. However, it is incompletely understood whether the resistance of Salmonella strains to CAMPs contributes to the development of gut infections. PhoPQ two-component system-dependent lipid A modifications confer resistance to CAMPs in S. enterica serovar Typhimurium. Therefore, we introduced mutations into the PhoPQ-regulated genes in an S. Typhimurium strain, obtaining pagP ugtL and pmrA mutant strains. Each mutant strain demonstrated a distinct spectrum of the resistance to CAMPs. Using streptomycin mouse model for Salmonella diarrhea, we show that the pagP ugtL, but not pmrA, mutant strain had a gut colonization defect. Furthermore, the pagP ugtL, but not pmrA, mutant strain had decreased outer membrane integrity and susceptibility to magainin 2, an alpha-helical CAMP. Taken together, the PagP- and UgtL-dependent resistance to CAMPs was demonstrated to contribute to sustained colonization in the gut. This may be due to the robust outer membrane of S. Typhimurium, inducing the resistance to alpha-helical CAMPs such as α-defensins. Our findings indicate that the development of resistance to CAMPs is required for the S. Typhimurium gut infection.